Physiol. Rev. 85: 811-844, 2005;
doi:10.1152/physrev.00022.2004
0031-9333/05 $18.00
Thin and Strong! The Bioengineering Dilemma in the Structural and Functional Design of the Blood-Gas Barrier
John N. Maina and
John B. West
School of Anatomical Sciences, Faculty of Health Sciences, The University of the Witwatersrand, Johannesburg, South Africa; and Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California
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ABSTRACT
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In gas exchangers, the tissue barrier, the partition that separates the respiratory media (water/air and hemolymph/blood), is exceptional for its remarkable thinness, striking strength, and vast surface area. These properties formed to meet conflicting roles: thinness was essential for efficient flux of oxygen by passive diffusion, and strength was crucial for maintaining structural integrity. What we have designated as "three-ply" or "laminated tripartite" architecture of the barrier appeared very early in the evolution of the vertebrate gas exchanger. The design is conspicuous in the water-blood barrier of the fish gills through the lungs of air-breathing vertebrates, where the plan first appeared in lungfishes (Dipnoi) some 400 million years ago. The similarity of the structural design of the barrier in respiratory organs of animals that remarkably differ phylogenetically, behaviorally, and ecologically shows that the construction has been highly conserved both vertically and horizontally, i.e., along and across the evolutionary continuum. It is conceivable that the blueprint may have been the only practical construction that could simultaneously grant satisfactory strength and promote gas exchange. In view of the very narrow allometric range of the thickness of the blood-gas barrier in the lungs of different-sized vertebrate groups, the measurement has seemingly been optimized. There is convincing, though indirect, evidence that the extracellular matrix and particularly the type IV collagen in the lamina densa of the basement membrane is the main stress-bearing component of the blood-gas barrier. Under extreme conditions of operation and in some disease states, the barrier fails with serious consequences. The lamina densa which in many parts of the blood-gas barrier is <50 nm thin is a lifeline in the true sense of the word.
One approach to uncovering biological design principles is to ask what constraints they must obey. Apart from the laws of physics and chemistry, most constraints arise from evolution, which has selected particular solutions from a vast range of possible ones.
Hartwell et al. (92)
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I. INTRODUCTION
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From inexact assessments and deductions that suggested that the mean partial pressure of oxygen in the pulmonary capillary blood exceeded that in the alveolar gas, until fairly recently (91), it was presumed that, in the lung, oxygen was actively absorbed (i.e., secreted) into the blood (see Ref. 67 for review and analysis of the historic debate). It is now certain that in all the evolved gas exchangers, be they water, air, or bimodal breathers, the flux of respiratory gases across the tissue barriers occurs entirely by passive diffusion along established partial pressure differences. In conformity with the physics of a passive process, the structural properties of a barrier influence the rate and efficiency of gas transfer. The diffusing capacity, or the conductance of a tissue barrier for oxygen, correlates directly with the surface area and inversely with the thickness of the partition (200).
Although compared with the closely located, visibly mechanically active heart, the lung may appear relatively inactive, for an organ that throughout life is subjected to changing internal and external pressures both by the pulsating heart and mechanical ventilation by the rhythmic contractions of the respiratory muscles, albeit passively, the lung is inherently a dynamic organ. Illustratively: in the human being, as much as 12,000 liters of air and 6,000 liters of blood per day are pumped into and through the lung (29); the lung is the only organ in the body across which the entire cardiac output and the systemic blood volume transits; of the total blood volume in the body, 
9% of it is contained in the lung (48), and pulmonary blood flow is pulsatile from the entrance of the pulmonary circulation to its outlet in the left atrium (126, 172), with the dampening of the pressure wave occurring in the blood capillary system (255).
Stemming from the physical properties of the respiratory medium utilized (air), lungs experience certain unique operational challenges: 1) compared with the water-blood barrier of the fish gills that separates fluid media of equivalent specific densities (water and blood), the blood-gas barrier of the lung partitions air and blood, materials that are substantially different; consequently, in the lung, external physical support similar to that conferred to the gills by water is lacking and thus the blood-gas barrier is subjected to tensions emanating from the weight of its tissue, its blood, and the prevailing intramural blood pressures (249). 2) While systemic blood vessels are physically anchored to the tissues in which they are located, pulmonary blood vessels are literally suspended in air by a diffuse fibroskeletal framework (237). States and factors such as the degree of inflation, perfusion pressure, surface tension, and hydrostatic pressure (56, 66, 118, 119, 224) determine the structure and organization of the connective tissue scaffold of the lung parenchyma.
The novel morphological states and physiological capacities that culminated in remarkable diversification and advancement of the modern animal life could not have happened without efficient respiratory organs. The question about why, when, and how the innovations arose, especially regarding the formation of a thin and extensive water/blood-gas barrier, is of particular interest to morphologists, physiologists, biophysicists, and evolutionary biologists in general. The challenges faced in evolving a structure of which the functional properties are totally at variance, thin to promote gas exchange and strong to tolerate tension, were formidable by any human engineering standards. (We have borrowed the word "design" from the engineers to describe the conception and assembly of what we have termed the three-ply or laminated tripartite architecture of the structural components that form the water/blood-gas barrier.)
While a complete understanding of the morphogenetic and molecular mechanisms by which the barrier was evolutionary fashioned is lacking, essentially comprising a thin epithelial cell that faces water/air, an extracellular matrix/interstitial space, and an endothelial cell that fronts the blood capillary, the three-ply design of the water/blood-gas barrier is highly conserved. Body designs that have changed little over the evolutionary continuum have been termed Bauplans (frozen cores) (227, 228). Such constructions are probably the only feasible and practical solutions to exacting functional requirements. The rarity of "fixed" designs in biology and their failure to evolve over hundreds of millions of years indicates nature's economy in establishing stable structures. It may connote the high cost of inaugurating and maintaining highly selected constructs. Discernment and study of the "defended" structural states are important for understanding the evolution of adaptive processes, i.e., the structural-functional correlations, and that of optimization in biology. The three-ply design of the water/blood-gas barrier has been in existence in the lungs of the lungfishes (Dipnoi) (108, 109, 128, 154), animals that have morphologically changed very little over their 400 million years of evolution (10, 195, 220). Likely to have arisen from a common ancestral lineage with the stock that gave rise to the tetrapods, lungfishes are arguably reported to be the closest living relative to the tetrapods, i.e., amphibians, reptiles, birds, and mammals (27, 170, 258, 260, 261). Located at an important evolutionary crossroad, the dipnoans offer an informative model for gaining insights into the functional design of the vertebrate body.
The ultrastructural morphology and morphometry of the vertebrate gas exchangers, including that of the blood-gas barrier, have been described and reviewed severally: in mammals (41, 233, 234, 236–238), in birds (124, 142–144, 147, 148), in reptiles (125, 134, 161, 165–168, 186, 189–192, 194), in amphibians (43, 44, 45, 80–85, 131, 156, 166, 168), and in lungfishes (108, 128, 154). The water-blood barrier of the piscine gills has been extensively studied (105, 110). The capability of the water/blood-gas barrier to tolerate stress and its failure under extreme conditions have, however, only been studied in the mammalian lung (reviewed in Refs. 247, 248, 250, 251).
This account comparatively examines the water/blood-gas barriers from the perspectives of their evolution and their structural and functional morphologies. It provides a comprehensive account of the compromise design that produced a functionally (mechanically) viable, thin tissue barrier that separates the respiratory fluid media in the gas exchangers. We have 1) shown that the three-ply design of the water/blood-gas barrier is a shared structural feature of the gas exchangers that have evolved in the mainstream vertebrate taxa; 2) debated and speculated on why, when, and how the barrier developed thinness while simultaneously preserving adequate strength for operation under conventional range of conditions; 3) taken into account that it has been inclusively exploited by diverse vertebrate taxa, the three-ply architecture of the water/blood-gas barrier has been conserved and perhaps optimized over its long period of evolution; 4) presented credible, though indirect, evidence that the strength of the blood-gas barrier can largely be attributed to the presence of type IV collagen in the lamina densa of the extracellular matrix; and 5) briefly discussed the extreme operational and pathological conditions and disease states under which the blood-gas barrier fails, with serious consequences. On account of scarcity and in certain cases, absolute lack of data on certain fundamental aspects of the evolution and morphogenesis of the blood-gas barrier (soft tissues like lungs are rarely, if ever, preserved by fossilization) and lack of extensive and meaningful molecular and genomic extrapolative studies (222), we are alert to the fact that certain deductions are presently conjectural. It is hoped that putative as they may be, such speculations will trigger further inquiry into an interesting area of biology.
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II. DESIGN OF THE BLOOD-GAS BARRIER FOR GAS EXCHANGE
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A. Flux of Oxygen Across the Blood-Gas Barrier: Biophysical Factors and Quantitative Considerations
No other molecular factor has had a singularly greater influence on the evolution and progress of animal life than oxygen (35, 86, 199). The advancement from the simple protozoan (unicellular) to the complex metazoan (multicellular) domains, transition from water breathing to air breathing, transformation from ectothermic-heterothermy to endothermic-homeothermy, and achievement of innovative locomotory capacities such as flight are but some of the consequential events that marked the change from low metabolic to highly aerobic states. Fluctuations in the levels of oxygen in the biosphere (86) set the cost and the efficiency of acquisition of molecular oxygen, fundamentally directing the nature and pace of evolutionary change.
On close scrutiny, one is impressed by the remarkable bioengineering challenges that were surmounted during the evolution of efficient, cost-effective respiratory structures and processes. Respiratory media (water/air and blood) had to be brought into close proximity and exposed to each other across an extensive, thin tissue barrier. To generate and maintain an adequate partial pressure gradient of oxygen (PO2), the respiratory fluid media had to be continuously moved and replenished. The tissue barrier had to withstand changing hemodynamic pressures from the blood capillary side, tolerate surface tension forces from the air fronting side, and encounter different physical, chemical, and biological insults. Over a lifetime, the barrier had to repair inevitable damages. Mechanical support had to be provided by well-placed connective tissue elements that did not intrusively compromise respiratory efficiency. Paradoxically, the refinements (i.e., thin and vast water/blood-gas barrier) that enhanced the respiratory efficiency inauspiciously conceded its effectiveness as a viable functional barrier and a meaningful physical deterrent of harmful inhaled microorganisms, allergens, carcinogens, toxic particles, and noxious gases. An assortment of lines of fortification was established to offset the contracted weaknesses/deficiencies. For example, a formidable selection of respiratory defenses that included airway secretions, cilia, respiratory reflexes (e.g., coughing), efficient lymphatic drainage, and surface (23, 24) and intravascular macrophages (147) were formed. Considering the many roles, including metabolic ones (7, 9, 64, 113), that the lung has acquired, the various structural requirements for optimal performance of the different roles have inevitably conflicted. Structural failure of the blood-gas barrier occurs under extreme states and conditions of operation.
Regarding the design of gas exchangers, structure relates to the form and organization of the constitutive parts that provide the means by which air and blood are brought into close proximity and exposed to each other while function appertains to mechanisms such as ventilation and perfusion, through which the respiratory fluid media are moved to maintain a high PO2. In the parenchyma of respiratory organs, blood capillaries anastomose profusely and in some cases protrude prominently into the respiratory spaces (see Fig. 2, A–D). The blood capillaries are virtually suspended in air (Fig. 1). The blood flow through the dense capillary network models a sheet (72, 141). Complex vascular architecture and delicate connective tissue network support the parenchyma (29, 234, 237, 239). For an oxygen flow (VO2) of 200 ml/min, only an average partial pressure difference of 0.057 kPa is needed for diffusion of oxygen across the blood-gas barrier, a process that occurs at a rate of 2. 3 x 10–5 cm2/s and is completed in 250–500 ms (88, 200, 246).
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FIG. 2. A: interalveolar septum (dashed lines) of the lung of the bushbaby, Galago senegalensis. c, Blood capillaries; r, red blood cells. Scale bar is 25 µm. [From Maina (142).] B: interalveolar septum of the lung of a vervet monkey, Cercopithecus aethiops, showing blood capillaries containing red blood cells (r). Scale bar is 15 µm. [From Maina (130a).] C: a blood capillary in the exchange tissue of the lung of the domestic fowl, Gallus domesticus, showing red blood cells (r) and blood-gas barrier separating blood from air (arrows). Scale bar is 5 µm. [From Maina (138a).] D: a blood capillary in the lung of a bat, Epomophorus wahlbergi, showing blood-gas barrier (arrow) separating air and blood. r, Red blood cells. Scale bar is 8 µm.
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FIG. 1. Schematic diagram showing a cross-section of a pulmonary blood capillary containing red blood cells. Oxygen diffuses through the air-hemoglobin pathway that is comprised of the blood-gas barrier, a plasma layer, and red blood cell cytoplasm where it is chemically bound to hemoglobin. The diffusing capacity of a tissue barrier for oxygen correlates directly with surface area (s) and inversely with thickness (t) (inset). [From Maina (132).]
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Given that gas exchangers transmit respiratory fluid media, water/air and blood through morphogenetically established conduits (bronchial airways and vascular channels) (33, 160) and diffusion of oxygen occurs across physical spaces en route to the mitochondrial furnaces, the designs of the respiratory organs invite mathematical analysis and modeling (19, 100, 132, 200, 230, 232, 240). Whilst generally considered a physiological parameter, the total morphometric diffusing capacity DLO2 is greatly influenced by the structural attributes of the blood-gas barrier (i.e., surface area and thickness) and the pulmonary capillary blood volume (Figs. 2–4). Respiratory physiologists recognized this fact very early. Roughton and Forster (200) separated DLo2 into "membrane diffusing capacity, DmO2," i.e., the flow of oxygen through the blood-gas barrier, and that of the "blood components, DeO2," the rate at which oxygen binds to the hemoglobin.
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FIG. 4. A: alveolar surface of the lung of the bushbaby, Galago senegalensis. Type I cells (arrows) that are thin and expansive cover respiratory surface. Blood capillaries (c) protrude into the alveolar space. Scale bar is 20 µm. [From Maina (141).] B: lung of a snake, the black mamba, Dendroaspis polylepis, showing blood capillaries anastomosing and protruding into the adjacent air space. Dashed lines delineate the interfaveolar septum. Scale bar is 50 µm. C: lung of the domestic fowl, Gallus domesticus, showing air capillaries surrounded by blood capillaries (c) that contain red blood cells (r). Scale bar is 10 µm. D: surface of a secondary lamella of the gills of a teleost fish, Alcolapia grahami, showing profuse vascular channels (v) that are separated by pillar cells. Scale bar is 20 µm. [From Maina (141).]
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With the use of relevant morphometric measurements (Figs. 1 and 3) and the physicochemical coefficients of permeation of oxygen through the various components, the diffusing capacities of the different parts of the air-hemoglobin pathway and the total (overall) value for the lung (DLO2) can be estimated (132, 153, 232, 240). According to Fick's first law of diffusion, oxygen flow rate across a tissue barrier is directly proportional to the cross-sectional surface area (S) and inversely proportional to the thickness of the barrier separating the respiratory media (Figs. 1 and 2, insets). Oxygen flow (VO2) is determined by the PO2 and the permeability coefficient (K) [i.e., the product of solubility and diffusion coefficients (
) and (D), respectively] through the components of the barrier. Thus
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Fick's law is analogous to Fourier's law of heat conduction in physics; heat flow (Q) is given by the relation
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where A is the cross-sectional surface area, l is the distance between the two ends of the conducting material, T1 and T2 are the difference in temperature between the two ends of the conductor, and k is the proportionality constant (called the thermal conductivity) specific to the material properties of the conductor.
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FIG. 3. A schematic diagram and an electron micrograph showing the barriers through which oxygen diffuses. These are the tissue barrier that is comprised of an epithelial cell, extracellular matrix, and an endothelial cell, plasma layer, and red blood cell (RBC) cytoplasm. The PO2 decreases with the diffusional distance (inset), i.e., as oxygen passes through the tissue barrier (t), plasma layer (p), and the red blood cell cytoplasm (t). Scale bar is 0.3 µm. [From Maina (142).]
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The total distance traversed by an oxygen molecule (here called the "air-hemoglobin pathway") includes the blood-gas (tissue) barrier, the plasma layer (space between the endothelial cell and the cell membrane of the erythrocyte), and the erythrocyte cytoplasm, i.e., the distance that an oxygen molecule travels before it is chemically bound to hemoglobin (Figs. 2 and 3). The components of the air-hemoglobin pathway are arranged in series (Fig. 3), i.e., an oxygen molecule sequentially passes through the structural components. The total resistance that the molecule encounters (Ro) is thus the sum of the individual resistances, i.e., those of the blood-gas barrier (t), the plasma layer (p), and the erythrocyte (e). Thus
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With the reciprocal of resistance being the conductance (i.e., the diffusing capacity), the DLO2 is in turn the sum of the reciprocals of the conductances of the components of the air-hemoglobin pathway, namely, the diffusing capacity of the tissue barrier (DtO2), that of the plasma layer (DpO2), and that of the erythrocyte (DeO2). Thus
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The total morphometric pulmonary diffusing capacity for oxygen (DLO2) offers an estimate of a gas exchanger capacity of transferring oxygen under ideal conditions, i.e., where inequalities of ventilation and perfusion are nonexistent and the entire blood-gas barrier is involved in the transfer oxygen. The parameter is meaningful in assessing and comparing gas exchange potentials of different respiratory organs.
Pathological and adaptive changes may occur in any of the components of the air-hemoglobin pathway. For example, edema increases the thickness of the blood-gas (tissue) barrier, dehydration may reduce the thickness of the plasma layer, and anemia may affect the oxygen binding characteristics of the hemoglobin. For example, while diving birds like penguins have relatively thick blood-gas barriers (129, 245), a feature alleged to forestall collapse of the air capillaries under hydrostatic pressures during dives (245), such birds have particularly large pulmonary capillary blood volumes (Vc) (129, 132, 150, 153). The large Vc gives a high DeO2 that in turn offsets the limitations caused by a thick tissue barrier (reflected in a low DtO2). In the Humboldt penguin, Spheniscus humboldti (150), and in the emperor penguin, Aptenodytes forsteri (245), with values of 0.53 and 0.66 µm, respectively, the harmonic mean thicknesses of the blood-gas barrier (
ht) are exceptionally thick (Table 1); while DtO2 itself is low, the high DeO2 raises DLO2 to match that of nondiving (flying) birds of equivalent body mass (144, 150).
An important caveat to remember in respiratory functional morphology (morphometry) is that analyzing structural components and making inferences based on individual measurements may potentially lead to erroneous conclusions regarding adaptive biologies, e.g., the efficiencies of different gas exchangers. This is because the constitutive components work as an integrated system and not individually. Moreover, certain trade-offs and compromises may be involved in the formation of their ultimate morphologies and morphometries. Notwithstanding the existing limitations, especially those relating to lack of physical coefficients of the binding of oxygen to hemoglobin and the permeation of oxygen through the structural components of the air-hemoglobin pathway in the gas exchangers of many species, pulmonary modeling is highly desirable.
B. Comparative Observations on the Structure of the Blood-Gas Barrier
In gas exchangers, the barrier across which molecular oxygen diffuses from an external respiratory medium (water/air) to blood is comprised of a motley crew of cellular elements and a suite of supporting structural components. Various epithelial cells (pneumocytes) line the surface; the extracellular matrix or interstitium contains sparsely scattered connective tissue elements like collagen, elastic tissue, and smooth muscle; while an endothelial cell lines the blood capillaries. Evidently a product of a bioengineering blueprint that utilizes minimal structural materials, the remarkably thin blood-gas barrier allows efficient exchange of respiratory gases by passive diffusion. In the particularly thin regions of the interalveolar septum of the mammalian lung (143) and between the air and blood capillaries of the avian lung, the barrier is pretty much formed by squamous (thin), parallel cytoplasmic extensions of the epithelial (type 1) and endothelial cells that are literally "glued" back to back, onto an extracellular matrix (Figs. 5 and 6). The architecture has been described as a three-ply or laminated tripartite design.
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FIG. 5. A: blood-gas barrier of the lung of the African lungfish, Protopterus aethiopicus, showing epithelial cell (e) extracellular matrix (arrow), endothelial cell (n), and plasma layer (p). Scale bar is 4 µm. B: blood-gas (tissue) barrier of the lung of a tree frog, Chiromantis petersi, showing an epithelial cell (e) extracellular matrix (arrow), endothelial cell (n), plasma layer (p), and red blood cell (r). Dashed circle represents the area where a red blood cell is pressing onto the tissue barrier. Scale bar is 3 µm. [From Maina (140a).] C: blood-gas (tissue) barrier of the lung of the pancake tortoise, Malacochersus tornieri, showing an epithelial cell (e) overlying extracellular matrix (arrow), endothelial cell (n), plasma layer (p), and red blood cell (r). Scale bar is 5 µm. D: blood-gas (tissue) barrier of the lung of the monitor lizard, Varanus exanthematicus, showing an epithelial cell (e), extracellular matrix (arrow), endothelial cell (n), plasma layer (p), and red blood cell (r). Scale bar is 5 µm. E: blood-gas (tissue) barrier of the lung of a snake, the black mamba, Dendroaspis polylepis, showing an epithelial cell (e), extracellular matrix (arrow), fusing endothelial cells (n), and plasma layer (p). Scale bar is 2 µm. [From Maina (134).] F: blood-gas (tissue) barrier of the lung of a snake, the sandboa, Eryx colubrinus, showing an epithelial cell (e), extracellular matrix (arrow), an endothelial cell (n), and plasma layer (p). Scale bar is 3 µm.
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FIG. 6. A–C: blood-gas barrier of the mammalian lung from, respectively, a bushbaby, Galago senegalensis; the naked mole rat, Heterocephalus glaber; and a bat, Miniopterus minor. e, Epithelial cell; arrow, extracellular matrix; n, endothelial cell; p, plasma layer. Scale bars are as follows: A, 3 µm; B, 3 µm; C, 2 µm. D–F: blood-gas (tissue) barrier of the avian lung from, respectively, the house sparrow, Passer domesticus; the emu, Dromaius novaehollandiae; and the black-headed gull, Larus ridibundus. e, Epithelial cell; arrow, extracellular matrix; n, endothelial cell; p, plasma layer; r red blood cell. Scale bars are as follows: D, 0.4 µm; E, 0.5 µm; F, 0.3 µm. [F from Maina (132).]
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1. The water-blood barrier of the fish gills
Gills are the archetypal water breathing organs (99, 105, 140). Those of teleosts are structurally the most complex. Commonly, four gill (branchial) arches give rise to hundreds of gill filaments that in turn originate thousands of secondary lamellae (Fig. 7, A and B). The hierarchical arrangement produces extensive respiratory surface area in the confined space under the opercular flap, without invoking undue resistance to water flow (100). In some species of fish, e.g., Barbus sophor, secondary lamellae give rise to tertiary lamellae (106). The secondary lamellae are semicircular flaps that are bilaterally located on gill filaments (Fig. 7, A–C); they are the functional (respiratory) units of the teleost gills. The lamellae are comprised of two parallel sheets of epithelial cells that are connected by pillar cells that are highly characteristic of the ultrastructure of the teleost gills (110) (Figs. 4D and 7, B, D, and E). Containing abundant intracytoplasmic microfibrillar elements (13, 104, 209), the cells are contractile. The pillar cells maintain the mechanical integrity of the vascular channels, where blood pressure may reach 90 mmHg (12 kPa) (13, 101), and regulate lamellar perfusion. The cytoplasmic flanges of the pillar cells form the innermost (endothelial) component of the water-blood barrier (110, 173) (Fig. 7, B, D, and E). An interstitial space that contains connective tissue and cellular elements as well as lymphatic vessels occurs between the endothelial cells and the epithelial cells (100) (Fig. 7, D and E). Although the structure of the water-blood barrier in the fish gills differs in certain aspects from the blood-gas barrier of the vertebrate lung, a three-ply design is positively perceptible (Fig. 7, B, D, and E). The architecture is evident from the gills of the archaic coelacanth Latimeria chalumnae species (102, 103) to the modern teleost species (105); the design has been conserved for a long time in diverse species of fish.
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FIG. 7. A: gills of a teleost fish, Alcolapia grahami, showing gill filaments (f) and secondary lamellae (s). Scale bar is 1 mm. [From Maina (140a).] B: a gill filament (f) giving rise to secondary lamellae (arrows) that contain vascular channels (v). m, Primary epithelium. Scale bar is 0.5 mm. [From Maina (142).] C: a secondary lamella (s) receiving blood from a gill filament artery through afferent vessels (a). e, Efferent lamella blood vessel. Scale bar is 0.20 mm. [From Maina (141).] D: a secondary lamella showing vascular channels containing red blood cells (r). w, Water; e, epithelial cells; p, pillar cells; dashed area, water-blood barrier. Scale bar is 40 µm. [From Maina (141).] E: a marginal channel (v) of a gill filament. w, Water; e, epithelial cells; n, endothelial cells; b, interstitial cell. Scale bar is 15 µm. F: the composite primary epithelium of a gill filament showing pavement (epithelial) cells (arrows) and numerous chloride cells (c). Scale bar is 30 µm.
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Gill epithelial lining is divided into respiratory and metabolic sites (30, 198). The complex vascular anatomy of the gills (73, 169, 180) is thought to be fundamental to the adjustment of the respiratory and osmoregulatory surface areas. Gas exchange largely occurs across the simple, thin secondary epithelium that covers the secondary lamellae (Fig. 7, B, D, and E), while metabolic functions, e.g., osmoregulation and ammonia/urea excretion, occur in the more elaborate primary epithelium that lines the gill filaments (121, 136). Chloride (mitochondria-rich) and mucus cells occur in the primary epithelium (Fig. 7F). Adjustment of the functional sites on fish gills optimizes respiratory and metabolic performances; a fish at rest maintains a small respiratory surface area to procure the needed amount of oxygen for its metabolizing tissues to remain aerobic without risking excessive loss or overloading of ions.
2. Relationship between three-ply (laminated, tripartite design) and evolution of open circulation
Occurring in, e.g., annelids cephalopods and vertebrates, while lacking in arthropods and most mollusks, closed circulation (where a continuous endothelial lining delimits the vascular conduits), can (from ontogenetic perspective) be associated with the formation of the three-ply design in the gas exchangers (32, 105). The transition from open to closed circulation is but one of the many quantum leaps that occurred in the process of the evolution and refinement of the respiratory organs and processes (139–141). In addition to occurring in the mainstream gas exchangers, i.e., gills and lungs, the three-ply design is manifest in the accessory respiratory organs such as the suprabranchial chamber membrane and the labyrinthine organs of bimodal breathing fish (107, 155) (Fig. 8, A and B), structures that develop from the gills (107). The air-blood barrier in the physostomatous swim bladders of fish, organs that are commonly used as accessory respiratory organs (162), presents a three-ply design (Fig. 8, C and D).
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FIG. 8. A: surface of the suprabranchial chamber membrane of the catfish, Clarias mossambicus, showing epithelial cells (arrows), vascular channels (v) containing red blood cells (r), and endothelial cell (e). Scale bar is 30 µm. B: close-up of surface vasculature of the suprabranchial chamber membrane of the catfish, Clarias mossambicus, showing a visibly laminated tripartite blood-gas barrier particularly in sites shown by dashed circles. Arrows, epithelial cells; v, vascular channels; a, air space. Scale bar is 15 µm. C and D: blood vessels (v) on the surface of the physostomous swim bladder of a fish, Alcolapia grahami. a, Air space; e, epithelial cell; arrows, extracellular matrix; n, endothelial cell. Scale bars are as follows: C, 15 µm; D, 8 µm.
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In the invertebrate animals with an open circulation, three-ply design is lacking in the respiratory organs. In the lung of the tropical terrestrial slug, Trichotoxon copleyi (133), epithelial cells attach onto basement membrane while an endothelial lining of the vascular channels is lacking (Fig. 9, A and B). The hemolymph comes into direct contact with the epithelial cells. In the gill filaments of the freshwater African crab, Potamon niloticus (135) (Fig. 9, C and D), the vascular channels are exclusively formed by epithelial cells (Fig. 9D). The cells attach onto a basement membrane that fronts the external respiratory medium (water) while the apical aspect faces the hemolymphatic channel. The low blood pressure in open circulatory systems may allow the formation of less complex and conceivably potentially weaker water/air-blood barriers. With a better constructed tissue barrier, closed circulation permitted higher blood pressure, shorter circulatory time, and more efficient perfusion of the body tissues, features that were vital for the greater metabolism in the more advanced animals (197).
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FIG. 9. A: lung of a slug, Trichotoxon copleyi, showing an endothelial cell (n) protruding into a hemolymphatic vessel. Dashed circle represents the area where an epithelial cell (e) lies next to an endothelial cell. Arrow, discontinuous endothelial cell lining; a, air space. Scale bar is 5 µm. [From Maina (133).] B: lung of a slug, Trichotoxon copleyi, showing epithelial cells (e) overlying extracellular matrix. Arrow and dashed circle show a thinned or discontinuous endothelial cell (n). v, Vascular channel. Scale bar is 20 µm. [From Maina (133).] C: hemolymphatic vessel (v) in a gill filament of a freshwater crab, Potamon niloticus, showing hemocytes (h). w, Water; e, epithelial cell. Scale bar is 50 µm. [From Maina (140b).] D: hemolymphatic channels (v) in a gill filament of the freshwater crab, Potamon niloticus, showing epithelial cells (e) meeting at regular intervals (arrows) to separate the channels. Scale bar is 30 µm. [From Maina (135).]
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3. Cellular and connective tissue elements of the blood-gas barrier
Together with the blood cells, the mammalian lung is reported to have an assortment of more than 40 different cell types (4, 25, 235). Less than 20 of them occur at the alveolar level (29) where the type 1 and type 2 cells are the major ones. With an average volume of 1,500 µm3 and covering a mean surface area of 5,000 µm2 (39, 40), the type 1 cells (squamous pneumocytes) have long extremely thin cytoplasmic extensions (Figs. 4A, 5, 6, and 10, A and D) that stretch over a distance of 50 µm from the cell body (perikaryon). The trilaminar substance in the cytoplasm of the type 1 cells of the avian lung is thought to constitute an intercapillary "skeletal" support system (117). While constituting only 10% of the total cell population, the type 1 cells cover as much as 96% of the alveolar surface (40). The type 2 cells (granular pneumocytes) are cuboidal in shape (Fig. 10B). Of an average volume of 550 µm3 and constituting 12% of the total cell population, the type 2 cells cover only 5% of the alveolar surface. Compared with the type 1 cells that are largely devoid of organelles, the type 2 cells are secretory. They are well endowed with organelles and have characteristic microvilli on their free surface (Fig. 10B). The type 2 cells secrete the surfactant, material that contains dipalmitoylphosphatidylcholine, a surface-active phospholipid substance that stabilizes the alveoli (36, 46, 78, 163, 187). Osmiophilic lamellated bodies, organelles that are characteristic to the type 2 cells, are the precursors of the surfactant (Fig. 10B). Interestingly, akin to the three-ply design of the water/blood-barrier, the immunochemical proximity of the constitutive protein components of the surfactant has been highly and widely conserved (196). Among vertebrates, the surfactant is believed to have a single evolutionary origin (181, 215). Although particularly well-known in the vertebrate lung, to varying extents, the surfactant occurs in a range of organs, e.g., the intestinal mucosae and the swimbladder of actinopterygian fish, mesothelial tissues (mesentery, peritoneum, and pleura), synovial cells, Eustachian tubes, and probably in the salivary glands, pancreas, and urinary tract (20). Type 3 (brush) cells occur rarely in the vertebrate lung (49, 84, 171). The cells are typically pyramidal in shape, their free surface has large blunted microvilli, the cytoplasm contains numerous glycogen granules, and abundant intracytoplasmic microfilaments form a cytoskeletal system. Type 3 cells have been associated with functions like chemoreception, absorption, and secretion (49).
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FIG. 10. A: type 1 epithelial cell (t1) of the lung of the tree frog, Chiromantis petersi, showing thin cytoplasmic extensions (arrows). i, Extracellular matrix; n, endothelial cell; c, blood vessel. Scale bar is 25 µm. [From Maina (142).] B: a type 2 epithelial cell (t2) of the lung of the tree frog, Chiromantis petersi, showing osmiophilic lamellated bodies (arrows). n, Endothelial cell. Scale bar is 1.5 µm. [From Maina (140).] C: alveolar macrophage (mc) of the lung of a bat, Pipistrellus pipistrellus. v, Vesicular bodies; arrows, filopodia; c, blood capillaries. Scale bar is 5 µm. D: surface of a faveolus of the lung of a snake, Black mamba, Dendroaspis polylepis, showing axonal profiles (a) in an interstitial space. e, Epithelial cell; n, endothelial cells; arrows, extracellular matrix; c, blood vessel. Scale bar is 5 µm. [From Maina (134).]
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In the vertebrate lungs, surface (free) macrophages protect the respiratory surface by phagocytosing pathogenic microorganisms (22, 131, 178) (Fig. 10C). The cells are so efficient that in disease-free lungs, the respiratory surface is practically sterile. Notwithstanding their protective role, macrophages can initiate and perpetuate a range of inflammatory diseases (22, 174). Surface macrophages occur in the amphibian lung (131, 244) but are reportedly lacking in the snake, Boa constrictor, lung (87). Interstitial and intravascular macrophages exist in the lungs of various species of birds and mammals (6, 21, 42, 146, 206). The interstitial space and the extracellular matrix of the blood-gas barrier, e.g., on the thicker side of the interalveolar septum of the mammalian lung, contain supportive and contractile elements such as collagen, elastic tissue, smooth muscle, and fibroblasts. Nerve axons occur in the interstitial space of the blood-gas barrier of the lungs of snakes (134) (Fig. 10D). With their long cytoplasmic extensions that contain numerous plasmalemmal or micropinocytotic vesicles, to an extent, endothelial cells resemble type 1 alveolar cells (Figs. 3, 4A, 5, 6, and 10, A and D). Epithelial cells are, however, less permeable to solutes and more selective to some ions (57). Endothelial cells constitute 41% of the entire population of lung cells (40) and are significantly involved in the metabolic functions of the lung (7). The extracellular matrix (Figs. 3, 5, 6, and 10, A, B, and D) is deposited by the epithelial and endothelial cells. The matrix maintains the normal cytoarchitecture of the epithelial and endothelial cells, serves as a molecular barrier to negatively charged macromolecules, prevents passage of noninflammatory cells, and in certain cases influences cell differentiation, morphogenesis, and movement of molecular factors (41, 123, 204).
In the vertebrate lungs, notable differences occur in the extents of the differentiation and location of the pneumocytes. In the lungs of lungfishes (Dipnoi) and amphibians, the cells are incompletely differentiated; with microvilli on the apical surface, rather cuboidal in shape, and containing osmiophilic lamellated bodies, the pneumocytes have shared morphological features of fully differentiated type 1 and 2 pneumocytes (15, 175, 179). Pulmonary pneumocytes have completely differentiated into type 1 and type 2 cells in the avian (parabronchial) and mammalian (bronchioalveolar) lungs. The division of the cells may have greatly contributed to the thinning of the blood-gas barrier: the metabolically active type 2 cells adopted a cuboidal shape and hence came to line little of the blood-gas barrier, while the type 1 cells were rendered practically metabolically inert, became extremely attenuated, and covered most of the respiratory surface. Moreover, the process of fine-tuning the thickness of the blood-gas barrier entailed displacement of the epithelial cell bodies (perikarya) away from the blood-gas barrier to sites where the blood capillaries adjoined and the location of the connective tissue elements in nonrespiratory sites (Fig. 11). For example, in the avian lung, the cell bodies of the type 1 cells (Fig. 12A) infrequently occur on the respiratory surface and type 2 cells and surface macrophages are totally confined to the atria and infundibulae, "distant" nonrespiratory sites (116, 117, 146). The interalveolar septum of the mammalian lung has thick (supportive) and thin (respiratory) sides; connective tissue elements such as collagen and elastic tissue are found on the thicker side. The lungs of the ectothermic vertebrates have thicker barriers compared with those of the endothermic ones (75, 147, 168) (Table 1).
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FIG. 11. A: an interstitial cell (arrow) and a granular pneumocyte (g) in a bat lung, Epomophorus wahlbergi. The cells are located away from a blood capillary (v). a, Alveoli. Scale bar is 10 µm. [From Maina et al. (152).] B: lung of a bushbaby, Galago senegalensis, showing type 2 (granular) pneumocytes (g) located at intercapillary junctions away from the blood-gas barrier. a, Alveoli; v, blood capillaries; t, a neutrophil. Scale bar is 5 µm. [From Maina (142).] C: lung of a bushbaby, Galago senegalensis, showing an interstitial cell (i) and a type 2 cell (g) located between blood capillaries (v). a, Alveoli. Scale bar is 8 µm. D: blood capillaries (v) in the lung of a bat, Epomophorus wahlbergi. i, Interstitial cell; e, epithelial cell. Scale bar is 15 µm. [From Maina et al. (152).] E: blood capillaries (v) in the lung of a bat, Cynopterus brachyotis. n, Endothelial cell; e, epithelial cell; i, interstitial cell; p, platelet; a, alveoli. Scale bar is 10 µm. F: junction between blood capillaries (v) in the lung of a vervet monkey, Cercopithecus aethiopicus, showing an interstitial cell (i) and collagen fibers (c). a, Alveoli; e, epithelial cell; n, endothelial cell. Scale bar is 3 µm.
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FIG. 12. A: lung of the graylag goose, Anser anser, showing a type 1 epithelial cell (e) and a necrotising one (boxed area). a, Air capillary; c, blood capillary. Scale bar is 10 µm. B and C: lung of a redwing, Turdus olivaceus, showing sites where air capillaries lie adjacent to each other and where epithelial cells (e and arrows) lie back to back: an extracellular matrix space is lacking in such sites. n, Endothelial cell; e, epithelial cell; c, blood capillary; r, red blood cell. Scale bars are 3 µm. D: lung of the blackheaded gull, Larus ridibundus, showing an area where blood capillaries (c) contact. Note the lack of cellular and connective tissue elements. n, Endothelial cell; e, epithelial cell; c, blood capillary. Scale bar is 2.5 µm. [From Maina and King (147).]
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4. Sporadic attenuation in the design of the blood-gas barrier
In the mammalian lung, thin and thick sides occur at opposite sides of the interalveolar septum, while in the avian lung the blood-gas barrier (the tissue barrier between the air and the blood capillaries) is of even thickness, i.e., respiratory and supportive sides do not exist. In the parabronchial lung, however, while the extracellular matrix is of uniform thickness, the endothelial cell component of the blood-gas barrier presents conspicuous unevenness (Figs. 3 and 12, B–D). The irregularity produces extremely thin parts between relatively thicker ones. Weibel (237) envisaged that if the same quantity of structural material is utilized in the construction, periodic thinning of the blood-gas barrier allows the effective diffusion mean thickness of the barrier (the harmonic mean thickness, ht) to be three times smaller than if it was of even thickness. Given that building a blood-gas barrier twice this increases the diffusing capacity by one-quarter of the original value (239), sporadic (irregular) design may be a compromise solution for enhancing respiratory efficiency while preserving structural integrity. The importance of uneven construction of the blood-gas barrier to respiratory function is reflected in the fact that the design occurs, though less conspicuously, in the water-blood barrier of the secondary lamellae of the fish gills (110) (Fig. 7, B, D, and E) and is particularly conspicuous in the lungs of the endothermic vertebrates, i.e., mammals and birds (147) (Figs. 5 and 6). In the mammalian lung, the degree of epithelial and endothelial cell attenuation is significantly greater on the thin side of the interalveolar septum, while epithelial cell attenuation is more marked than the endothelial one on the thick and thin sides (47). In the lungs of some vertebrate taxa, e.g., those of amphibians (168) and in the water-blood barrier of the secondary lamellae of the fish gills (110), an interstitial space is intercalated between the epithelial and endothelial cells; collagen and elastic tissue fibers, smooth muscle fibers, nerve fibers, lymphatic spaces, and fibroblasts occur (Figs. 5, A and F, 6B, 7, D and E, 10, A and D, and 11, D–F). In the thin respiratory parts of the interalveolar septum of the mammalian lung and in the blood-gas barrier of the avian lung, a thin extracellular matrix layer separates the epithelial and endothelial cells (Fig. 6). Interestingly, in the avian lung, in sites where air capillaries lie next to each other, epithelial cells lie back to back, with an extracellular matrix space lacking (Fig. 12, B and C). As demonstrated on the cells of the renal tubules by Welling and Grantham (243), on their own cells cannot tolerate significant tension. The lack of an extracellular matrix space between the epithelial and the endothelial cells in the sites where air capillaries lie adjacent to each other (areas that in the "fixed" lung should experience little tension) provides indirect evidence that at least in the avian lung, the stress-bearing component of the three-ply blood-gas barrier may be attributable to the extracellular matrix. This deduction is further supported by the fact that while the endothelial and epithelial cells manifest remarkable sporadic attenuation, the extracellular matrix maintains constant thickness (Fig. 6, D–F). The construction of the blood-gas barrier in the avian lung, where epithelial cells alone separate air capillaries, has been permitted by the rigidity of the lung. Between the ventilatory cycles, the volume of the avian lung changes by a mere 1.4% (111). Suspended in a virtually inflexible construction, the areas where air capillaries lie adjacent to each other should expectedly be subjected to minimal tension.
C. Structural-Functional Correlations in the Design of the Blood-Gas Barrier
Before the 1940s when sound, reliable, and reproducible quantitative methods were formulated or modified from those used in disciplines like engineering and geology to analyze biological tissues (31, 34, 54, 55, 95, 230, 231), comparative pulmonary morphology was largely descriptive. Qualitative features like the degree of vascularity were used as relative indicators of respiratory efficiency. Plentiful comparative data now exist to allow far-reaching deductions to be made on the means and strategies that different animals utilize to procure molecular oxygen.
Pulmonary morphometric data show that the thickness of the water/blood-gas barrier correlates with properties such as body mass, phylogenetic stage of advancement , life-style pursued, and habitat occupied (51–53, 75, 105, 127, 132, 147, 148, 168, 191). Regarding the thickness of the blood-gas barrier, the most meaningful estimator of the diffusing capacity (or conductance) is the harmonic mean thickness (ht). Determined from the reciprocal of the mean of the sum of the reciprocals of representative intercept length measurements that are taken orthogonally, i.e., perpendicular to the plane at which the blood-gas barrier has been sectioned (to offset the effect of obliqueness of tissue cutting) and ranked on a logarithmic scale to weight the smaller measurements (90, 232, 241), ht is determined as
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where n is the total number of intercepts measured and i=1n1/1i is the sum of the reciprocals of the intercepts, i.e., the measurements of the thickness of the blood-gas barrier.
The emphasis of the thinner parts of the blood-gas barrier in the calculation of ht makes practical sense in so far as much of the diffusion of oxygen across the blood-gas barrier occurs across such areas. It is vital to underscore that the ht does not provide the absolute measure of the thinness of the blood-gas barrier and hence reflect its strength but rather defines the measure of the thickness that appropriately epitomizes the resistance (and hence the conductance) that the barrier presents to diffusing oxygen molecules. Estimation of the strength of the blood-gas barrier from the perspective of its thickness requires measurement of its thinnest parts and better still estimation of the surface area that such parts contribute to the entire measure (16). In accord to the well-known axiom (3), that "a chain is only as strong as its weakest link," it is a poor design for the blood-gas barrier to be too thin to tolerate tension under normal conditions of operation and to be too thick to meaningfully allow flux of oxygen by passive diffusion. Anticipated loading and necessary safety margin of operation should determine the overall design of the blood-gas barrier. An optimal design is one that confers adequate strength while allowing efficient diffusion.
The arithmetic mean thicknesses (t) and the ht in the amphibian, reptilian, and mammalian lungs differ substantially (75, 168, 188). Furthermore, except for the epithelial cell, the volume densities (proportions) of the components of the blood-gas barrier, i.e., the epithelium, interstitium/extracellular matrix, and the endothelium, vary. While in the three taxa the epithelium invariably forms 31% of the volume of the blood-gas barrier, in amphibians, reptiles, and mammals, respectively, the interstitium/extracellular matrix forms 43, 44, and 41% and the endothelium forms 26, 25, and 28% of it (168). In the avian lung, however, the endothelium constitutes much of the blood-gas barrier (67%), while the extracellular matrix and the epithelium comprise 21 and 12%, respectively (147). Although generally thicker than the blood-gas barrier of lungs, the water-blood barrier of the fish gills may be as thin as 0.2 µm in certain species (105, 122, 138). In the various vertebrate species examined by Meban (168), on average, the mean t of the blood-gas barrier was 1.61 µm in the mammalian lung and, respectively, 2.17 and 2.04 µm in the amphibian and reptilian lungs. The minimum ht of the blood-gas barrier in the avian lung is 0.068 µm (132, 147), that in mammalian lung is 0.20 µm (75), and the values in the reptilian and amphibian lungs are 0.22 and 0.21 µm, respectively (168).
The ratio of the t to ht defines the degree of attenuation and hence the unevenness of the thickness of the blood-gas barrier (241). In the vertebrate lung, the highest ratio (8:1) was reported in the avian lung by Maina and King (147). Corresponding values in the mammalian, reptilian, and amphibian lungs are, respectively, 3:1, 2:1, and 1.3:1 (169) (Table 1). Morphological observations show conspicuous corrugation of the blood-gas barrier of the avian lung (Figs. 5 and 6) compared with those of other vertebrates (Fig. 6, D–F); of the three structural components of the blood-gas barrier, the endothelial cell is markedly the most uneven.
The ht in the lungs of various vertebrate taxa are given in Table 1. Among mammals, bats, the only volant taxon, generally have the thinnest barriers (149, 152, 159). The thinnest barrier (0.120 µm) has been reported in the lung of the flying fox, Phyllostomus hastatus (159). Among the nonflying mammals, the remarkably small, metabolically highly active shrew, Suncus etruscus (65, 210), has the thinnest blood-gas barrier (0.23 µm) (76). In birds, the thinnest blood-gas barrier (0.099 µm) has been reported in the African rock martin, Hirundo fuligula (127), and the violet-eared hummingbird, Colibri coruscans (51), two small, highly energetic species. The generally small passerine birds, a highly successful group that comprises of 5,739 species (>60% of the total number of extant avian species) (8, 207) and that operates at a relatively higher body temperature of 42°C compared with that of 40°C of other birds and the lower one of 38°C of mammals (5, 120), have relatively thinner blood-gas barriers (127). Exceptionally thick blood-gas barriers occur in the lungs of large, nonflying birds: ht is 0.530 µm in the lung of the Humboldti penguin, Spheniscus humboldti (150); in the emu, Dromaius novaehollandiae, the value is 0.232 µm (151); in the domestic fowl, Gallus gallus variant domesticus, it is 0.318 µm (2); and in the ostrich, Struthio camelus, it measures 0.560 µm (158). The thick barrier in the penguin lung purportedly averts collapse of the air capillaries during dives (245). Among the air-breathing vertebrates on which data are available, the blood-gas barrier is thickest in the lungs of the low metabolism amphibians, the common newt, Triturus vulgaris (2.34 µm) and the Italian crested newt, Triturus cristatus (2.20 µm) (168); these animals utilize accessory respiratory structures like the skin and the buccal cavity to meet their overall oxygen needs.
1. Optimization of the thickness of the blood-gas barrier
In the vertebrate lungs, the thickness of the blood-gas barrier appears to have been allometrically optimized. This consideration is based on the fact that the parameter changes very little with increasing body mass (Fig. 13). Illustratively, although mammals span a colossal range of body mass from the minute 2.5 g Etruscan shrew, S. etruscus, to the 150-ton bowhead whale, Balaena mysticetus, a factorial difference of 60 x 106, the thickness of the blood-gas barrier (ht) of the lung of the shrew (0.230 µm) (76) differs from that of 0.350 µm (t) of a whale (94) by a factor of only 1.3. In birds, the thickness of the blood-gas barrier in the 7.3 g violet-eared hummingbird, Colibri coruscans (the smallest bird on which data are available), is 0.099 µm (51), while that of an immature 40-kg ostrich, Struthio camelus (the heaviest bird on which ht is available), is 0.56 µm (158); the body mass factorial difference is 5 x 103 while that of the thickness of the barrier is 6. In bats where the heaviest species, the flying foxes, weigh 1.5 kg, the thickness of the blood-gas barrier in the tiny 5 g pipistrelle, Pipistrellus pipistrellus, is 0.206 µm compared with that of 0.303 µm in Pteropus poliocephalus (149, 159); the body mass factorial difference is 185 while that of the thickness of the blood-gas barrier is only 1.5. The remarkable thinness of the blood-gas barrier in the avian lung together with paucity of surface (free) macrophages on the respiratory surface (116, 146, 178) are thought to predispose birds to pulmonary infections and pathological afflictions.
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III. DESIGN OF THE BLOOD-GAS BARRIER FOR STRENGTH
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A. Components of the Blood-Gas Barrier
Unless otherwise stated, this section will specifically address the blood-gas barrier of the mammalian lung. This is unfortunately because hardly any data exist regarding the minimum thickness, strength, and failure of the blood-gas barrier in the lungs of the other vertebrate taxa. Indeed, even for the mammalian lung itself, details are only available for the dog, rabbit, rat, human, and horse (Thoroughbred) lungs.
In discussing the strength of the blood-gas barrier, we should first recognize the differences in the composition of the thin and thick sides of the interalveolar septum. In many lungs the blood-gas barrier is polarized in the sense that one side is extremely thin while the other side is substantially thicker. As pointed out in section IIB, the thin side is made up of a fine protoplasmic extension of a type 1 alveolar cell, the thin cell body of a capillary endothelial cell, and an interstitium or extracellular matrix between these two cellular layers. Covering the alveolar epithelial layer is an aqueous surface lining layer containing pulmonary surfactant. This thin fluid layer with its very low surface tension makes only a small contribution to the strength of the barrier (176). The primary function of this thin side of the blood-gas barrier is to allow efficient gas exchange by passive diffusion, and this function requires its extreme thinness.
In contrast, the thick side of the blood-gas barrier apparently has other functions. Of course some gas exchange may occur across it, but because its thickness is several times that of the thin side, its diffusion resistance is high and its efficiency for gas exchange is low. One of its functions is to allow fluid exchange across the pulmonary capillary, and it is noteworthy that in early interstitial pulmonary edema, there is substantial thickening of this portion of the blood-gas barrier as a result of fluid accumulation, while there are no morphological changes on the thin side (63, 217). Here it should be emphasized that fluid apparently moves out of the pulmonary capillary into the interstitium whenever the capillary pressure rises. For example, Staub (211) showed in awake sheep that very soon after an intravenous infusion of saline or dextran there is a measurable rise in lymph flow from the lung as would be expected from the disturbance of the Starling equilibrium. Indeed, it is likely that on exercise, the inevitable rise in pulmonary capillary pressure will result in fluid movement out of the capillary into the interstitium of the lung, and at the end of the exercise when the capillary pressure falls, the fluid will reenter the capillary from the interstitium.
The thick side of the blood-gas barrier has an additional function as emphasized by Weibel (234). It accommodates the type I collagen fibers that make a major contribution to the structural scaffolding of the lung in the alveolar region and elsewhere. These fibers thread their way along the alveolar wall, crossing from one side to the other, and as they pass adjacent to a capillary lumen they are accommodated in the thick side of the blood-gas barrier. This anatomical arrangement is responsible for the polarization of the blood-gas barrier because the region containing the type I collagen fibers needs to be relatively wide to accommodate them, while on the other side of the capillary lumen in the absence of these fibers, the barrier can afford to be extremely thin. The extracellular matrix on the thin side presumably plays little role in maintaining the shape of the alveolar region of the lung, but it is crucial in maintaining the integrity of the blood-gas barrier itself so that it can withstand the stresses resulting from increases in capillary transmural pressure or the longitudinal tension in the alveolar wall.
The structural scaffold resulting from the type I collagen fibers is anchored at the hilum and forms a support for both the airways and blood vessels as it penetrates deeper into the lung. One of its functions is to divide the lung into a series of lobes and bronchopulmonary segments. At the alveolar level, this fibrous network is responsible for maintaining the geometry of the alveolar ducts and the alveoli themselves. For example, the intra-acinar airways including the respiratory bronchioles and alveolar ducts contain abundant fibers that make a mesh encircling the mouths of the alveoli. The concentration of the type I collagen of the connective tissue is particularly strong in the rings that demarcate the alveolar ducts.
It is generally assumed that the most vulnerable region of the blood-gas barrier from the point of view of mechanical integrity is the thin side because, other things being equal, the stresses will be highest there. However, it should be emphasized that the distribution of stresses on the thick side is unknown. In fact, ultrastructural studies of stress failure of pulmonary capillaries sometimes show disruptions on the thick side of the blood-gas barrier (for example, see Fig. 19B), emphasizing that our knowledge of the distribution of stresses is incomplete.
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FIG. 19. Examples of stress failure in pulmonary capillaries. A: disruption of the capillary endothelial cell (arrows) but the alveolar epithelium and two basement membranes are intact. B: disruption of an alveolar epithelial cell at the top (arrows), and disruption of a capillary endothelial cell near the bottom (arrows). A blood platelet is adhering to the exposed basement membrane below. C: disruption of all layers of the capillary wall with a red blood cell apparently passing through the opening. D: scanning electron micrograph showing breaks in the alveolar epithelium. [A and B modified from West et al. (253); C from Tsukimoto et al. (223); D from West and Mathieu-Costello (251).]
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Many morphometric studies have been carried out on the thickness of the blood-gas barrier (74, 75, 234) (see Table 1), but unfortunately few of these give direct information about the distribution o
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