Physiology_Levy

Physiology_Levy. Because the enhanced sympathetic drive and the reduced parasympathetic inhibition of the sinoatrial node continue during exercise, tachycardia persists. If the workload is moderate and constant, the heart rate reaches a certain level and remains there throughout the period of exercise. However, if the workload increases, the heart rate increases concomitantly until a plateau of approximately 180 beats per minute is reached during strenuous exercise. In contrast to the large increase in heart rate, the increase in stroke volume is only approximately 10% to 35%, the larger values occurring in trained individuals (see Fig. 19.17 ). In well-trained distance runners, whose cardiac output can reach six to seven times the resting level, stroke volume attains approximately twice the resting value.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Thus the increase in cardiac output observed during exercise is correlated principally with an increase in heart rate. If the baroreceptors are denervated, the cardiac output and heart rate responses to exercise are small in comparison with those in individuals with normally innervated baroreceptors. However, with total cardiac denervation, exercise still increases cardiac output as much as it does in normal individuals. This increase in cardiac output is achieved chiefly by means of an elevated stroke volume. However, if a β-adrenergic receptor antagonist is given to dogs with denervated hearts, exercise performance is impaired. The β-adrenergic receptor antagonist prevents the cardiac acceleration and enhanced contractility caused by increased amounts of circulating catecholamines. Therefore, the increase in cardiac output necessary for maximal exercise performance is limited.


Physiology_Levy

Physiology_Levy. In addition to the contribution made by sympathetically mediated constriction of the capacitance vessels in both exercising and nonexercising parts of the body, venous return is aided by the auxiliary pumping action of the working skeletal muscles and the muscles of respiration (see also ). The intermittently contracting muscles compress the veins that course through them. Because the venous valves are oriented toward the heart, the contracting muscle pumps blood back toward the right atrium (see ). In exercise, the flow of venous blood to the heart is also aided by the deeper and more frequent respirations that increase the pressure gradient between the abdominal and thoracic veins (intrathoracic pressure becomes more negative during exercise).


Physiology_Levy

Physiology_Levy. In humans, blood reservoirs do not contribute much to the circulating blood volume. In fact, blood volume is usually reduced slightly during exercise, as evidenced by a rise in the hematocrit ratio. This decrease in blood volume is caused by water loss externally through sweating and enhanced ventilation and by fluid movement into the contracting muscle. However, fluid loss is counteracted in several ways. Fluid loss from the vascular compartment into the contracting muscles eventually reaches a plateau as interstitial fluid pressure rises and opposes the increased hydrostatic pressure in capillaries of the active muscle. Fluid loss is partially offset by movement of fluid from the splanchnic regions and inactive muscle into the bloodstream. This influx of fluid results from (1) a decrease in hydrostatic pressure in the capillaries of these tissues and (2) an increase in plasma osmolarity because of movement of osmotically active molecules into blood from the contracting muscle.


Physiology_Levy

Physiology_Levy. in hydrostatic pressure in the capillaries of these tissues and (2) an increase in plasma osmolarity because of movement of osmotically active molecules into blood from the contracting muscle. Reduction in urine formation by the kidneys also helps conserve body water.


Physiology_Levy

Physiology_Levy. The large volume of venous blood returning to the heart is so effectively pumped through the lungs and out into the aorta that Pv remains essentially constant. Thus the Frank-Starling mechanism of a greater initial fiber length does not account for the greater stroke volume in moderate exercise. Radiographs of individuals at rest and during exercise reveal a decrease in heart size during exercise. However, during maximal or near-maximal exercise, right atrial pressure and end-diastolic ventricular volume do increase, and the Frank-Starling mechanism contributes to the enhanced stroke volume in very vigorous exercise.


Physiology_Levy

Physiology_Levy. •Fig. 19.18 Cardiacandvascularfunctioncurvesaregreatlyalteredduringstrenuousexercise,whichallowscardiacoutputtoincreasefourfoldtofivefold.TheoperatingpointofthecardiovascularsystemmovesfrompointAtopointB.Thecardiacfunctioncurveduringstrenuousexerciseistheresultofincreasedheartrate,strokevolume,andcontractility.Thevascularfunctioncurvereflectsgreatlydecreasedtotalperipheralresistanceandincreasedmeancirculatorypressure.Atthenewoperatingpoint(pointB),cardiacoutputisincreasedmorethanfourfold,butfillingpressureisincreasedonlyslightly. In an active, healthy (untrained) individual, the mechanisms previously described typically lead to a fourfold to fivefold increase in cardiac output during vigorous exercise ( Fig. 19.18 ). Increased cardiac output is the fundamental means by which more O2 is delivered to exercising muscles (see


Physiology_Levy

Physiology_Levy. Fig. 19.18 ). Increased cardiac output is the fundamental means by which more O2 is delivered to exercising muscles (see Fig. 19.17 ). The cardiac function curve during exercise reflects increased stroke volume (up to ≈1.5-fold) and heart rate (up to ≈3-fold). The vascular function curve during dynamic exercise reflects a marked decrease in peripheral resistance (changed slope) and an increase in mean circulatory filling pressure (changed intercept), which result from increased venous constriction (tone) in the skeletal muscle “pump,” and the respiratory “pump.” In these conditions, the cardiovascular system is able to operate at a new point (point B in Fig. 19.18 ), in which cardiac output is increased while filling pressure is little changed. The graphical analysis (see Fig. 19.18 ) shows that without the systemic changes in vascular function, even a heart beating strongly and fast would be able to produce only a small increase in cardiac output.


Physiology_Levy

Physiology_Levy. Fig. 19.18 ) shows that without the systemic changes in vascular function, even a heart beating strongly and fast would be able to produce only a small increase in cardiac output. If exercise involves a large proportion of the body musculature, as in running or swimming, the reduction in total vascular resistance can be considerable. Nevertheless, arterial pressure starts to rise with the onset of exercise, and the increase in blood pressure approximately parallels the severity of the exercise performed (see


Physiology_Levy

Physiology_Levy. Fig. 19.17 ). Therefore, the increase in cardiac output is proportionally greater than the decrease in TPR. The vasoconstriction produced in the inactive tissues by the sympathetic nervous system (and to some extent by the release of catecholamines from the adrenal medulla) is important for maintenance of normal or increased blood pressure. Sympathectomy or drug-induced blockade of the adrenergic sympathetic nerve fibers decreases arterial pressure (hypotension) during exercise. Sympathetic neural activity also elicits vasoconstriction in active skeletal muscle when additional muscles are recruited. In experiments in which one leg is working at maximal levels and then the other leg starts to work, blood flow decreases in the first working leg. Furthermore, blood levels of norepinephrine rise significantly during exercise, and most of the norepinephrine is released from sympathetic nerves to the active muscles.


Physiology_Levy

Physiology_Levy. As body temperature rises during exercise, the skin vessels dilate in response to thermal stimulation of the heat-regulating center in the hypothalamus, and TPR decreases further. This reduction in TPR would reduce blood pressure were it not for the increased cardiac output and the constriction of arterioles in the renal, splanchnic, and other tissues. In general, Pa rises during exercise as a result of the increase in cardiac output. However, the effect of enhanced cardiac output is offset by an overall decrease in TPR, and therefore mean blood pressure increases only slightly. Vasoconstriction in the inactive vascular beds helps maintain normal arterial blood pressure for adequate perfusion of the active tissues. The actual Pa attained during exercise thus represents a balance between cardiac output and TPR (see ). Systolic pressure usually increases more than diastolic pressure, which results in an increase in pulse pressure (see


Physiology_Levy

Physiology_Levy. Fig. 19.17 ). The larger pulse pressure is primarily attributable to a greater stroke volume, but also to more rapid ejection of blood by the left ventricle and diminished peripheral runoff during the brief ventricular ejection period (see also


Physiology_Levy

Physiology_Levy. During exhaustive exercise, the compensatory mechanisms begin to fail. The heart rate attains a maximal level of approximately 180 beats per minute, and stroke volume reaches a plateau. The heart rate may then decrease, which results in a fall in blood pressure. The exercising individual also frequently becomes dehydrated. Sympathetic vasoconstrictor activity supersedes the vasodilator influence on vessels of the skin so that the rate of heat loss is decreased. Body temperature is normally elevated during exercise. A reduction in heat loss through cutaneous vasoconstriction can lead to very high body temperatures and to acute distress during severe exercise. Tissue pH and blood pH decrease as a result of increased production of lactic acid and CO2. The reduced pH may be a key factor that determines •Fig. 19.19 Cardiovascularadjustmentsinexercise.Plus signs indicateincreasedactivity,andminus signs


Physiology_Levy

Physiology_Levy. of increased production of lactic acid and CO2. The reduced pH may be a key factor that determines •Fig. 19.19 Cardiovascularadjustmentsinexercise.Plus signs indicateincreasedactivity,andminus signs indicatedecreasedactivity.C,vasoconstrictoractivity;D,vasodilatoractivity;IX,glossopharyngeal nerve;VR,vasomotorregion;X,vagusnerve.


Physiology_Levy

Physiology_Levy. the maximal amount of exercise that a given individual can tolerate. Muscle pain, a subjective feeling of exhaustion, and loss of the will to continue determine exercise tolerance. A summary of the neural and local effects of exercise on the cardiovascular system is diagrammed in Fig. 19.19 When exercise stops, the heart rate and cardiac output quickly decrease: The sympathetic drive to the heart is essentially removed. In contrast, TPR remains low for some time after the exercise is stopped, presumably because vasodilator metabolites have accumulated in the muscles during the exercise period. As a result of the reduced cardiac output and persistence of vasodilation in the muscles, arterial pressure falls, often below preexercise levels, for brief periods. Blood pressure is then stabilized at normal levels by the baroreceptor reflexes. Limits of Exercise Performance


Physiology_Levy

Physiology_Levy. The two main factors that limit skeletal muscle performance in humans are the rate of O2 use by the muscles and the O2 supply to the muscles. However, O2 use by muscle is probably not a critical factor. During exercise, maximal O2 consumption (maximal V˜O2) by a large percentage of the body’s muscle mass is unchanged or increases only slightly when additional muscles are activated. In fact, during exercise of a large muscle mass, as in vigorous bicycling, the addition of bilateral arm exercise without change in the cycling effort produces only a small increase in cardiac output and maximal VO2. However, the additional arm exercise decreases blood flow to the legs. This centrally mediated (baroreceptor reflex) vasoconstriction during maximal cardiac output prevents the fall in blood pressure that would otherwise be caused by metabolically induced vasodilation in the active muscle. If use of O2 by muscles were a significant limiting factor, recruitment of more contracting muscles would


Physiology_Levy

Physiology_Levy. that would otherwise be caused by metabolically induced vasodilation in the active muscle. If use of O2 by muscles were a significant limiting factor, recruitment of more contracting muscles would entail the use of much more O2 to meet the enhanced O2 requirements.


Physiology_Levy

Physiology_Levy. Limitation of the O2 supply could be caused by inadequate oxygenation of blood in the lungs or limitation of the supply of O2-laden blood to the muscles. Failure by the lungs to oxygenate blood fully can be ruled out because even with the most strenuous exercise at sea level, arterial blood is fully saturated with O2. Therefore, O2 delivery to the active muscles (or blood flow because the arterial blood O2 content is normal) appears to be the limiting factor in muscle performance. This limitation could be caused by the inability to increase cardiac output beyond a critical level. In turn, this inability is caused by a limitation in stroke volume because the heart rate reaches maximal levels before maximal V˜O2 is reached. Hence, the major factor that limits muscle performance is the pumping capacity of the heart.


Physiology_Levy

Physiology_Levy. The response of the cardiovascular system to regular exercise is to increase its capacity to deliver O2 to the active muscles and improve the ability of the muscle to use O2. Maximal


Physiology_Levy

Physiology_Levy. VO2 varies with the level of physical conditioning. Train ing progressively increases maximal VO2, which reaches a plateau at the highest level of conditioning. Highly trained athletes have a lower resting heart rate, a greater stroke volume, and lower peripheral resistance than they had before training or after deconditioning. The low resting heart rate is caused by a higher vagal tone and a lower sympathetic tone. During exercise, the maximal heart rate of a trained individual is the same as that in an untrained person, but it is attained at a higher level of exercise. A trained person also exhibits low vascular resistance in the muscles. If an individual exercises one leg regularly over an extended period and does not exercise the other leg, vascular resistance is lower and maximal V˜O2 is higher in the “trained” leg than in the “untrained” leg.


Physiology_Levy

Physiology_Levy. Physical conditioning is also associated with greater extraction of O2 from the blood (greater arteriovenous O2 difference) by the muscles. With long-term training, capillary density in skeletal muscle increases. Also, an increase in the number of arterioles may account for the decrease in muscle vascular resistance. The number of mitochondria increases, as does the number of oxidative enzymes in mitochondria. In addition, levels of adenosine triphosphatase (ATPase) activity, myoglobin, and enzymes involved in lipid metabolism increase in response to physical conditioning. Endurancetraining,suchasrunningorswimming,increasesleftventricularvolumewithoutincreasingleftventricularwallthickness.Incontrast,strengthexercises,suchasweightlifting,increaseleftventricularwallthickness(hypertrophy)withlittleeffectonventricularvolume.However,thisincreaseinwallthicknessissmallinrelationtothatobservedinchronichypertension,inwhichafterloadispersistentlyelevatedbecauseofhighperipheralresistance.


Physiology_Levy

Physiology_Levy. The cardiovascular system is the system mainly affected in an individual who has lost a large quantity of blood. Arterial systolic, diastolic, and pulse pressures decrease, and the arterial pulse is rapid and feeble. The cutaneous veins collapse, and they fill slowly when compressed centrally. The skin is pale, moist, and slightly cyanotic. Respiration is rapid but may be shallow or deep. Course of Arterial Blood Pressure Changes Cardiac output decreases as a result of blood loss. The amount of blood removed when it is donated is approximately 10% of total blood volume; its removal is well tolerated, and mean arterial blood pressure changes little. This is not the case when greater amounts are lost from the circulation. The changes in Pa evoked by acute hemorrhage are illustrated in


Physiology_Levy

Physiology_Levy. Fig. 19.19 . If sufficient blood is rapidly withdrawn to decrease Pa to 50 mm Hg, the pressure then tends to rise spontaneously toward the control level over the next 20 or 30 minutes. In some individuals (curve A in Fig. 19.20 ), this trend continues, and normal pressure is regained within a few hours. In others (curve B in Fig. 19.20 ), the pressure rises initially after the cessation of hemorrhage. The pressure then begins to decline, and it continues to fall at an accelerating rate until death ensues. This progressive deterioration in cardiovascular function is termed hemorrhagic shock. At some time after the hemorrhage, the deterioration in the cardiovascular system becomes irreversible. A lethal outcome in patients with hemorrhagic shock can be prevented only temporarily by any known therapy, including massive transfusions of donor blood.


Physiology_Levy

Physiology_Levy. •Fig. 19.20 Changes in Mean Arterial Pressure After Rapid Hem-orrhage. Attime0,rapidlossofbloodcausesareductioninthemeanarterialpressureto50mmHg.Afteraperiodinwhichthepressurereturnstowardthecontrollevel,someindividualscontinuetoimprove(curveA)untilthecontrolpressureisattained.However,inotherindividuals,thepressurebeginstodecline(curveB)untildeathensues.–2 –1 0 0 25 50 75 100 1 2 3 4 5 A B 6 7 Time (hr) Mean arterial pressure (mm Hg) The changes in arterial pressure immediately after acute blood loss (see


Physiology_Levy

Physiology_Levy. The changes in arterial pressure immediately after acute blood loss (see Fig. 19.20 ) indicate that certain compensatory mechanisms must be operative. Any mechanism that raises arterial blood pressure toward normal in response to a reduction in pressure is designated a negative feedback mechanism. This mechanism is termed negative because the direction of the secondary change in pressure is opposite the direction of the initiating change after the acute blood loss. The following negative feedback responses are evoked: baroreceptor reflexes, (2) chemoreceptor reflexes, (3) cerebral ischemia responses, (4) reabsorption of tissue fluids, release of endogenous vasoconstrictor substances, and renal conservation of salt and water.


Physiology_Levy

Physiology_Levy. The reductions in Pa and pulse pressure during hemorrhage decrease stimulation of the baroreceptors in the carotid •Fig. 19.21 Changes in Mean Aortic Pressure in Response to an 8% Blood Loss in Three Conditions. A, Thecarotidsinusbaroreceptorswereintactandtheaorticreflexeswereinterrupted.B, Theaorticreflexeswereintactandthecarotidsinusreflexeswereinterrupted.C, Allsinoaorticreflexeswereabrogated.(DatafromShepherdJT.Circulation. 1974;50:418.DerivedfromthedataofEdisAJ.Am J Physiol. 1971;221:1352.) ). Several cardiovascular responses are thus evoked, all of which tend to restore arterial pressure to the normal level. Such responses include reduction of vagal tone and enhancement of sympathetic tone, increased heart rate, and enhanced myocardial contractility. The increased sympathetic tone also produces generalized venoconstriction, which has the same hemodynamic consequences as transfusion of blood (see


Physiology_Levy

Physiology_Levy. The increased sympathetic tone also produces generalized venoconstriction, which has the same hemodynamic consequences as transfusion of blood (see Fig. 19.9). Sym pathetic activation constricts certain blood reservoirs. This vasoconstriction acts as an autotransfusion of blood into the circulation. In humans, the cutaneous, pulmonary, and hepatic branches of the vasculature constitute the principal blood reservoirs. Generalized arteriolar constriction is a prominent response to the reduced baroreceptor stimulation during hemorrhage. The reflex increase in peripheral resistance minimizes the fall in arterial pressure caused by the reduction in cardiac output. Fig. 19.21 shows the effect of an 8% blood loss on mean aortic pressure. When both vagus nerves were cut to eliminate the influence of the aortic arch baroreceptors and only the carotid sinus baroreceptors were operative (see


Physiology_Levy

Physiology_Levy. Fig. 19.21A), this hemorrhage decreased mean aortic pressure by 14%. This pressure change did not differ significantly from the decline in pressure (12%) evoked by the same hemorrhage before vagotomy (not shown). When the carotid sinuses were denervated and the aortic baroreceptor reflexes were intact, the 8% blood loss decreased mean aortic pressure by 38% (see Fig. 19.21B). Hence, the carotid sinus baroreceptors were more effective than the aortic baroreceptors in attenuating the fall in pressure. However, when both sets of afferent baroreceptor pathways were interrupted (see Fig. 19.21C), an 8% blood loss reduced arterial pressure by 48%.


Physiology_Levy

Physiology_Levy. Fig. 19.21C), an 8% blood loss reduced arterial pressure by 48%. Arteriolar constriction is widespread during hemorrhage but it is by no means uniform. Vasoconstriction is most pronounced in the cutaneous, skeletal muscle, and splanchnic vascular beds, and it is slight or absent in the cerebral and coronary circulations in response to hemorrhage. In many instances, cerebral and coronary vascular resistance is diminished. The reduced cardiac output is redistributed to favor flow through the brain and the heart. In the early stages of mild to moderate hemorrhage, renal resistance changes only slightly. The tendency for increased sympathetic activity to constrict the renal vessels is counteracted by autoregulatory mechanisms (see ). With more prolonged and severe hemorrhage, however, renal vasoconstriction becomes intense.


Physiology_Levy

Physiology_Levy. The renal and splanchnic vasoconstriction during hemorrhage is least severe in the heart and brain. However, if such constriction persists too long, it may be detrimental. Frequently, patients survive the acute hypotensive period of a prolonged, severe hemorrhage, only to die several days later from the kidney failure that results from renal ischemia. Intestinal ischemia may also have dire effects. For example, intestinal bleeding and extensive sloughing of the mucosa can occur after only a few hours of hemorrhagic hypotension. Furthermore, the diminished splanchnic flow swells the centrilobular cells in the liver. The resulting obstruction of the hepatic sinusoids causes portal venous pressure to rise, and this response intensifies intestinal blood loss.


Physiology_Levy

Physiology_Levy. Reductions in arterial pressure below approximately 60 mm Hg do not evoke any additional responses through the baroreceptor reflexes because this pressure level constitutes the threshold for stimulation (see ). However, low arterial pressure may stimulate peripheral chemoreceptors because inadequacy of local blood flow leads to hypoxia in the chemoreceptor tissue. Chemoreceptor excitation may then enhance the already existent peripheral vasoconstriction evoked by the baroreceptor reflexes. In addition, respiratory stimulation assists venous return by the auxiliary pumping mechanism described earlier (see also


Physiology_Levy

Physiology_Levy. When arterial pressure falls below approximately 40 mm Hg as a consequence of blood loss, the resulting cerebral ischemia activates the sympathoadrenal system. The discharge by sympathetic nerves is several times greater than the maximal neural activity that occurs when the baroreceptors cease to be stimulated. The vasoconstriction and increase in myocardial contractility may be pronounced. With more severe degrees of cerebral ischemia, however, the vagal centers also become activated. The resulting bradycardia aggravates the hypotension that initiated the cerebral ischemia Reabsorption of Tissue Fluids The arterial hypotension, arteriolar constriction, and reduced venous pressure during hemorrhagic hypotension cause the hydrostatic pressure in the capillaries to drop. The balance of these forces promotes the net reabsorption of interstitial fluid into the vascular compartment (see ). The rapidity of this response is displayed in


Physiology_Levy

Physiology_Levy. Fig. 19.22 . When 45% of the estimated blood volume is removed over a 30-minute period, mean arterial blood pressure declines rapidly and then is largely restored to nearly the control level. Plasma colloid osmotic pressure declines markedly during the bleeding and continues to decrease more gradually for several hours. The reduction in colloid osmotic pressure reflects dilution of the blood by tissue fluids that contain little protein.


Physiology_Levy

Physiology_Levy. Considerable quantities of fluid may thus be drawn into the circulation during hemorrhage. Approximately 0.25 mL of fluid per minute per kilogram of body weight may be reabsorbed by the capillaries. Thus approximately 1 L of fluid per hour might be autoinfused from the interstitial spaces into the circulatory system of an average individual after acute blood loss. Substantial quantities of fluid may shift slowly from the intracellular space to the extracellular space. This fluid exchange is probably mediated by secretion of cortisol from the adrenal cortex in response to hemorrhage. Cortisol is essential for the full restoration of plasma volume after hemorrhage. The catecholamines epinephrine and norepinephrine are released from the adrenal medulla in response to the same stimuli that evoke widespread sympathetic nervous discharge (see


Physiology_Levy

Physiology_Levy. The catecholamines epinephrine and norepinephrine are released from the adrenal medulla in response to the same stimuli that evoke widespread sympathetic nervous discharge (see Chapter 43). Blood levels of catecholamines are high during and after hemorrhage. When blood loss is such that arterial pressure is reduced to 40 mm Hg, the level of catecholamines increases as much as 50-fold. Epinephrine comes almost exclusively from the adrenal medulla, whereas norepinephrine is derived from both the adrenal medulla and peripheral sympathetic nerve endings. These humoral substances reinforce the effects of the sympathetic nervous activity listed previously. Vasopressin (antidiuretic hormone), a potent vasoconstrictor, is secreted by the posterior pituitary gland in response to hemorrhage (see 41). The plasma concentration of vasopressin rises progressively as arterial blood pressure diminishes (


Physiology_Levy

Physiology_Levy. The plasma concentration of vasopressin rises progressively as arterial blood pressure diminishes ( Fig. 19.23 ). The receptors responsible for the augmented release of vasopressin are the aortic arch and carotid sinus baroreceptors (high pressure) and stretch receptors in the left atrium (low pressure). The diminished renal perfusion during hemorrhagic hypotension leads to the secretion of renin from the juxtaglomerular apparatus (see Chapter 35). This enzyme acts on a plasma protein, angiotensinogen, to form the decapeptide angiotensin I, which in turn is cleaved to the active octapeptide angiotensin II by angiotensin-converting enzyme; angiotensin II is a very powerful vasoconstrictor. Renal Conservation of Salt and Water Fluid and electrolytes are conserved by the kidneys during hemorrhage in response to various stimuli, including increased secretion of vasopressin, as noted previously (see


Physiology_Levy

Physiology_Levy. Fig. 19.23 ), and increased renal sympathetic nerve activity, which enhances NaCl reabsorption by the nephron (decreased excretion). The lower arterial pressure decreases •Fig. 19.22 Changesinarterialbloodpressureandplasmacolloid osmoticpressureinresponsetowithdrawalof45%oftheestimated•Fig. 19.23 Meanpercentagechangesinarterialbloodpressureandbloodvolumeovera30-minuteperiod,beginningattime0.(Redrawnplasmavasopressinconcentrationinresponsetobloodloss.(RedrawnfromZweifachBW.Anesthesiology. 1974;41:157.)fromShenYT,etal.Circ Res. 1991;68:1422.) the glomerular filtration rate, which also curtails the excretion of water and electrolytes. In addition, the elevated levels of angiotensin II, as described earlier, stimulate the release of aldosterone from the adrenal cortex. Aldosterone, in turn, stimulates reabsorption of NaCl by the nephrons. Thus NaCl and water excretion is decreased (see also Chapter 35).


Physiology_Levy

Physiology_Levy. Chapter 35). In contrast to negative feedback mechanisms, hemorrhage also evokes latent positive feedback mechanisms. These mechanisms exaggerate any primary change initiated by the blood loss. Specifically, positive feedback mechanisms aggravate the hypotension induced by blood loss and tend to initiate vicious cycles, which may lead to death.


Physiology_Levy

Physiology_Levy. Whether a positive feedback mechanism will lead to a vicious cycle depends on the gain of that mechanism. Gain is the ratio of the secondary change evoked by a given mechanism to the initiating change itself. A gain greater than 1 induces a vicious cycle; a gain of less than 1 does not. Consider a positive feedback mechanism with a gain of 2. If Pa were to decrease by 10 mm Hg, a positive feedback mechanism with a gain of 2 would then evoke a secondary reduction in pressure of 20 mm Hg, which in turn would cause a further decrease of 40 mm Hg. Thus each change would induce a subsequent one that is twice as great. Hence, Pa would decline at an ever-increasing rate until death occurred. This process is depicted in curve B in Fig. 19.20


Physiology_Levy

Physiology_Levy. Fig. 19.20 Conversely, a positive feedback mechanism with a gain of 0.5 also exaggerates any change in Pa, but the change would not necessarily lead to death. If arterial pressure suddenly decreased by 10 mm Hg, a positive feedback mechanism would initiate a secondary, additional fall of 5 mm Hg. This decrease, in turn, would provoke a further decrease of 2.5 mm Hg. The process would continue in ever-diminishing steps until arterial pressure approached an equilibrium value. Some of the more important positive feedback mechanisms that are evident during hemorrhage include (1) cardiac failure, (2) acidosis, (3) central nervous system depression, (4) aberrations in blood clotting, and (5) depression of the mononuclear phagocytic system (MPS). These mechanisms are discussed next. Shifts to the right in ventricular function curves, particularly in the later stages of hemorrhagic shock (


Physiology_Levy

Physiology_Levy. These mechanisms are discussed next. Shifts to the right in ventricular function curves, particularly in the later stages of hemorrhagic shock ( Fig. 19.24 ), provide evidence of a progressive depression in myocardial contractility during hemorrhage. *The MPS (previously called the reticuloendothelial system) consists of macrophages that are distributed throughout the body. They are derived from bone marrow and exist for a short period in circulating blood as monocytes. They then migrate into tissues, where they phagocytose foreign material and present antigens to lymphocytes to initiate the adaptive immune response. Cells of the MPS include the Kupffer cells of the liver, alveolar macrophages, microglia, and Langerhans cells.


Physiology_Levy

Physiology_Levy. •Fig. 19.24 Ventricular Function Curves for the Left Ventricle During the Course of Hemorrhagic Shock. Curve A representsthecontrolfunctioncurve;curves B toF representtimeafterthehemor-rhage:117minutes(curve B), 247minutes(curve C), 280minutes(curve D), 295minutes(curve E), and310minutes(curve F). (RedrawnfromCrowellJW,GuytonAC.Am J Physiol. 1962;203:248.)–2 0 2 4 6 8 10 12 0 200 400 600 800 1000 1200 1400 1600 A E F C D B Left atrial pressure (mm Hg) Cardiac output (mL/min) The hypotension induced by hemorrhage reduces coronary blood flow and therefore depresses ventricular function. The consequent reduction in cardiac output further reduces arterial pressure, a classic example of a positive feedback mechanism. Furthermore, reduced blood flow to peripheral tissues leads to an accumulation of vasodilator metabolites that decrease peripheral resistance and therefore aggravate the fall in arterial pressure.


Physiology_Levy

Physiology_Levy. The inadequate blood flow during hemorrhage affects the metabolism of all cells. The decreased O2 delivery to cells accelerates tissue production of lactic acid and other acid metabolites. Moreover, impaired kidney function prevents adequate excretion of the excess H+ , and generalized metabolic acidosis ensues. The resulting depressant effect of acidosis on the heart is a further reduction in tissue perfusion, which aggravates the metabolic acidosis. Acidosis also reduces the reactivity of the heart and resistance vessels to neurally released and circulating catecholamines and thereby intensifies the hypotension.


Physiology_Levy

Physiology_Levy. The hypotension in shock reduces cerebral blood flow. Moderate degrees of cerebral ischemia induce pronounced sympathetic nervous stimulation of the heart, arterioles, and veins, as noted earlier. In severe hypotension, however, the cardiovascular centers in the brainstem eventually become depressed because of inadequate cerebral blood flow. The resulting loss of sympathetic tone then reduces cardiac output and peripheral resistance. The consequent reduction in Pa intensifies the inadequate cerebral perfusion.


Physiology_Levy

Physiology_Levy. Endogenous opioids, such as enkephalins and βendorphin, may be released into the brain substance and into the circulation in response to the same stresses that provoke circulatory shock. Opioids are stored, along with catecholamines, in secretory granules in the adrenal medulla and in sympathetic nerve terminals, and they are released together in response to stress. Similar stimuli cause the release of β-endorphin and adrenocorticotropic hormone from the anterior pituitary gland. Opioids depress the brainstem centers that mediate some of the compensatory autonomic adaptations to blood loss, endotoxemia, and other shock-provoking stress. Conversely, the opoid antagonist naloxone improves cardiovascular function and rates of survival in various forms of shock.


Physiology_Levy

Physiology_Levy. The alterations in blood clotting after hemorrhage are typically biphasic. An initial phase of hypercoagulability is followed by a secondary phase of hypocoagulability and fibrinolysis. In the initial phase, platelets and leukocytes adhere to the vascular endothelium, and intravascular clots, or thrombi, develop within a few minutes of the onset of severe hemorrhage. This phenomenon, called disseminated intravascular coagulation (DIC), occurs when thrombin is activated and causes widespread deposition of fibrin within narrow and medium-diameter vessels.


Physiology_Levy

Physiology_Levy. The initial phase is further enhanced by the release of thromboxane A2 from various ischemic tissues. Thromboxane A2 aggregates platelets. As more platelets aggregate, more thromboxane A2 is released and more platelets are trapped. This form of positive feedback intensifies and prolongs the clotting tendency. Inflammatory cytokines (interleukin-6, tumor necrosis factor) also contribute to DIC. The rate of mortality from certain standard shock-provoking procedures has been reduced considerably by the administration of anticoagulants such as heparin. In the later stages of hemorrhagic hypotension, the clotting time is prolonged, and fibrinolysis is prominent. Fibrinolysis occurs when clotting factors and platelets are depleted. Depression of the Mononuclear Phagocytic System


Physiology_Levy

Physiology_Levy. During the course of hemorrhagic hypotension, MPS function becomes depressed. The phagocytic activity of the MPS is modulated by an opsonic protein. The opsonic activity in plasma diminishes during shock, and this change may account in part for the depression in MPS function. As a result, antibacterial and antitoxin defense mechanisms are impaired. Hypoperfusion also suppresses the barrier function of the adherens junctions and tight junctions in the 1. Two important relationships between cardiac output (Qh) and central venous pressure (Pv) prevail in the cardiovascular system. With regard to the heart, Qh varies directly with Pv (or preload) over a very wide range of Pv. This relationship is represented by the cardiac function curve, and it expresses the Frank-Starling mechanism. In the vascular system, Pv varies intestinal epithelium. Endotoxins from the normal bacterial flora of the intestine constantly enter the circulation. Ordinarily, they are inactivated by the MPS, principally


Physiology_Levy

Physiology_Levy. system, Pv varies intestinal epithelium. Endotoxins from the normal bacterial flora of the intestine constantly enter the circulation. Ordinarily, they are inactivated by the MPS, principally in the liver. Disruption of the intestinal epithelial barrier, together with depression of the MPS, allows these endotoxins to invade the general circulation. Endotoxins produce profound, generalized vasodilation, mainly by inducing the synthesis of an isoform of nitric oxide synthase in the smooth muscle of blood vessels throughout the body. The profound vasodilation aggravates the hemodynamic changes caused by blood loss.


Physiology_Levy

Physiology_Levy. In addition to their role in inactivating endotoxin, macrophages release many of the mediators associated with shock. These mediators include acid hydrolases, neutral proteases, oxygen free radicals, certain coagulation factors, and the following arachidonic acid derivatives: prostaglandins, thromboxanes, and leukotrienes. Macrophages also release certain monokines that modulate temperature regulation, intermediary metabolism, hormone secretion, and the immune system. Interactions of Positive and Negative Feedback Mechanisms


Physiology_Levy

Physiology_Levy. Interactions of Positive and Negative Feedback Mechanisms Hemorrhage provokes a multitude of circulatory and metabolic derangements. Some of these changes are compensatory, and others are decompensatory. Some of these feedback mechanisms possess high gain and others possess low gain. Furthermore, the gain of any specific mechanism varies with the severity of the hemorrhage. For example, with only a slight loss of blood, Pa is maintained within the normal range and the gain of the baroreceptor reflexes is high. With greater losses of blood, when Pa is below 60 mm Hg (i.e., below the threshold for the baroreceptors), further reductions in pressure have no additional influence through the baroreceptor reflexes. Hence, below this critical pressure, the baroreceptor reflex gain is zero or near zero.


Physiology_Levy

Physiology_Levy. In general, with minor degrees of blood loss, the gains of negative feedback mechanisms are high, whereas those of positive feedback mechanisms are low. The opposite is true with more severe hemorrhage. The gains of the various mechanisms add algebraically. Therefore, whether a vicious cycle develops depends on whether the sum of the positive and negative gains exceeds 1. Total gains in excess of 1 are, of course, more likely to occur with severe losses of blood. Therefore, to avert a vicious cycle, serious hemorrhages must be treated quickly and intensively, preferably by whole blood transfusion, before the process becomes irreversible. inversely with Qh. This relationship is represented by the vascular function curve, and it reflects the fact that as Qh increases, a greater fraction of the total blood volume resides in the arteries and a smaller volume resides in the veins.


Physiology_Levy

Physiology_Levy. 2. The principal cardiac mechanisms that govern cardiac output are the changes in numbers of myocardial cross-bridges that interact and in the affinity of the contractile proteins for Ca++ . The principal factors that govern the vascular function curve are arterial and venous compliance, peripheral vascular resistance, and total blood volume. 3. The equilibrium values of Qh and Pv that prevail under a given set of conditions are determined by the intersection of the cardiac and vascular function curves. At very low and very high heart rates, the heart is unable to produce adequate Qh. At very low heart rates, the increase in filling during diastole cannot compensate for the small number of cardiac contractions per minute. At very high heart rates, the large number of contractions per minute cannot compensate for the inadequate filling time. 4.


Physiology_Levy

Physiology_Levy. 4. Gravity influences Qh because the veins are so compliant, and substantial quantities of blood tend to pool in the veins of dependent portions of the body. Respiration changes the pressure gradient between the intrathoracic and extrathoracic veins. Hence, respiration serves as an auxiliary pump, which may affect the mean level of Qh and induce rhythmic changes in stroke volume during the various phases of the respiratory cycle. 5. In anticipation of exercise, vagus nerve impulses to the heart are inhibited and the sympathetic nervous system is activated by central command. The result is an increase in heart rate, myocardial contractile force, and regional vascular resistance. In addition, vascular resistance increases in the skin, kidneys, splanchnic regions, and inactive muscles and decreases markedly in the active muscles. The overall effect is a pronounced reduction in total peripheral resistance,


Physiology_Levy

Physiology_Levy. Eijsvogels TMH, Fernandez AB, Thompson PD. Are there deleterious cardiac effects of acute and chronic endurance exercise? Physiol Rev. 2016;96:99. Fernandes T, Baraúna VG, Negrão CE, et al. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am J Physiol. 2015;309:H543. Gruen RL, Brohi K, Schreiber M, et al. Haemorrhage control in severely injured patients. Lancet. 2012;380:1099.


Physiology_Levy

Physiology_Levy. Gruen RL, Brohi K, Schreiber M, et al. Haemorrhage control in severely injured patients. Lancet. 2012;380:1099. which, along with the auxiliary pumping action of the contracting skeletal muscles, greatly increases venous return. The increases in heart rate and myocardial contractility, both induced by the activation of cardiac sympathetic nerves, enables the heart to transfer blood to the pulmonary and systemic circulations, thereby increasing cardiac output. Stroke volume increases only slightly. O2 consumption and blood O2 extraction increase, and systolic pressure and mean blood pressure increase slightly. As body temperature rises during exercise, the skin blood vessels dilate. However, when the heart rate becomes maximal during severe exercise, the skin vessels constrict. This increases the effective blood volume but causes greater increases in body temperature and a feeling of exhaustion. The limiting factor in exercise performance is delivery of blood to the active muscles.


Physiology_Levy

Physiology_Levy. 6. Acute blood loss induces tachycardia, hypotension, generalized arteriolar constriction, and generalized venoconstriction. Acute blood loss invokes a number of negative feedback (compensatory) mechanisms, such as baroreceptor and chemoreceptor reflexes, responses to moderate cerebral ischemia, reabsorption of tissue fluids, release of endogenous vasoconstrictors, and renal conservation of water and electrolytes. Acute blood loss also invokes a number of positive feedback (decompensatory) mechanisms, such as cardiac failure, acidosis, central nervous system depression, aberrations in blood coagulation, and depression of the mononuclear phagocytic system. The outcome of acute blood loss depends on the sum of gains of the positive and negative feedback mechanisms and on the interactions between these mechanisms.


Physiology_Levy

Physiology_Levy. Laughlin MH, Korthuis RJ, Duncker DJ, et al. Control of blood flow to cardiac and skeletal muscles during exercise. In: Rowell LB, Shepherd JT, eds. Handbook of Physiology, Section 12: Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Oxford University Press; 1996. Lavie CJ, Arena R, Swift DL, et al. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes. Circ Res. 2015;117:207. Valparaiso AP, Vicente DA, Bograd BA, et al. Modeling acute traumatic injury. J Surg Res. 2015;194:220. SECTION 5The Respiratory System MICHELLE M. CLOUTIER AND ROGER S. THRALL Upon completion of this chapter, the student should be able to answer the following questions: 1. Explain the anatomical structure/function relationships of the upper and lower components of the respiratory system. 2. Compare and contrast the pulmonary and bronchial circulatory systems. 3.


Physiology_Levy

Physiology_Levy. Explain the anatomical structure/function relationships of the upper and lower components of the respiratory system. 2. Compare and contrast the pulmonary and bronchial circulatory systems. 3. Explain the relationships between innervation and muscles in the control of respiration. 4. Compare and contrast the roles of the conducting airways and components of the respiratory unit. 5. Compare and contrast the effects of stimulation of the parasympathetic and sympathetic nervous systems on respiratory responses. 6 Describe lung development and alveolar repair after injury to regeneration of normal architecture.


Physiology_Levy

Physiology_Levy. 6 Describe lung development and alveolar repair after injury to regeneration of normal architecture. he primary function of the lungs is gas exchange, which consists of movement of oxygen (O2) into the body and removal of carbon dioxide (CO2). This chapter provides an overview of lung anatomical structure/ function relationships (i.e., upper and lower airways, the two circulatory systems, innervation, and muscles), lung development (at the embryo stage and throughout life), and lung repair. This chapter is designed to provide a broad conceptual understanding of structure/function interactions and is not intended to afford a comprehensive understanding of individual lung structures and anatomy.


Physiology_Levy

Physiology_Levy. The lungs are contained in a space with a volume of approximately 4 L, but they have a surface area for gas exchange that is the size of a tennis court (≈85 m2). This large surface area is composed of myriads of independently functioning respiratory units. Unlike the heart, but like the kidneys, the lungs demonstrate functional unity; that is, each unit is structurally identical and functions just like every other unit. Because the divisions of the lung and the sites of disease are designated by their anatomical locations (e.g., right upper lobe, left lower lobe), it is essential to understand pulmonary anatomy in order to comprehend respiratory physiology and pathophysiological alterations in respiratory diseases. Upper Airways: Nose, Sinuses, and Pharynx


Physiology_Levy

Physiology_Levy. Upper Airways: Nose, Sinuses, and Pharynx The respiratory system begins at the nose and ends in the most distal alveolus. Thus the nasal cavity, the posterior pharynx, the glottis and vocal cords, the trachea, and all divisions of the tracheobronchial tree are included in the respiratory system. The upper airway consists of all structures from the nose to the vocal cords, including sinuses and the larynx, whereas the lower airway consists of the trachea, airways, and alveoli. The upper airways “condition” inspired air so that by the time air reaches the trachea, inspired air is at body temperature and fully humidified. The nose also functions to filter, entrap, and clear particles larger than 10 µm in size. The interior of the nose is lined by respiratory epithelial cells interspersed with surface secretory cells. These secretory cells produce important immunoglobulins, inflammatory mediators, and interferons, which are the first line of host defense.


Physiology_Levy

Physiology_Levy. The paranasal sinuses (frontal, maxillary, sphenoid, and ethmoid) are lined by ciliated epithelial cells and surround the nasal passages ( Fig. 20.1A).


Physiology_Levy

Physiology_Levy. Fig. 20.1A). The cilia facilitate the movement of mucus from the upper airways and clear the main nasal passages approximately every 15 minutes. The functions of the sinuses are (1) to lessen the weight of the skull, which makes upright posture easier; (2) to offer resonance to the voice; and (3) to protect the brain from frontal trauma. The fluid covering their surfaces is continually being propelled into the nose. In some sinuses (e.g., the maxillary sinus), the opening (ostium) is at the upper edge, which makes them particularly susceptible to retention of mucus. The ostia are readily obstructed by nasal edema (swelling), and retention of secretions and secondary infection (sinusitis) can result. The volume of the nose in an adult is approximately 20 mL, but its surface area is greatly increased by the nasal turbinates, which are a series of three continuous ribbons of tissue that protrude into the nasal cavity (see


Physiology_Levy

Physiology_Levy. Fig. 20.1B ). The nose enables the sense of smell. Neuronal endings in the roof of the nose above the superior turbinate carry impulses through the cribriform plate to the olfactory bulb. The pharynx is divided into three sections: the nasopharynx, oropharynx, and laryngopharynx. Important • Fig. 20.1 Illustrations of Upper Airway Anatomy.A, Anterior view of the paranasal sinuses. B, Lateral view of the nasal passage structures demonstrating the superior, middle, and inferior turbinates and the sinus ostia. C, Lateral midsagittal section view of the head and neck, showing the three divisions of the pharynx (nasopharynx, oropharynx, and laryngopharynx) and surrounding upper airway structures. CHAPTER 20 Introduction to the Respiratory System 435 structures within these regions include the epiglottis, vocal cords, and arytenoid cartilage which is attached to the vocal cords (see


Physiology_Levy

Physiology_Levy. CHAPTER 20 Introduction to the Respiratory System 435 structures within these regions include the epiglottis, vocal cords, and arytenoid cartilage which is attached to the vocal cords (see Fig. 20.1C ). The nasopharynx (2 to 3 cm wide and 3 to 4 cm long) is the most anterior and lies behind the nose. In this region, the nose and mouth are connected via an isthmus (canals) that enables both oral and nasal breathing. Also, the nasopharynx contains small masses of lymphoid tissue (adenoids), also known as pharyngeal tonsils, which fight infections. The nasopharynx is connected to the middle ear cavity via the eustachian tubes, which aid in equalizing pressure in the ear to atmospheric pressure; thus they represent a drainage pathway of lymphatic fluid between the throat, nose, and ears. This network of structures provides a means of fighting infections but also is a common location for infections in the head.


Physiology_Levy

Physiology_Levy. The soft palate separates the nasopharynx and the oropharynx, which ends at the epiglottis. The laryngopharynx begins at the epiglottis and ends at the esophagus. Its major role is to help regulate the passage of food into the esophagus and air into the lungs. With some infections, these structures can become edematous and contribute significantly to airflow resistance. The epiglottis and arytenoid cartilage (attached to the vocal cords) cover or act as a hood over the vocal cords during swallowing. Thus under normal circumstances, the epiglottis and arytenoid cartilage function to prevent aspiration of food and liquid into the lower respiratory tract. The act of swallowing food after mastication (chewing) usually occurs within 2 seconds, and it is closely synchronized with muscle reflexes that coordinate opening and closing of the airway. Hence, air is allowed to enter the lower airways, and food and liquids are kept out. Patients with some neuromuscular diseases have altered muscle


Physiology_Levy

Physiology_Levy. that coordinate opening and closing of the airway. Hence, air is allowed to enter the lower airways, and food and liquids are kept out. Patients with some neuromuscular diseases have altered muscle reflexes and can lose this coordinated swallowing mechanism. Such patients may become susceptible to aspiration of food and liquid, which poses a risk for pneumonia.


Physiology_Levy

Physiology_Levy. Lower Airways: Trachea, Bronchi, Bronchioles, and Respiratory Unit The right lung, located in the right hemithorax, is divided into three lobes (upper, middle, and lower) by two interlobular fissures (oblique, horizontal), whereas the left lung, located in the left hemithorax, is divided into two lobes (upper, including the lingula, a tongue-like projection of the anterior aspect of the upper lobe, and lower) by an oblique fissure (


Physiology_Levy

Physiology_Levy. Fig. 20.2 ). Both the right and left lungs are covered by a thin membrane called the visceral pleura and are encased by another membrane called the parietal pleura. The interface of these two pleurae allows for smooth gliding of the lung as it expands in the chest and produces a potential space. Air can enter between the visceral and parietal pleurae by trauma, surgery, or rupture of a group of alveoli; the resulting condition is a pneumothorax. Fluid can also enter this space and create a pleural effusion or, in the case of severe infection, an empyema. •Fig. 20.2 Illustrations of the Topography of the Lung With Anterior and Posterior Views, Demon-strating the Lobes, Segments, and Fissures. Thefissures(orchasms)demarcatethelobesineachlung.Numbersrefertospecificbronchopulmonarysegments,asdepictedin


Physiology_Levy

Physiology_Levy. Fig.20.3 .SVC,superiorvenacava.Lateral 4 Anterior 3 Anterior 3 1 1 Apical 1 Apical 1 Medial 5 Inferior 5 Superior 4 Superior 6 Posterior basal 10 POSTERIOR VIEW Left Right ANTERIOR VIEW LeftRight Posterior 2 2 Lateral basal 9 Lateral basal 9 Posterior basal 10 Superior 6 8 8 8 Heart Anterior basal Lower lobe Anterior basal Oblique fissure SVC Trachea Upper lobe Middle lobe Lower lobe Anterior basal Oblique fissure Aortic arch Apical Upper lobe Lower lobe Upper lobe Lower lobe Upper lobe Posterior Apical Horizontalfissure The trachea branches into two main stem bronchi ( Fig. 20.3 ). These main stem bronchi then divide (like the branches of a tree) into lobar bronchi (one for each lobe), which in turn divide into segmental bronchi (Fig. 20.4 Fig. 20.3 ) and then into smaller and smaller branches (bronchioles) until ending in the alveolus ( Fig.


Physiology_Levy

Physiology_Levy. 20.4 Fig. 20.3 ) and then into smaller and smaller branches (bronchioles) until ending in the alveolus ( Fig. 20.5 ). Bronchi and bronchioles differ not only in size but also by the presence of cartilage, the type of epithelium, and their blood supply ( Table 20.1). Beyond the segmental bronchi, the airways divide in a dichotomous or asymmetrical branching pattern. Bronchi, distinguished by their size and the presence of cartilage, eventually become terminal bronchioles, which are the smallest airways without alveoli. Each branching of an airway results in an increase in the number of airways with smaller diameters; as a result, the total surface area for the next generation of branches increases. Terminal bronchioles terminate in an opening (duct) to a group of alveoli and are called respiratory bronchioles.


Physiology_Levy

Physiology_Levy. The region of the lung supplied by a segmental bronchus is called a bronchopulmonary segment and is the functional anatomical unit of the lung. Because of their structure, bronchopulmonary segments that have become irreversibly diseased can easily be removed surgically. The basic physiological unit of the lung is the gas-exchanging unit (respiratory unit), which consists of the respiratory bronchioles, the alveolar ducts, and the alveoli (see Figs. 20.4 20.5). The bronchi, which contain cartilage, and the terminal bronchioles (i.e., lacking alveoli), in which cartilage is absent, serve to move gas from the airways to the alveoli and are referred to as the conducting airways. This area of the lung (≈150 mL in volume) does not participate in gas exchange and forms the anatomical dead space. The respiratory bronchioles with alveoli and the area beginning •Fig. 20.3 Illustration of Bronchopulmonary Segments, Anterior View. Thenumberscorrespondtothosein


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fig.20.2 .Upper lobe Middle lobe Lower lobe Upper lobe Lingula Thyroid cartilage Cricoid cartilage Trachea Left main stem bronchus Right main stem bronchus 12 3 4 8 9 10 5 1 2 3 4 8 77 6 6 9 10 5 •Fig. 20.4 Illustration of Conducting Airways and Alveolar Units of the Lung. Therelativesizeofthealveolarunitisgreatlyenlarged.Numbersatthebottomindicatetheapproximatenumberofgenerationsfromtracheatoalveoli,whichmayvaryfromasfewas10toasmanyas23.(FromWeibelER.Morphometry of the Human Lung. Heidelberg:Springer-Verlag;1963.) with the respiratory bronchioles to the alveoli are where all gas exchange occurs. This region is only approximately 5 mm long, but it is the largest volume of the lung, at a volume of approximately 2500 mL and with a surface area of 70 m2 when the lung and chest wall are at the resting volume (see Table 20.1


Physiology_Levy

Physiology_Levy. Table 20.1 The alveoli are polygonal in shape and approximately 250 µm in diameter. Alveolar spaces are responsible for most of the lung’s volume; these spaces are divided by tissue known collectively as the interstitium. The interstitium is composed primarily of lung collagen fibers and is a space in which fluid and cells can potentially accumulate. An adult has approximately 5 × 108 alveoli ( Fig. 20.6 ), which are composed of type I and type II epithelial cells. Under normal conditions, type I and type II cells exist in a 1 : 1 ratio. The type I cell occupies 96% to 98% of the surface area of the alveolus, and it is the primary site for gas exchange. The thin cytoplasm of type I cells is ideal for optimal gas diffusion. In addition, the basement membrane of type I cells and the capillary endothelium are fused, which minimizes the distance for gas diffusion and thereby facilitates gas exchange.


Physiology_Levy

Physiology_Levy. Type II cells are cuboidal and usually found in the “corners” of the alveolus, where they occupy 2% to 4% of the surface area. During embryonic development, the alveolar epithelium is composed entirely of type II cells, and only very late in gestation do they differentiate into type I cells and form the “normal” alveolar epithelium for optimal gas exchange. Also, type II cells synthesize pulmonary surfactant (see ), which reduces surface tension (nonsticking properties) in the alveolus and thereby promotes less resistance during inhalation and exhalation. Gas exchange occurs in the alveoli through a dense mesh-like network of capillaries and alveoli called the alveolar-capillary network. The barrier between gas in the alveoli and the red blood cell is only 1 to 2 µm thick and consists of type I alveolar epithelial cells, capillary endothelial cells, and their respective basement membranes. O2 and CO2 passively diffuse across this barrier into plasma and red blood cells (see


Physiology_Levy

Physiology_Levy. Chapter 24). Red blood cells pass through the network in less than 1 second, which is sufficient time for CO2 and O2 gas exchange. Circulatory Systems in the Lung The circulation to the lung is unique in its duality and ability to accommodate large volumes of blood at low pressure. The lung has two separate blood supplies, one •Fig. 20.5 The Airway From the Terminal Bronchiole to the Alveo-lus. Notetheabsenceofalveoliintheterminalbronchiole.A,alveolus;RB,respiratorybronchiole;TB,terminalbronchiole.


Physiology_Levy

Physiology_Levy. Notallimportantobstructivelungdiseasesinvolvetheairwaysdirectly.Emphysema isanirreversible,obstructivelungdiseasecommoninpeoplewhosmoke.Thepathogenesisinvolvesaprogressivedestructionoftheelastictissuesinthelungwithalossofalveolar/capillarystructure.Themechanismsoftissuedestructionareunclearbutmayinvolveproteolyticenzymesandothertoxiccompoundsincigarettesmoke.Emphysemaalsooccursinnonsmokingindividualswiththegeneticdisorderα1-antitrypsin deficiency, causedbytheinabilitytoregulateproteolyticenzymes,particularlyelastase. for the uptake of O2 and removal of CO2 from the body (pulmonary circulation) and the other to supply O2 to lung tissue (bronchial circulation; Fig. 20.7


Physiology_Levy

Physiology_Levy. The pulmonary circulation begins in the right atrium of the heart. Deoxygenated blood from the right atrium enters the right ventricle via the tricuspid valve, and it is then pumped under low pressure (9 to 24 mm Hg) into the pulmonary artery (pulmonary trunk), which is approximately 3 cm 200 µmPVCTB PARB AD A PV PV A I A A C C C II M10 µm 200 µm PAPA A A A I I I I EL C R COL E * E Nu 1.0 µmB •Fig. 20.6 Alveoli. A. Theterminalrespiratoryunitconsistsofthealveoli(A)andthealveolarducts(AD)arisingfromarespiratorybronchiole(RB).Eachunitisapproximatelyspherical,assuggestedbythedashed outline. Pulmonaryvenousvessels(PV)haveaperipherallocation.PA,pulmonaryartery;TB,terminalbronchiole.Inset, typeIandtypeIIalveolarepithelialcells.Alargefractionofthealveolarwallconsistsofcapillaries(C)andtheircontents.B.Illustrationofacross-sectionofanalveolarwall,showingthepathofdiffusionofO2andCO2.Thethinsideofthealveolarwallbarrier(short double arrow) consistsoftypeIepithelium(I),interstitium(asterisk)


Physiology_Levy

Physiology_Levy. in diameter, and branches quickly (5 cm from the right progressively smaller series of branching vessels—arteries ventricle) into the right and left main pulmonary arteries, (diameter, >500 µm); arterioles (diameter, 10 to 200 µm); which supply blood to the right and left lungs, respectively. and capillaries (diameter, <10 µm)—that end in a complex The arteries of the pulmonary circulation are the only arter-mesh-like network of capillaries. The sequential branching ies in the body that carry deoxygenated blood. The deoxy-pattern of the pulmonary arteries follows the pattern of genated blood in the pulmonary arteries passes through a airway branching.


Physiology_Levy

Physiology_Levy. •Fig. 20.7 Illustrationoftheanatomicalrelationshipofthepulmonaryartery,thebronchialartery,theairways,andthelymphaticvessels.A,alveoli;AD,alveolarducts;RB,respiratorybronchioles;TB,terminalbronchioles.AD AD AD AD RB TB Lymphatics Lymphatics Vasomotor nerves Pulmonary vein Bronchomotor nerve Pulmonary artery Bronchial artery Bronchus A A A A A The functions of the pulmonary circulatory system are (1) to reoxygenate the blood and release CO2, (2) to aid in fluid balance in the lung, and (3) to distribute metabolic products to and from the lung. Red blood cells are oxygenated in the capillaries that surround the alveoli, where the pulmonary capillary bed and the alveoli come together in the alveolar wall in a unique configuration for optimal gas exchange. Gas exchange occurs through this alveolar-capillary network (see


Physiology_Levy

Physiology_Levy. The total blood volume of the pulmonary circulation is approximately 500 mL, which is approximately 10% of the circulating blood volume. Approximately 75 mL of blood is present in the alveolar-capillary network of healthy adults at any one time. The pulmonary capillary bed is the largest vascular bed in the body. It covers a surface area of 70 to 80 m2, which is nearly as large as the alveolar surface area. During exercise, the pulmonary capillary blood volume increases from 75 mL to as high as 200 mL because of the recruitment of new capillaries as the result of an increase in pressure and flow. This recruitment of new capillaries is a unique feature of the lungs, and it allows for compensation in periods of stress, as in the case of exercise.


Physiology_Levy

Physiology_Levy. The oxygenated blood leaves the alveolus through a network of small pulmonary venules (15 to 500 µm in diameter) and veins. These small vessels quickly coalesce to form larger pulmonary veins (>500 µm in diameter), through which the oxygenated blood returns to the left atrium of the heart. In contrast to arteries, arterioles, and capillaries, which closely follow the branching patterns of the airways, venules and veins run quite distant from the airways. Structure of the Pulmonary Circulation


Physiology_Levy

Physiology_Levy. The arteries of the pulmonary circulation have thin walls, with minimal smooth muscle. They are seven times more compliant than systemic vessels, and they are easily distensible. This highly compliant state of the pulmonary arterial vessels requires lower pressure for blood flow through the pulmonary circulation than do the more muscular, noncompliant arterial walls of the systemic circulation. The vessels in the pulmonary circulation, under normal circumstances, are in a dilated state and have larger diameters than do similar arteries in the systemic system. All of these factors contribute to a very compliant, low-resistance circulatory system, which aids in the flow of blood through the pulmonary circulation via the relatively weak pumping action of the right ventricle. This low-resistance, low-work system also explains why the right ventricle is less muscular than the left ventricle. The pressure gradient differential for the pulmonary circulation from the pulmonary artery to the


Physiology_Levy

Physiology_Levy. low-work system also explains why the right ventricle is less muscular than the left ventricle. The pressure gradient differential for the pulmonary circulation from the pulmonary artery to the left atrium is only 6 mm Hg (14 mm Hg in the pulmonary artery minus 8 mm Hg in the left atrium). This pressure gradient differential is less than 7% of the pressure gradient differential of 87 mm Hg present in the systemic circulation (90 mm Hg in the aorta minus 3 mm Hg in the right atrium).


Physiology_Levy

Physiology_Levy. Structures of the Extra-Alveolar and Alveolar Vessels and the Pulmonary Microcirculation


Physiology_Levy

Physiology_Levy. Although not well defined anatomically, vessels in the pulmonary circulation can be divided into three categories (extra-alveolar, alveolar, and microcirculation) on the basis of differences in their physiological properties. The extra-alveolar vessels (arteries, arterioles, veins, and venules) are larger than their systemic counterparts. They are not influenced by alveolar pressure changes, but they are affected by intrapleural and interstitial pressure changes. Thus the caliber of extra-alveolar vessels is affected by lung volume and by lung elastin. At high lung volumes, the decrease in pleural pressure increases the caliber of extra-alveolar vessels, whereas at low lung volumes, an increase in pleural pressure decreases vessel caliber. In contrast, alveolar capillaries reside within the interalveolar septa, and they are very sensitive to changes in alveolar pressure but not to changes in pleural or interstitial pressure. Positive-pressure ventilation increases alveolar pressure


Physiology_Levy

Physiology_Levy. the interalveolar septa, and they are very sensitive to changes in alveolar pressure but not to changes in pleural or interstitial pressure. Positive-pressure ventilation increases alveolar pressure and compresses these capillaries and thus blocks blood flow. The pulmonary microcirculation comprises the small vessels that participate in liquid and solute exchange in maintenance of fluid balance in the lung.


Physiology_Levy

Physiology_Levy. Structure of the Alveolar-Capillary Network The sequential branching of the pulmonary arteries culminates in a dense mesh-like network of capillaries that surround alveoli. This alveolar-capillary network is composed of thin epithelial cells of the alveolus and endothelial cells of the vessels and their supportive matrix, and it has an alveolar surface area of approximately 85 m2 (the approximate size of a tennis court). The structural matrix and the tissue components of this alveolar-capillary network provide the only barrier between gas in the airway and blood in the capillary. The cells of this barrier, which is 1 to 2 µm thick, include type I alveolar epithelial cells, capillary endothelial cells, and their respective basement membranes, which are back to back (see


Physiology_Levy

Physiology_Levy. Fig. 20.6B ). Surrounded mostly by air, this alveolar-capillary network is an ideal environment for gas exchange. Red blood cells pass through the capillary component of this network in single file in less than 1 second, which is sufficient time for CO2 and O2 gas exchange. In addition to gas exchange, the alveolar-capillary network regulates the amount of fluid within the lung. At the pulmonary capillary level, the balance between hydrostatic and oncotic pressure across the wall of the capillary results in a small net movement of fluid out of the vessels into the interstitial space. The fluid is then removed from the lung interstitium by the lymphatic system and enters the circulation via the vena cava in the area of the lung hilus. In normal adults, an average of 30 mL of fluid per hour is returned to the circulation via this route.


Physiology_Levy

Physiology_Levy. The bronchial circulation is a distinct system, separate from the pulmonary circulation in the lung, that provides systemic arterial blood to the trachea, upper airways, surface secretory cells, glands, nerves, visceral pleural surfaces, lymph nodes, pulmonary arteries, and pulmonary veins. The bronchial circulation is similar in structure to the systemic circulatory system and perfuses the upper respiratory tract; it does not reach the terminal or respiratory bronchioles or the


Physiology_Levy

Physiology_Levy. CHAPTER 20 Introduction to the Respiratory System alveoli. Venous blood from the capillaries of the bronchial circulation flows to the heart through either true bronchial veins or bronchopulmonary veins. True bronchial veins are present in the region of the lung hilus, and blood flows into the azygos, hemiazygos, or intercostal veins before entering the right atrium. The bronchopulmonary veins are formed through a network of tributaries from the bronchial and pulmonary circulatory vessels that anastomose and form vessels with an admixture of blood from both circulatory systems. Blood from these anastomosed vessels returns to the left atrium through pulmonary veins. Approximately two thirds of the total bronchial circulation is returned to the heart via the pulmonary veins and this anastomosis route.


Physiology_Levy

Physiology_Levy. The bronchial circulation receives only approximately 1% of total cardiac output; in comparison, the pulmonary circulation receives almost 100%. In the presence of diseases such as cystic fibrosis, the bronchial arteries, which normally receive only 1% to 2% of cardiac output, increase in size (hypertrophy) and receive as much as 10% to 20% of the cardiac output. The erosion of inflamed tissue into these vessels as a result of bacterial infection is responsible for the hemoptysis (coughing up blood) that can occur in this disease. Breathing is automatic and under control of the central nervous system (CNS). The lungs are innervated by the autonomic nervous system of the peripheral nervous system (PNS), which is under CNS control ( Fig. 20.8). The autonomic nervous system has four distinct components: parasympathetic, sympathetic, nonadrenergic noncholinergic inhibitory, and nonadrenergic noncholinergic stimulatory.


Physiology_Levy

Physiology_Levy. Fig. 20.8). The autonomic nervous system has four distinct components: parasympathetic, sympathetic, nonadrenergic noncholinergic inhibitory, and nonadrenergic noncholinergic stimulatory. Stimulation of the parasympathetic system leads to airway smooth muscle constriction, blood vessel dilation, and increased glandular cell secretion, whereas stimulation of the sympathetic system causes relaxation of the airway smooth muscle, constriction of blood vessels, and inhibition of glandular secretion (see Fig. 26.1 ). The functional unit of the autonomic nervous system is composed of preganglionic and postganglionic neurons in the CNS and postganglionic neurons in the ganglia of the specific organ. As with most organ systems, the CNS and PNS work in concert to maintain homeostasis. There is no voluntary motor innervation in the lung, nor are there pain fibers. Pain fibers are found only in the pleura.


Physiology_Levy

Physiology_Levy. The parasympathetic innervation of the lung originates from the medulla in the brainstem (cranial nerve X, the vagus nerve). Preganglionic fibers from the vagal nuclei descend in the vagus nerve to ganglia adjacent to airways and blood vessels in the lung. Postganglionic fibers from the ganglia then complete the network by innervating smooth muscle cells, blood vessels, and bronchial epithelial cells (including goblet cells and submucosal glands). In the lungs, both preganglionic and postganglionic fibers •Fig. 20.8 Innervation of the Lung. Theautonomicinnervation(motorandsensory)ofthelungandthesomatic(motor)nervesupplytotheintercostalmusclesanddiaphragmaredepicted.


Physiology_Levy

Physiology_Levy. contain excitatory (cholinergic) and inhibitory (nonadrenergic) motor neurons. Acetylcholine and substance P are neurotransmitters of excitatory motor neurons; dynorphin and vasoactive intestinal peptide are neurotransmitters of inhibitory motor neurons. Parasympathetic stimulation through the vagus nerve is responsible for the slightly constricted smooth muscle tone in a normal resting lung. Parasympathetic fibers also innervate the bronchial glands, and these fibers, when stimulated, increase the synthesis of mucus glycoprotein, which increases the viscosity of mucus. Parasympathetic innervation is greatest in the larger airways and most limited in the smaller conducting airways in the periphery.


Physiology_Levy

Physiology_Levy. Whereas the response of the parasympathetic nervous system is very specific and local, the response of the sympathetic nervous system tends to be more general. Mucous glands and blood vessels are heavily innervated by the sympathetic nervous system; however, airway smooth muscle is not. Neurotransmitters of the adrenergic nerves include norepinephrine and dopamine, although dopamine has no influence on the lung. Stimulation of the sympathetic nerves in mucous glands increases water secretion. This disrupts the balanced response of increased water and increased viscosity between the sympathetic and parasympathetic pathways. Adrenergic fibers are absent in humans. In addition to those in the sympathetic and parasympathetic systems, afferent nerve endings are present in the epithelium and in smooth muscle cells in the lung. Central Control of Respiration


Physiology_Levy

Physiology_Levy. Central Control of Respiration Breathing is an automatic, rhythmic, and centrally regulated process with voluntary control. The CNS, particularly the brainstem, functions as the main control center for respiration ( Fig. 20.9 ). Regulation of respiration requires (1) generation and maintenance of a respiratory rhythm; (2) modulation of this rhythm by sensory feedback loops and reflexes that allow adaptation to various conditions while minimizing energy costs; and (3) recruitment of respiratory muscles that can contract appropriately for gas exchange. Control of respiration is described in greater detail in


Physiology_Levy

Physiology_Levy. Cerebral cortex Respiratory center, medulla Spinal cord Respiratory muscles Lung and chest wall Alveolar-capillary barrier BloodPerfusion Mechano-receptors Chemo-receptors PCO2, PO2, pH Diffusion Ventilation Nerve impulses Nerve impulses Force displacement •Fig. 20.9 Block Diagram of the Respiratory Control System, Demonstrating Relationships Between the Respiratory Control Center and Muscles of Respiration. Therespiratorycenterneurons,dispersedintoseveralgroupsinthemedulla,demonstratespontaneouscyclicactivitybutarestronglyinfluencedbystimulidescendingfromthecerebralcortex(volitionalcontrol)andfromtwosensoryloops:mechanoreceptorandchemoreceptorpathways.Ventilationandperfusionoccurtogetherneartheendofthecycle,andtheiroutputdeterminespartialpressuresofarterialandalveolarcarbondioxide(PCO2)andoxygen(PO2)and,inpart,arterialhydrogenionconcentration(pH).Theseoutputsfeedbacktotherespiratorycenterviachemoreceptorandmechanoreceptorsensorypathways. Muscles of Respiration


Physiology_Levy

Physiology_Levy. Muscles of Respiration The major muscles of respiration include the diaphragm, the external intercostal muscles, and the scalene muscles, all of which are skeletal muscles. Skeletal muscles provide the driving force for ventilation; the force of contraction increases when they are stretched and decreases when they are shortened. The force of contraction of respiratory muscles increases at larger lung volumes. The diaphragm is the major muscle of respiration, and it divides the thoracic cavity from the abdominal cavity ( Fig.


Physiology_Levy

Physiology_Levy. The diaphragm is the major muscle of respiration, and it divides the thoracic cavity from the abdominal cavity ( Fig. 20.10). Contraction of the diaphragm forces the abdominal contents downward and forward. This increases the vertical dimension of the chest cavity and creates a pressure difference between the thorax and abdomen. In adults, the diaphragm can generate airway pressures of up to 150 to 200 cm H2O during maximal inspiratory effort. During quiet breathing (tidal breathing), the diaphragm moves approximately 1 cm; however, during deep-breathing maneuvers (vital capacity), the diaphragm can move as much as 10 cm. The diaphragm CHAPTER 20 Introduction to the Respiratory System is innervated by the right and left phrenic nerves, whose origins are at the third to fifth cervical segments of the spinal cord (C3 to C5). The other important muscles of inspiration are the external intercostal muscles, which pull the ribs upward and forward during inspiration (see


Physiology_Levy

Physiology_Levy. The other important muscles of inspiration are the external intercostal muscles, which pull the ribs upward and forward during inspiration (see Fig. 20.10 ). This causes an increase in both the lateral and anteroposterior diameters of the thorax. Innervation of the external intercostal muscles originates from intercostal nerves that arise from the same level of the spinal cord (T1 and T2). Paralysis of these muscles has no significant effect on respiration because respiration is dependent primarily on the diaphragm. This is why individuals with injuries to the lower spinal cord can breathe on their own; it is only when the injury is above C3 that an individual is completely dependent on a ventilator.


Physiology_Levy

Physiology_Levy. Accessory muscles of inspiration (the scalene muscles, which elevate the sternocleidomastoid muscles; the alae nasi, which cause nasal flaring; and small muscles in the neck and head) do not contract during normal breathing. However, they do contract vigorously during exercise, and when airway obstruction is significant, they actively pull up the rib cage. During normal breathing, they anchor the sternum and upper ribs. Because the upper airway must remain patent during inspiration, the pharyngeal wall muscles (genioglossus and arytenoid) are also considered muscles of inspiration. All the rib cage muscles are voluntary muscles that are supplied by intercostal arteries and veins and innervated by motor and sensory intercostal nerves.


Physiology_Levy

Physiology_Levy. Exhalation during normal breathing is passive, but it becomes active during exercise and hyperventilation. The most important muscles of exhalation are those of the abdominal wall (rectus abdominis, internal and external oblique, and transversus abdominis) and the internal intercostal muscles, which oppose the external intercostal muscles (i.e., they pull the ribs downward and inward). The inspiratory muscles do the work of breathing. During normal breathing, this workload is low, and the inspiratory muscles have significant reserve. Respiratory muscles can be trained to do more work, but there is a limit to the work that they can perform. Respiratory muscle weakness can impair movement of the chest wall, and respiratory muscle fatigue is a major factor in the development of respiratory failure. Lung Embryology, Development, Aging, and Repair


Physiology_Levy

Physiology_Levy. Lung Embryology, Development, Aging, and Repair The epithelium of the lung arises as a pouch from the primitive foregut at approximately 22 to 26 days after fertilization of the ovum. This single lung bud branches into primitive right and left lungs. Over the next 2 to 3 weeks, further branching occurs to create the irregular dichotomous branching pattern. The pathologist Lynne Reid described “three laws of lung development”: (1) The bronchial tree has developed by week 16 of intrauterine Diaphragm (domes descend, increasing longitudinal dimension of chest and elevating lower ribs) A Muscles of inspiration Internal intercostals, except parasternal intercartilaginous muscles (depress ribs) Abdominal muscles (depress lower ribs, compress abdominal contents) Muscles of expiration


Physiology_Levy

Physiology_Levy. Abdominal muscles (depress lower ribs, compress abdominal contents) Muscles of expiration Because respiratory muscles provide the driving force for ventilation, diseases that affect the mechanical properties of the lung affect the muscles of respiration. For example, in chronic obstructive pulmonary disease (COPD), the work of breathing is increased secondary to airflow obstruction. Exhalation no longer is passive but instead requires active, expiratory muscle contraction. In addition, total lung capacity is increased (see ). The larger total lung capacity forces the diaphragm downward, shortens the muscle fibers, life; (2) alveoli develop after birth, the number of alveoli increases until the age of 8 years, and the size of alveoli increases until growth of the chest wall is completed at adulthood; and (3) the development of preacinar vessels (arteries and veins) parallels that of the airways, whereas that of intra-acinar vessels parallels that of the alveoli.


Physiology_Levy

Physiology_Levy. and decreases the radius of curvature. As a result, the function and efficiency of the diaphragm are decreased. Respiratory muscles can fatigue just as other skeletal muscles do when the workload increases. Respiratory muscles can also weaken in patients with neuromuscular diseases (e.g., Guillain-Barré syndrome, myasthenia gravis). In these diseases, sufficient weakness of the respiratory muscles can impair movement of the chest wall and result in respiratory failure, even though the mechanical properties of the lung and chest wall are normal.


Physiology_Levy

Physiology_Levy. Thus intrauterine events that occur before 16 weeks of gestation will affect the number of airways. A condition known as congenital diaphragmatic hernia is an example of a congenital lung disease. It occurs at 6 to 8 weeks of gestation and is due to failure of the pleuroperitoneal canal to close and thereby separate the chest and abdominal cavities; the presence of the abdominal contents in the lung hemithorax results in abnormal lung growth with a decrease in the number of airways and alveoli. Before the birth of an affected infant, the alveolar epithelium is composed solely of type II epithelial cells, and it is not until birth that these cells differentiate into type I epithelial cells.


Physiology_Levy

Physiology_Levy. Growth of the lungs is similar and relatively proportional to growth in body length and stature. The rate of development is fastest in the neonatal and preadolescent periods (≈11 years of age), and girls’ lungs mature earlier than boys’. Although the growth rate of the lung slows after adolescence, the body and lung increase in size steadily until adulthood. Improvement in lung function occurs at all stages of growth development; however, once optimal size has been attained in early adulthood (20 to 25 years of age), lung function starts to decline with age. The decrease in lung function with age, estimated at less than 1% per year, appears to begin earlier and proceed faster in individuals who smoke or are exposed to toxic environmental factors. The major physiological insufficiencies caused by aging involve ventilatory capacity and responses, especially during exercise, and they result in abnormal ventilation with normal perfusion. In addition, gas diffusion decreases with age,


Physiology_Levy

Physiology_Levy. caused by aging involve ventilatory capacity and responses, especially during exercise, and they result in abnormal ventilation with normal perfusion. In addition, gas diffusion decreases with age, probably as a result of a decrease in alveolar surface area. Age-related decreases in lung function and altered structure parallel biochemical observations of increased levels of elastin within the lung, which could explain some of the functional abnormalities.


Physiology_Levy

Physiology_Levy. TypeIcellslackfreeradicalscavengers(i.e.,superoxidedismutase)andaresusceptibletoinjuryanddeathinducedbytoxicO2compoundsandfreeradical(i.e.,H2O2,OH− ,andO2−).Invariousinflammatorylungdiseases,typeIcellsdie,andthealveolarepitheliumtherebybecomesdenuded,withincreasedvascularpermeabilityandensuingfluidaccumulation(impairedgasexchange).TypeIIcellshavesuperoxidedismutaseandarethusmoreresistanttothetoxicoxygenradicals.TheycansurvivetoproliferateanddifferentiateintotypeIcellstorestorethenormalalveolararchitecture.ThistypeofresponseisdependentonanintactbasementmembranetosupporttheproliferationoftypeIIcellsandisanexampleof“phylogenyrecapitulatingontogeny.”Ifthebasementmembranecannotberepopulated,thenthebody’srecourseforrepairiscollagendepositionandscarformation,whichisnotconducivetogas 1. The lungs demonstrate anatomical and physiological unity; that is, each unit (bronchopulmonary segment) is structurally identical and functions just like every other unit. 2.


Physiology_Levy

Physiology_Levy. The lungs demonstrate anatomical and physiological unity; that is, each unit (bronchopulmonary segment) is structurally identical and functions just like every other unit. 2. The upper airways (nose, sinuses, pharynx) condition inspired air for temperature, humidity, and atmospheric pressure, and they control, via the epiglottis, the flow of air into the lungs and food/fluids into the esophagus. 3. Components of the lower airways (trachea, bronchi, bronchioles) are considered conducting airways in which air is transported to the gas-exchanging respiratory units composed of respiratory bronchioles, alveolar ducts, and alveoli. 4.


Physiology_Levy

Physiology_Levy. The lungs have unique, dual circulatory systems. The pulmonary circulatory system has the ability to accommodate large volumes of blood at low pressure and brings deoxygenated blood from the right ventricle to the gas-exchanging units in the lung. The


Physiology_Levy

Physiology_Levy. pulmonary circulatory system has the ability to accommodate large volumes of blood at low pressure and brings deoxygenated blood from the right ventricle to the gas-exchanging units in the lung. The exchange.Inlungdiseasethatinvolvesscarformation(i.e.,pulmonaryfibrosis),thetotallungvolumedecreasesasaresultofthelossofalveoliandimpairmentofO2diffusionintothecapillariesbyathickened,nonpermeablematrix.Historically,idiopathicpulmonaryfibrosishasbeenverydifficulttotreatbecauseofthelackofspecifictherapeutics,whichcaninhibitcollagendeposition.Twotherapeuticcompounds(pirfenidoneandnintedanib)havebeenshowninclinicaltrialstoslowtheprogressionofthediseaseandimproveoutcomesinpatientswithidiopathicpulmonaryfibrosis.Pirfenidoneisasmalllow-molecular-weightcompoundwithanti-inflammatoryproperties(itdecreasesprocollagentypesIandIIsynthesis),andnintedanibisatyrosinekinaseinhibitor(inhibitsvascularendothelialgrowthfactorandfibroblast-derivedgrowthfactor).


Physiology_Levy

Physiology_Levy. bronchial circulation arises from the aorta and provides nourishment (O2) to the lung parenchyma. 5. Breathing is automatic; the lungs are innervated by the autonomic nervous system of the PNS while under the control of the CNS. Parasympathetic stimulation results in constriction of airway smooth muscles (airway narrowing) whereas sympathetic stimulation results in relaxation of airway smooth muscles (airway opening). 6. Inspiration is the active phase of breathing. The diaphragm is the major muscle of respiration, and its contraction creates a pressure difference (mechanoreceptor response) between the thorax and diaphragm (negative pressure in the chest), which induces inspiration. 7. The respiratory center is located in the medulla and regulates respiration with input from sensory (mechanoreceptor and chemoreceptor) feedback loops. Burri PH. Structural aspects of postnatal lung development—alveolar formation and growth. Biol Neonate. 2006;89:313-322.


Physiology_Levy

Physiology_Levy. Burri PH. Structural aspects of postnatal lung development—alveolar formation and growth. Biol Neonate. 2006;89:313-322. Hameed A, Sherkheli MA, Hussain A, Ul-haq R. Molecular and physiological determinants of pulmonary developmental biology: a review. Am J Biomed Res. 2013;1:13-24. Harding R, Pinkertton KE, eds. The Lung: Development, Aging and the Environment. 2nd ed. London: Academic Press; 2014. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2007;70:431-457. Reynolds HY. Lung inflammation and fibrosis: an alveolar macrophage-centered perspective from the 1970s to 1980s. Am J Respir Crit Care Med. 2005;171:98-102. Satir P, Christensen ST. Overview of structure and function of mammalian cilia. Annu Rev Physiol. 2007;69:377-400. Shannon JM, Hyatt BA. Epithelial cell-mesenchymal interactions in the developing lung. Annu Rev Physiol. 2004;66:625-645.


Physiology_Levy

Physiology_Levy. Shannon JM, Hyatt BA. Epithelial cell-mesenchymal interactions in the developing lung. Annu Rev Physiol. 2004;66:625-645. Warburton D, El-Hashash A, Carraro G, et al. Lung organogenesis. Curr Top Devel Bio. 2010;90:73-158. Upon completion of this chapter, the student should be able to answer the following questions: 1. Define the different pressures in the respiratory system. 2. Explain how a pressure gradient is created. 3. Define the different volumes in the lung, and describe how they are measured. 4. Explain how static lung mechanics determines lung volumes. 5. Define lung compliance. 6. Explain how surfactant affects lung compliance, and describe its importance in maintaining unequal alveolar volumes.


Physiology_Levy

Physiology_Levy. o achieve its primary function of gas exchange, air must be moved in and out of the lung. The mechanical properties of the lung and chest wall determine the ease or difficulty of this air movement. Lung mechanics is the study of the mechanical properties of the lung and chest wall (including the diaphragm, abdominal cavity, and anterior abdominal muscles). Lung mechanics is important for how the lungs work both normally and in the presence of disease, inasmuch as most lung diseases affect the mechanical properties of the lungs, chest wall, or both. In addition, death from lung disease is almost always due to respiratory muscle fatigue, which results from an inability of the respiratory muscles to overcome the altered mechanical properties of the lungs, chest wall, or both. Lung mechanics includes static mechanics (the mechanical properties of a lung whose volume is not changing with time) and dynamic mechanics (properties of a lung whose volume is changing with time). Dynamic


Physiology_Levy

Physiology_Levy. includes static mechanics (the mechanical properties of a lung whose volume is not changing with time) and dynamic mechanics (properties of a lung whose volume is changing with time). Dynamic mechanics of the lung and chest wall are described in


Physiology_Levy

Physiology_Levy. Chapter 22. Pressures in the Respiratory System


Physiology_Levy

Physiology_Levy. In healthy people, the lungs and chest wall move together as a unit. Between these structures is the pleural space, which under normal conditions is best thought of as a potential (or virtual) space. Because the lungs and chest wall move together, changes in their respective volumes are equal during inspiration and exhalation. Volume changes in the lungs and chest wall are driven by changes in the surrounding pressure. In accordance with convention, pressures inside the lungs and chest wall are referenced in relation to atmospheric pressure, which is considered 0. Thus a negative pressure in the pleural space is a pressure that is lower than atmospheric pressure. Also in accordance with convention, pressures across surfaces such as the lungs or chest wall have been defined as the difference between the pressure inside and the pressure outside the surface. The pressure differences across the lung and across the chest wall are defined as the transmural (across a wall or surface)


Physiology_Levy

Physiology_Levy. between the pressure inside and the pressure outside the surface. The pressure differences across the lung and across the chest wall are defined as the transmural (across a wall or surface) pressures. For the lung, this transmural pressure is called the transpulmonary (or translung) pressure (PL), and it is defined as the pressure difference between the air spaces (alveolar pressure [PA]) and the pressure surrounding the lung (pleural pressure [Ppl]):


Physiology_Levy

Physiology_Levy. Equation 21.1 The transmural pressure across the chest wall (Pw) is the difference between pleural (inside) pressure (Ppl) and the pressure surrounding the chest wall (Pb), which is the atmospheric pressure or body surface pressure: Equation 21.2 The pressure across the respiratory system (Prs) is the sum of the pressure across the lung and the pressure across the chest wall: Equation 21.3


Physiology_Levy

Physiology_Levy. Equation 21.3 Air flows into and out of the lungs from areas of higher pressure to areas of lower pressure. In the absence of a pressure gradient, there is no airflow. Thus at end inspiration and at the end of exhalation, which are periods of time when there is no airflow, alveolar pressure (PA) is the same as atmospheric pressure (Pb), and there is no pressure gradient (Pb − PA = 0). Pleural pressure at these same times, however, is not 0. Before inspiration begins, the pleural pressure in normal individuals is approximately −3 to −5 cm H2O. Therefore, the pressure in the pleural space is negative in relation to atmospheric pressure. This negative pressure is created by the inward elastic recoil pressure of the lung, and it acts to “pull the lung” away from the chest wall. The lung is not able, however, to pull away from the chest wall, inasmuch as the two function as a unit. Thus the inward elastic recoil pressure of the lung is balanced by the outward recoil of the chest wall.


Physiology_Levy

Physiology_Levy. With the onset of inspiration, the muscles of the diaphragm and chest wall contract, which causes a downward movement of the diaphragm and an outward and upward movement of the rib cage. As a result, pleural pressure decreases during inspiration. This negative pleural pressure is transmitted across the lung tissue and results in a decrease in alveolar pressure. As alveolar pressure decreases below 0 (i.e., from atmospheric pressure to a lower pressure), gas moves into the airways when the glottis is open. As gas flows into the airways to the alveoli, the pressure gradient along the airways decreases, and flow stops when there is no longer a pressure gradient from atmospheric to alveolar pressure. The decrease in pleural pressure at the start of inspiration secondary to inspiratory muscle contraction is and gas again flows from a higher (alveolar) pressure to a lower (atmospheric) pressure. In the alveoli, the driving force for exhalation is the sum of the elastic recoil of the lungs


Physiology_Levy

Physiology_Levy. contraction is and gas again flows from a higher (alveolar) pressure to a lower (atmospheric) pressure. In the alveoli, the driving force for exhalation is the sum of the elastic recoil of the lungs and pleural pressure (see ). This relationship between changes in pressure, changes in airflow, and changes in volume during inspiration and exhalation is displayed in


Physiology_Levy

Physiology_Levy. Fig. 21.2. During tidal volume breathing in normal individuals, the decrease in alveolar pressure at the start of inspiration is small (1 to 3 cm H2O). It is much larger in individuals with airway obstruction because of the larger pressure drop that occurs across obstructed airways. Airflow stops in the absence of a pressure gradient, which occurs whenever alveolar pressure and atmospheric pressure are equal. (Fig. 21.3 ) and the factors that determine these volumes are important components of lung mechanics greater than the transmitted fall in alveolar pressure, and, as a result, transpulmonary pressure at the start of inspiration 0.5 is positive (see Eq. 21.1). Positive transpulmonary pressure 0.4 is necessary to increase lung volume, and lung volume increases with increasing transpulmonary pressure ( Fig.


Physiology_Levy

Physiology_Levy. Eq. 21.1). Positive transpulmonary pressure 0.4 is necessary to increase lung volume, and lung volume increases with increasing transpulmonary pressure ( Fig. 21.1 ). Similarly, during inspiration, the chest wall expands to a larger volume. Because pleural pressure is negative in 0.1 relation to atmospheric pressure during quiet breathing, 0 the transmural pressure across the chest wall is negative Eq. 21.2


Physiology_Levy

Physiology_Levy. Eq. 21.2 On exhalation, the diaphragm moves higher into the chest, pleural pressure increases (i.e., becomes less nega tive), alveolar pressure becomes positive, the glottis opens, +0.5 –0.5 •Fig. 21.1 Volume of the Lung as a Function of the Transpulmonary Pressure in Health and Disease. Asthetranspulmonarypressureincreases,lungvolumeincreases.Alsoshownarethechangesinlungvolumeinthepresenceofemphysemaandpulmonaryfibrosis.Notethatforthesamechangeintranspulmonarypressure,inthepresenceofeitherofthesetypesofdiseases,thechangesinlungvolumearedifferent.TLC,totallungcapacity(thetotalvolumeofgasinthelung).