Bom pulmão - Swiss Med J 2009

8/2/2019 Bom pulmo - Swiss Med J 2009

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Review article: Medical Intelligence S W I S S M E D W K L Y 2 0 0 9 ; 1 3 9 ( 2 7 2 8 ) : 3 7 5 3 8 6 w w w . s m w . c h

Peer reviewed article

375

What makes a good lung?

The morphometric basis of lung function

Ewald R. Weibel

Institute of Anatomy, University of Bern, Bern, Switzerland

The functional capacity of the human lung asgas exchanger is to a large extent determined bystructural design. Quantitative structure-functioncorrelations can be established by morphometry.A very large surface of air-blood contact, togetherwith a very thin tissue barrier, are required to per-mit adequate oxygen uptake under work condi-tions. However, these design features also poseproblems, such as how to ventilate and perfusethis large surface evenly and efciently, or how to

ensure mechanical stability against surface forceswith a minimum of supporting tissue. The discus-sion focuses on the extent to which novel designprinciples are used to overcome such problems bydesigning the airways as a fractal tree and thebre support system as a tensegrity structure.

Key words: pulmonary diffusion capacity;bronchial tree; pulmonary acinus; gas exchange; lungmechanics; morphometry; fractal geometry; tensegrity

Summary

The design of the human lung is impressive.The largest organ in our body is built with onlyabout half a litre of tissue that separates roughlythe same amount of blood from a large but vary-ing air volume of several litres. And this tissuesupports a very large gas exchange surface be-tween air and blood nearly the size of a tenniscourt that must be ventilated and perfused withblood. This suggests that lung design is the resultof bioengineering optimisation, making it a goodlung serving its function, gas exchange, well andefciently.

But is this design really essential in all its

aspects? Do we need such a large surface, for ex-ample? We know of course that a loss of gasexchange tissue, as occurs in pulmonary emphy-sema, leads to severe impairment of the gas ex-change function. Indeed, the functional impair-ment is often much more severe than one wouldexpect from the mere loss of alveoli and capillar-ies, because the distortion of peripheral airwayscauses maldistribution of air and blood supply tothe gas exchange units. Similarly, the structuralchanges in brosis result in impaired gas ex-change due to thickening of the barrier, but

equally by deformation of the airway system andthe blood vessels. It thus appears that any alter-ation to the delicate and well-organised structureof the pulmonary gas exchanger and its support-ing structures leads to a loss of gas exchange func-tion. The question is whether, and on what basis,

we can understand and estimate the pathophysio-logical importance of such structural alterations.

I was confronted with this type of question inFebruary 1959 by two eminent cardiopulmonaryscientists, Andr F. Cournand and Dickinson W.Richards, at Bellevue Hospital in New York aftergiving a seminar on the structural basis of collat-eral circulation to the lung, a study done inZurich [1]. Cournand and Richards had beenawarded the Nobel Prize in Physiology or Medi-cine in 1956 for their seminal work on the pul-monary circulation which had been rendered pos-sible after their introduction of cardiac catheteri-

sation [2]. By this approach they were able, amongother things, to measure mixed venous oxygentension. Together with estimates of arterial andinspired PO2 and of O2 uptake, they now hadmeasurements of the four most important func-tional input parameters for the pulmonary gas ex-changer, but otherwise the lung was a black box:what happened inside the lung could at best beimagined and modelled. But, to accomplish this,essential data on the organisation and perform-ance of the gas exchanger were lacking [3, 4]. Inparticular, it was apparent that structure should

have a denable effect on function, as evidencedfrom the disturbances of gas exchange in certaindisease states, but little was known of this subject. After my seminar, therefore, Cournand invitedme to join his Cardio-Pulmonary Laboratory andoffered me a job. When I asked him what he ex-

Introduction: a personal history

No conflict of

interest to declare.


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pected of me he bluntly said: Do anything on thestructure of the lung that is of interest to physiol-ogy. For a young Swiss morphologist that was achallenge, and I accepted.

But: what is of interest to physiology? Whatcan a morphologist contribute to the understand-ing of the functional processes that occur deep inthe lung, inaccessible to direct observation? The

answer to these questions came soon after my ar-rival at Bellevue Hospital from Domingo M.Gomez, a Cuban cardiologist and biomathemati-cian [5] who had ed Fidel Castros revolutionand been given refuge by Andr Cournand. Withhis sharp mind for theoretical consideration ofphysiological principles, and motivated by Cour-nands questions about what is happening in theblack box, he had been engaged in developingmodels of pulmonary function and in particulargas exchange. So he asked me questions such ashow many alveoli are there in the human lung?

As there was no information to be found on thiswe developed a method for counting particlesand arrived at an estimate of about 300 millionalveoli in an adult human lung [6]; using a moreappropriate method this number was recentlycorrected to 480 million [7].

But that was not what Gomez really wantedto know. He wanted to use this number to calcu-late parameters such as the alveolar surface areaby means of simple geometric models in order toestimate the role of the internal lung surface indelivering oxygen to the capillary blood. What he wished to arrive at was a theoretical value ofthe conductance of the lung for diffusive gasexchange, equivalent to the pulmonary diffusingcapacity DLO2. This functionally most importantparameter had been analysed just two years beforeby Roughton and Forster [8], who proposed a

model for DLO2 with two sequential steps: thebarriers diffusion conductance and the bloodsconductance and O2 binding properties. Thismodel suggested that structural parametersshould be important determinants of pulmonarygas exchange capacity. It thus was clear that whatreally interested physiologists were accuratequantitative data on lung structure that could be

used in formulating models of lung function.The programme I had to engage in was what

we would later call morphometry of the humanlung, a really vast and also challenging pro-gramme because the methods of obtaining suchinformation were not readily available at the time.The problem was that, to study alveoli and capil-laries, or the tissue barrier and its cells, thin sec-tions and the microscope had to be used. This in-troduced two serious problems: (1) what one islooking at in the microscope is a minuscule frac-tion of a very large organ, and so we have a sam-

pling problem; (2) perhaps more seriously, thethree-dimensional alveolar surface appears on thesection as a linear trace, and thus the problem washow to estimate the 3D surface area from 2Dmeasurements on sections. This was again a sam-pling problem, but one related to the geometricprobability of hitting a surface with a sectionplane as a geometric probe [9]. Sound solutions tosuch problems depended primarily on collabora-tion with mathematicians [1012] and this led tothe development of a powerful set of measuringmethods called stereology [1317]. Stereology isstill the state-of-the-art methodology to obtainefciently accurate quantitative information oncell, tissue and organ structure [18, 19]. And in1960 it provided me with the tools to undertakethe study of lung structure in a way that was ofinterest to physiology [20].

376What makes a good lung?

The morphometric basis of pulmonary gas exchange

The model that Domingo Gomez wanted to

formulate was based on the equation introducedin 1909 by Christian Bohr [21] describing the O2uptake V

.

O2 as the product of the O2 partial pres-sure difference between alveolar air and capillaryblood as driving force, and the conductance of thesystem called the pulmonary diffusing capacityDLO2:

V.

O2 = (PAO2 PbO2)DLO2. As suggested above, DLO2 is largely deter-

mined by morphometric parameters of the alveo-lar-capillary complex. Figs. 14 show that the cap-illaries form a very dense network in the alveolar

septa; the capillaries are about the size of an ery-throcyte and they are exposed to alveolar air onboth sides. We also note that the barrier separat-ing the erythrocytes from the air is composed of atissue membrane made of thin lamellae of ep-ithelial and endothelial cells joined by a very thin

interstitial space or simply a basement membrane

(g. 4) and a layer of blood plasma; these are thelayers that must be traversed by diffusion drivenby the O2 partial pressure difference between airand blood. The oxygen molecules then enter theerythrocyte to be eventually bound to haemoglo-bin, a process determined by the combination ofdiffusion and chemical reaction between oxygenand haemoglobin. Roughton and Forster [8]proposed a model for DLO2 that divides the totalconductance into two serially arranged partialconductances, one for the membrane, DMO2, andone for the erythrocytes, DeO2. The conductance

DLO2 is obtained by adding the two partial resist-ances, i.e. the reciprocals of the conductances:DLO2-1 = DMO2-1 + DeO2-1.

The two partial conductances can be formu-lated as a function of the determinant morphome-tric parameters, together with appropriate physi-


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377

cal coefcients [22, 23]. Thus the membrane con-ductance is

DMO2 = KO2[S(a) + S(c)]/2thbwhere KO2 is the diffusion coefcient for oxygenin the tissue, S(a) and S(c) are the alveolar andcapillary surface area respectively, which are aver-aged to dene the gas exchange surface; thb is theharmonic mean thickness of the barrier measured

as the distance between the alveolar surface andthe erythrocyte membrane, i.e. tissue and plasmalayers combined into one layer [24]. The diffusionconductance of the erythrocytes is a more com-plex phenomenon because oxygen molecules thatdiffuse into the haemoglobin mass also enter abinding reaction with haemoglobin; as there is noeasy solution for this complex process, Roughtonand Forster [8] proposed a simple relationship:

DeO2 = O2V(c)where V(c) is the volume of capillary blood, andthe factor O2 is the reaction rate of oxygen with

whole blood as measured in vitro, a factor difcultto estimate experimentally [25, 26].It is evident that this model of the pulmonary

diffusing capacity DLO2 formulates the quantita-tive effect of lung structure on gas exchange func-tion on the basis of morphometric data: surfaceareas, volumes and barrier thickness. Such datawere not available in 1959, and there was no obvi-ous way of obtaining them; hence the task wewere facing was (1) to develop the necessary mor-phometric methods, (2) to prepare reasonablyxed lungs from normal humans, and (3) to per-form the measurements that yielded a set of datausable in the model calculations. But this turnedout to be a lengthy and difcult process. Becausegas exchange occurs in structures at the sub-mi-crometer scale, electron microscopy is required toachieve adequate resolution; the human lungspecimens available at the outset of the pro-gramme were adequate for light microscopy [6,27], but xation for electron microscopy wasachievable only for small animal lungs [28]. Also,efcient stereological methods had to be devel-oped that would allow accurate estimates of mi-crostructural parameters in very large specimens.

All these methods were gradually developed overthe ensuing years until, in 1978, Peter Gehr andMarianne Bachofen had obtained all the neces-sary estimates on a set of normal human lungs andcould calculate DLO2 for the rst time [29]; thesedata, in part revised on the basis of later studies[24] are reported in table 1.

The rst remarkable nding is that the areaof the alveolar gas exchange surface is on theorder of 130 m2, an area equivalent to about ofa singles tennis court, and that the capillary sur-face area is similar. The capillary blood volume

amounts to about 200 ml; spread out over thislarge surface this represents an extremely thinlayer of blood, just about half as thick as an ery-throcyte, because the capillary is contained in thewalls between two alveoli and is thus exposed toair on both sides of the septum (gs. 2 and 4). As

S W I S S M E D W K L Y 2 0 0 9 ; 1 3 9 ( 2 7 2 8 ) : 3 7 5 3 8 6 w w w . s m w . c h

Figure 1

Scanning electron

micrograph of human

lung parenchyma.

Alveolar duct is sur-

rounded by alveoli,

which are separated

by thin septa.

Figure 2

In the alveolar wall,

shown in a scanning

electron micrograph

from a human lung,

the capillary blood

with its erythrocytes

is separated from

the air by a very thin

tissue barrier.

Figure 3

Unit of capillary

network in alveolar

wall connected to

terminal branches

of pulmonary artery

and vein; blood

plasma labeled

with colloidal gold.

Figure 4

Alveolar capillary

bounded by endothe-

lial cell sits in alveo-

lar septum lined by

type 1 epithelial cells

on both sides. Note

thin tissue barrier ontop and slightly

thicker barrier with

some connective tis-

sue fibres and fibro-

blasts at bottom.

Morphometric data (mean 1 SE)

Total lung volume (60% TLC) 4340 285 ml

Alveolar surface area 130 12 m2

Capillary surface area 115 12 m2

Capillary volume 194 30 ml

Tissue barrier harmonic mean thickness 0.62 0.04 m

Total barrier harmonic mean thickness 1.11 0.1 m

Diffusing capacity DLO2 158 ml/min/ mm Hg

a Data from Gehr et al. [29] and Weibel et al. [24].

Table 1

Morphometric esti-

mate of DLO2 for

young, healthy adult

humans of 70 kg

body weight,

measuring 175 cm

in heighta.


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we note from g. 4, the tissue barrier between airand blood varies greatly in thickness, from thethicker parts where epithelial or endothelial cellsas well as bre strands are contained, to the muchvaster thin parts where the barrier correspondsmerely to two very thin cytoplasmic lamellae ofthe endothelial and type 1 epithelial cells sepa-

rated by a single basement membrane; the aver-age thickness of this tissue barrier amounts toabout 1.6 m. This estimates tissue mass but isnot relevant for the estimation of diffusion con-ductance: because O2 ow across the barrier is in- versely proportional to local thickness, it isgreatly favoured by the thin parts. The relevantthickness estimate is therefore the harmonicmean, i.e. the mean of the reciprocal thicknesses,and this is estimated at 0.6 m (table 1). On theother hand, the model for calculating DMO2 isformulated to require an estimate of the harmonicmean total barrier thickness, tissue and plasmataken together [24]; the justication for thischoice is that diffusion across these layers is muchfaster than blood ow, and thus the plasma layer isquasi-static; total barrier thickness in the humanlung is estimated at a little over 1 m, and thusnearly twice the tissue barrier (table 1).

With all these estimates at hand we can nowcalculate a theoretical value for the pulmonarydiffusing capacity DLO2. This yields a value ofabout 150 mLO2 per min for a PO2 difference of1 mm Hg, and we nd that the two serial resist-ances of membrane and erythrocytes contribute

about equally to the overall resistance. This theo-retical value means that an O2 uptake of 400mL/min, what a normal human would need underresting conditions, can be achieved with a PO2 dif-ference of only 3 mm Hg. This seems very low,and we know that physiological estimates of DLO2in the clinical laboratory are commonly found tobe about 30 mLmin1mm Hg1, thus 15 of the the-oretical value. Does the theoretical value of 150make any sense? Probably yes, because an O2 up-take rate of 400 and a DLO2 of 30 correspond to aperson completely at rest, but the lung can hardly

be designed to satisfy merely this condition. Assoon as we engage in any kind of activity O2 needsincrease rapidly and in heavy exercise easily reachan O2 uptake rate of 4 L/min, hence 10-fold theresting value, and the lung must be t to allowthis high ow rate as well. Physiological estimates

of DLO2 in heavy exercise yield values of the orderof 100 mlmin1mm Hg1 [30], which is closer tothe theoretical value but still somewhat lower.

The rst question is whether we can trust thetheoretical value of DLO2 calculated from accu-rate morphometric data and using the best avail-able physical coefcients. This cannot easily bedetermined on the human lung, and hence we

must have recourse to experimental studies wherephysiological and morphometric measurementscan be done on the same lungs and under exerciseconditions. One such set of studies is the assess-ment of the functional loss of gas exchange capac-ity following reduction of the gas exchange struc-ture by partial pneumonectomy in dogs [31, 32].In these studies the pulmonary diffusing capacitywas estimated using CO as a tracer gas that bindsavidly to haemoglobin, and the theoretical valueof DLCO was calculated with the same morpho-metric approach as described above, except that

physical coefcients for CO rather than O2 wereused. These studies have shown that the func-tional estimate of DLCO under heavy exerciseconditions agrees with the morphometric esti-mate: two years after left pneumonectomy, where40% of the gas exchange tissue is lost, the physio-logical as well as the morphometric DLCO werereduced to 70% of controls (g. 5); this is higherthan expected for the 60% residual lung, becausethe capillary network becomes enlarged sincenow the entire blood ow must pass through thereduced vascular system, but there is no tissuegrowth [32]. This general nding was conrmedin further studies [33], and thus we can apparentlyaccept the theoretical estimate of DLO2 in generaland for the human lung in particular.

We must therefore conclude that, in contrastto dogs, the human lung has an excess gas ex-change capacity by a factor of about 1.5. It is in-teresting that this has a corollary in earlier nd-ings comparing goats to dogs and cows to horses,i.e. normal sedentary animals to notoriouslyathletic species [34, 35]: whereas the dogs andhorses fully exploited their pulmonary diffusingcapacity in heavy exercise, both the goat and the

cow did not: they had an excess DLO2 of about30%, which is thus similar to what we found innormal humans. It is now interesting to notethat well-trained human athletes, such asmarathon runners, achieve a maximal O2 con-sumption rate that is about 1.5 times higher thanthe untrained normal human of the same size[36]. It may now be speculated that the athletesfully use the diffusing capacity of their lungs, thusexploiting the reserve to supply O2 to their muscleat the higher rate. And we may further speculatethat in athletes the lung can become a limiting

factor for endurance performance. A number ofarguments could be advanced in support of such ahypothesis: the rst is that apparently, in theadult, the lung is unable to increase its gas ex-change structures to accommodate the higher O2ux rate required by exercise training, whereas we


Figure 5

Effect of left pneu-

monectomy in dogs

on pulmonary diffus-

ing capacity for CO,

estimated physiologi-

cally by rebreathing

technique at increas-

ing exercise intensi-

ties measured by

blood flow (left), and

morphometrically(right) before and

after pneumonec-

tomy. Adapted from

[32, 65].


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379

know that muscles increase their mitochondriaand capillaries under such conditions [37]. Thisfailure to adjust lung structures to need is alsoshown in the pneumonectomy studies on dogs,where true compensatory growth of lung struc-tures, capillaries and alveolar walls, occurred onlyif the pneumonectomy was performed in puppiesbut not in adults [38].

This then leads to the conclusion that a goodlung is made of a gas exchanger designed to offer

a large surface and a thin barrier, to ensure the O2supply required when we work at a high rate.That DLO2 is designed with a certain excess ca-pacity appears to serve as a safety factor to ensureoxygenation of the blood even when workingunder unfavourable conditions, and it may enableathletes to train their muscles and the supplyingvasculature up to the limit set by the capacity of

the pulmonary gas exchanger.


Problems of servicing a very large surface and stabilising it with little tissue

The two key design features of a good lungare hence a very large surface area and a very thintissue barrier, features that are precarious and

raise two questions of physiological signicance:(1) how is it possible to accommodate this surfacewithin the limited space of the chest cavity andstill allow for efcient ventilation and perfusion;

and (2) how is it possible to support, maintain, andstabilise a surface area of the size of a tennis courtwith so little tissue?

With respect to the rst question the bioengi-neering problems to be solved by design are (a)how to build a sprinkler system to supply a fewhundred million gas exchange units with O2-richair and with blood, and (b) how to fold up a sheetof 130 m2 to t into a space of 5 liters equivalentto packing a letter into a thimble while ensuringprecise connections of the sprinkler system to thesurface units. The solution found is to developboth these features together during morphogene-sis of lung structure, and the result shows thatprinciples of fractal geometry [3941] come intoplay both in designing airways and blood vesselsand in the process of folding up the surface: air-ways form a space-lling tree on whose terminalgenerations the gas exchange surface is formed.

Lung morphogenesis starts with an anlage inthe form of an epithelial tube derived from theforegut, which branches sideways forming the twolung buds. These grow and branch by dichotomyinto the mesenchyme of the visceral pleura (g. 6),by a fractal pattern of growth and division to form

a space-lling structure until eventually a tree of23 generations is formed. Blood vessels form inthe mesenchyme as a vascular network around thetips of the airways, connected to branches of thepulmonary arteries that lie close to the developingairway tubes, whereas the pulmonary veins lie inthe septa (g. 6). The result of this is a system ofthree closely related trees (g. 7): the pulmonaryarteries branch in parallel with the airways whosecourse they closely follow, whereas the pulmonaryveins take an intermediate position between bron-cho-arterial units, using interlobular or interseg-

mental septa as guiding structures.The gas exchange surface forms on the wall ofthe most peripheral generations of the airway treetubes by a complex process: while the mes-enchyme is reduced to thin sheets, a capillary net-work forms in close association with the epithelial

Figure 6

Section of foetal

human lung showing

the branching of ep-

ithelial airway tubes

by dichotomy within

the mesenchyme con-

taining branches of

the pulmonary artery

(close to airways) and

veins (in septa).

Figure 7

A resin cast of the

human airway tree

shows the dichoto-

mous branching of

the bronchi from the

trachea and the sys-

tematic reduction of

airway diameter and

length with progres-

sive branching. In the

left lung the pul-

monary arteries (red)

and veins (blue) are

also shown.

Figure 8

Scanning electron

micrograph of alveo-

lar ducts and sacs in

a perfusion fixed

rabbit lung.


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airway lining. The capillaries thus become inter-calated between two air saccules to be exposed toair on both sides; secondarily, alveoli are formedby pulling in septa with a network of strong con-nective tissue bres which will constitute thewalls of the alveolar ducts [42]. The packing ofthe large surface into a limited space is thus

achieved by sequential subdivision of an originallysimple bubble into a foam-like structure (g. 8),a process that follows principles of fractal geome-try [39, 40] as the surface increases by systematicinternal crumpling without increasing the con-taining volume.


Designing the airway tree for efcient ventilation

If we rst consider the airway tree moreclosely we note that, in spite of some irregularity,its branching pattern is basically the same at alllevels, from the large airways to the small periph-eral bronchioles (g. 7): as the airway divides intotwo branches the length and diameter of thedaughter branches are reduced by a constant fac-

tor, at least from the trachea out to the terminalbronchioles; this feature is called self-similarbranching and is one of the hallmarks of fractaltrees [39, 40], as represented by the model tree ofMandelbrot (g. 9), which in fact represents thebasic features of the bronchial tree quite well.This has fundamental consequences for the func-tional design of the airway tree: such a structure isnaturally space-lling, i.e. its tips are rather ho-mogeneously distributed in the lung space, withthe functional consequence that the distancealong the airways from the trachea to the terminal

(gas exchange) units is approximately the same forall units whether they are located near the pleuraor near the central airways, a design property thatfavours homogeneous ventilation of all units.Thisis, of course, a gross simplication as there is con-siderable irregularity resulting from the fact thatthe two daughter branches may have different di-

ameters and lengths to accommodate to the localspace conditions, so that there is some degree ofvariation in the path length to the terminal units[27]. But the main point here is to nd the basicconstruction principle by which all points in a de-ned space, here the chest cavity, can be reachedin the most efcient manner; reality, of course, isnot as perfect as the models predict and this maycontribute to uneven ventilation, for example.

When, in 1962, Domingo Gomez and Ianalysed the cast of a human bronchial tree simi-lar to the one shown in g. 7 we found, by search-ing for a basic construction principle, that the di-ameter of the airways was reduced with each gen-eration by an approximately constant factor (g.10) that, on average, was equal to the cube root of or 0.79 [6]. It turns out that this factor corre-sponds to an optimised hydrodynamic conditionof air ow in a branched tube system as formu-lated in the Hess-Murray law [43, 44], whichtends to minimise (a) work to overcome ow re-sistance as well as (b) dead space volume. It thusappears that the airway tree is designed accordingto optimality principles with respect to hydrody-namics. However, a recent re-analysis of these

data by Mauroy and Sapoval [45] revealed that thereduction factor is about 0.85, and thus a littlelarger than the ideal factor of 0.79. What thismeans is that ow resistance falls gradually to-wards the smaller airways [46]. This has been in-terpreted as a safety factor preventing the ill-ef-fects of increased ow resistance in bronchioles when narrowed by the action of their smoothmuscle sleeve or by interstitial oedema such as oc-curs in asthma. This safety factor is paid off by aslightly larger dead-space volume, but this fact isof lesser consequence: we should remember that

the volume of the airway tube increases with thesquare of the diameter, whereas, according to thelaw of Poiseuille, resistance is affected in propor-tion to the 4th power of the diameter.

Figure 9

Fractal tree of Man-

delbrot. From [39]

by permission.

Figure 10

Average diameter of

airways in human

lung decreases with

generations of airway

branching.


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381

If we now consider the way in which the air-way system leads into the gas exchanger, we notethat, for a human airway tree with an average of23 generations of dichotomous branching, gener-ations 014 are conducting airways (g. 11) lined

by a bronchial epithelium and with the branchingproperties described above. In generation 15, onaverage, alveoli with gas exchange surface beginto be incorporated in the airway wall and the rstorder respiratory (or transitional) bronchiole isformed. After about three generations the airwaywall is completely decorated with alveoli; alveolar

ducts thus formed (g. 12) continue to branchuntil, in the last generation, the alveolar sac isblind-ending (gs. 8 and 11).Accordingly, genera-tions 1523 form what is called a pulmonary aci-nus, the unit of the gas exchanger that is venti-

lated by one transitional bronchiole: on inspira-tion fresh air ows along the conducting airwaysinto the acinus, and all of the approx. 10 000 alve-oli of an acinus receive O2-rich air from the samesupply source, and this may have functional impli-cations.

This architecture is therefore very differentfrom the classical models of the gas exchanger asit appears in most textbooks, where a bubble-likealveolus, associated with a capillary, is attached tothe end of the last airway branch (g. 13a). As aresult of the combined development of the airwaytree and the gas exchange surface, as describedabove, the gas exchange units, basically repre-sented by alveoli, are arranged on the surface ofthe alveolar ducts, forming the approx. 8 terminalgenerations of the airway tree (g. 11 and 13b).Thus, when O2-rich air reaches into these acinarairways during inspiration, the sequentiallyarranged alveoli are ventilated in series (g. 13b):the most central alveoli see fresh air whereas theair reaching more peripheral alveoli has alreadylost some O2 on its passage through some gas ex-change units. This is functionally signicant be-cause the arrangement of the blood vessels is dif-

ferent: capillary network units, which are aboutthe size of an alveolus, are supplied by a terminalbranch of the pulmonary artery and drained by asimilar venous branch (g. 2), so that all capillaryunits receive mixed venous blood of the same O2content. As a result, we can say that the alveolar-capillary gas exchange units are perfused in paral-lel whereas they are ventilated in series (g. 13b).Since gas exchange occurs wherever mixed ve-nous blood is exposed to O2-rich alveolar air, wemay suspect that central alveoli are favoured, thedriving force for diffusive O2 uptake being high,


Figure 11

Model of airway

branching in human

lung by regularised

dichotomy from tra-

chea (generation z = 0)

to alveolar ductsand sacs (generations

20 to 23).The first 14

generations are

purely conducting;

transitional airways

(generation 15) lead

into the acinar air-

ways with alveoli

branching over eight

generations (z).

Modified after [27].

Figure 12

Terminal conducting

airways branch by

dichotomy and lead

into the alveolar

ducts that constitute

the pulmonary

acinus.

Figure 13

Models of ventilation-perfusion relationship in the mam-

malian pulmonary gas exchanger. A. Parallel ventilation/

parallel perfusion. B. Serial ventilation/parallel perfusion.

[From 47]

Architecture of the gas exchanger and its functional consequences


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corresponding to the difference between inspiredand mixed venous PO2. This extracts some O2from the air in the alveolar ducts so that a PO2 gra-dient forms along the acinar airways (g. 13b), aprocess called screening which may cause theO2 concentration in the air space to become verylow towards the periphery [47]. This may well in-troduce a functional problem, namely the dangerthat the last alveoli do not receive enough O2 tooxygenate the blood, which would cause venous

shunts to occur. This could be of great functionalsignicance because, as a result of sequentialbranching, the last generation of acinar airwayscontains at least half the entire gas exchange sur-face (g. 14) and thus must receive an adequate O2supply.

In order to estimate the importance ofscreening we must note that, upon inspiration,fresh air ows into the rst orders of acinar air-ways deeper in exercise than in resting ventila-tion but beyond this the air ow velocity be-comes so slow that O2 proceeds to the more pe-

ripheral generations by diffusion in the air phase[47]. Hence gas exchange is dependent on twodiffusion steps: O2 diffusion through the air phaseto the gas exchange surface, and O2 diffusionacross the barrier into the blood. Screening is de-termined by the relationship between the conduc-tance to reach the gas exchange surface and theconductance to cross the barrier into the blood.Each of these conductances is determined by aphysical factor and a morphometric parameter:

the physical factors are DO2, the O2 diffusion coef-cient in air, and WO2, the O2 permeability of thebarrier; the morphometric parameters are S(A),the gas exchange surface that determines the con-ductance to cross the barrier, and L(ac), the size ofthe acinus that determines the conductance toreach the surface. The physical analysis of thisprocess predicts that screening becomes a prob-

lem if the ratio of the physical factors DO2/WO2 islarger than the ratio of morphometric parametersS(A)/L(ac) [47]. Optimal conditions are ensured ifthese two ratios are about equal: the physical fac-tors being given quantities, the morphometric pa-rameters must be adjusted to match them duringmorphogenesis. A detailed analysis of this situa-tion has shown that the morphometric propertiesof the mammalian acinus, including the human,are indeed well matched to the physical condi-tions, so as to avoid screening [47, 48]. Problemsmay, however, occur in some disease states, for ex-

ample in emphysema where the size of the acinusis enlarged and the surface area reduced, causingthe morphometric ratio S(A)/L(ac) to be muchsmaller than the physical ratio DO2/ WO2; this re-sults in severe screening, is one of the importantcontributing factors to impaired gas exchange,and may explain why gas exchange disturbancecan be much greater than the mere loss of alveolarsurface area would predict.

What is then the virtue of this architecture where the gas exchange surface is distributedalong the last generations of branching airways?The rst point is that packing of the alveolar sur-face into a very limited space is maximised, thusoptimising the conditions for ventilation of thesurface by diffusion. By limiting the size of theacinus the conditions for ventilation by air owcan be optimised by (a) designing a well propor-tioned branched bronchial tube system (seeabove) with (b) a smooth surface, that, above all,can also be provided with a catchy surface liningdesigned to capture the load of nanoparticles etc. which should be prevented from reaching thealveoli, thus serving as a cleansing device for in-spired air [49]; by enwrapping the particles in a

lm of surfactant they are made hydrophilic andcan thus be displaced into the hypophase [50, 51],where they may be removed, e.g. by macrophages,or penetrate through the tissue into the capillaries[52]. Mammalian lungs are apparently designedin a highly favourable way, considering all theseboundary conditions. With respect to the archi-tecture of the gas exchanger in the acinus, the ruleis that smaller is better but not too small [47].


Figure 14

Alveolar ducts in aci-

nus of human lung

shown in silicon rub-

ber cast spread out

to show the course

of the subsequent

branchings.The

curved line marks the

approximate bound-

ary to the last genera-

tion, to show that thisgeneration of alveo-

lar sacs comprises

over half the gas ex-

change area of the

acinus.

The problem of maintaining stability of the airspace complexity

Perhaps one of the most remarkable featuresof lung structure is that a rather extensive andcomplex architecture is established with so little

tissue for support: the very large gas exchange sur-face is supported by a tissue sheet less than 1 mthick, which is exposed to blood pressure on the


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383

side of the capillaries and to surface forces on theair side. Such a structure can only be maintainedstable by adequate design of the supporting struc-tures.

The rst design feature of importance is theestablishment of a bre continuum which per- vades the entire lung tissue system from thepleura to the major airways. This bre system can

be divided into three parts (g. 15): the axial bre system, anchored in the hilum,

forms the wall of airways all the way out tothe alveolar ducts and sacs in the acinus, andthus establishes a branched axial scaffold oflung parenchyma (g. 16);

the peripheral bre system originates in theconnective tissue bag of the visceral pleuraand extends into lung parenchyma as a hierar-chical system of interlobular septa, and is thuslocated at the periphery of the acini;

the septal bre system forms within the alveolar

walls in close association with the capillarynetwork and is anchored in both the axial andthe peripheral bre systems, thus establishinga bre continuum that spans across the acinusas a 3D maze (gs. 16 and 17).Examining the architecture of the alveolar

septum in more detail, we note rst that its verydelicate network of elastic and collagen bers isinterwoven with the capillary network (g. 18),the bre strands thus appearing alternately onone side or the other of the capillary; this measureis designed to efciently reduce the thickness andthe diffusion resistance of the air-blood barrier,leaving half the capillary surface with a minimalbarrier composed only of the endothelial and ep-ithelial leaets with a fused basement membrane(g. 4). This arrangement also allows the capillarynetwork to be supported in a simple fashion witha minimum of bres spanning between the pe-ripheral bres of interlobular septa to the strongaxial bre tracts forming the wall of the alveolarduct (g. 16). There are no loose ends in this bresystem (g. 17).

This bre system is now under constant ten-sion through the outward pull of the visceral

pleura which is transmitted to the septal bresand the axial bre system. The lung thus becomesa tensegrity structure [53, 54] whose form ismaintained by the tension on the bre contin-uum; if one bre of this continuum is cut thestructure will collapse, at least in the part of thealveolar complex that hangs together in the aci-nus; this results in deformation of the peripheralairways in emphysema, particularly in its cen-trilobular form where parts of the axial bre sys-tem are snapped, causing collapse of the periph-eral airways.

But is this bre continuum enough to sta-bilise the complex inner architecture of lungparenchyma? The answer is no, the problembeing surface tension in the small bubbles thatwould tend to collapse the alveolar complex, espe-cially since alveoli are all open to the airway sys-


Figure 15

Fiber continuum of

human lung with

axial fibres deriving

from the airways

(red), peripheral fi-

bres connected to the

pleura (black) and

septal fibres in alveo-

lar walls (green).

Figure 16

The relation between axial, septal and peripheral fibers in an alveolar duct and their

relation to the surface forces acting on the alveolar complex, marked by arrows; these

tend to shrink alveoli and to push on the free edge of the alveolar septa at the alveolar

duct, which is supported by a strong fibre bundle of the axial network (see fig. 17B).

Figure 17

Alveolar duct shown (A) in scanning electron micrograph to illustrate the relation of

alveoli, septa and ducts with the network of alveolar entrance rings forming the wall

of the duct, and (B) in light micrograph where the elastic fibres are stained black todemonstrate the strong fiber support of the free edge of the alveolar septa.


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tem.The bre system cannot support the tensionsthat form, for example, on the free edge of thealveolar entrance rings (g. 17 and 18a). To pre-vent collapse the alveolar surface is provided witha duplex lining layer (g. 19), with a watery hy-pophase that smoothes surface irregularities,topped by a lm of surfactant at the air-liquid in-terface [55, 56], secreted by the type 2 alveolar ep-

ithelial cells (g. 20) [57, 58]. This lm has dy-namic properties that enable the lung to copewith the problems associated with ventilation dy-namics [59, 60]: on expiration alveoli becomesmaller, and this would cause the surface force toincrease, with the danger of alveolar collapse. Butdue to its biophysical properties [61] the phos-pholipid surfactant lm reduces its surface ten-sion to nearly zero as it is compressed when thealveoli shrink, with the result that the collapsingsurface forces vanish; upon inspiration the alveolican then re-expand easily. In this dynamic processthe bre continuum plays a central role as it dis-tributes the forces generated by the respiratorymuscles in the chest and diaphragm to the alveo-lar septa throughout the lung, thus ensuring thatthe gas exchange surface remains unfolded toallow diffusion of O2 from the air into capillaryblood.


Figure 18

Model of capillary

network in alveolar

septum (compare

with fig. 2) inter-

woven with the

meshwork of connec-

tive tissue fibres

(green) with strong

fibre bundle in free

edge of septum at

right.

Figure 19

Alveolar septum of

human lung fixed by

perfusion through

blood vessels shows

alveolar lining layer

in crevices between

capillaries (C) topped

by surfactant film

that appears as a fine

black line. Note thetype II cell with

lamellar bodies and

the fold in thin tissue

barrier.

How to build and maintain a thin air-blood barrier

As shown in g. 4, the tissue barrier separat-ing air and blood consists of two cell layers, eachwith a basement membrane, and a very slim inter-stitial space in between that is even reduced to thefused basement membranes in the thinnest parts.The capillary endothelium is of a uniform squa-mous cell type with the thin cytoplasmic leaetsconsisting of two plasma membranes with a smallamount of cytoplasmic matrix and some vesicles.

The alveolar epithelium, in contrast, is a mosaic oftwo cell types (g. 21): the type I cell has somesimilarity with endothelial cells, in that it alsoforms thin cytoplasmic leaets (g. 4); the type IIcell is inserted in the epithelial lining as a cuboidalcell (gs. 20 and 21). While type I cells cover 97%of the alveolar surface they constitute only 13 ofthe epithelial cells in number, and even thoughthey appear as small cells they are in fact twiceas voluminous as the type II cells [62].

The rich cytoplasm of type II cell with endo-plasmic reticulum, Golgi complex, granules and

lamellar bodies (g. 20) serves its function as se-cretory cell for the different constituents of thesurfactant complex, phospholipid lm as well asthe surfactant-associated proteins [57, 58]. Thetype I cell, on the other hand, is a very special celltype in that its form is complex: it is not a simple

Figure 20

Type 2 alveolar

epithelial cell as

secretory cell for

surfactant stored in

lamellar bodies

(black).

Figure 21

Surface of the alveo-

lar wall in the human

lung seen by scan-

ning electron mi-

croscopy reveals a

mosaic of alveolar

epithelium made

of type I and type II

(EP2) cells. Arrows

indicate boundary

of the cytoplasmic

leaflet of the type Icell which extends

over many capillaries

(C). Note the two

interalveolar pores

of Kohn (PK). N = nu-

cleus of type I cell.


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385

squamous cell like that of the endothelium.Rather, it forms multiple branches that penetrateacross the alveolar septum where they formpatches of the lining on the opposite side; thesepatches were long recognised as a peculiarity ofthe alveolar epithelium and were called kernlosePlatten as they appear devoid of a nucleus [63].This cell architecture has two important conse-

quences: (1) the cells are vulnerable because of thevast extension of the very thin cytoplasmic leaets

5000 m2 for each nucleus , and (2) they are un-able to divide by mitosis. As a result, any defect inthe epithelial lining must be repaired by type IIcells that also serve as precursor cells for the en-tire epithelial cell population. To maintain a tissuesheet as thin as the air-blood barrier depends cru-cially on the integrity and vitality of the twobounding cell layers that also must be tight

enough to prevent any leakage of uid into thelikewise slim interstitial space [64].


What then makes a good lung?

We have seen that the functional capacity ofthe lung as gas exchanger requires a very largesurface of contact between air and blood to bemaintained with an exceedingly small amount oftissue for support.This in turn demands an ingen-ious architectural design by observing rules offractal geometry in the packing of the large sur-face into the limited space of the chest cavity, aswell as in designing a system of airways and bloodvessels which reach all points on the gas exchangesurface evenly and efciently. The resulting hier-archical design with small acini attached to abranched bronchial tree then allows economicaluse of bres and cells to provide mechanical sup-port for the very delicate structure whereby stabil-ity of the air-exposed surface is achieved by thedynamic properties of alveolar surfactant. This

taken together makes a good lung, t to provideour organs with the oxygen they need at rest andin work [65].

I like to thank all those many collaborators who have

so signicantly contributed over many years to the sci-ence at the base of the story told here, in particular H. and

M. Bachofen, P. Burri, L. Cruz-Orive, M. Filoche,P. Gehr, J. Gil, H. Hoppeler, C. Hsia, B. Sapoval,S. Schrch, and the late C. R. Taylor.

Correspondence:Ewald R. WeibelInstitute of AnatomyUniversity of BernBaltzerstrasse 2CH-3000 Bern 9

E-Mail: [email protected]

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