Physiology_Levy

Physiology_Levy. 1000 strokes per minute, with a power forward stroke and a slow return or recovery stroke. During their power forward stroke, the tips of the cilia extend upward into the viscous mucus layer and thereby move it and the entrapped particles. On the reverse beat, the cilia release the mucus and withdraw completely into the sol layer. Cilia in the nasopharynx beat in the direction that propels the mucus into the pharynx, whereas cilia in the trachea propel mucus upward toward the pharynx, where it is swallowed.


Physiology_Levy

Physiology_Levy. In general, deposition of particles in the lung depends on the particle’s size, density, and shape; the distance over which it has to travel; airflow speed; and the relative humidity of the air. The four major mechanisms for deposition are impaction, sedimentation, interception, and brownian movement. Particle characteristics and properties, which influence the mechanism of deposition, are listed in 26.2 . In general, particles larger than 10 µm are deposited by impaction in the nasal passages and do not penetrate into the lower respiratory tract. Particles 2 to 10 µm in size Sedimentation0.2to2.0InterceptionNABrownianmovement<0.2 NA,notapplicable.


Physiology_Levy

Physiology_Levy. are deposited in the lower respiratory tract predominantly by inertial impaction at points of turbulent airflow (i.e., nasopharynx, trachea, and bronchi) and at airway bifurcations because their tendency to move in a straight direction prevents them from changing directions rapidly. In more distal areas, where airflow is slower, smaller particles (0.2 to 2 µm) are deposited on the surface by sedimentation as a result of gravity. For substances with elongated shapes (i.e., asbestos, silica), the mechanism of deposition is interception. The elongated particle’s center of gravity is compatible with the flow of air; however, when the distal tip of the particulate comes in contact with a cell or mucus layer, deposition is facilitated. Particles smaller than 0.2 µm are deposited in the smaller airways and alveoli and are influenced mainly by their diffusion coefficient and brownian motion. Unlike the deposition of larger particles in the upper airways, particle density does not influence


Physiology_Levy

Physiology_Levy. airways and alveoli and are influenced mainly by their diffusion coefficient and brownian motion. Unlike the deposition of larger particles in the upper airways, particle density does not influence diffusion of these smaller particles, and deposition is enhanced with decreased size. These smaller particles come in contact with the alveolar epithelium, where cilia and the mucociliary transport system do not exist; thus they are removed by the phagocytic activity of alveolar macrophages or absorption into the interstitium with subsequent clearance by lymphatic drainage. Although most alveolar macrophages are adjacent to the epithelium of the alveolus, some are located in the terminal airways and interstitial space.


Physiology_Levy

Physiology_Levy. In the conducting airways, the mucociliary clearance system transports deposited particles from the terminal bronchioles to the major airways, where they are coughed up and either expectorated or swallowed. Deposited particles can be removed in a matter of minutes to hours. In the trachea and main bronchi, the rate of particle clearance is 5 to 20 µm/minute, but it is slower in the bronchioles (0.5 to 1 µm/minute). In general, the longer an inhaled material remains in the airways, the greater is the probability that the material will cause lung damage. The region from the terminal bronchioles to the alveoli is devoid of ciliated cells and is considered the “Achilles heel” in what is otherwise a highly effective system. The relatively slow rate of particle clearance in this area, which is mediated by macrophages, renders it the most common location for many occupational lung diseases.


Physiology_Levy


Physiology_Levy

Physiology_Levy. In nonmucosal tissues (e.g., spleen, liver, kidney), the body’s primary defense is the classical proinflammatory adaptive, antigen-specific immune response orchestrated in the local draining lymph nodes with afferent and efferent lymph flow. The major adaptive immune cells in the systemic immune system are T lymphocytes with αβ T cell receptors (TCRαβ T cells) for specific antigen recognition and plasma B cells that synthesize immunoglobulin M (IgM) and immunoglobulin G (IgG) complement–binding antibodies, which can induce inflammation. However, mucosal tissues (i.e., those of the respiratory, gastrointestinal, and urinary systems, as well as the eyes, nose, throat, and mouth) must constantly discriminate between what is harmful and what is not, and although inflammation is protective, it usually disrupts the normal physiologic processes and is not desirable unless absolutely necessary. Accordingly, mucosal tissues have developed specialized “noninflammatory” defense mechanisms, which


Physiology_Levy

Physiology_Levy. usually disrupts the normal physiologic processes and is not desirable unless absolutely necessary. Accordingly, mucosal tissues have developed specialized “noninflammatory” defense mechanisms, which form the basis of the mucosal immune system and can function independently of the systemic immune system. The mucosal immune system contains both specialized innate lymphoid cells (macrophages, natural killer cells, dendritic cells [DCs]) and adaptive T lymphocytes with γδ T cell receptors (TCRγδ T cells) and plasma B cells that synthesize immunoglobulin A (IgA), a nonclassical complement-binding antibody. These innate and unique adaptive responses can prevent or limit responses to foreign nonpathological agents while eliminating pathological agents/substances with little or no inflammation. In addition, if this front-line defense system fails or is bypassed, the lungs do have a classical adaptive immune response system in which lymphatic drainage is via the mediastinal lymph node located


Physiology_Levy

Physiology_Levy. addition, if this front-line defense system fails or is bypassed, the lungs do have a classical adaptive immune response system in which lymphatic drainage is via the mediastinal lymph node located in the upper region of the thoracic cavity adjacent to the main left-right lung bifurcation.


Physiology_Levy

Physiology_Levy. A distinctive feature of the mucosal immune system is that antigens are processed through lymphoid aggregates rather than through a true lymph node. Unlike a true lymph node, which has afferent and efferent lymph flow, lymphoid aggregates have only afferent drainage of material into the aggregate without efferent flow. This lymphoid network is commonly referred to as mucosa-associated lymphoid tissue (MALT); in the gastrointestinal tract, it is referred to as gut-associated lymphoid tissue (GALT); and in the lungs, it is known as bronchus-associated lymphoid tissue (BALT;


Physiology_Levy

Physiology_Levy. Fig. 26.2 ). BALT is present in the conducting airways, where the epithelium is composed mainly of ciliated cells with consistent mucus flow. However, an interesting feature of BALT is that its airway epithelium is not ciliated; it is referred to as a lymphoepithelium, which creates a break in the mucus flow (like a drain) and allows the substances/ particulates to be processed in the lymphoid aggregate (or follicle).


Physiology_Levy

Physiology_Levy. It appears that there is communication between mucosal tissues and that sensitization via one organ is transposed to all MALT/BALT tissues via a lymphatic-like drainage network. The systemic immune system and MALT/BALT may work independently of each other, and the fact that one is sensitized may not be true of the other. This may serve as a defense mechanism in limiting sensitization only to mucosal tissue. Lymphocytes also cluster in smaller numbers and density in what is referred to as tertiary ectopic lymphoid tissue (TELT), in which they can also process antigens (see Fig. 26.2, A ). Another prominent feature is a diffuse submucosal and intraepithelial network of solitary lymphocytes and innate lymphoid cells scattered throughout the respiratory tract. Because inhaled particles are broadly dispersed throughout the respiratory tract, each type of lymphoid cell and tissue (BALT, TELT, and solitary lymphocytes) play important and unique roles in the overall defense of the lungs.


Physiology_Levy

Physiology_Levy. One of the specialized features of MALT, GALT, and BALT is a unique antibody system in which specialized features • Fig. 26.2 Representation of Bronchus-Associated Lymphoid Tissue (BALT)/Tertiary Ectopic Lymphoid Tissue (TELT), M Cells, and Immunoglobulin a (IgA) Synthesis.A, M cells located in mucosal epithelium endocytose antigen in the lumen and transport it for processing to loosely organized submucosal pockets of lymphoid cells, predominantly lymphocytes and macrophages (TELT). B, Diagram of a mucous membrane, showing secretion of IgA antibodies in response to antigen endocytosed by M cells. Activated B cells differentiate into IgA-producing plasma cells (lymphocytes) and migrate from the densely organized lymphoid follicle (in bronchus-associated lymphoid tissue [BALT]) to the nearby submucosa, where they secret IgA.


Physiology_Levy

Physiology_Levy. of the IgA antibody (non–complement-fixing, J chain for transport, and dimeric structure for stability in the airway lumen) are used. In submucosal areas, plasma cells synthesize and secrete IgA, which migrates to the submucosal surface of epithelial cells, where it binds to a surface protein •Fig. 26.3 Structure and Formation of Secretory Immunoglobulin a (IgA). A, SecretoryIgAconsistsofatleasttwoIgAmoleculesthatarecovalentlylinkedviaJchainandcovalentlyassociatedwiththesecretorycomponent.Thesecretorycomponentcontainsfiveimmunoglobulin-likedomainsandislinkedtodimericIgAthroughbindingtoanIgAheavychain.B, SecretoryIgAisformedduringtransportthroughepithelialcells.Poly-Ig,polymericimmunoglobulin. receptor, polymeric immunoglobulin (poly-Ig;


Physiology_Levy

Physiology_Levy. receptor, polymeric immunoglobulin (poly-Ig; Fig. 26.3 ). The poly-Ig receptor aids in the pinocytosis of IgA into the epithelial cell and its eventual secretion into the airway lumen. During exocytosis of the IgA complex, the poly-Ig is enzymatically cleaved, and a portion of it, the secretory piece, remains associated with the complex. The secretory piece stays attached to the IgA complex in the airway and helps protect it from proteolytic cleavage. The IgA-antigen immune complex does not bind complement in the same classical manner as do other immune complexes, and thus its proinflammatory properties are limited. The IgA-antibody system is very effective in binding particulates and viruses to form a large complex, which promotes its removal via the mucociliary clearance system, before they invade epithelial cells.


Physiology_Levy

Physiology_Levy. Most classical adaptive immune T lymphocytes are CD3+ cells with TCRs that are composed of α and β chains (TCRαβ T cells). These cells mature in the thymus and egress mostly to lymph nodes and the spleen. The classical activation of TCRαβ cells requires antigen processing/ presentation, typically via the major histocompatibility complex, in a DC, usually to induce an inflammatory response. CD3+ T lymphocytes with TCRs expressing γ and δ chains (TCRγδ T cells) also mature in the thymus, but the majority of these cells egress to mucosal tissues (i.e., lung, intestines, and skin) and represent only a minority of T cells in the peripheral blood and systemic lymphoid tissues. TCRγδ T cells, often referred to as intraepithelial lymphocytes, preferentially localize to submucosal sites and


Physiology_Levy

Physiology_Levy. BALT,bronchus-associatedlymphoidtissue;IFN-γ,interferonγ;IgA,IgE,IgG,andIgM,immunoglobulinsA,E,G,andM;IL-10,interleukin10;iNKT,invariantnaturalkillerT;NK,naturalkiller;TCR,Tcellreceptor;TELT,tertiaryectopiclymphoidtissue;Th1andTh2,Thelper1andThelper2. epithelium and are considered a first line of defense of epithelial surfaces.


Physiology_Levy

Physiology_Levy. In contrast to TCRαβ T cells, the classical antigen activation of TCRγδ T cells does not require antigen processing or presentation by DCs. Of interest is that TCRγδ T cells have been shown to be capable of responding to antigen either in the manner of an innate cellular response, via pathogen-associated molecular patterns (PAMPs, described later in this chapter), or, in some circumstances, in the manner of a classical TCRαβ T cell response. Whether this variation in responsiveness is due to the presence of subpopulations of TCRγδ T cells or to plasticity (alterations) of the same cell is not clear. Because these cells express this unique duality, they are considered to be a link between adaptive and innate immune responses. Furthermore, TCRγδ cells can respond immediately to antigen and generally do not demonstrate memory. In contrast to the typical TCRαβ T cell proinflammatory response, TCRγδ T cells can provide protection without inducing inflammation. TCRγδ T cells have been shown


Physiology_Levy

Physiology_Levy. do not demonstrate memory. In contrast to the typical TCRαβ T cell proinflammatory response, TCRγδ T cells can provide protection without inducing inflammation. TCRγδ T cells have been shown to expand in response to viral and bacterial infections and synthesize either proinflammatory cytokines (interleukin [IL]–17, interferon [IFN]–γ) or regulatory/ suppressive cytokines (transforming growth factor β [TGFβ], lymphocyte-activation gene 3). TCRγδ T cells also suppress the immunoglobulin E (IgE) response to inhaled antigen, further preventing allergen-induced inflammation.


Physiology_Levy

Physiology_Levy. Innate lymphoid cells (ILCs) generally fall into four categories, TCRγδ T cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and subpopulations of each ( 26.3 ). ILCs are distinctively different from adaptive immune cells by their lack of “antigen” specificity for the offending agents and their ability to distinguish self from non-self through recognition of PAMPs present on the pathogens. Since most inhaled substances are nonpathogenic, the body has developed a specialized recognition system to identify harmful pathogenic substances and organisms. Rather than specific antigen recognition, this system enables discrimination of self from non-self material through the recognition of PAMPs on the pathogenic organisms/substances, which are then recognized by a family of receptors on host defense cells (i.e., ILCs) called pattern recognition receptors (PRRs). PAMPs are common distinguishing features on many pathogens and are composed of peptidoglycans,


Physiology_Levy

Physiology_Levy. by a family of receptors on host defense cells (i.e., ILCs) called pattern recognition receptors (PRRs). PAMPs are common distinguishing features on many pathogens and are composed of peptidoglycans, lipopolysaccharides, and unmethylated 5′-C-phosphate-G-3′ (CpG) DNA, which bind to their corresponding PPRs on ILCs. There are two major classifications for PRRs: toll-like receptors (TLRs), which are expressed mainly on cell surfaces, and nucleotide-oligomerization domain (NOD) receptors, which are expressed intracellularly in the cytoplasma of ILCs. Both of these pathways activate nuclear factor Kβ (NFKβ), a transcription factor, which stimulates release of proinflammatory cytokines, as well the antiviral type I interferons (IFN-α and IFN-β). The TLRs are a family of transmembrane proteins with different specificities for various pathogens. TLR-2 is specific for lipoteichoic acids associated with gram-positive bacteria, whereas TLR-4 is specific for lipopolysaccharide (endotoxin), a


Physiology_Levy

Physiology_Levy. with different specificities for various pathogens. TLR-2 is specific for lipoteichoic acids associated with gram-positive bacteria, whereas TLR-4 is specific for lipopolysaccharide (endotoxin), a product of gram-negative bacteria. In the lung, bronchial epithelial cells, macrophages, DCs, mast cells, eosinophils, and alveolar type II epithelial cells express both TLR-2 and TLR-4. Other TLRs are specific for viruses: TLR-3 binds to double-stranded RNA viruses, and TLR-7 and TLR-8 bind to single-stranded RNA viruses. NK cells express TLR-3, TLR-7, and TLR-8 and plasmacytoid DCs, eosinophils, and B cells express TLR-7. A variety of phagocytic cells and DCs in the lung and other mucosal tissues also express TLRs. Thus in addition to classical phagocytic cells, bronchial and alveolar epithelial cells play active roles in host defense by means of the PAMP-PRR nexus.


Physiology_Levy

Physiology_Levy. Perhaps the most unique and intriguing aspect of this specialized mucosal defense system is the ability of ILCs to respond to pathogens immediately, as opposed to the days or weeks it takes to mount a classical TCRαβ T cell adaptive immune response with clonal expansion and memory. The fast response, and the lack thereof for innocuous substances, are highly advantageous in the mucosal tissues, which are common sites for parasitic invasion and toxic chemical exposure. In addition, many of the ILCs demonstrate plasticity, meaning that they can be induced by the environment (i.e., cytokines) to alter their functionality to either a proinflammatory or regulatory (suppressive) phentoype.


Physiology_Levy

Physiology_Levy. Both macrophages and DCs originate in the bone marrow but vary somewhat in their differentiation lineage: Macrophages develop through the common myeloid-granulocyte/ macrophage progenitor linage with other granulocytic cells (basophils, mast cells, eosinophils, neutrophils), and DCs develop through either the common lymphoid progenitor or the common myeloid progenitor lineages. Macrophages and DCs are the first nonepithelial cells to contact and respond to a foreign substance. In the lungs, there are three major types of macrophages (alveolar, M-1 [proinflammatory], and M-2 [regulatory]) and two types of DCs (conventional and plasmacytoid).


Physiology_Levy

Physiology_Levy. If the inhaled foreign material stays within the airspace in the lower respiratory system (alveolar ducts and alveoli), it will probably be phagocytized by alveolar macrophages. However, if the foreign material/organism penetrates and reaches submucosal areas, it will come into contact with M-1 or M-2 macrophages and conventional or plasmacytoid DCs. Alveolar macrophages are found mostly in the alveolus adjacent to the epithelium and less frequently in the terminal airways and interstitial space. They migrate freely throughout the alveolar spaces and serve as a first line of defense in the terminal bronchioles and alveoli. They phagocytize foreign particles and substances, as well as surfactant and cellular debris from dead cells. For a particle/organism that is phagocytized by a macrophage, the major mechanisms of destruction include formation of O2 radicals, enzyme activity, and halogen derivatives within lysosomes.


Physiology_Levy

Physiology_Levy. The phagocytic activity of the macrophage inhibits the binding of particulates to the alveolar epithelium and their subsequent penetration into the interstitium. The alveolar macrophage also transports engulfed particles to ciliated regions of the mucociliary transport system for elimination and thus provides an important link between the alveolar spaces, the postterminal bronchiole “Achilles heel” region, and the mucociliary clearance system.


Physiology_Levy

Physiology_Levy. In addition, alveolar macrophages and M-2 macrophages present in the submucosa can also suppress T cell activity by direct contact or by the secretion of soluble factors such as nitric acid, prostaglandin E2, and the immunosuppressive cytokines (IL-10 and TGF-β). M-1 macrophages are also located in submucosal sites and represent the classical “proinflammatory” phagocytic cell, with similar killing capabilities as those of alveolar macrophages. In addition, the T helper 2 (Th2) proinflammatory (and proasthma) cytokines IL-4 and IL-13 have been shown to promote the differentiation of M-1 macrophages into regulatory/suppressive M-2 macrophages, which demonstrates the plasticity of these cells. The ability of these macrophage populations to demonstrate plasticity and dispose of foreign material rapidly with either a proinflammatory or regulatory response considerably enhances the lung defense system and is a unique contributor to the overall mucosal defense system.


Physiology_Levy

Physiology_Levy. Conventional DCs reside in the submucosa of lung and other mucosa tissues and are considered the major antigen-presenting cells. They are usually in a resting immature state in which they function as sentinels to capture and process antigen, after which they mature and migrate to the local draining lymph node (mediastinal node for the lungs). At this node, they present antigen to T cells, which initiates an adaptive immune response, either proinflammatory or suppressive, depending on the antigen and DC. CD103+ DCs have been shown to induce regulatory/suppressor T cells by means of their synthesis and secretion of TGF-β and indoleamine dioxygenase. Plasmacytoid DCs are located in similar submucosal areas but function more in an antiviral role, as opposed to antigen presentation; upon viral activation, they rapidly secrete the antiviral cytokine IFN-γ. Macrophages and DCs commonly synthesize and secrete many similar cytokines, depending on the stimulus; such cytokines include IL-1β


Physiology_Levy

Physiology_Levy. activation, they rapidly secrete the antiviral cytokine IFN-γ. Macrophages and DCs commonly synthesize and secrete many similar cytokines, depending on the stimulus; such cytokines include IL-1β (which activates vascular endothelium and lymphocytes), IL-6 (which activates lymphocytes and enhances antibody production), IL-12 (which activates NK cells, CD4 T cells to Th1 T cells), tumor necrosis factor α (which activates vascular endothelium and increases permeability), IL-8 (which recruits neutrophis, basophils, and T cells), and IFN-γ (which has antiviral effects).


Physiology_Levy

Physiology_Levy. NK cells originate in the bone marrow and differentiate through the common lymphoid progenitor lineage . They are neither T or B cells, and resident populations of functionally active NK and invariant natural killer T (iNKT) cells are present in mucosal sites and the lung interstitium. NK cells are a major component of the body’s innate immune system of defense against invading pathogens such as herpesviruses, various bacterial infections, and tumor cells. NK cells can be activated by interferons (IFN-α and IFN-β) and other macrophage-derived cytokines (IL-12 and IL-18), which enhances their killing capabilities. The mechanism of killing is through the release of granular enzymes (granzymes, perforins, and serine esterases), which create holes or pores within the target cell membranes and thereby cause cell death. In addition, NK cells can synthesize IFN-γ, which is capable of inhibiting viral infections and stimulating CD4 and CD8 T cell responses.


Physiology_Levy

Physiology_Levy. NK cells have a complicated set of receptors to recognize a wide array of infectious bacteria and viruses. Individuals who lack NK cells are very prone to herpesvirus infections and often have recurrent infection. The iNKT cells belong to a category of lymphoid cells termed innate-like lymphocytes, reside together with TCRγδ cells in mucosal tissues, and have antigen receptors with limited diversity, unlike the adaptive immune cells. These types of cells are thought to be links between innate and adaptive immunity. A critical aspect of the link is that these cells can respond must faster than cells of the classical adaptive immune response, limiting early damage until the adaptive response can mobilize a stronger defense. The iNKT cells have an invariant T cell receptor α chain and, on activation, secrete the regulatory cytokines IL-10 and IFN-γ. Epithelial Cells and Commensal Microbiota Protect the Lumen of the Airways


Physiology_Levy

Physiology_Levy. Epithelial Cells and Commensal Microbiota Protect the Lumen of the Airways Airway epithelial cells can produce and secret both antibacterial enzymes and amphipathic (hydrophilic–positively charged) antimicrobial peptides, which generally target and disrupt cell wall components of the bacteria, which leads to cell death. Lysozyme, elastase, hydrolases, and secretory phospholipase A2 are examples of antibacterial enzymes targeted at various pathogens. Antimicrobial peptides are typically cationic peptides synthesized as propeptides and activated through cleavage of an anionic propiece. Peptides secreted from epithelial cells and alveolar macrophages usually enter the mucosal fluid, whereas peptides secreted from submucosal macrophages typically stay within the local tissue.


Physiology_Levy

Physiology_Levy. There are three classes of antimicrobial peptides: defensins, cathelicidins, and histatins. Defensins, which are categorized as α and β can disrupt cell membranes within minutes and are very effective on bacteria, fungi, and viruses. β–Defensins are synthesized in alveolar type II cells, are stored in lamellar bodies, and are a component of surfactant. α–Defensins are synthesized and stored within epithelial cells, macrophages, and neutrophils. Cathelicidins are stored in secondary granules and activated intracellularly by fusion of the phagosomes with the granule or also directly by elastase. In the lungs, cathelicidins are secreted from lung type II epithelial cells, as well as from neutrophils and macrophages. Histatins are present mainly in the oral cavity and are more specific for pathogenic fungi. Although it is not clear whether they exist in the respiratory tract, the carbodydrate-binding proteins (lectins) in the gut can directly kill Gram-positive bacteria by binding to


Physiology_Levy

Physiology_Levy. pathogenic fungi. Although it is not clear whether they exist in the respiratory tract, the carbodydrate-binding proteins (lectins) in the gut can directly kill Gram-positive bacteria by binding to their cell walls. Furthermore, lactoferrins and lysozyme present in epithelial cells have been shown to have bacteriostatic and bactericidal effects; the precise mechanism by which this occurs is not clearly understood, although it is postulated that they may work synergistically with iron and calcium.


Physiology_Levy

Physiology_Levy. The human microbiome, especially the gut, has received a lot of attention, and exploration into the role of these commensal microorganisms in health and disease is rapidly developing. Although much is known about the gut microbiome, the lung microbiome has been difficult to explore. Once thought to be a sterile environment, the lung remains a difficult site to sample for a variety of reasons, including subject safety during sampling (invasive procedures), complexity and variety of epithelial surfaces throughout the respiratory tract, and the simple fact that far fewer bacteria are available to sample. Furthermore, the lumen ecosystem and epithelium of the respiratory tract differ considerably along the respiratory tract, from the upper airways to the alveoli; it is likely that the density and types of bacteria residing in these various regions also differ. It is clear, however, that the lung does have a microbiome, and three primary phyla appear to be represented: Bacteroidetes


Physiology_Levy

Physiology_Levy. and types of bacteria residing in these various regions also differ. It is clear, however, that the lung does have a microbiome, and three primary phyla appear to be represented: Bacteroidetes (Prevotella, Bacteroides), Firmicutes (Veillonella, Streptococcus, Staphylococcus), and Proteobacteria (Pseudomonas, Haemophilus, Moraxella, Neisseria, Acinetobacter).


Physiology_Levy

Physiology_Levy. Alterations in the lung microbiome have been shown to be associated with several pulmonary conditions (including asthma, cystic fibrosis, and chronic obstructive pulmonary disease) and with lung transplantation. The increased rate of asthma in children has been linked to the increased rate of antibiotic use, which has a vast effect on the microbiome. Organisms in the Proteobacteria (Haemophilus, Moraxella) and Firmicutes (Streptococcus) phyla have been shown to correlate with asthma. An experimental study in mice showed an improvement in asthma when Proteobacteria organisms were replaced with Bacteriodetes organisms, which coincided with an increase in regulatory T cells and suppression of the Th2 proinflammatory cytokines prominent in the pathogenesis of asthma.


Physiology_Levy

Physiology_Levy. From a therapeutic standpoint, the use of probiotics to maintain a “normal” microbiome has proved useful in treating infectious diseases in the gut, and the use of probiotic therapy in patients with chronic lung infections (e.g., cystic fibrosis, upper respiratory tract infections) have been promising. The precise mechanism or mechanisms by which the bacteria may “protect” the lungs is still poorly understood but probably varies considerably according to the microorganism.


Physiology_Levy

Physiology_Levy. It has been shown that Bifidobacterium can activate DCs and TLRs to secrete IL-10 and retinoic acid, mediators capable of inducing regulatory T cells, which downregulate the Th2 inflammatory response. From a causative perspective, histamine, a major component of mast cell granules and secreted from Lactobacillus organisms, has been shown to have an association with priming DCs to stimulate Th2 inflammatory responses, as seen in individuals with asthma. In addition, it has been shown that ILCs can play a role in influencing the microbiome through their ability to bind to receptors on epithelial cells, thus altering the interaction of the epithelium with the microorganisms and possibly promoting colonization of either pathogenic or nonpathogenic microorganisms. Much is still to be learned and absorbed from future studies of the lung microbiome.


Physiology_Levy

Physiology_Levy. By far the most common pathological conditions associated with mucosal tissue are allergic responses (e.g., allergic asthma, allergic rhinitis, and food and skin allergies). Some common human allergens include components of inhaled house dust mites, cockroaches, and cat dander, as well as bee stings and ingestion of peanuts. One of the most common drug allergens is penicillin, which can bind to many endogenous proteins and also alter their antigenicity.


Physiology_Levy

Physiology_Levy. As previously described, the predominant antibody response in MALT is IgA; however, in an allergic response, IgE is the predominant antibody. It is generated by a switchover mechanism induced by the synthesis of IL-4 from Th2-primed CD4 T cells. The IL-4 induces the antibody-producing B cells to switch over from synthesizing IgG antibodies to IgE. IgE binds to the surface of mast cells in the submucosa through its crystallizable fragment (constant) region of the antibody molecule. Upon reexposure to the inhaled antigen and its subsequent migration from the airway lumen to the submucosa, the allergen then binds to the antigen-binding fragment region of the IgE molecule, which forms an immune complex (IgE-Ag) on the surface of the mast cell.


Physiology_Levy

Physiology_Levy. The final step is that IgE-Ag complexes must crosslink with other IgE-Ag complexes on the surface of the mast cell, which induce intracellular signaling pathways to initiate degranulation and immediate release of preformed Th2 mediators (histamine, heparin, prostaglandins, leukotrienes, IL-4, IL-5, IL-13, proteases). These mediators induce the classical signs of asthma: smooth muscle constriction


Physiology_Levy

Physiology_Levy. The inflammatory response can resolve spontaneously or as a result of therapy (bronchodilator or anti-inflammatory drugs, such as corticosteroids). Low-grade inflammation may persist and result in a process called airway remodeling, manifested by permanent, irreversible structural changes such as submucosal fibrosis and airway smooth muscle hypertrophy. The mechanisms responsible for airway remodeling in allergic diseases are not clearly understood, but chemokines and cytokines such as TGF-β, a potent profibrotic cytokine, play important roles. Thus a very elegant, highly effective defensive system against infectious and parasitic organisms is “tricked” into responding to an innocuous substance, an allergen, as if it were harmful and initiates its defenses; the result is allergic airway disease. Metabolic Functions of the Lung


Physiology_Levy

Physiology_Levy. Metabolic Functions of the Lung The lungs are exposed to and metabolize a wide variety of xenobiotic substances. The endothelial cells within the lung capillary bed have a large surface area that receives very high blood flow, and lung endothelial cells have developed various mechanisms and cell surface receptors to metabolize xenobiotics. Most of the metabolic processing of inhaled or ingested xenobiotic compounds occurs enzymatically within the liver and intestinal tract with members of the cytochrome P-450 (CYP) enzyme families (e.g., CYP1, CYP2, CYP3). The lungs and other organs also selectively participate in the processing of xenobiotics and typically have lower levels of cytochrome P-450 enzymes. Prominent cytochrome P-450 enzymes in the lung include CYP1B1, CYP2B6, CYP2E1, CYP2J2, CYP3A5, and CYP1A1, the last of which is present in high levels in people who smoke cigarettes.


Physiology_Levy

Physiology_Levy. Drugs for the treatment of asthma and chronic obstructive pulmonary disease—such as corticosteroids, long-acting β2 receptor agonists, leukotriene receptor antagonists, and methylxanthines—are degraded enzymatically in the lungs. In addition, a wide array of endogenous substances are metabolized by endothelial cells within the pulmonary capillary bed, including vasoactive amines, cytokines, lipid mediators, and proteins. Box 26.1 provides a list of compounds metabolized in the lung. Metabolism can occur • BOX 26.1 Compounds Metabolized in the Lungs (bronchoconstriction), eosinophil recruitment and activa-Vasoactiveaminestion (inflammation), and connective tissue remodeling. Cytokines Symptoms of wheezing, coughing, and shortness of breath occur within minutes, followed by a late response of eosinophilia and airway inflammation.


Physiology_Levy

Physiology_Levy. Symptoms of wheezing, coughing, and shortness of breath occur within minutes, followed by a late response of eosinophilia and airway inflammation. through either intracellular or extracellular processing of endogenous substances that pass though the capillaries or by direct synthesis and secretion by endothelial cells. For example, angiotensin I is activated by angiotensinconverting enzyme, which is on the surface of endothelial cells. Serotonin, a vasoconstrictor, binds to a specific receptor on the surface of endothelial cells and is internalized and metabolized inside cells. Approximately 80% of the serotonin entering the lungs is metabolized in a single pass through the pulmonary capillary bed.


Physiology_Levy

Physiology_Levy. Endothelial cells also have surface receptors for bradykinin, tumor necrosis factor, components of the complement system, immunoglobulin crystallizable fragments, and adhesion molecules. In addition, vascular endothelial cells synthesize and secrete prostacyclin, endothelin, clotting factors, nitric oxide, prostaglandins, and cytokines. Vascular endothelial cells, however, lack 5-lipoxygenase and are not able to synthesize leukotrienes (smooth muscle constrictors). Compounds not metabolized by the pulmonary capillary bed include epinephrine, dopamine, histamine, isoproterenol, angiotensin II, and substance P. Angiotensin-convertingenzyme(ACE)ispresentinsmallindentations(caveolae)onthesurfaceofpulmonaryendothelialcellsandcatalyzestheconversionofthephysiologicalinactiveangiotensinItotheactiveangiotensinII,apotentvasoconstrictor.Thisisamajormechanisminthebody’sabilitytosupplysystemiclevelsofangiotensinIIandthusinfluencebloodpressure(see Chapter36).


Physiology_Levy

Physiology_Levy. Chapter36). ThetherapeuticuseofACEinhibitorsisimportantinthemanagementofpatientswithhighbloodpressure. Thelungsplayakeyroleinthemetabolismofmanyprodrugs,whichareinactive,intoactivedrugs.Administrationofprodrugsimprovestheamountofactivedrugdeliveredtotheirtargetsinthebody.Inmanycases,inactiveprecursorprodrugsaredeliveredsystemicallyorlocally(throughinhalation)tothelungs,wheretheyareactivatedinsitu.Anexampleofthisisbeclomethasonedipropionate(Qvar,BeconaseAQ),amedicationinhaledbypatientswithasthma,whichisactivatedbyesteraseswithinthelungtotheactiveform17-beclamethasonemonopropionate. 1. The respiratory system has developed unique structural (mucociliary transport system) and immunological (mucosal immune system) features to cope with the constant environmental exposure to foreign substances; these features limit or inhibit inflammation. 2. The three components of the mucociliary transport system are the sol phase (periciliary fluid), the gel phase (mucus), and cilia. 3.


Physiology_Levy

Physiology_Levy. 2. The three components of the mucociliary transport system are the sol phase (periciliary fluid), the gel phase (mucus), and cilia. 3. The depth of the periciliary fluid layer is maintained by the balance between Cl− secretion and Na+ absorption and is essential to normal ciliary beating. 4. Mucus is a complex macromolecule composed of glycoproteins, proteins, electrolytes, and water. It has low viscosity and high elastic mechanical properties. 5. Goblet cells, Clara cells, and the mucous and serous cells residing in the tracheobronchial glands produce mucus. 6.


Physiology_Levy

Physiology_Levy. 5. Goblet cells, Clara cells, and the mucous and serous cells residing in the tracheobronchial glands produce mucus. 6. Particle deposition in the lung is dependent on their size, density, and shape; the distance traveled; airflow speed; and relative humidity. The major mechanisms for particle deposition are impaction (particles larger than 10 µm, in nasal passages, and particles 2 to 10 µm, in the nasopharynx, trachea, and bronchi), sedimentation (particles 0.2 to 2 µm in size, in distal airways), interception (particles with elongated shape, in the lower airways), and brownian movement (particles smaller than 0.2 µm, in the alveoli). 7. The respiratory system is part of the mucosal immune system, which is composed of the intestinal (GALT), the respiratory (BALT), and urinary tract systems. These systems do not contain true lymph nodes with afferent and efferent lymph flow; they are composed mainly of nonencapsulated lymph nodules without true lymphatic drainage. 8.


Physiology_Levy

Physiology_Levy. 8. The nonciliated lymphoepithelium of BALT establishes a break in the mucociliary blanket that acts as a drain to facilitate the collection and immune processing of foreign particulates throughout the conducting airways. 9. TCRγδ T cells, IgA synthesizing plasma cells, NK cells, and alveolar macrophages are highly specialized innate and adaptive immune cells unique to the anti-inflammatory defense system in the lung and other mucosal tissues. Cua DJ, Tato CM. Innate IL-17–producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10:479-489. Dickson RP, Erb-Downward JR, Martinez FJ, Huffnagle GB. The microbiome and the respiratory tract. Annu Rev Physiol. 2016;78:481-504. Martin TR, Frevert CW. Innate immunity in the lungs. Proc Am Thorac Soc. 2005;2:403-411. McKenize AN, Spits H, Eberl G. Innate lymphoid cells in inflammation and immunity. Immunity. 2014;41:366-374.


Physiology_Levy

Physiology_Levy. McKenize AN, Spits H, Eberl G. Innate lymphoid cells in inflammation and immunity. Immunity. 2014;41:366-374. Monticelli LA, Sonnenberg GF, Abt MC, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12:1045-1054. Olsson B, Bondesson E, Borgström L, et al. Pulmonary drug metabolism, clearance, and adsorption. In: Smyth HDC, Hickey AJ, eds. Controlled Pulmonary Drug Delivery. New York: Springer; 2011:21-51. Spits H, Artis D, Colonna M, et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13: 145-149. Vantourout P, Hayday A. The inbetweeners: innate-like lymphocytes. Six of the best: unique contributions of γδ T cells to immunology. Nat Rev Immunol. 2014;13:88-100. Wine JJ. Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system. Auton Neurosci. 2007;133:35-54.


Physiology_Levy

Physiology_Levy. Wine JJ. Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system. Auton Neurosci. 2007;133:35-54. SECTION 6Gastrointestinal Physiology KIM E. BARRETT AND HELEN E. RAYBOULD Chapter 27 Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract Chapter 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal Chapter 29 The Gastric Phase of the Integrated Response to a Meal Chapter 30 The Small Intestinal Phase of the Integrated Response to a Meal Chapter 31 The Colonic Phase of the Integrated Response to a Meal Chapter 32 Transport and Metabolic Functions of the Liver Upon completion of this chapter the student should be able to answer the following questions: 1. What is the neural innervation of the GI tract, and how is GI function regulated? 2. What are some examples of neural, paracrine, and humoral regulation of GI function?


Physiology_Levy

Physiology_Levy. he gastrointestinal (GI) tract consists of the alimentary tract from the mouth to the anus and includes the associated glandular organs that empty their contents into the tract. The overall function of the GI tract is to absorb nutrients and water into the circulation and eliminate waste products. The major physiological processes that occur in the GI tract are motility, secretion, digestion, and absorption. Most of the nutrients in the diet of mammals are taken in as solids and as macromolecules that are not readily transported across cell membranes to enter the circulation. Thus digestion consists of physical and chemical modification of food such that absorption can occur across intestinal epithelial cells. Digestion and absorption require motility of the muscular wall of the GI tract to move the contents along the tract and to mix the food with secretions. Secretions from the GI tract and associated organs consist of enzymes, biological detergents, and ions that provide an


Physiology_Levy

Physiology_Levy. tract to move the contents along the tract and to mix the food with secretions. Secretions from the GI tract and associated organs consist of enzymes, biological detergents, and ions that provide an intraluminal environment optimized for digestion and absorption. These physiological processes are highly regulated to maximize digestion and absorption, and the GI tract is endowed with complex regulatory systems to ensure this occurs. In addition the GI tract absorbs drugs administered by the oral or rectal routes.


Physiology_Levy

Physiology_Levy. The GI tract also serves as an important organ for excretion of substances. It stores and excretes waste substances from ingested food materials and excretes products from the liver such as cholesterol, steroids, and drug metabolites (all sharing the common property of being lipid-soluble molecules). When considering the physiology of the GI tract, it is important to remember that it is a long tube that is in contact with the body’s external environment. As such, it is vulnerable to infectious microorganisms that can enter along with food and water. To protect itself the GI tract possesses a complex system of defenses consisting of immune cells and other nonspecific defense mechanisms. In fact the GI tract represents the largest immune organ of the body. This chapter provides an overview of the functional anatomy and general principles of regulation in the GI system.


Physiology_Levy

Physiology_Levy. The structure of the GI tract varies greatly from region to region, but there are common features in the overall organization of the tissue. Essentially the GI tract is a hollow tube divided into major functional segments; the major structures along the tube are the mouth, pharynx, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, and anus ( Fig. 27.1 ). Together the duodenum, jejunum, and ileum make up the small intestine, and the colon is sometimes referred to as the large intestine. Associated with the tube are blind-ending glandular structures that are invaginations of the lining of the tube; these glands empty their secretions into the gut lumen (e.g., Brunner’s glands in the duodenum, which secrete copious amounts of HCO3 −). Additionally there are glandular organs attached to the tube via ducts through which secretions empty into the gut lumen—for example, the salivary glands and pancreas.


Physiology_Levy

Physiology_Levy. The major structures along the GI tract have many functions. One important function is storage; the stomach and colon are important storage organs for processed food (also referred to as chyme) and exhibit specialization in terms of both their functional anatomy (e.g., shape and size) and control mechanisms (characteristics of smooth muscle to produce tonic contractions) that enable them to perform this function efficiently. The predominant function of the small intestine is digestion and absorption; the major specialization of this region of the GI tract is a large surface area over which absorption can occur. The colon reabsorbs water and ions to ensure they do not get eliminated from the body. Ingested food is moved along the GI tract by the action of muscle in its walls. Separating the regions of the GI tract are also specialized muscle structures called sphincters. These function to isolate one region from the next and provide selective retention of contents or prevent backflow,


Physiology_Levy

Physiology_Levy. regions of the GI tract are also specialized muscle structures called sphincters. These function to isolate one region from the next and provide selective retention of contents or prevent backflow, or both.


Physiology_Levy

Physiology_Levy. The blood supply to the intestine is important for carrying absorbed nutrients to the rest of the body. Unlike other organ systems of the body, venous drainage from the GI tract does not return directly to the heart but first enters • Fig. 27.1 General anatomy of the GI system and its division into functional segments. the portal circulation leading to the liver. Thus the liver is unusual in receiving a considerable part of its blood supply from other than the arterial circulation. GI blood flow is also notable for its dynamic regulation. Splanchnic blood flow receives about 25% of cardiac output, an amount disproportionate to the mass of the GI tract it supplies. After a meal, blood can also be diverted from muscle to the GI tract to subserve the metabolic needs of the gut wall and also to remove absorbed nutrients.


Physiology_Levy

Physiology_Levy. The lymphatic drainage of the GI tract is important for the transport of lipid-soluble substances that are absorbed across the GI tract wall. As we will see later, lipids and other lipid-soluble molecules (including some vitamins and drugs) are packaged into particles that are too large to pass into the capillaries and instead pass into lymph vessels in the intestinal wall. These lymph vessels drain into larger lymph ducts, which finally drain into the thoracic duct and thus into the systemic circulation on the arterial side. This has major physiological implications in lipid metabolism and also in the ability of drugs to be delivered straight into the systemic circulation. The wall of the tubular gut is made up of layers consisting of specialized cells ( Fig. 27.2


Physiology_Levy

Physiology_Levy. The wall of the tubular gut is made up of layers consisting of specialized cells ( Fig. 27.2 The mucosa is the innermost layer of the GI tract. It consists of the epithelium, the lamina propria, and the muscularis mucosae. The epithelium is a single layer of specialized cells that line the lumen of the GI tract. It forms a continuous layer along the tube and with the glands and organs that drain into the lumen of the tube. Within this cell layer are • Fig. 27.2 General organization of the layers composing the wall of the GI tract.


Physiology_Levy

Physiology_Levy. a number of specialized epithelial cells; the most abundant are cells termed absorptive enterocytes, which express many proteins important for digestion and absorption of macronutrients. Enteroendocrine cells contain secretory granules that release regulatory peptides and amines to help regulate GI function. In addition, cells in the gastric mucosa are specialized for production of protons, and mucin-producing cells throughout the GI tract produce a glycoprotein (mucin) that helps protect the GI tract and lubricate the luminal contents.


Physiology_Levy

Physiology_Levy. The columnar epithelial cells are linked together by intercellular connections called tight junctions. These junctions are complexes of intracellular and transmembrane proteins, and the tightness of these junctions is regulated throughout the postprandial period. The nature of the epithelium varies greatly from one part of the digestive tract to another, depending on the predominant function of that region. For example, the intestinal epithelium is designed for absorption; these cells mediate selective uptake of nutrients, ions, and water. In contrast, the esophagus has a squamous epithelium that has no absorptive role. It is a conduit for transportation of swallowed food and thus needs some protection, provided by the squamous epithelium, from rough food such as fiber.


Physiology_Levy

Physiology_Levy. The surface area of the epithelium is arranged into villi and crypts (Fig. 27.3 ). Villi are finger-like projections that serve to increase the surface area of the mucosa. Crypts are invaginations or folds in the epithelium. The epithelium lining the GI tract is continuously renewed and replaced by dividing cells; in humans this process takes about 3 days. These proliferating cells are localized to the crypts, where there is a proliferative zone of intestinal stem cells. •Fig. 27.3 Comparisonofthemorphologyoftheepitheliumofthesmallintestineandcolon. The lamina propria immediately below the epithelium consists largely of loose connective tissue that contains collagen and elastin fibrils (see


Physiology_Levy

Physiology_Levy. The lamina propria immediately below the epithelium consists largely of loose connective tissue that contains collagen and elastin fibrils (see Fig. 27.2 ). The lamina propria is rich in several types of glands and contains lymph vessels and nodules, capillaries, and nerve fibers. The muscularis mucosae is the thin innermost layer of intestinal smooth muscle. When seen through an endoscope, the mucosa has folds and ridges that are caused by contractions of the muscularis mucosae. The next layer is the submucosa (see Fig. 27.2 ), which consists largely of loose connective tissue with collagen and elastin fibrils. In some regions of the GI tract, glands (invaginations or folds of the mucosa) are present in the submucosa. The larger nerve trunks, blood vessels, and lymph vessels of the intestinal wall lie in the submucosa, together with one of the plexuses of the enteric nervous system (ENS), the submucosal plexus.


Physiology_Levy

Physiology_Levy. The muscularis externa, or muscularis propria, typically consists of two substantial layers of smooth muscle cells: an inner circular layer and an outer longitudinal layer (see Fig. 27.2 ). Muscle fibers in the circular muscle layer are oriented circumferentially, whereas muscle fibers in the longitudinal muscle layer are oriented along the longitudinal axis of the tube. In humans and most mammals, the circular muscle layer of the small intestine is subdivided into an inner dense circular layer that consists of smaller, more closely packed cells, and an outer circular layer. Between the circular and longitudinal layers of muscle lies the other plexus of the ENS, the myenteric plexus. Contractions of the muscularis externa mix and circulate the contents of the lumen and propel them along the GI tract.


Physiology_Levy

Physiology_Levy. The wall of the GI tract contains many interconnected neurons. The submucosa contains a dense network of nerve cells called the submucosal plexus (also referred to as Meissner’s plexus). The prominent myenteric plexus (Auerbach’s plexus) is located between the circular and longitudinal smooth muscle layers. These intramural plexuses constitute the ENS. The ENS helps integrate the motor and secretory activities of the GI system. If the sympathetic and parasympathetic nerves to the gut are cut, many motor and secretory activities continue because the ENS directly controls these processes. The serosa, or adventitia, is the outermost layer of the GI tract and consists of a layer of squamous mesothelial cells (see


Physiology_Levy

Physiology_Levy. The serosa, or adventitia, is the outermost layer of the GI tract and consists of a layer of squamous mesothelial cells (see Fig. 27.2 ). It is part of the mesentery that lines the surface of the abdominal wall and suspends the organs within the abdominal cavity. The mesenteric membranes secrete a thin viscous fluid that helps lubricate the abdominal organs so movement of the organs can occur as the muscle layers contract and relax. Regulatory Mechanisms in the Gastrointestinal Tract


Physiology_Levy

Physiology_Levy. Regulatory Mechanisms in the Gastrointestinal Tract Unlike the cardiovascular or respiratory systems, the GI tract undergoes periods of relative quiescence (intermeal period) and periods of intense activity after the intake of food (postprandial period). Consequently the GI tract has to detect and respond appropriately to food intake. In addition the macronutrient content of a meal can vary considerably, and there have to be mechanisms that can detect this and mount appropriate physiological responses. Thus the GI tract has to communicate with associated organs such as the pancreas. Finally, because the GI tract is essentially a long tube, there have to be mechanisms by which events occurring in the proximal portion of the GI tract are signaled to the more distal parts, and vice versa. There are three principal control mechanisms involved in the regulation of GI function: endocrine, paracrine, and neurocrine (Fig. 27.4


Physiology_Levy

Physiology_Levy. There are three principal control mechanisms involved in the regulation of GI function: endocrine, paracrine, and neurocrine (Fig. 27.4 Endocrine regulation describes the process whereby the sensing cell in the GI tract, an enteroendocrine cell (EEC), responds to a stimulus by secreting a regulatory peptide or hormone that travels via the bloodstream to target cells removed from the point of secretion. Cells responding to a GI hormone express specific receptors for the hormone. Hormones released from the GI tract have effects on cells located in other regions of the GI tract and also on glandular structures associated with the GI tract, such as the pancreas. In addition, GI hormones have effects on other tissues that have no direct role in digestion and absorption, including endocrine cells in liver and brain. EECs are packed with secretory granules, the products of which are released from the cell in response to chemical and mechanical stimuli to the wall of the GI tract (Fig.


Physiology_Levy

Physiology_Levy. EECs are packed with secretory granules, the products of which are released from the cell in response to chemical and mechanical stimuli to the wall of the GI tract (Fig. 27.5 ). In addition, EECs can be stimulated by neural input or other factors not associated with a meal. The most common EECs in the gut wall are referred to as the “open” type; these cells have an apical membrane that is in contact with the lumen of the GI tract (generally regarded as the location where sensing occurs) and a basolateral membrane through which secretion occurs. There are also “closed”-type EECs that do not have part of their membrane in contact with the luminal surface of the gut; an example is the enterochromaffin-like (ECL) cell in the gastric epithelium, which secretes histamine. There are many examples of hormones secreted by the GI tract (see


Physiology_Levy

Physiology_Levy. There are many examples of hormones secreted by the GI tract (see Table 27.1 ); it is worth remembering that the first hormone ever identified was the GI hormone secretin. One of the most well-characterized GI hormones is gastrin, which is released from endocrine cells located in the wall of the distal part of the stomach. Release of gastrin is stimulated by activation of parasympathetic outflow to the GI tract, and gastrin potently stimulates gastric acid secretion in the postprandial period. •Fig. 27.4 ThethreemechanismsbywhichfunctionintheGItractisregulatedintheintegratedresponsetoameal.


Physiology_Levy

Physiology_Levy. •Fig. 27.4 ThethreemechanismsbywhichfunctionintheGItractisregulatedintheintegratedresponsetoameal. Paracrine regulation describes the process whereby a chemical messenger or regulatory peptide is released from a sensing cell (often an EEC) in the intestinal wall that acts on a nearby target cell by diffusion through the interstitial space. Paracrine agents exert their actions on several different cell types in the wall of the GI tract, including smooth muscle cells, absorptive enterocytes, secretory cells in glands, and even on other EECs. There are several important paracrine agents, and they are listed in


Physiology_Levy

Physiology_Levy. Table 27.1 along with their site of production, site of action, and function. An important paracrine mediator in the gut wall is histamine. In the stomach, histamine is stored and released by ECL cells located in the gastric glands. Histamine diffuses through the interstitial space in the lamina propria to neighboring parietal cells and stimulates production of acid. Serotonin (5-hydroxytryptamine [5-HT]), released from enteric neurons, mucosal mast cells, and specialized EECs called enterochromaffin cells, regulates smooth muscle function and water absorption across the intestinal wall. There are other paracrine mediators in the gut wall, including prostaglandins, adenosine, and nitric oxide (NO); the functions of these mediators are not well described, but they are capable of producing changes in GI function. Fig. 27.5 Electronmicrographofanopen-typeendocrinecellintheGItract.Notethemicrovilliattheapicalprojectionandthesecretorygranulesinthebasolateralportionofthecell.(FromBarrett


Physiology_Levy

Physiology_Levy. Fig. 27.5 Electronmicrographofanopen-typeendocrinecellintheGItract.Notethemicrovilliattheapicalprojectionandthesecretorygranulesinthebasolateralportionofthecell.(FromBarrett K. Gastrointestinal Physiology [Lange Physiology Series]. NewYork:McGraw-Hill;2005.)(CourtesyofLeonardR.Johnson,Ph.D.) Many substances can be both paracrine and endocrine regulators of GI function. For example, cholecystokinin, which is released from the duodenum in response to dietary protein and lipid, acts locally on nerve terminals in a paracrine fashion and also affects the pancreas. This will be discussed in more detail in Neural Regulation of Gastrointestinal Function


Physiology_Levy

Physiology_Levy. Neural Regulation of Gastrointestinal Function Nerves and neurotransmitters play an important role in regulating the function of the GI tract. In its simplest form, neural regulation occurs when a neurotransmitter is released from a nerve terminal located in the GI tract and the neurotransmitter has an effect on the cell that is innervated. However, in some cases there are no synapses between motor nerves and effector cells in the GI tract. Neural regulation of GI function is very important within an organ, as well as between distant parts of the GI tract.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Neural regulation of the GI tract is surprisingly complex. The gut is innervated by two sets of nerves, the extrinsic and intrinsic nervous systems. The extrinsic nervous system is defined as nerves that innervate the gut, with cell bodies located outside the gut wall; these extrinsic nerves are part of the autonomic nervous system (ANS). The intrinsic nervous system, also referred to as the enteric nervous system, has cell bodies that are contained within the wall of the gut (submucosal and myenteric plexuses). Some GI functions are highly dependent on the extrinsic nervous system, yet others can take place independently of the extrinsic nervous system and are mediated entirely by the ENS. However, extrinsic nerves can often modulate intrinsic nervous system function (


Physiology_Levy

Physiology_Levy. Fig. 27.6 •Fig. 27.6 HierarchicalneuralcontrolofGIfunction.StimulitotheGItractfromameal(e.g.,chemical,mechanical,osmotic)willactivateboththeintrinsicandextrinsicsensory(afferent)pathways,whichinturnwillactivatetheextrinsicandintrinsicneuralreflexpathways. Extrinsic neural innervation to the gut is via the two major subdivisions of the ANS, namely, parasympathetic and sympathetic innervation ( Fig. 27.7 ). Parasympathetic innervation to the gut is via the vagus and pelvic nerves. The vagus nerve, the 10th cranial nerve, innervates the esophagus, stomach, gallbladder, pancreas, first part of the intestine, cecum, and the proximal part of the colon. The pelvic nerves innervate the distal part of the colon and the anorectal region, in addition to the other pelvic organs that are not part of the GI tract.


Physiology_Levy

Physiology_Levy. Consistent with the typical organization of the parasympathetic nervous system, the preganglionic nerve cell bodies lie in the brainstem (vagus) or the sacral spinal cord (pelvic). Axons from these neurons run in the nerves to the gut (vagus and pelvic nerves, respectively), where they synapse with postganglionic neurons in the wall of the organ, which in this case are enteric neurons in the gut wall. There is no direct innervation of these efferent nerves to effector cells within the wall of the gut; the transmission pathway is always via a neuron in the ENS. Consistent with transmission in the ANS, the synapse between preganglionic and postganglionic neurons is an obligatory nicotinic synapse. That is, the synapse between preganglionic and postganglionic neurons is mediated via acetylcholine released from the nerve terminal and acting at nicotinic receptors localized on the postganglionic neuron, which in this case is an intrinsic neuron.


Physiology_Levy

Physiology_Levy. Sympathetic innervation is supplied by cell bodies in the spinal cord and fibers that terminate in the prevertebral ganglia (celiac, superior, and inferior mesenteric ganglia); these are the preganglionic neurons. These nerve fibers synapse with postganglionic neurons in the ganglia, and the fibers leave the ganglia and reach the end organ along the major blood vessels and their branches. Rarely there is a synapse in the paravertebral (chain) ganglia, as seen with sympathetic innervation of other organ systems. Some vasoconstrictor sympathetic fibers directly innervate blood vessels of the GI tract, and other sympathetic fibers innervate glandular structures in the wall of the gut. The ANS, both parasympathetic and sympathetic, also carries the fibers of afferent (toward the central nervous system [CNS]) neurons; these are sensory in nature. The cell bodies for the vagal afferents are in the nodose


Physiology_Levy

Physiology_Levy. SuperiorcervicalganglionPrevertebral ganglia1. Celiac2. Superior mesenteric3. Inferior mesenteric 123 •Fig. 27.7 ExtrinsicinnervationoftheGItract,consistingoftheparasympathetic(A)andsympathetic(B)subdivisionsoftheautonomicnervoussystem.


Physiology_Levy

Physiology_Levy. ganglion. These neurons have a central projection terminating in the nucleus of the tractus solitarius in the brainstem and the other terminal in the gut wall. The cell bodies of the spinal afferent neurons that run with the sympathetic pathway are segmentally organized and are found in the dorsal root ganglia. Peripheral terminals of the spinal and vagal afferents are located in all layers of the gut wall, where they detect information about the state of the gut. Afferent neurons send this information to the CNS. Information sent to the CNS relays the nature of the luminal contents (e.g., acidity, nutrient content, osmolality of the luminal contents), as well as the degree of stretch or contraction in smooth muscle. Afferent innervation is also responsible for transmitting painful stimuli to the CNS.


Physiology_Levy

Physiology_Levy. The components of a reflex pathway—afferents, inter-neurons, and efferent neurons—exist within the extrinsic innervation to the GI tract. These reflexes can be mediated entirely via the vagus nerve (termed a vagovagal reflex), which has both afferent and efferent fibers. The vagal afferents send sensory information to the CNS, where they synapse with an interneuron, which then drives activity in the efferent motor neuron. These extrinsic reflexes are very important in regulating GI function after ingestion of a meal. An example of an important vagovagal reflex is the gastric receptive relaxation reflex, in which distention of the stomach results in relaxation of the smooth muscle in the stomach; this allows filling of the stomach to occur without an increase in intraluminal pressure.


Physiology_Levy

Physiology_Levy. In general, as with other visceral organ systems, the parasympathetic and sympathetic nervous systems tend to work in opposition. However, this is not as simple as in the cardiovascular system, for example. Activation of the parasympathetic nervous system is important in the integrative response to a meal and is discussed in the following chapters. The parasympathetic nervous system generally results in activation of physiological processes in the gut wall, although there are notable exceptions. In contrast, the sympathetic nervous system tends to be inhibitory to GI function and is more frequently activated in pathophysiological circumstances. Overall, sympathetic activation inhibits smooth muscle function. The exception to this is the sympathetic innervation of GI sphincters, in which sympathetic activation tends to induce contraction of smooth muscle. Moreover, the sympathetic nervous system is notably important in regulation of blood flow in the GI tract.


Physiology_Levy

Physiology_Levy. The ENS is made up of two major plexuses, which are collections of nerve cell bodies (ganglia) and their fibers, all originating in the wall of the gut ( Fig. 27.8). The myenteric plexus lies between the longitudinal and circular muscle layers, and the submucosal plexus lies in the submucosa. Interganglionic strands link neurons in the two plexuses.


Physiology_Levy

Physiology_Levy. Neurons in the ENS are characterized functionally as afferent neurons, interneurons, or efferent neurons, similar to neurons in the extrinsic part of the ANS. Thus all components of a reflex pathway can be contained within the ENS. Stimuli in the wall of the gut are detected by afferent neurons, which activate interneurons and then efferent neurons to alter function. In this way the ENS can act autonomously from extrinsic innervation. However, neurons in the ENS, as we have already seen, are innervated by extrinsic neurons, and thus the function of these reflex pathways can be modulated by the extrinsic nervous system. Because the ENS is capable of performing its own integrative functions and complex reflex pathways, it is sometimes referred to as the “little brain in the gut” as a result of its importance and complexity. It is estimated that there are as many neurons in the ENS as in the spinal cord. In addition, many GI hormones also act as neurotransmitters in the ENS and in the


Physiology_Levy

Physiology_Levy. of its importance and complexity. It is estimated that there are as many neurons in the ENS as in the spinal cord. In addition, many GI hormones also act as neurotransmitters in the ENS and in the brain in regions involved in autonomic outflow. These mediators and regulatory peptides are thus • Fig. 27.8 The enteric nervous system in the wall of the GI tract.


Physiology_Levy

Physiology_Levy. referred to as brain-gut peptides, and the extrinsic and intrinsic components innervating the gut are sometimes referred to as the brain-gut axis. Response of the GI Tract to a Meal


Physiology_Levy

Physiology_Levy. Response of the GI Tract to a Meal This introductory chapter provides a broad overview of the anatomy and regulatory mechanisms in the GI tract. In the following chapters there will be discussion of the integrated response to a meal to provide the details of GI physiology. The response to a meal is classically divided into phases: cephalic, oral, esophageal, gastric, duodenal, and intestinal. In each phase the meal presents certain stimuli (e.g., chemical, mechanical, and osmotic) that activate different pathways (e.g., neural, paracrine, and humoral reflexes) that result in changes in effector function (e.g., secretion and motility). There is considerable crosstalk between the regulatory mechanisms that have been outlined, and this will be discussed in the next chapters. As with maintenance of homeostasis in other systems of the body, control of GI function requires complex regulatory mechanisms to sense and act in a dynamic fashion. 1.


Physiology_Levy

Physiology_Levy. 1. The GI tract is a tube subdivided into regions that subserve different functions associated with digestion and absorption. 2. The lining of the GI tract is subdivided into layers— the mucosal, submucosal, and muscle layers. 3. There are three major control mechanisms: hormonal, paracrine, and neurocrine. 4. The innervation of the GI tract is particularly interesting because it consists of two interacting components, extrinsic and intrinsic. 5. Extrinsic innervation (cell bodies outside the wall of the GI tract) consists of the two subdivisions of the Baldwin GS. Posttranslational modification of gastrointestinal peptides. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Brierley SM, et al. Innervation of the gastrointestinal tract by spinal and vagal afferent nerves. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012.


Physiology_Levy

Physiology_Levy. Brierley SM, et al. Innervation of the gastrointestinal tract by spinal and vagal afferent nerves. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Brookes SJ, et al. Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol. 2013;10:286-296. Chao C, Hellmich MR. Gastrointestinal peptides: gastrin, cholecystokinin, somatostatin and ghrelin. In: Johnson LR, ed. ANS: parasympathetic and sympathetic. Both have an important sensory (afferent) component. 6. The intrinsic or enteric nervous system (cell bodies in the wall of the GI tract) can act independently of extrinsic neural innervation. 7. When a meal is in different regions of the tract, sensory mechanisms detect the presence of the nutrients and mount appropriate physiological responses in that region of the tract, as well as in more distal regions. These responses are mediated by endocrine, paracrine, and neurocrine pathways.


Physiology_Levy

Physiology_Levy. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9:286-294. Gomez GA, et al. Postpyloric gastrointestinal peptides. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Parker HE, et al. The role of gut endocrine cells in control of metabolism and appetite. Exp Physiol. 2014;99:1116-1120. Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95:513-548. 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal Upon completion of this chapter the student should be able to answer the following questions: 1. What are the structures of the functional anatomy of salivary glands, including their secretory elements? 2. What are the cephalic and oral phases (what, why, how it happens) of the response to a meal? 3.


Physiology_Levy

Physiology_Levy. 2. What are the cephalic and oral phases (what, why, how it happens) of the response to a meal? 3. What are the general principles of secretion along the gastrointestinal (GI) tract (where do secretions come from, what are the components)? 4. How do the components of secretion vary with the gland or region of the GI tract? 5. What is the correlation between the composition and functions of salivary secretion? 6. How are primary and secondary secretion within salivary glands generated and regulated? 7. What is the sequence of events in swallowing? 8. What are the stimulus and neural pathways generating primary and secondary esophageal peristalsis? 9. What changes in gastric motility take place during swallowing, and what is the significance? 10. What are the major functions of the esophagus and associated structures in terms of protection and propulsion?


Physiology_Levy

Physiology_Levy. 10. What are the major functions of the esophagus and associated structures in terms of protection and propulsion? his chapter will describe the processes that occur in the gastrointestinal (GI) tract in the early stages of the integrated response to a meal. There are changes in GI tract physiology (1) before food is ingested (the cephalic phase), (2) when ingested food is in the mouth (the oral phase), and (3) when food is transferred from the mouth to the esophagus (the esophageal phase). The responses of the GI tract to the presence of food are mainly associated with preparing the GI tract for digestion and absorption.


Physiology_Levy

Physiology_Levy. The main feature of the cephalic phase is activation of the GI tract in readiness for the meal. The stimuli involved are cognitive and include anticipation or thinking about the consumption of food, olfactory input, visual input (seeing or smelling appetizing food when hungry), and auditory input. The latter may be an unexpected link but was clearly demonstrated in the classic conditioning experiments of Pavlov, in which he paired an auditory stimulus to the presentation of food to dogs; eventually the auditory stimulus alone could stimulate secretion. A real-life analogy is presumably being told that dinner is ready. All these stimuli result in an increase in excitatory parasympathetic neural outflow to the gut. Sensory input (e.g., smell) stimulates sensory nerves that activate parasympathetic outflow from the brainstem. Higher brain sites (e.g., limbic system, hypothalamus, cortex) are also involved in the cognitive components of this response. The response can be both positive and


Physiology_Levy

Physiology_Levy. outflow from the brainstem. Higher brain sites (e.g., limbic system, hypothalamus, cortex) are also involved in the cognitive components of this response. The response can be both positive and negative; thus anticipation of food and a person’s psychological status, such as anxiety, can alter the cognitive response to a meal. However, the final common pathway is activation of the dorsal motor nucleus in the brainstem, the region where the cell bodies of the vagal preganglionic neurons arise. Activation of the nucleus leads to increased activity in efferent fibers passing to the GI tract in the vagus nerve. In turn the efferent fibers activate the postganglionic motor neurons (referred to as motor because their activation results in change of function of an effector cell). Increased parasympathetic outflow enhances salivary secretion, gastric acid secretion, pancreatic enzyme secretion, gallbladder contraction, and relaxation of the sphincter of Oddi (the sphincter between the common


Physiology_Levy

Physiology_Levy. outflow enhances salivary secretion, gastric acid secretion, pancreatic enzyme secretion, gallbladder contraction, and relaxation of the sphincter of Oddi (the sphincter between the common bile duct and duodenum). All these responses enhance the ability of the GI tract to receive and digest the incoming food. The salivary response is mediated via the ninth cranial nerve; the remaining responses are mediated via the vagus nerve.


Physiology_Levy

Physiology_Levy. Many of the features of the oral phase are indistinguishable from the cephalic phase. The only difference is that food is in contact with the surface of the GI tract. Thus there are additional stimuli generated from the mouth, both mechanical and chemical (taste). However, many of CHAPTER 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal the responses initiated by the presence of food in the oral cavity are identical to those initiated in the cephalic phase, because the efferent pathway is the same. The responses specifically initiated in the mouth, which consist mainly of the stimulation of salivary secretion, will be discussed next.


Physiology_Levy

Physiology_Levy. The mouth is important for the mechanical disruption of food and for initiation of digestion. Chewing subdivides and mixes the food with the enzymes salivary amylase and lingual lipase and with the glycoprotein mucin, which lubricates food for chewing and swallowing. Minimal absorption occurs in the mouth, although alcohol and some drugs are absorbed from the oral cavity, and this can be clinically important. However, as with the cephalic phase, it is important to realize that stimulation of the oral cavity initiates responses in the more distal GI tract, including increased gastric acid secretion, increased pancreatic enzyme secretion, gallbladder contraction, and relaxation of the sphincter of Oddi, mediated via the efferent vagal pathway. Properties of Secretion


Physiology_Levy

Physiology_Levy. Secretions in the GI tract come from glands associated with the tract (salivary glands, pancreas, and liver), from glands formed by the gut wall itself (e.g., submucosal glands in esophagus and duodenum), and from the intestinal mucosa itself. The exact nature of the secretory products can vary tremendously, depending on the function of that region of the GI tract. However, these secretions have several characteristics in common. Secretions from the GI tract and associated glands include water, electrolytes, protein, and humoral agents. Water is essential for generating an aqueous environment for efficient enzyme action. Secretion of electrolytes is important for generation of osmotic gradients to drive the movement of water. Digestive enzymes in secreted fluid catalyze the breakdown of macronutrients in ingested food. Moreover, many additional proteins secreted along the GI tract have specialized functions, some of which are fairly well understood, such as those of mucin and


Physiology_Levy

Physiology_Levy. of macronutrients in ingested food. Moreover, many additional proteins secreted along the GI tract have specialized functions, some of which are fairly well understood, such as those of mucin and immunoglobulins, and others that are only just beginning to be understood, such as those of trefoil peptides.


Physiology_Levy

Physiology_Levy. Secretion is initiated by multiple signals associated with the meal, including chemical, osmotic, and mechanical components. Secretion is elicited by the action of specific effector substances called secretagogues acting on secretory cells. Secretagogues work in one of the three ways that have already been described in Chapter 27—endocrine, paracrine, and neurocrine. Constituents of Secretions Inorganic secretory components are region or gland specific, depending on the particular conditions required in that part of the GI tract. The inorganic components are electrolytes, including H+ and HCO3 − . Two examples of different secretions include acid (HCl) in the stomach, which is important to activate pepsin and start protein digestion, and HCO3 − in the duodenum, which neutralizes gastric acid and provides optimal conditions for the action of digestive enzymes in the small intestine.


Physiology_Levy

Physiology_Levy. Organic secretory components are also gland or organ specific and depend on the function of that region of the gut. The organic constituents are enzymes (for digestion), mucin (for lubrication and mucosal protection), and other factors such as growth factors, immunoglobulins, bile acids, and absorptive factors. During the cephalic and oral phases of the meal, considerable stimulation of salivary secretion takes place. Saliva has a variety of functions, including those important for the integrative responses to a meal and for other physiological processes ( Box 28.1 ). The main functions of saliva in digestion include lubrication and moistening of food for swallowing, solubilization of material for taste, initiation of carbohydrate digestion, and clearance and neutralization of refluxed gastric secretions in the esophagus. Saliva also has antibacterial actions that are important for overall health of the oral cavity and teeth. Functional Anatomy of the Salivary Glands


Physiology_Levy

Physiology_Levy. Functional Anatomy of the Salivary Glands There are three pairs of major salivary glands: parotid, submandibular, and sublingual. In addition, many smaller glands are found on the tongue, lips, and palate. These glands are the typical tubuloalveolar structures of glands located in the GI tract ( Fig. 28.1 ). The acinar portion of the gland is classified according to its major secretion: serous (“watery”), mucous, or mixed. The parotid gland produces mainly serous secretion, the sublingual gland secretes mainly mucus, and the submandibular gland produces a mixed secretion.


Physiology_Levy

Physiology_Levy. Cells in the secretory end pieces, or acini, are called acinar cells and are characterized by basally located nuclei, abundant rough endoplasmic reticulum, and apically located secretory granules that contain the enzyme amylase and other secreted proteins. There are also mucous cells in the acinus; the granules in these cells are larger and contain the specialized glycoprotein mucin. There are three kinds of ducts in the gland that transport secretions from the acinus to the opening in the mouth and also modify the secretion: intercalated ducts drain acinar fluid into larger •BOX 28.1FunctionsofSalivaandChewing


Physiology_Levy

Physiology_Levy. Disruption of food to produce smaller particles Formation of a bolus for swallowing Initiation of starch and lipid digestion Facilitation of taste Production of intraluminal stimuli in the stomach Regulation of food intake and ingestive behavior Cleansing of the mouth and selective antibacterial action Neutralization of refluxed gastric contents Mucosal growth and protection in the rest of the GI tract Aid in speech 522 SECTION6Berne & Levy Physiology • Fig.28.1General structure of tubuloalveolar secretory glands (e.g., salivary glands, pancreas) associ-ated with the digestive tract. Demilune of serous cells Serous cell Basement membrane Intercalated duct Mucous cell Salivary duct (secretory) ducts, the striated ducts, which then empty into even larger excretory ducts. In addition, a single large duct from each gland drains saliva to the mouth. The ductal cells lining the striated ducts, in particular, modify the ionic composition and osmolarity of saliva. Composition of Saliva


Physiology_Levy

Physiology_Levy. Composition of Saliva The important properties of saliva are a large flow rate relative to the mass of gland, low osmolarity, high K+ concentration, and organic constituents, including enzymes (amylase, lipase), mucin, and growth factors. The latter are not important in the integrated response to a meal but are essential for long-term maintenance of the lining of the GI tract. The inorganic composition is entirely dependent on the stimulus and the rate of salivary flow. In humans, salivary secretion is always hypotonic. The major components are − , Ca++ , Mg++ Na+ , K+ , HCO3 , and Cl− . Fluoride can be secreted in saliva, and fluoride secretion forms the basis of oral fluoride treatment for prevention of dental caries. The concentration of ions varies with the rate of secretion; the flow rate of salivary secretion is stimulated during the postprandial period.


Physiology_Levy

Physiology_Levy. The primary secretion is produced by acinar cells in the secretory end pieces (or acini) and is modified by duct cells as saliva passes through the ducts. The primary secretion is isotonic, and the concentration of the major ions is similar to that in plasma. Secretion is driven predominantly by Ca++-dependent signaling, which opens apical Cl− channels in the acinar cells. Cl− therefore flows out into the duct lumen and establishes an osmotic and electrical gradient. Because the epithelium of the acinus is relatively leaky, Na+ and water then follow across the epithelium via the tight junctions (i.e., via paracellular transport). Transcellular water movement may also occur, mediated by aquaporin 5 water channels. The amylase content and rate of fluid secretion vary with the type and level of stimulus. As the fluid passes along the ducts, the excretory and striated duct cells modify the ionic composition of the primary secretion to produce the secondary secretion. The duct cells


Physiology_Levy

Physiology_Levy. level of stimulus. As the fluid passes along the ducts, the excretory and striated duct cells modify the ionic composition of the primary secretion to produce the secondary secretion. The duct cells reabsorb Na+ and Cl− , and secrete K+ and HCO3 − into the lumen. Na+ is exchanged for protons, but some of the secreted protons are then reabsorbed in exchange for K+ . HCO3 − on the other hand is secreted only in exchange for Cl−, thereby alkalinizing salivary secretion.


Physiology_Levy

Physiology_Levy. At rest, final salivary secretion is hypotonic and slightly alkaline. The alkalinity of saliva is important in restricting microbial growth in the mouth, as well as in neutralizing refluxed gastric acid once the saliva is swallowed. When salivary secretion is stimulated, there is a small decrease in the K+ concentration (but it always remains above plasma concentrations), the Na+ concentration increases toward plasma levels, and Cl− and HCO3 − concentrations increase, thus the secreted fluid becomes even more alkaline ( Fig. 28.2 ). Note that HCO3 − secretion can be directly stimulated by the action of secretagogues on duct cells. The duct epithelium is relatively tight and lacks expression of aquaporin, and therefore water cannot follow the ions rapidly enough to maintain isotonicity at moderate or high flow rates during stimulated salivary secretion. Thus with


Physiology_Levy

Physiology_Levy. CHAPTER 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal 1.0 2.0 3.0 4.0 Flow of saliva (mL/min) Na+ Saliva Plasma Cl– K+ Cl– Na+ K+ HCO– 3 HCO– 3 Amylase-containing PRIMARY SECRETION (nearly isotonic; levels of Na+, K+, Cl–, and probably HCO3 similar to plasma) Modification of ionic content • Fig. 28.2 A, The composition of salivary secretion as a function of the salivary flow rate compared with the concentration of ions in plasma. Saliva is hypotonic to plasma at all flow rates. [HCO3 −] in saliva exceeds that in plasma except at very low flow rates. B, Schematic representation of the two-stage model of salivary secretion. The primary secretion containing amylase and electrolytes is produced in the acinar cell. The concentration of electrolytes in plasma is similar to that in the primary secretion, but it is modified as it passes through ducts that absorb Na+ and Cl− and secrete K+ and HCO3 − .


Physiology_Levy

Physiology_Levy. an increase in secretion rate, there is less time for ionic modification by the duct cells, and the resulting saliva more closely resembles the primary secretion and therefore plasma. However, [HCO3 −] remains high because secretion from duct cells and possibly acinar cells is stimulated (see Fig. 28.2). The organic constituents of saliva—proteins and glycoproteins—are synthesized, stored, and secreted by the acinar cells. The major products are amylase (an enzyme that initiates starch digestion), lipase (important for lipid digestion), glycoprotein (mucin, which forms mucus when hydrated), and lysozyme (attacks bacterial cell walls to limit colonization of bacteria in the mouth). Although salivary amylase begins the process of digestion of carbohydrates, it is not required in healthy adults because of the excess of pancreatic amylase. Similarly the importance of lingual lipase is unclear. Metabolism and Blood Flow of Salivary Glands


Physiology_Levy

Physiology_Levy. Metabolism and Blood Flow of Salivary Glands The salivary glands produce a prodigious flow of saliva. The maximal rate of saliva production in humans is about 1 mL/ min/g of gland; thus at this rate, the glands are producing their own weight in saliva each minute. Salivary glands have a high rate of metabolism and high blood flow; both are proportional to the rate of saliva formation. Blood flow to maximally secreting salivary glands is approximately 10 times that of an equal mass of actively contracting skeletal muscle. Stimulation of the parasympathetic nerves to salivary glands increases blood flow by dilating the vasculature of the glands. Vasoactive intestinal polypeptide (VIP) and acetylcholine are released from parasympathetic nerve terminals in the salivary glands and are vasodilatory during secretion. Regulation of Salivary Secretion


Physiology_Levy

Physiology_Levy. Regulation of Salivary Secretion Control of salivary secretion is exclusively neural. In contrast, control of most other GI secretions is primarily hormonal. Salivary secretion is stimulated by both the sympathetic and parasympathetic subdivisions of the autonomic nervous system. Excitation of either sympathetic or parasympathetic nerves to the salivary glands stimulates salivary secretion. Primary physiological control of the salivary glands during the response to a meal is by the parasympathetic nervous system. If the parasympathetic supply is interrupted, salivation is severely impaired and the salivary glands atrophy.


Physiology_Levy

Physiology_Levy. Sympathetic fibers to the salivary glands stem from the superior cervical ganglion. Preganglionic parasympathetic fibers travel via branches of the facial and glossopharyngeal nerves (cranial nerves VII and IX, respectively). These fibers form synapses with postganglionic neurons in ganglia in or near the salivary glands. The acinar cells and ducts are supplied with parasympathetic nerve endings. Parasympathetic stimulation increases synthesis and secretion of salivary amylase and mucins, enhances the transport activities of the ductular epithelium, greatly increases blood flow to the glands, and stimulates glandular metabolism and growth. Ionic Mechanisms of Salivary Secretion


Physiology_Levy

Physiology_Levy. Ionic Mechanisms of Salivary Secretion Fig. 28.3 shows a simplified view of the mechanisms of ion secretion by serous acinar cells. The basolateral membrane of the cell contains Na+,K+-ATPase and an Na+-K+-2Cl− symporter. The concentration gradient for Na+ across the basolateral membrane, which is dependent on Na+,K+-ATPase, provides the driving force for entry of Na+ , K+ , and Cl− into the cell. Cl− and HCO3 − leave the acinar cell and enter the lumen via an anion channel located in the apical membrane of the acinar cell. This secretion of anions drives the entry of Na+ and thus water into the acinar lumen across the relatively leaky tight junctions. Acinar cell fluid secretion is strongly enhanced in response to elevations in intracellular [Ca++] as a result of activation of the muscarinic receptor for acetylcholine.


Physiology_Levy

Physiology_Levy. Acinar cell fluid secretion is strongly enhanced in response to elevations in intracellular [Ca++] as a result of activation of the muscarinic receptor for acetylcholine. Fig. 28.4 shows a simplified model of ion transport processes in epithelial cells of the excretory and striated ducts. Na+,K+-ATPase located in the basolateral membrane maintains the electrochemical gradients for Na+ and K+ that drive most of the other ionic transport processes of the cell. In the apical membrane the parallel operation of the Na+/ H+ antiporter, the Cl−/HCO3 − antiporter, and the H+/K+ antiporter results in absorption of Na+ and Cl− from the lumen and secretion of K+ and HCO3 − into the lumen. The relative impermeability of the ductular epithelium to water prevents the ducts from absorbing too much water by osmosis. • Fig.28.3Ionic transport mechanism involved in the secretion of amylase and electrolytes in salivary acinar cells. ATP2Cl–HCO3LumenofacinusNa˜Na˜Na˜Cl°Na˜K˜K˜K˜K˜°H˜


Physiology_Levy

Physiology_Levy. • Fig.28.3Ionic transport mechanism involved in the secretion of amylase and electrolytes in salivary acinar cells. ATP2Cl–HCO3LumenofacinusNa˜Na˜Na˜Cl°Na˜K˜K˜K˜K˜°H˜ Swallowing can be initiated voluntarily, but thereafter it is almost entirely under reflex control. The swallowing reflex is a rigidly ordered sequence of events that propel food from the mouth to the pharynx and from there to the stomach. This reflex also inhibits respiration and prevents entrance of food into the trachea during swallowing. The afferent limb of the swallowing reflex begins when touch receptors, most notably those near the opening of the pharynx, are stimulated. Sensory impulses from these receptors are transmitted to an area in the medulla and lower pons called the swallowing center. Motor impulses travel from the swallowing center to the musculature of the pharynx and upper esophagus via various cranial nerves and to the remainder of the esophagus by vagal motor neurons.


Physiology_Levy

Physiology_Levy. The timing of events in swallowing is shown in Fig. 28.5 . The voluntary phase of swallowing is initiated when the tip of the tongue separates a bolus of food from the mass of food in the mouth. First the tip of the tongue and later the more posterior portions of the tongue press against the hard palate. The action of the tongue moves the bolus upward and then backward into the mouth. The bolus is forced into the pharynx, where it stimulates the touch receptors CHAPTER 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal • Fig.28.4Ionic transport mechanism involved in secretion and absorption in epithelial cells of the striated and excretory duct of the salivary gland. ATPHCO3LumenofductNa˜Na˜Na˜Na˜Cl°Cl°K˜K˜K˜°H˜H˜H˜


Physiology_Levy

Physiology_Levy. The acinar cells and duct cells of the salivary glands respond to both cholinergic and adrenergic agonists. Nerves stimulate the release of acetylcholine, norepinephrine, substance P, and VIP by salivary glands, and these hormones increase the secretion of amylase and the flow of saliva. These neurotransmitters act mainly by elevating the intracellular concentration of cyclic adenosine monophosphate (cAMP) and by increasing the concentration of Ca++ in the cytosol. Acetylcholine and substance P, acting on muscarinic and tachykinin receptors, respectively, increase the cytosolic concentration of Ca++ in serous acinar cells. In contrast, norepinephrine, acting on β receptors, and VIP, binding to its receptor, elevate the cAMP concentration in acinar cells. Agonists that elevate the cAMP concentration in serous acinar cells elicit a secretion that is rich in amylase; agonists that mobilize Ca++ elicit a secretion that is more voluminous but has a lower concentration of amylase.


Physiology_Levy

Physiology_Levy. cAMP concentration in serous acinar cells elicit a secretion that is rich in amylase; agonists that mobilize Ca++ elicit a secretion that is more voluminous but has a lower concentration of amylase. Ca++-mobilizing agonists may also elevate the concentration of cyclic guanosine monophosphate (cGMP), which may mediate the trophic effects evoked by these agonists.


Physiology_Levy

Physiology_Levy. that initiate the swallowing reflex. The pharyngeal phase of swallowing involves the following sequence of events, which occur in less than 1 second: 1. The soft palate is pulled upward and the palatopharyngeal folds move inward toward one another; these movements 0.2 0.4 0.6 0.8 1.0 1.2 Time (sec) Bolus in mouth Bolus moves through pharynx and UES Bolus enters esophagus Tongue thrust up and back Nasopharynx closed Larynx elevated Airway closed UES open Pharynx contracts • Fig. 28.5 Timing of motor events in the pharynx and UES during a swallow. Xerostomia, or dry mouth, is caused by impaired salivary secretion. It can be congenital or develop as part of an autoimmune process. The decrease in secretion reduces the pH in the oral cavity, which causes tooth decay and is associated with esophageal erosions. Reduced secretion also causes difficulty swallowing.


Physiology_Levy

Physiology_Levy. The ability to measure and monitor a wide range of molecular components that are indicative of overall health is useful in diagnosis and monitoring. Saliva is easy to access, and collection of it is noninvasive. It is used to identify individuals with disease (presence of biomarkers) and to monitor the progress of affected individuals under treatment. In endocrinology, levels of steroids can be measured in the free form rather than as the free and bound form, as in plasma (e.g., the stress hormone cortisol and the sex hormones estradiol, progesterone, and testosterone). Viral infections such as human immunodeficiency virus (HIV), herpes, hepatitis C, and Epstein-Barr virus infection can be detected by polymerase chain reaction (PCR) techniques. Bacterial infections, such as Helicobacter pylori, can likewise be detected in saliva, and saliva is also used for monitoring drug levels.


Physiology_Levy

Physiology_Levy. prevent reflux of food into the nasopharynx and open a narrow passage through which food moves into the pharynx. 2. The vocal cords are pulled together and the larynx is moved forward and upward against the epiglottis; these actions prevent food from entering the trachea and help open the upper esophageal sphincter (UES). 3. The UES relaxes to receive the bolus of food. 4. The superior constrictor muscles of the pharynx then contract strongly to force the bolus deeply into the pharynx. A peristaltic wave is initiated with contraction of the pharyngeal superior constrictor muscles, and the wave moves toward the esophagus. This wave forces the bolus of food through the relaxed UES. During the pharyngeal stage of swallowing, respiration is also reflexively inhibited. After the bolus of food passes the UES, a reflex action causes the sphincter to constrict.