Acute and Chronic Inflammation

Davis Massey, M.D., D.D.S.

Assigned Reading




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Dilute Destroy Isolate Initiate repair

Acute and chronic forms

Acute inflammation

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Vasodilation Vascular leakage and edema Leukocyte emigration (mostly PMNs)


Brief arteriolar vasoconstriction followed by vasodilation
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Accounts for warmth and redness Opens microvascular beds Increased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into interstitium (vascular permeability still not increased yet)

Vascular leakage  Vascular permeability (leakiness) commences   Transudate gives way to exudate (proteinrich) Increases interstitial osmotic pressure contributing to edema (water and ions) .

brief (15 – 30 min. leukotrienes cause an early.) immediate transient response in the form of endothelial cell contraction that widens intercellular gaps of venules (not arterioles.Vascular leakage  Five mechanisms known to cause vascular leakiness  Histamines. bradykinins. capillaries) .

detachment) making them leaky until they are repaired (immediate sustained response). lasting 24 hrs or more) Severe injuries may cause immediate direct endothelial cell damage (necrosis. . IL-1) induce endothelial cell junction retraction through cytoskeleton reorganization (4 – 6 hrs post injury.Vascular leakage   Cytokine mediators (TNF. or may cause delayed damage as in thermal or UV injury.

Vascular leakage   (cont’d) or some bacterial toxins (delayed prolonged leakage) Marginating and endothelial cell-adherent leukocytes may pile-up and damage the endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent endothelial cell injury) making the vessel leaky .

Vascular leakage  Certain mediators (VEGF) may cause increased transcytosis via intracellular vesicles which travel from the luminal to basement membrane surface of the endothelial cell  All or any combination of these events may occur in response to a given stimulus .

Leukocyte cellular events  Leukocytes leave the vasculature routinely through the following sequence of events:    Margination and rolling Adhesion and transmigration Chemotaxis and activation Phagocytosis and degranulation Leukocyte-induced tissue injury  They are then free to participate in:   .

Margination and Rolling   With increased vascular permeability. fluid leaves the vessel causing leukocytes to settleout of the central flow column and “marginate” along the endothelial surface Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium like a tumbleweed until it eventually comes to a stop as mutual adhesion reaches a peak .

CD34. endothelium). L-selectin (leukocytes) bind other surface molecules (i.Margination and Rolling  Early rolling adhesion mediated by selectin family:  E-selectin (endothelium).. P-selectin (platelets. Sialyl-Lewis X-modified GP) that are upregulated on endothelium by cytokines (TNF. IL-1) at injury sites .e.

Mac-1. VCAM-1  Leukocyte: LFA-1.Adhesion   Rolling comes to a stop and adhesion results Other sets of adhesion molecules participate: Endothelial: ICAM-1. VCAM-1 binds VLA-4)   Ordinarily down-regulated or in an inactive conformation. VLA-4 (ICAM-1 binds LFA-1/Mac-1. but inflammation alters this .

Transmigration (diapedesis)   Occurs after firm adhesion within the systemic venules and pulmonary capillaries via PECAM –1 (CD31) Must then cross basement membrane   Collagenases Integrins .

lymphocytes.Transmigration (diapedesis)  Early in inflammatory response mostly PMNs. but as cytokine and chemotactic signals change with progression of inflammatory response. alteration of endothelial cell adhesion molecule expression activates other populations of leukocytes to adhere (monocytes. etc) .

g. IL-8) LTB4 (AA metabolite)  Chemotactic agents bind surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements .Chemotaxis  Leukocytes follow chemical gradient to site of injury (chemotaxis)     Soluble bacterial products Complement components (C5a) Cytokines (chemokine family e..

Chemotaxis and Activation  Leukocytes:   extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxis undergo activation:    Prepare AA metabolites from phospholipids Prepare for degranulation and release of lysosomal enzymes (oxidative burst) Regulate leukocyte adhesion molecule affinity as needed .

leukocytes:    Recognize and attach Engulf (form phagocytic vacuole) Kill (degrade) .Phagocytosis and Degranulation  Once at site of injury.

Fc portion of IgG) Corresponding receptors on leukocytes (FcR. CR1. 3) leads to binding . immunoglobulin (C3b. 2.Recognition and Binding   Opsonized by serum complement.

Phagocytosis and Degranulation   Triggers an oxidative burst (next slide) engulfment and formation of vacuole which fuses with lysosomal granule membrane (phagolysosome) Granules discharge within phagolysosome and extracellularly (degranulation) .

Oxidative burst  Reactive oxygen species formed through oxidative burst that includes:     Increased oxygen consumption Glycogenolysis Increased glucose oxidation Formation of superoxide ion  2O2 + NADPH  2O2-rad + NADP+ + H+ (NADPH oxidase)  O2 + 2H+  H2O2 (dismutase) .

an oxidant/antimicrobial agent Therefore. or lipid/protein peroxidation . PMNs can kill by halogenation.).Reactive oxygen species    Hydrogen peroxide alone insufficient MPO (azurophilic granules) converts hydrogen peroxide to HOCl.(in presence of Cl.

Degradation and Clean-up    Reactive end-products only active within phagolysosome Hydrogen peroxide broken down to water and oxygen by catalase Dead microorganisms degraded by lysosomal acid hydrolases .

Leukocyte granules  Other antimicrobials in leukocyte granules:     Bactericidal permeability increasing protein (BPI) Lysozyme Lactoferrin Defensins (punch holes in membranes) .

emphysema) . flat) Membranolytic substances (urate crystals) Persistent leukocyte activation (RA.Leukocyte-induced tissue injury  Destructive enzymes may enter extracellular space in event of:     Premature degranulation Frustrated phagocytosis (large.

and defect in Eand P-selectin sugar epitopes (LAD-2) Microtubule assembly defect leads to impaired locomotion and lysosomal degranulation (Chediak-Higashi Syndrome)  Defects of chemotaxis/phagocytosis:  .Defects of leukocyte function  Defects of adhesion:   LFA-1 and Mac-1 subunit defects lead to impaired adhesion (LAD-1) Absence of sialyl-Lewis X.

therefore no oxygen-dependent killing mechanism (chronic granulomatous disease) .Defects of leukocyte function  Defects of microbicidal activity:  Deficiency of NADPH oxidase that generates superoxide.

Chemical mediators  Plasma-derived:   Complement. sequestered and released (mast cell histamine) Synthesized as needed (prostaglandin)  Cell-derived:   . coagulation factors Many in “pro-form” requiring activation (enzymatic cleavage) Preformed. kinins.

or are scavenged (antioxidants) . are inactivated enzymatically (kininase).Chemical mediators    May or may not utilize a specific cell surface receptor for activity May also signal target cells to release other effector molecules that either amplify or inhibit initial response (regulation) Are tightly regulated:  Quickly decay (AA metabolites).

basophils. released by mast cells. immune reactions (IgEmast cell FcR). neuropeptides. leukocyte-derived histamine-releasing peptides . junctional widening.Specific mediators  Vasoactive amines  Histamine: vasodilation and venular endothelial cell contraction. heat). cytokines (IL-1. IL-8). platelets in response to injury (trauma. anaphylatoxins (C3a. C5a fragments).

Specific mediators  Serotonin: vasodilatory effects similar to those of histamine. platelet dense-body granules. release triggered by platelet aggregation Clotting system Complement Kinins  Plasma proteases    .

basement membrane.Clotting cascade  Cascade of plasma proteases     Hageman factor (factor XII) Collagen. activated platelets converts XII to XIIa (active form) Ultimately converts soluble fibrinogen to insoluble fibrin clot Factor XIIa simultaneously activates the “brakes” through the fibrinolytic system to prevent continuous clot propagation .

g. bronchial smooth muscle) Causes pain Rapidly inactivated (kininases) .Kinin system  Leads to formation of bradykinin from cleavage of precursor (HMWK)      Vascular permeability Arteriolar dilation Non-vascular smooth muscle contraction (e..

C3bi) .Complement system  Components C1-C9 present in inactive form   Activated via classic (C1) or alternative (C3) pathways to generate MAC (C5 – C9) that punch holes in microbe membranes In acute inflammation    Vasodilation. mast cell degranulation (C3a. increases integrin avidity (C5a) As an opsonin. vascular permeability. C5a) Leukocyte chemotaxin. increases phagocytosis (C3b.

COX blocked by aspirin and NSAIDS .Specific Mediators  Arachidonic acid metabolites (eicosanoids)  Prostaglandins and thromboxane: via cyclooxygenase pathway. but also protective (gastric mucosa). cause vasodilation and prolong edema.

Specific Mediators  Leukotrienes: via lipoxygenase pathway. vasoconstrictors. increases leukocyte adhesion (integrin conformation)  PAF (platelet activating factor)  . and bronchospasm Derived also from cell membrane phospholipid. increased vascular permeability. causes vasodilation. are chemotaxins. cause increased vascular permeability.

etc. IFN- are especially important in inflammation.. Increase endothelial cell adhesion molecule expression. . TNF- and -. etc.. etc. telling them how to behave. activation and aggregation of PMNs.More specific mediators  Cytokines    Protein cell products that act as a message to other cells. IL-1.

Specific mediators  Nitric Oxide   short-acting soluble free-radical gas with many functions Produced by endothelial cells. macrophages. causes:    Vascular smooth muscle relaxation and vasodilation Kills microbes in activated macrophages Counteracts platelet adhesion. aggregation. and degranulation .

attempts at phagocytosis. Acid proteases (only active within lysosomes). Neutral proteases such as elastase and collagenase are destructive in ECM. .Specific mediators  Lysosomal components     Leak from PMNs and macrophages after demise. Counteracted by serum and ECM antiproteases. etc.

Possible outcomes of acute inflammation  Complete resolution   Little tissue damage Capable of regeneration In tissues unable to regenerate Excessive fibrin deposition organized into fibrous tissue  Scarring (fibrosis)   .

Outcomes (cont’d)   Abscess formation occurs with some bacterial or fungal infections Progression to chronic inflammation (next) .

TB) Prolonged toxic agent exposure (silica) Autoimmune disease states (RA. plasma cell (mononuclear cell) infiltration Tissue destruction by inflammatory cells Attempts at repair with fibrosis and angiogenesis (new vessel formation) When acute phase cannot be resolved    Persistent injury or infection (ulcer. macrophage.Chronic inflammation     Lymphocyte. SLE) .

etc. Kupffer cells.The Players (mononuclear phagocyte system)  Macrophages    Scattered all over (microglia. alveolar macrophages. and other products of inflammation . Circulate as monocytes and reach site of injury within 24 – 48 hrs and transform Become activated by T cell-derived cytokines. sinus histiocytes. endotoxins.

The Players  T and B lymphocytes   Antigen-activated (via macrophages and dendritic cells) Release macrophage-activating cytokines (in turn. macrophages release lymphocyteactivating cytokines until inflammatory stimulus is removed) Terminally differentiated B cells  Plasma cells  .

or at allergic (IgE-mediated) sites  Eosinophils  .The Players  Produce antibodies Found especially at sites of parasitic infection.

which engulf and surround indigestible foreign bodies (mycobacteria. suture material) Resemble squamous cells. therefore called “epithelioid” granulomas . capsulatum. H. silica.Granulomatous Inflammation   Clusters of T cell-activated macrophages.

Lymph Nodes and Lymphatics  Lymphatics drain tissues    Flow increased in inflammation Antigen to the lymph node Toxins. otherwise bacteremia ensues Tissue-resident macrophages must then prevent overwhelming infection . lymphangitis Usually contained there. infectious agents also to the node    Lymphadenitis.

) Often walled-off if persistent  Fibrinous    Suppurative   .. protein-poor effusion (e.g.Patterns of acute and chronic inflammation  Serous  Watery. blister) Fibrin accumulation Either entirely removed or becomes fibrotic Presence of pus (pyogenic staph spp.

toxins. vascular insufficiency .Patterns (cont’d)  Ulceration    Necrotic and eroded epithelial surface Underlying acute and chronic inflammation Trauma.

IL-6. TNF) acutephase reactions including    Anorexia Skeletal muscle protein degradation Hypotension  Leukocytosis  Elevated white blood cell count . IL-1.Systemic effects  Fever  One of the easily recognized cytokinemediated (esp.

Systemic effects (cont’d)    Bacterial infection (neutrophilia) Parasitic infection (eosinophilia) Viral infection (lymphocytosis) .

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