Respiratory Physiology: The Essentials

r Structure and Function How the Architecture 01the LungSubserves Its Function

Blood-Gas Interface Airways and Airflow Blood Vessels and Flow

Stability of Alveoli Removal of Inhaled Particles

We begin with a short review of the refationships between structure and function in the fungoFirst we look at blood-gas interface where the exchange of the respiratory gases occurs. Next we look at how oxygen is brought to the interface through the airways, and then how the blood removes the oxygen from the lung. Finally two potential problemsof the lung are briefly addressed: how the alveoli maintaintheir stability, and how the lung is kept clean in a polluted

environment.

The lung is for gas exc ha nge . Its prime fun ct ion is to a llow oxygen to move fro m the air into the venous blood and carbon dioxide [Q move o ut. The lun g does

other jobs too. It metabo lizes some compounds, filters unwanted mater ials from the c ircul ation, an d acts as a reservo ir for blood. But its cardin al fun ction is to C X~ change gas, and we shall therefo re beg in a t th e blood -gas interface where the gas excha nge occurs.

Blood-Gas Interface

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Oxy gen and carbon dioxide move between air and blood by simple diffusion, that is, from an area of high to low partial pressure, * much as water runs downhill. Pick's law of diffusion states that the am oun t of gas that moves acro ss a sheet of t issue is proportional to the area of the sheet but inversely proporti onal to its thickness. The blood- gas ba rrier is exceedingly thin (Figure I-I) and h as an area of be tween 50 and 100 square meters. It is therefore well suited to its funct ion of gas exchange. How is it possible to obtain such a prodigious surface are a for diffusion inside the limited thorac ic cav ity?This is done by wrapping the small blood vessels (cap illaries) around an en ormo us number of small air sacs called alveoli (Figure 1-2). There are abou t 300 mill ion alveo li in the hu man lung, eac h abou t 1/3 mm in diam eter. If th ey were spheres," their to tal surface area would be 85 square me ters, but the ir volume only 4 liters. By co ntrast , a single sph ere of this vo lume wo uld have an int ern al surface area of on ly 1/100 square mete r. Thus, the lung gene rates this large diffusion area by be ing divided in to myriad un its. Gas is brough t to one side of the blood-gas interface by airways, an d blood to the othe r side by blood ,'essels.

Airways and Airflow T he a irways consist of a se ries of bra nching tubes wh ich be co me n arrower, sho rter, and more numerous as th ey penetrat e deeper in to the lun g (Figure I ~J) . T he trachea divides in to righ t and left main bronchi, which in turn d ivide in to 10' bar , then segme nta l bronchi. This process co n tin ues down to the tenninal bran, chioles, wh ich are the sma llest a irways without alveo li. All of these bronch i make up the conducting airways. T h eir function is to lead inspired air to th e gas ex , ch an ging regions of the lung (Figure 1,4). Beca use the co nduct ing airways con, tai n no alveo li and therefore take no part in gas exc hange, the y const itute the ana tomic dead space. Its volume is about 150 ml. The termin al bro nch ioles divide into respiratory bronchioles, whic h h ave oc casional alveoli budding from their walls. Finally, we come to the alveolar dU ClS , wh ich are completely lined with alveoli. This alv eo lated region of the lung where the gas exc ha nge occ urs is known as the respiratory zone. T h e portion of lun g dis, Figure

la r w a t Th e eryth r t lo n), a pla sm a a nd a ~

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* The part ial pressure of a gas is found by mu lriplving its concentrat ion

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by the to ta l pressure. For example, dry air has 20.93% 0 ,. Its partia l pressure (Po) at sea level (barom etric pressure 760 mm Hg] is 20.93/ 100 X 760 = 159 rom Hg. When air is inhaled into the upper airways, it is war med and moistened, and th e wate r vapo r pressure is th en 47 mm Hg, so tha t the tot al dry gas pressure is only 760 - 47 = 713 mm Hg. The Po , of inspired air is therefore 20.93/ 100 X 713 = 149 mm Hg . A liq uid exposed to a gas un til equ ilibration take s plac e h as th e same parti al pressure as the gas. For a more complete description of th e gas laws, see App endix A. Th e alveoli are not sphe rical hut polyhedral. No r is th e whole of their surface available for diffusion (see Figure 1, 1). These numbers are th erefore only approx imate .

Structure and Function

3

Figure 1-1. Elect ro n microg raph showing a pulmona ry capill ary (C) in the alv eolar wall. Note the extremel y th in blood -gas barri er of abo ut 0.3 u rn in some pl aces. The large arrow ind icates the diffusi on pat h fro m alveolar gas to th e interio r of t he eryt hrocyte (ECI and includes t he lay er of surfactant (not shown in th e preparation ), alve olar epitheli um (EP), interst it ium (IN), capill ary endoth elium (EN), and pl asm a. Parts of stru ctura l cell s call ed fibroblasts (FBI, baseme nt membrane (8M ), and a nu cleu s of an endot helia l cell are also seen.

Figure 1-3. Cas awa y, allov 'r-:; ol es t o be s~~ "

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Figure 1-2. Sect ion of lu ng showing m any alveo li and a sma ll bronchio le. Th e pu lm onary capil lar ies run in t he w alls of the alv eo li (Figure 1-1). The holes in t he alve olar walls are the pores of Kahn.

but th e respir 3 liters durine During i drawn in to"

tion of the J intercost al of the thorax. ~ flow. like war

Structure and Function

5

Figure 1-3. Cast of the airwa y s of a human lu ng. The alveoli hav e been pruned

aw ay, allowing t he con ducti ng airwa ys from t he trach ea to the termina l bro nchioles to be seen.

tal to a termi nal bronc hiole forms an ana tomical un it called the acinus. The d isranee from the terminal bronchiole to the most distal alveolus is only a few mrn, but the respiratory zone makes up most of the lung, its volume being about 2.5 to 3 liters dur ing rest. During inspirati on, th e volume of the th oracic cavity increases and air is drawn into the lung. The incr ease in volume is brought about par tly by contraction of th e diaph ragm, wh ich causes it to descend, and partly by the actio n of th e int ercostal muscles, which raise th e ribs, thu s increasing the cross-sectional area of the thorax. Inspired air flows down to about the terminal bronchio les by bulk flow, like water th rough a hose. Beyond that point, the combined cross-sectiona l

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Figure 4-8. Ex plan atio n of th e u nev en di stributio n of blood fl ow in the lu ng, base d on the p ressu res affecti ng t he cap illa ries .

Farther down th e lung (zone 2) , pulmonary arterial pressure inc reases bec ause of the hydrosta tic effect and now excee ds alveolar pressure. However, veno us pressure is still very low and is less th an alveolar p ressure, and thi s leads to remarkablc pressure -flow cha ract eristics. Unde r these cond it ions, blood flow is determ ined by the difference between arterial and alveo lar pressures (nor the usual art erial-veno us pressure difference ). In deed , ven ous pressure ha s no influen ce on flow unless it exc eeds alveolar pressure. This behavior can be modeled with a flexible rubber tube inside a glass chamher (Figure 4~9) . W hen chamber pressure is grea ter th an downstr eam pressure, the rubber tube collapses at its downstream end, and the pressure in the tube at th is poin t limi ts now, The pulmonary capillary bed is clearly very d ifferent from a rubber tube. Ne vertheless, the ove rall beh avior is similar and is often called the S tarling resistor, sluice, or waterfall effect. Because arterial pressure is increasing down the zone but alveolar pressure is the same th roughout the lung, the pressure difference respo nsible for flow increases. In add ition, increasing recruitmen t of capillaries occurs down th is zone. In zone 3 , veno us pressure now exceeds alveolar pressure, and flow is determine d in the usual way by the arrerial-veno us pressure difference. The increase in blood flow down thi s region of the lung is apparen tly caused chiefly by distension of the capillaries. T he pressure withi n them (lying hetween arte rial and venous) increases do wn th e zone while th e pressure outside (alveolar) remains constan t. T h us, th eir tran smural pressure rises and, indeed, measuremen ts show that their mea n width increases. Recruitmen t of previously closed vessels may also play some part in th e increase in blood flow down this zone.

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Figu re 4-9. Tw o Star lin g resisto rs, each co nsisti ng of a th in ru bb er t u be inside a container. When cham ber pr essu re exceeds downstream pressure as in A, flow is independent of downstream pressur e. How ever, w hen do w nst ream pr essur e ex ceeds cha mber pr essu re as in B, flow is dete rmi ned by t he upstream -downstream difference.

The sche me shown in Figure 4 ~8 summarizes th e role played by the capillaries in deter min ing th e distri bution of blood £10\,,', A t. low lung volumes, th e resistan ce of the extra-alveo lar vessels becom es impo rtant, and a reduction of regional blood rlow is seen , start ing first at the base of the lun g, where the paren ch yma is least expanded (see Figurc 7-8). This region of reduced blood flow is sometimes called zone 4 and can be exp lained by th e n arrowin g of th e extra-alveo lar vessels, wh ich occurs whe n th e lung aro und th em is poorly inflated (Figure 4-6). There are othe r factors causing une ven ness of blood flow in th e lun g. In some an imals, some regions of the lung appear to h ave an intrinsically higher vascular resistance. There is also evide nc e th at blood flow dec reases along the acinus with pet iph eral pans less well supplied with blood . Some measurements suggest that the periphe ral region s of th e whole lung receive less blood flow th an the central regions. Finally, th e com plex , partl y random arrangeme n t of blood vessels and capillaries (Figure 1-6) causes some inequality of blood flow.

Active Control of the Circulation \Ve hav e seen that passive facto rs dominate the vascular resistance and the distribution o( flow in the pulmonary circu lati on under normal conditions. Howeyer, a remarka ble act ive response occ urs when th e POz of alveo lar gas is reduced. This is known as hypoxic pulmonaT)' vasoconstriction andconsists of con traction of smooth muscle in the walls ofthe small arterioles in th e hypoxic region. T he pre~ cise mechani sm of th is response is not kn own, but it occurs in excised isolat ed lung and so does not depend on cent ral ner vous connecti on s. Excised segmen ts - pulmon ary artery can be sh own to con stric t if the ir en vironment is made hvpoxic so th at it may be a local act ion of th e hypoxia on th e artery itself O ne h ypoth esis is th at cells in the perivasc ular tissue release some vasoconstricto r substance in response to hypoxia, but an intensive search for th e med iato r h as not

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heen successful. Interest ingly, it is the Po , of the alveolar gas, not the pulmonary arte rial blood , th at ch iefly derenn in es.. . t. h-;; response. This can b e proved by perfusing a lung wirh blood of a high Po , while keeping rhe alveolar Po , low. Unde r these cond itio ns the respo nse occurs. The vessel wall presumably beco mes hypoxic through diffusion of oxygen over the very shor t distance from th e wall to the surrounding alveoli. Recall th at a small pulmonary artery' is very closely surrounded by alveoli (comp are th e proximity of alveoli to the small pulmo nary vein in Figure 4-3) . The stimulus-response curve of th is constr ict ion is very nonlinear ( Figure 4-10 ). \X1h en the alveolar po ! is alte red in the region above 100 mm Hg, little ch ange in vascular resistance is seen. However, when the alveolar Po ~ is reduced below approximately 70 mm Hg, mark ed vasoconstriction may cc curvand at a very low Po , the local blood flow may be almost abolished. The mechan ism of h ypoxic pulmon ary vasoconstrict ion rema ins obscure in spite of a grea t deal of research. Rece n t studies suggest that in h ibit ion of volt agegated pot assium ch annels and membrane depolarization may be involved, lead; ing to increased calcium ion concen trat ions in th e cytoplasm. A n in crease in cytopl asmic ca lcium ion co ncen trat ion is the major trigger for smooth muscle co n trac tion . End otheliurn-der ived vasoact ive substances play a role. N itr ic ox ide (l"O) has been shown to be an endo the lium-de rived relaxing facto r for blood vessels. Ir is formed h om Largin in e via catalysis by end othelial N O syn thase (eN O S) and is a fina l com mon pathway for a variety of biological processes. NO act ivates soluble guanylate cyclase and increases the syn thesis of guanosine 3',5' ~ cyclic mono phosph are (cyclic G MP), whic h leads to smoo th muscle relaxat ion.

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irors of NO synt hase augment hypoxic pulmon ary vasoconstriction in cal preparations, and inhaled NO reduces hypoxic pulmonary vasoconst ricm h umans. The required inh aled concentration of i'0 is ext remely low c t 20 ppm), and the gas is very roxie at h igh conce ntrations. Disruption of c. -OS gene has been shown to cause pulmonary hypertension in an imal

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. ulrnon arv vascular endothelial cells also release pote nt vasoconstr ictors as endorhelin- I (ET -l) and thromboxane A, (TXA,) . Thei r roles in I r hysioloJ::Y and disease are the subject of inten se study. Blockers of enneli n recepto rs have been used clin ically to treat patien ts with pulmon ary -rerrensio n . Hvpoxic vasoco nstric tion has th e effect of d irecting blood flow away from hv- regions of lung. T hese regions may result from bronchial obst ruction, and ... vert ing blood flow the deleterious effec ts on gas exchange are reduced. At _ altitude, generalized pulmonary vasoconstric tion occu rs, leading to a rise in nary arte rial pressure. But probably the most importan t situation in which , mechanism operates is at birth . During fetal life, the pulmon ary vascular re-AnCe is very high, part lv because of hypox ic vasoconst riction, an d only some orthe cardiac output goes th rough th e lungs (see Figure 9,5). When the first Ah oxygenates the alveoli, th e vascular resistan ce falls dramatically because of ion of vascular smoot h muscle, and the pulmonary blood flow increases usly. Jroer active responses of the pulmonary circulat ion have been described . A blood plI causes vasoconstriction, especiall y when alveolar h ypoxia is pre-. There is also evidenc e th at th e auto nomi c nervous system exerts a weak -01. an inc rease in sympathetic outflow causing stiffening of the walls of the na ry arteries and vasoconstriction.

" 'YPoxic Pulmonary Vasoconstriction • Alveolar hypoxia constricts small pulmonary arteries Probably a direct effe ct of the low P02 on vascular smoo th muscle Cr tical at birth in the transition from placental to air breathing Directs blood flow away from poorly vent ilated areas of the diseased lung in ' ''e adult

Water Balance in the Lung ;e only 0.3

urn of tissue separates the capillary blood from the air in th e lung _ e 1- 1), the problem of keeping th e alveoli free of fluid is critical. Fluid exec across the capillary endo thelium is believed to obey Starling's law. T he e rend ing to push fluid out of the capillary is the capi llary h ydrostatic pressure .;: the h ydrostatic pressure in the in terst itial fluid, or Pc - Pi. The force te nd, _ . fu ll fluid in is the colloid osmoti c pressure of th e proteins of the blood mi char of the protein s of the interstitial fluid, or 7Tc - 'ITt- This force depends on

the reflection coefficien t IT, which ind icates the effectiveness of th e capillary wall in preve n ting the passage of protei ns across it. Thus, net fluid out = K[(P, - P;) - a (", - " ;)]

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where K is a con stan t called the filtra tion coefficient. U nfortu na tely, the practical use of th is equation is limited because of our ig~ noranc e of many of the va lues. The colloid osmot ic pressure wit hin th e capillary is about 28 mm I-Ig. The capillary h ydrostat ic pteSSUle is probab ly about halfway between arterial an d veno us pressure but is much h igher at the bottom of t he lung th an at th e top. The colloid osmotic pressure of the in terstitial fluid is not known but is about 20 mm Hg in lung lymph . However, thi s value may be h igher than that in the int erstitial fluid around the capillaries. The in terstitial h ydrostatic pressure is unknown , but some measuremen ts sh ow it is substan tially below atmosphe ric pressure. It is probable that the net pressure of th e Sta rling equation is outward, ca using a small lymph flow of perhaps 20 ml/hr in human s under normal cond itions. W he re does fluid go when it leaves the cap illaries?Figure 4-11 sh ows th at fluid whic h leaks out into th e int erst itium of the alveolar wall trac ks thro ugh the in terstitial space to th e perivascular and peribronch ial space with in the lung. Numerous lympha tics run in th e perivascular spaces, and th ese help to transport th e fluid to the h ilar lymph nodes. In addition, the pressure in these perivascular

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Perivascular space Figure 4-11. Tw o pos sible pat hs for f lu id th at m ove s out of pul mon ary capi ll aries. Flui d t hat enters the int erst itium ini tia lly fin ds it s wa y in to th e perivascula r and pe ribron chia l spa ces . Later fl uid may cross th e alve ol ar wa ll , fil ling alveolar spaces.

spaces is low, thu s forming a natural sump for the dra inage of fluid (compare Figure 4 ~ Z ) . The earliest form of pulmona ry edema + is characterized by engorgement of these peribronchi al and perivascular spaces and is known as in terstitial edema. The rare of lymph flow from the lung increases considerably if th e capillary prcs~ sure is raised over a long period. In a later stage of pulmonary edema, fluid may cross th e alveolar epithel ium into the alveolar spaces (Figure 4-11 ). W hen this occurs, the alveoli fill with fluid one by one , and because they are then un ventilated, no oxygenation of the blood passing through th em is possible. What prompts fluid to start moving across into the alveolar spaces is not known, but it may be th at th is occurs when th e maximal draina ge rate th rough th e inte rstitial space is exceeded and the pressure the re rises too high. Fluid that reach es the alveolar spaces is actively pumped out by a sod ium, pot assium, AT Pase pump in epithelial cells. A lveolar edema is much more serious than in terstitial edema because of the int erference with pulmona ry gas exchange.

Other Functions of the Pulmonary Circulation The chief functio n of th e pulmonary circulation is to move blood to an d from th e blood-gas barr ier so that gas excha nge ca n occur. However, it ha s ot her importan t func tions. O ne is to act as a reservoir for blood. W e saw th at th e lung has a rcmarkable ability to reduce its pulmonary vascular resistan ce as its vascular pres~ sures are raised thr~h th e mech an isms of recruitmen t and disten sion (Figure 4~5) . The same mechanisms allow the lung to increase its blood volume with relativelv small rises in pulmon ary arterial or venous pressures. This occurs, for example, whe n a subject lies down after standing. Blood then drains from th e legs in to th e lung. Another function of th e lung is to filte r blood. Small blood thrombi are removed from the circulation before they can reach the brain or other vita l organs. Man y wh ite blood cells are trapped by the lung and later released, although th e value of this is not clear.

Metabolic Functions of the Lung T he lung has importan t metabolic funct ions in add ition to gas exch an ge. A nuruber of vasoact ive substanc es are metaboli zed by the lung (T able 4-1). Because th e lung is th e only organ except th e heart that rece ives the whole circulation. it is un iquely suited to modifying blood-borne substan ces. A substan tial fraction of all the vascular end ot helial cells in the body are located in th e lung. T he meta bolic functions of the vascular end othelium are only briefly dealt with here because man y fall within the province of pharmacology.

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For a more exte n sive discussion of pulmonary edema, sec the co mpa nion volume, JB West: Pulmonary Pathophysiology- The Essentials , cd 6. Baltimore. Lippincott Wil liams & Wilkins, 2003.

Table 4-1. Fate of Substances in the Pulmonary Circulation Sub stance

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Peptides Ang iote nsin I Angiotensin II Vasopressin Bradykinin Amines Seroto nin Norepinephrine Histamine Dopamine Arachidonic acid metabolites Prostaglandin E2 and F2a Prostag landin A, Prostacyclin IPGI,) Leukot rienes

Fate

Converted to angiot ensin II by ACE Unaffe cted Unaffe cte d Up to 80 % inactivated Almost co mpletely removed Up to 30% remove d Not affected Not affected Almost complete ly remo ved Not affected Not affe ct ed Almost completely removed

The on ly known example of biological activatio n by passage th rough th e pulmonary circulat ion is th e conve rsion of the relatively inactive polypeptide, an giotensin I, to th e poten t vasoconstr ictor, angiotensin II. The latt er, which is up to 50 time s more ac tive th an its precursor , is unaffected by passage th rough th e lung. The conversion of angiotensin I is catalyzed by th e enzyme, angiotensin . convert ing enzyme or AC E, which is located in small pits in the surface of th e cap illary endo thel ial cells. Man y vasoactive substances are completely or parti ally inactivated d uring pas· sage through the lung. Bradykinin is largely inact ivated (up to 80% ), an d the en zyme respon sible is angiote nsin-convert ing enzyme, ACE. The lung is the major site of inact ivation of serotonin (5· hydroxytrypramine) , but th is is not by enzvmati e degradat ion, but by an uptake and storage process (T able 4-1). Some of the seroto nin may he transferred to platelets in th e lung or stored in some other way and released du ring an aphylax is. The prostagland ins E lo Ez, and FZn are also inactivate d in th e lung, which is a rich source of th e respons ible enzymes. No repinephrine is also taken up by th e lung to some extent (up to 30%). Histami ne appears not to be affected by th e in tact lung but is readily inact ivated by slices. Some vasoactive mat erials pass th rough th e lung withou t sign ifican t gain or loss of act ivity. These include epine ph rine, prostaglandins A l and A ZI angiotensin II, and vasopressin (ADH). Several vasoactive and bronchoactive substances are metabolized in the lung and may be released in to th e circulation under certain condi tions. Importan t among these at e the arach idonic acid metabolites (Figure 4-12). Ar achi donic acid is formed through the act ion of the enzyme phospholipase A z on phospho lipid bound [0 cell membranes. T here are two major syn thetic pathways, the ini tial reacti ons being cata lyzed by the enzymes lipoxygen ase and cyclooxygenase, respectively. The first produces th e leukotrienes wh ich include th e medi ator mi g. inally described as slow-reacting substa nce of anaphylaxis (S RS-A ). T hese com-

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Prostaglandins, Thrc mboxana A 2

Figure 4-12. Two pathwa ys of arach id onic acid me ta bo lism . Th e teu kot ne nes are g enerated by t he Iipoxy gena se pat hw ay, w hil e t he p ro staglan din s and t hro m bo xane A 2 com e from th e cyclo oxyge nase path w ay .

rounds cause airway constr ict ion an d may h ave an important ro le in asth rna." O ther leukorrienes arc in volved in inflammatory respon ses. The prostaglandins are potent vasoconstrictors or vasodilators. PGE2 plays an importan t role in the fetus because it helps to relax the pa tent d uctu s arteriosus. Prostaglandins also affect platelet aggrega tion and are ac t ive in other syste ms such as the kallikrein -k in in clo tti ng casca de. T h ey also rnav h ave a role in th e bronchoc onstrict io n of asth ma . T he re is also evidence tha t the lung plays a ro le in th e clotting mechani sm of blooJ under normal and abno rmal conditions. For example, th ere are a large nu mbe r of mast cel ls con ta in ing hepar in in th e in tersti t ium. In addition , the lung is ab le to sec rete spec ial immunoglobulin s, particular ly IgA , in the bron chial rnucus wh ich con tribute to its defen ses again st infect io n . Synthet ic func tio n s of the lung include th e syn thesis of phos pholipids such as dipalmirovl phospharidvlcholin e, wh ich is a compone nt of pulmo nary surfactant (see C ha pter 7). Prot ein syn thesis is also clear ly important because co llagen and elas tin for m the struc t ural framework of th e lung. U nde r some co nditio ns, proteases are app aren tly liberared from leukocytes in th e lung, ca using breakdown of collagen an d elastin , an d th is may result in emphysema. A nothe r sign ificant area is carbo h ydrate rn etebolisrn , especially th e elabor at ion of mucopolvsaccharides of bronch ial mucus.

QUESTIONS For each question, choose th e one best answer. 1. The ratio of total syste mic vascular resistance to pulmo nary vascular resistance is about : A. 2 : 1 B. 3 : 1 C. 5 : 1 D. 10 : 1

E. 20 : 1 :i:

For more details, see JB West: Pulmonary Pathophysiology- T he Essentials, cd 6. Hait i more, Lippinco tt \V ill iams & Wilkins, 2003.

2.

All of the following statements about the ext ra-alveolar vess els of the lung are true EXCEPT: A. They are pul led open by radial traction of alveolar wall s. 8 . They tend to be narrowed by smooth mus cle and elast ic tissue in t heir w alls. C. They are exposed to alveolar pressu re. D. On the arterial side they constrict in response to alveolar hypoxia. E. Their caliber is increased by lung inflation. 3 . A patient w ith pulm ona ry vascular disease has me an pulmo nary arterial and venous pres sures of 55 and 5 mm Hg, resp ect ively, w hile the cardiac output is 3 liters per min ute . W hat is his pulmonary vascular resistance in rnm Hg . titer " . min .

4.

5.

A. B. C D. E.

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A

2.5

1.7

2.5 5

17 In a norm al subject all of the following contr ibut e to the fall in pulmonary vascular resistance on exercise EXCEPT: A. Increase in pulm onary arterial pressure. B. Increase in pulmonary venous pressure, C. Recruitm ent of pulrnonarv capillaries. D. Distension of pulmonary capillaries . E. Alveolar hypoxia. In a me asurem ent of cardiac out put usi ng the Fick Principle the O 2 concentrations of mixed ve nous and arterial blood are 16 and 20 mi · 100 m t". respect ively, and the O 2 consumption is 300 ml m in- ' . The cardiac output in liters ' m in - 1 is:

B. 5 C. 7.5 D. 10 E. 75 6 . In zone 2 of the lung all of the fol low ing statements are true EXCEPT: ~ A. Arterial pressure exceeds alveolar pressure . \. - B. Alveolar pressure exceeds venous pre ssure . C. Arterial pressu re exceeds venous pressu re. D. Blood flow is determ ined by arter ial pres sure mi nus alveo lar press ure. E. Blood flo w is determ ined by arterial pressure mi nus ve nous pressu re. 7 . Pulmonary vasc ular res istance is reduced by: A. Removal of one lung. B. Breath ing a 10% oxygen m ixtur e. C. Exhaling from func t ional residual capacity to residual volume . D. Acu tely increasing pulmona ry venous press ure. E. M echanically venti lating the lung wit h posit ive pressure.

8. All of the following stateme nts about hypoxic pulmonary vasoconstriction are true EXCEPT: A. It depends more on the P 0 2 of mixed venous blood than alveolar gas. B. It is important in the transition f rom placental to air respiration. C. Its mechanism involves K+ channels in vascular smooth muscle. D. It partly diverts blood f low from poorly ventilated regions of diseased lungs. E. It is reduced by inhaling low concentratio ns of nitric oxide. 9. If the pressure in the capillaries and interstitial space at the top of the lung are 3 and 0 rnrn Hg, respectively, and the colloid osmotic pressures of the blood and inters titial fluid are 25 and 5 mm Hg, respecti vely, wh at is th e net pressure in mm Hg moving fluid into the capillaries?

A

17

B.

20

C. 23 D. 27 E. 33 10. The metabolic funct ions of the lung include all of the foll owing EXCEPT: A. Convert ing angioten sin-1 to angiotensin-2. B. Inactivating bradykinin, C. Removing serotonin .: D. Removing leukotri enes. E. Generating erythropo ietin.

Ve ntilation-Perfusion Relationships How Matching of Gas and Blood Determines Gas Exchange

gen Transport from A ir to -"'SS ues

ventilat ion sion t ent ilat ion-Perfusio n Ratio _ ect of Altering the entilation-Perfusion Ratio a Lu ng Unit . nal Gas Exchange in the ng

Effect of Ventilation-Perfusion Inequality on Overall Ga s Exchange Distributions of VentilationPerfusion Ratios Ventil ation-Perfusion In equality as a Cause of CO 2 Retention Measurement of VentilationPerfusion Inequality

- 's chapter is devoted to the primary function of the lung, that is gas exchange. ~rst a

theoretical idea! lung is considered. Then we reviewthree mechanisms

, ypoxemia including hvpoventitetion, diffusion limitation and shunt. The difficult concept 01 ventilation-perfusion inequalityis then introduced, and to illusrrste this the regional differences of gas exchange in the upright human lung are described. Then we examine how ventilation-perfusioninequality impairs overet;gas exchange. It is emphasizedthat this is true not only 01 oxygen but 3 so carbon dioxide. Methods of measuring ventitstion-pettusion inequality are ___ _ _ _ . en briefly discussed.

So far we h ave cons idered the movement of air to and from the blood-gas interface, th e diffusion of gas across it, and th e movement of blood to and from th e barrier. It would be na tural to assume th at if all these processes were adequate , normal gas exchange with in th e lung would be assured. Unfortuna tely, th is is not so because the matching of ventilation and blood flow with in various regions of the lung iscritical for adequat e gas exchange. Ind eed. mismatch ing of ventilation and blood flow is responsible for most of the defecti ve gas exchange in pulmonary d iseases. In th is section we shall look closely at the importan t (but difficult ) subject of h ow the relation s between ventilation and blood flow det ermi ne gas exc hange. First, however, we shall exa mine two relati vely simple causes of impairmen t of gas exch ange- hypoventilati on and sh unt. Because all of the se sit uations result in hypoxemia , th at is, in an abnormally low PO z in arterial blood. it is useful to take a prelimin ary look at normal O 2 transfer.

Oxygen Transport From Air to Tissues Figure 5 ~ 1 shows how th e Po , falls as the gas moves from the atmosphe re in whic h we live to the mitochondria where it is ut ilized. The POz of air is 20.93% of th e total dry gas pressure (th at is, excluding water vapor). At sea level, th e barometric pressure is 760 mm Hg, and at the body temperatu re of 37°C, the water vapor pres~ sure of moist inspired gas (wh ich is fully saturated with water vapor) is 47 mm Hg. Thus, the Po, of inspired air is (20 .93/ 100) X (760 - 47 ) or 149 mm H g (say 150). Figure 5-1 is drawn for a h ypotheti cal perfect lung, and it shows th at by th e time the 0 , h as reached th e alveoli, the Po, ha s fallen ro abo ut 100 mm Hg, that is, by one- th ird. This is because th e POz of alveolar gas is determin ed by a balance

150

Air Lung and blood

r»

I

E E

100

,

;or Perfect

,f

•. --")f-------... ----. . ----50

Hypoventilati on

Tissues

a Atmosphere - - - - - - --

--+_ Mitoch ondria

Figure 5-1. Schem e of t he O2 partial pressure s from air to t issues. The soli d li ne shows a hyp oth eti cal perfect sit uation, and t he bro ken li ne depicts hypoventi lati on. Hypoventilation depresses the P02 in the alv eolar gas and, therefo re, in th e tissu es.

"""'''''''.'f1 rwo processes: the removal of 0, by pulmonary capillary blood on the replenishment by alveolar ventilation on the othe r. ......v, alveolar ventil .ulon is not contin uous hut is breath -by-breath . Howc fluctuation in alveo lar Po z with each breath is only about 3 mm Hg, bee tidal volume is small compared with th e volume of gas in the lung, so ress can be regarded as conti nuous.} T he rate of removal of O 2 from the ( _ ~ verned by the O 2 consumption of the tissues and varies lit tle under rest_ =Jlditi? ns. In practice, the refore, th e alveolar POz is largely determined by ) ~ el ot alveolar ven tilation. T he same applies to the alveolar Peo 2' wh ich is ly about 40 mm Hg, "ben the systemic arterial blood reach es the tissue capillaries, O 2 diffuses to tochondria whe re th e Po , is much lower. The "tissue" Po z probably differs ierably throughout the body, and in some cells at least, th e Po z is as low as - H~. However, the lung is an essential link in th e chain of O, transport, an d rease of Po z in arterial blood must result in a lower tissue Po z' othe r things rs: equal. For the same reasons, impaired pulmonary gas excha nge causes a rise ;."an:l. and its continual

-;ue

Peo,.

r Cau ses of Hypoxemia • - vpoventit atton

--.. ;fusi on limitation

S

unt

entitation-perf usion inequality

Hypoventilation e have seen th at th e level of alveolar POz is de termined by a balance between rate of removal of 0 , by the blood (which is set by the metabo lic demands of tissues] and the rate of replenishment of Oz by alveolar ven tilation . T hus, if alveolar ventilation is abnormally low, the alveolar PO z falls. For similar rea'. th e PC-D, rises. This is known as hypoventilation (Figure 5-1). Ca uses of h ypoven tila tion includ e such drugs as morphine and barbiturates . h depress th e cent ral dr ive to the respiratory muscles, damage to the chest lor paralysis of the respiratory muscles, and a high resistance to breathing (for mple, very den se gas at great depth underwater) . Hypoven n lanon always .:aI.." O an increased alveolar and, the refore, arterial Pear The relationship be-eeen alveolar ventilation and PCOl was derived on p. 18:

Pc o ,

Veo,

= - V·-xK A

.ere Vco~ is th e CO 2 production , VA is the alveolar ventilation , and K is a conscant. This·mean s th at if the alveo lar ventila tion is halved, the PCOl is doub led, " ...lOCe a steady state has been established.

The relat ionship between th e fall in POz and the rise in Pco, that occurs in hypoventilation can be calcul ated from th e alveolar gas equation if we know th e compos ition of inspired gas and th e respirator y exchange ratio R. The lat ter is given by th e CO, ptoduc tion/O , consumpti on and is de termined by the metabolism of th e tissues in a steady state. It: is sometimes known as the respiratory quot ient . A simplified form of the alveo lar gas equa tion is

PAo,

P ALU z

=

Plo z - - -R-

+F

whe re F is a small correc tion factor (typically abou t 2 mm Hg), which we can ig-

C note. This equation shows that if R has its normal value oi~Jhe fall in alveo-

lar P02 is sligh tly greater than is the rise in Peo2 J uring hypoventilation. T he full version of th e equat ion is given in Appendix A. Hypovemilation always reduce s the alveolar and art erial P0 2 except when th e subject breathes an enriche d O 2 mixtu re. In th is case, the added amount of O 2 per breath can easily make up for th e reduced flow of inspired gas (t ry question 3 on p. 72).

.: ,II

Hypoventilation • Always increases the Peo;? • Decreases the POz unless additional Oa is inspired • Hypoxemia is easy to reverse by adding O 2

~S

1

Sho uld alveo lar ventilation be suddenly increased (for exampl e, by voluntary hyperven til ation), it may take several minu tes for th e alve ola r Po z and Peo 2to assume their new steady state va lues. T h is is because of the different O 2 and CO 2 stores in th e bod y. The CO2 stores are much grea ter tha n the O2 stores because of th e large amoun t of CO, in the form of bicarbona te in the blood and interstitial fluid (see C ha pter 6). T her efore, the alveola r Pe a , takes longer to co me to equilibrium, and during the nonsteadv state. the R value of expired gas is high as th e CO2 sto res are washed out. Opposite changes occ ur with th e onset of h vpoventilat ion .

Diffusion Figure 5-1 shows th at in a perfect lung, th e PO z of arterial blood would be th e same as that in alveolar gas. In real life, th is is not so. O ne reason is that although the Po, of th e blood rises closet and closet to th at of alveolar gas as the blood traverses the pulmonary capillary (Figure 3-3) , it can never quite reach it. U nde r normal cond itio ns, the POz difference betwe en alveolar gas and end-capillary blood resulting from incomplete d iffusion is immeasurably small but is shown schematically in Figure 5 ~2 . As we have seen, th e difference can become larger during exercise, or when the blood-gas barrier is th ickened. or if a low O 2 mixture is inhaled (Figure 3-3B).

150

Air

1~?C9 G "j cal

rn

I

E E

100

Art

N

0

o,

50

Diffusion Shunt

Tissues

a ) Mitochondria

Atmosphe re

Figure 5-2. Schem e of O 2 transfer from air to tissues show ing the dep ression of art erial P02 caused by diffusion and shunt',

Shunt Another reason why the POl of arterial blood is less th an that in alveo lar gas is shunted blood. Shunt refers ro blood rhar en ters rhe arrerial system wirhour going rhrough ventilated areas of lung. In the normal lung, some of the bronch ial art ery blood is collected by the pulmonary veins after it has perfused th e bronchi and its 0 ;2 has bee n partly deple ted. A nother source is a small amount of coronary venous blood which drains directly into rhe cavity of the left vent ricle thro ugh the Thebesian veins. The effect of the addition of th is pootly oxygenated blood is to depress the arterial POr So me patie nts have an abnormal vascular connection be; [ween a small pulmona ry artery and vein (pulmonary arteriovenous fistula). In patients with heart disease, there may be a direct additio n of veno us blood to ar-

terial blood across a defect between the right and left sides of the heart. W hen the shunt is caused by the addirion of mixed venous blood to blood drain ing from the capillaries, it is possible to calculate the amount of the shunt

rlow (Figure 5-3) . The total amount of 0 , leaving the system is th e total blood rlow QT mult ipl ied by the 0 , concentration in the art erial blood C ao " or QT X Cae,. This must equal the sum of the amounts of 0, in th e sh unt ed blood, Qs X C vo" and end-c apillary blood, (QT - Qs) X C c' 0,. Thus,

QT X C ae,

=

Qs X eva ,

+ (QT - Qs) X Cc'o ,

Rearranging gives

CC 0 2 - Cao 2 Cc o 2

Cvo 2

The 0 , conc en tra tion of end-capillary blood is usually calculated from the alveo lar P0 2 and the oxygen dissoc iation curve (see next chapter).

AS

CC'0 2 - Ca02

aT

CC'02- CV02

Figure 5-3. Me asureme nt of shunt flow. The oxygen carri ed in th e arterial blood equa ls the sum ofth e oxyg en carr ied in t he capillary blood and that in th e shunt ed

blood (see text).

"

'",.

W he n the sh unt is caused by blood tha t does not have the same O 2 concentration as mixed veno us blood (for example, bronchi al vein blood), it is gene rally not possible to calc ulate its true magnitude. However, it is often useful to calculate an "as if" sh unt, that is, what th e sh unt would be if the observed depression of ~ / arterial O z concen tration were caused by the add itio n of mixed venous blood . 'I:-- A n important feature of a sh unt is that th e hypoxemia cannot be abolished by giving th e subject 100% 0, to breathe. This is because the sh unted blood that bypasses ven tilated alveoli is never exposed to the higher alveola r POz so tha t it continues to depress th e art erial P O l' Howeve r, some elevation of the art erial P0 2 occurs because of the 0, added to th e capillary blood of vent ilated lung. Most of the added 0 , is in the dissolved form, rathe r tha n attached to hemoglobin, because the blood th at is perfusing ventilated alveoli is nearly fully saturated (see next cha pte r) . G iving the subject 100% O 2 to breathe is a ~sensitive mea'suremen r of shunt because whe n the P0 2 is h igh, a small depression ofa rteri al O a conce n tration causes a relativel y large fall in P 0 2 due to th e almost flat slope of th e 0 , d issociation curve in th is region (Figure 5-4). A sh unt usually does not result in a raised Pcoz in arte rial blood , even tho ugh the shunted blood is rich in COz. The reason is tha t th e chemorecep tors sense any elevation of arterial PCOz and they respond by increasing the ventilatio n. This reduces the Pco , of the unsh un ted blood until the arterial Pcoz is no~l. Indeed , in some patien ts with a shunt, th e arte rial Peo z is low because the hypoxemia increases respiratory driv e (see C hap ter 8).

11

Shunt r.:~ ~

• Hypoxemia responds poorly to added inspire d O2 2 is inspired, the arterial P0 2 does not rise to the expected level- a useful diagnostic test • If the shunt is caused by mixed venous blood. its size can be calculated from the shunt equation

• Wh en 100% O

O2 dissociation curve

~~~-~~~~~~~~~~~~~~~~~~~~~~~~ - ---~•} •• •,,, , E

15

s

~ ,,""'' , , , , , ,,', • ,,

•• ••, ,

c .Q 10

,,

"§

"go s

•,

,, ,, •,

,, ,, ,,

o

" 5

-o

200

~--

400

--600

Figure 5-4. Depression of arte ria l P02 by shunt during 100% O2 breathing . Th e additio n of a sma ll am ou nt of shunted bloo d w ith its lo w O2 co ncentrat io n greatly reduces the P02 of arteri al b lo od . This is becau se the O2 di ssociation curve is nearjv fl at when the P 0 2 is very hig h.

The Ventilation-Perfusion Ratio So far we have considered three of th e four causes of hypoxemia: hypoventilat ion, diffusion, and shunt. W e now come to th e last cause, which is both the cornmonest and th e most difficult to understand, namely, ven tilation-perfusion inequality. It turns out th at if ven tilat ion and blood flow are mismat ch ed in various regions of the lung, impairment of both 0 , and CO, transfer results. The key to understanding how th is happens is th e ventilation -perfusion ratio. Consider a model of a lung unit (Figure 2-1) in which the uptake of 0 , is being mimicked using dye and water (Figure 5-5) . Powdered dye is continuously poured into the un it to represen t th e addi tion of O 2 by alveolar ventilation. Water is pumped continuously th rough th e unit to represent th e blood. flow which removes the O 2, A stirrer mixes th e alveolar con ten ts, a process normally accomplished by gaseous diffusion . The key question is: wha t determin es the concen tration of dye (or O 2 ) in th e alveolar compartment and, th erefore, in th e eft1uen t water (or blood )? It is cle ar that borh the rat e at whi ch the dye is added (ve n tilat ion) and tn~'~ ta te at whic h wate r is pumped (bl ood flow) will affect the co nc en tra tion of dye in the mode l. What may no t be int uitively cle ar is th at the conc en tra tion of dye ./

Powdered dye V

"~y':0o;0

~

"0 :-.:

... .. . ... ... .. ... . o

Concentrati on

via

Water

a- -_) -----'

:\\ 0

0

00"¥"O".. •

0

•

"

•

0

• 0° • •

_ ' ----'0' - ' -

0

•

•

~::

0

•• ° '----,--

•• • •

~

Figure 5-5. M ode l to il lustrat e how t he ve nt ilatio n-perfus io n rat io determ in es t he P02 in a lung un it. Pow dered dye is added by v enti lat io n at th e rate V and rem ov ed by blo od f low Q t o repres ent t he f actors co ntrolling alveo lar P02' Th e concentrat io n of dye is giv en by V/ Q.

is determined by th e ra ti o of th ese ra te s. In other wor ds, if d ye is added at the rate of V gm . min - 1 and wate r is pumped th rou gh at Q liters ' min - 1, the concen tr ation of dye in th e alveolar compa rt ment and effluen t wate r is VIQ gm . liter- J • "lIn exactl y the same way, th e concen trati on of O 2 (or bet ter, Po z) in any lung unit is det ermined by the rat io of ventilat ion to blood flow, and not only O 2 but CO 2 , N 21 an d any other gas th at is presen t under steady state cond itions. T his is th e reason why th e ventilation-perfusion ratio plays such a key role in pulmonary gas exchange.

Effect of Altering the Ventilation -Perfusion Ratio of a Lung Unit Let us take a closer look at th e way altera tions in the ven tilation-perfusion ratio of a lung unit affect its gas excha nge. Figure 5-6A shows th e POz and Peo z in a uni t with a normal ven tilation-perfusion ratio (abo ut I- see Figure 2-1). The inspired air has a Po, of 150 mm Hg (Figure 5-1) and a P= , of zero. The mixed venous blood entering th e uni t has a Po, of 40 mm Hg and P= , of 45 mm Hg. The alveolar Po, of 100 mm Hg is derermined by a balance between th e addition of 0, by ventilation and its removal by blood flow. The normal alveolar P= , of • 40 mm Hg is set similarly. N ow suppose that the ven tilation-perfusion ratio of [he unit is gradually reduced by obstrucring its vent ilation, leaving its blood flow unch an ged (Figure 5-6B). lr is clear that rhe 0, in th e unit will fall and rhe CO, will rise, although

O2 = 150 mm Hg

A

~~~~--,

::;

CO,= 45

J ,Y"'f' '''"'

a,v1

1

0 2 = 150

CO,= 40 0 2= 4~0!J-.~~=-l---..

"'" ? ,-

".

c

1

O2 = 100

O 2 = 40

CO 2 = 45

"

C

\ V\ :.(

.J

CO 2 = 0

B

2(

C02= 0

"'"

Decreasing

Increasing

VA/a

VA/a

Fig ure 5-6. Effec t of alte ring th e ve nti lation-p erfusion rati o o n th e a lu ng un it .

P02

and Pee, in

th e relat ive cha nges of these two are not immediately obvious." However, we can easily predic t what will even tu ally h appe n when the ventilation is completely abolished (v en tilation-perfusion rati o of zero ). Now th e O 2 an d CO2 of alveo lar gas an d end- cap illary blood must he the same as those of mixed venous hlood. (In practice, comp let ely ob stru cted un its eve n tually co llapse, but we can n eglect such long-term effec ts at the mo ment.) Note that we are assuming that wh at h appen s in one lung un it ou t of a very large n umber does not affect the co mpos ition of the mixed venous blood , Suppose instead that the vent ilat ion-perfusion rat io is increased by grad ually obstruct in g blood flow (Figure 5-6C) . No w th e 0, rises and the CO, falls, even wa lly reaching the co mpo sit ion of inspired gas when blood flow is abolished [ven t ilat ion -perfusion rat io of infinity). T h us, as the ventilation- perfusion rat io of the unit is alte red, its gas co mpos it ion approac hes that of mixed venous blood or inspired gas. A co nve nie nt way of dep icting th ese changes is to use the 0 2-C02 d iagram (Pigure 5-7) . In this, POz is plott ed on th e X axis, and Peo z is plotted on th e Y axis. First, locate the normal alveo lar gas composition, point A (Po, = 100, Pco , = 40) . If we assume that blood equilibrates with alveo lar gas at the end of the capillary (Figure 3-3), th is point can equa lly well represent the end-capillary blood. Next find the

* The alveolar gas equation is not applicable here because the respiratory exchange ratio is not constant . The appropriate equation is

IIA ~ 8.63 . R . Q

(Cao, - Cvo,)

~ o

50 rn

I

v~ o - - t - -_ _-:~ Dec reasing

E E

'itAI Q

Normal

A

i s o

50

100

L~ I

150

.

"

Figure 5-7. OTCOZ diagram showing a venti lation-perfusion ratio line. The POz and Pee, of a lung unit move along thi s line f rom th e mi xed veno us point to the insp ired gas point I as its ventilation -perfu sion ratio is increased (compa re Figure 5-6).

'""

mixed veno us point v (Po, = 40, Peo, = 45). The bar above v means "mixed" or "mean." Fina lly, find the inspired point I (POI = 150 , Pc o , = 0 ). Also, note the sim ilarities betwe en Figures 5-6 and 5 -7.

v

I'

..'

~

T he line joining to I passing through A shows the cha nges in alveolar gas (and end-capillary blood) composition that can occur when the ventil ation. perfusion ratio is eithe r dec reased below normal (A ~ 'V) or increased above normal (A -e 1). Indeed, thi s line indicates all the possible alveolar gas compositions ·n a lung that is supplied with gas of composition I and blood of composition v. For example , such a lung co uld not contain an alveolus with a POz of 70. and Pcoz of 30 mm Hg, because th is poi nt does no t lie on the ventilatio n-perfusio n line. However, this alveo lar co mposition could ex ist if the mixed veno us blood or inspired gas were changed so that the line then passed through this point.

D

Regional Gas Exchange in the Lung The way in which the ventila tion-perfusion ratio of a lung unit determines its gas

exchange can be graphically illustrated by looking at the differences tha t occur down the upright lung. We saw in Figures 2~ 7 and 4-7 that ventilation increases

slowly from top to bottom of th e lung and blood flow increases more rapidly (Figure 5-8 ). A s a consequence , the ventilation-perfusion ratio is abnormally high at

th e top of the lung (where the blood flow is minimal) and much lower at th e bottom. We can now use these regional differences in ventilat ion-perfusion ratio on an

O,·CO, diagram (Figure 5-7) to depict th e resultin g differences in gas exchange. Figure 5-9 shows the upright lung divided into imaginary horizontal "slices," each o f wh ich is located o n the ventilation -perfusion line by its own ve ntilationperfusion ratio. This ratio is high at the apex so that thi s point is found toward

the right end of the line, while the base of th e lung is to the left of normal (com-

.15

3

50

0 0 Pressure (em water)

Figure 7-5. Compa rison of press ure-vo lu me curves of air-filled and safine-fllled lungs (cat) . Op en ci rcles, inf lation; closed circles, def lation . Note that the salinefilled lung has a higher compliance and also much less hy steresis than the air filled lung.

It is now known th at some of th e cells lin ing the alveoli secrete a materi al that profound ly lowers th e surface tension of th e alveolar lining fluid. Surfactant is a phospholipid, and dipa lmitoyl phosphat idylcholin e (OPPC ) is an important constituent. A lveolar epit he lial cells are of two types. T ype I cells have th e shape of a fried egg with long cytoplasmic extensions spreading out thinly over th e alveolar walls (Figure 1-1). T ype II cells are more compact (Figure 7-6), and electron microscopy sho ws lamel lated bodies within them that are extruded into th e alveoli an d transform into surfactant. Some of m e surfacta nt can be washed out of an imallungs by rinsing them with saline. The phospholipid OPPC is synthesized in th e lung from fatt y acids th at at e either extract ed from the blood or are themselves synt hesized in th e lung. Synt hesis is fast, and th ere is a rapid turnover of surfact ant. If the blood flow to a region of lung is abolished as th e result of an em bolus, for example , th e surfactant there may be depleted. Surfactant is formed relati vely late in fet al life, and babies born without adequate amounts develop respiratory d istress and may die. The effects of this material on surface ten sion can be studied with a surface balance (Figure 7·7) . This consists of a tray containing saline on which a small amount of test material is placed . The area of the surface is th en alternately expanded and compressed by a movable barrier while rhe surface ten sion is measured from th e force exerted on a platinum strip. Pure saline gives a surface ten sion of about 70 dynes/em, regardless of th e area of its surface. Adding detergent reduces th e surface ten sion, but again this is independ ent of area. Wh en lung washings are placed on th e saline, the curve shown in Figure 7-7B is obtained. No te th at the surface ten sion changes greatl y with th e surface area and m at ther e

Figure 7-6. Electron micrograph of ty pe \I epit helial cell (x 10,OOO). Note th e lam ellated bodies (LB), large nu cl eus, and mi crovilli (arrows). The in set at top right is a scanni ng electro n m icro grap h showing the surf ace view of a typ e II cell wi th its characteristic dist rib utio n of mi crovi lli (x3400).

is hysteresis (compa re Figure 7~3 ) . Note also th at the surface ten sion falls to ex, tremclv low values whe n th e area is small. How does surfactant reduce the surface te nsion so much ? A pparen tly the molecules of DPPC are h ydrophobic at one end and h ydroph ilic at the ot her, and th ey align themselves in the surface. W he n thi s occurs, the ir in ter molecular re, pulsive forces oppose the normal attracting forces between th e liquid surface molecules that are responsible for surface tension . The reduct ion in surface ten , sion is grea ter whe n the film is compressed because the molecules of DPPC are the n crowded closer together and repel each ot her more. What arc the physiolog ical advan tages of surfacta n t? First, a low surface ten, sion in th e alveoli increases the compliance of the lung and reduces the work of expa nding it with each breath. Next, stability of the alveoli is pro mote d. TIle 300 million alveoli appear to be inh erentl y unsta ble beca use areas of atelectasis (co llapse) often form in the presen ce of d isease. This is a comp lex subject, but one wav of looking at the lun g is to regard it as a collection of millions of tiny bubbles (alt ho ugh th is is clear ly an oversimplification) . In such an arrangement , the re is

Force transducer

100

-

''""

.IT

i"

'"

.z '"

'I

50

Water 11

II

I'i

t~

1;j

m

?if

I

i

11 Detergent

a:

a

25

50

75

Surface tension (dynes/ em)

A

B

Figure 7-7. A. Surface ba lan ce. The ar ea of th e surf ace is alter ed, and the surface te nsion is measu red from th e f or ce exe rte d on a plat inum strip dip ped into th e surf ace. B. Plots of surface t ensio n and area obtained with a surfa ce balance. Note that lu ng wash ing s show a change in surface tens ion w ith area and t hat th e minim al ten sion is ve ry smal l. The axe s are chosen t o allow a com paris on w ith the pressure-volu me cur ve of th e lung (Fig ures 7 ~ 3 and 7-5).

a ten dency for small bubb les to collapse and blow up large ones. Figure 7-4C shows th at the pressure generated by the surface forces in a bubble is in versely proportional to its radius, with the result that if the surface tensions arc the same, the pressure inside a small bubble exceeds th at in a large bubble. However, Figure 7 ~ 7 sho ws that whe n lun g washings are present, a small surface area is associated with a small surface tension. Thus, the ten dency for small alveoli to empty into large alveoli is apparentl y reduced . ">, ; A thi rd role of surfac tant is to help to keep th e alveoli dry. Just as th e surface ten sion forces tend to co llapse alveo li, th ey also ten d tiJsu~k fluid into the alveo lar spaces from the cap illaries. In effect , th e surface tension of th e curved alveo lar surface reduces th e h ydrostatic pressure in thc t issue outside th e capillari es. By reduc ing th ese surface forces, surfactan t prevents the tr an sudation of fluid . W ha t are the consequen ces of loss of surfactant? On the basis of its func tions discussed above , we would expect these to be stiff lungs (low compliance), areas of ate lectasis, and alveoli filled with transudat e. Indeed, these are the pat hophysiological feat ures of th e "infant respiratory distress syndrome,' and thi s disease is caused by an absence of th is cruci al material. It is now possible to treat the se tnfants by instilling syn thes ized surfactant int o th e lung. Pulmo nary Surfactant • • • •

Reduces the surface tension of the alveolar lining layer Produced by type II alveolar epithelial cells Contains dipalmitoyl phosphatidylcholine Absence results in reduced lung compliance, alveolar atelectasis, and tendency to pulmonary edema

There is another mechan ism tha t apparen tly con tributes to the stab ility of the alveoli in th e lung. Figures 1-2, 1-7, an d 4-3 remind us that all the alveoli (excep t those immed iately adjacent to th e pleural surface) are surrounded by other alveoli and are the refore supported by each other. In a structure such as this with many connecting links, any tend ency for one group of un its to reduce or increase its volume relat ive [0 the rest of th e structure is opposed. For example, if a group of alveoli has a tendency to collapse, large expanding forces will be developed on them beca use the surroundi ng parenchyma is expanded. This support offered to lung uni ts by those surroundi ng them is ter med "inte rdependence." The same factors explain the developmen t of low pressures around large blood vessels and airways as the lung expands (Figure 4-2) .

Cause of Regional Differences in Ventilat io n \Y,fe saw in Figure 2-7 th at the lower regions of the lung ventilate more tha n do the upper zones, and this is a convenient place to discuss th e cause of these topographical differences. It has been sho wn that the in trapleural pressure is less negative at the bottom rhan th e top of the lung (Figure 7-8). The reason for thi s is the weight of th e lung. A n yth ing th at is supported requ ires a larger pressure below it th an above it to balance the down ward-acti ng weigh t forces, and the lung, which is partly supported by the rib cage and d iaph ragm, is no exception. T h us, th e pressure near th e base is higher (less negative) th an at the apex.

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Intrapleural pressure (ern H20) Figure 7-8. Exp lanatio n of the regio nal di fferences of ve nt ilat io n down t he lu ng . Becau se of t he w eight of t he lung, t he intr apl eu ral pressu re is less nega t ive at t he base t han at the apex. A s a co nseq uence , t he basal lun g is relativ ely co mpressed in its rest in g st ate b ut exp and s m or e o n in sp ir ation t ha n t he ap ex.

Figure 7~8 sho ws th e way in which th e volume of a portion of lung (for example, a lobe ) expands as th e pressure around it is dec reased (compare Figure 7-1) . The pressure inside th e lung is th e same as atmospheric pressure. Not e th at the lun g is easier to inflate at low volumes than at h igh volumes, where it beco mes stiffer. Because the expanding pressure at th e base of th e lung is small, this region has a small resting volume. However, because it is situated on a stee p part of the pressurevolume curve, it expands well on inspirat ion . By con trast, the apex of th e lung has a large expanding pressure, a big resting volume, and small cha nge in volu me in inspirat ion . * No w when we talk of regional differenc es in ven tilation , we mea n the change in volume per unit resti ng volume. It is cle ar from Figure 7-8 tha t the base of the lung h as bot h a larger ch ange in volume and smaller rest ing volume th an the apex. Thus, its ven t ilat ion is grea ter. N ot e the paradox that , alth ough the base of the lung is relati vel y poorly expa nde d compared with the ape x, it is better ve nt ilated . The same explan ati on ca n be given for thc large ventila tion of depend ent lung in both the supine an d latera l positions. A remarkable change in the distribution of ventilation occurs at low lung volumes. Figure 7-9 is similar to Figure 7· 8 except tha t it represents the situa t ion at

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