Lung Biology Laboratory, Departments of 1 Medicine and 2 Pediatrics, Georgetown University School of Medicine, Washington, District of Columbia 20007-2197
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ABSTRACT |
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The lung's only known essential
function is to provide sufficient alveolar surface to meet the
organism's need for oxygen and elimination of CO2. The
importance of the magnitude of alveolar surface area (Sa) to
O2 uptake (O2) is supported
by the presence among mammals of a direct linear relationship between
Sa and
O2. This match has been achieved,
despite the higher body mass-specific
O2
of small organisms compared with large, by a greater subdivision of
alveolar surface, not by a larger relative lung volume in small organisms. This highly conserved relationship between alveolar architecture and
O2 suggests the
presence of similarly conserved mechanisms that control the onset,
rate, and cessation of alveolus formation and alveolar size, which are
also influenced by retinoids and thyroid and corticosteroid hormones.
Furthermore, the "call for oxygen" is met at a breathing rate and
tidal volume at which the work of breathing is lowest. Thus there is a
complex, fascinating, but poorly understood, signaling relationship
among
O2, the neural regulation of
breathing, and lung architecture, composition, and mechanics.
oxygen consumption; hyperoxia; hypoxia; calorie restriction; corticosteroid hormones; retinoids; thyroid hormone
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INTRODUCTION |
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THE LUNG'S ONLY KNOWN
ESSENTIAL function is to provide sufficient gas-exchange surface
to satisfy the organism's need for oxygen and elimination of carbon
dioxide. The central importance of lung architecture to oxygen uptake
or, as elegantly put by Krogh (79), to the "call for
oxygen," is supported by the presence, across the entire
range of mammalian body mass, of a direct linear relationship
between alveolar surface area (Sa) and O2 uptake (O2) (Fig.
1) (143). This match has
been achieved, in spite of the higher body mass-specific
O2 of small organisms compared with
large, by a greater subdivision of the alveolar surface (Fig. 2), not by a larger relative lung volume
in small organisms (143). The highly conserved
relationship among alveolar size, number, Sa, and
O2 suggests the presence of similarly
conserved, but minimally understood, mechanisms that control the onset,
rate, and cessation of alveolus formation as well as the distance
between, and length of, alveolar septa. Furthermore, the organism's
call for oxygen is met at a breathing rate and tidal volume at which the work of breathing, and therefore its energy cost, is at a nadir
(Fig. 3) (2, 40, 105, 109, 122,
128). Thus we propose that there is a complex, fascinating, but
poorly understood, signaling relationship among
O2, the neural regulation of breathing,
and lung architecture, composition, and mechanics.
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In this paper we review and try to synthesize, interpret, and understand some recent and old findings about the formation of alveoli, its regulation, and the plasticity of the architecture of the lung's gas-exchange region. We do not review development of the fetal lung, for which there are several recent reviews (61, 107, 150); we review only selected insights from studies on mutant animals, and we do not review the lung's architectural response to pneumonectomy.
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FORMATION OF ALVEOLI: TIMING, ARCHITECTURAL METHODS, AND SITES |
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To facilitate exposition and to conform to the literature (5, 25, 26, 95), we call the gas-exchange structures of the architecturally immature lung alveolar saccules, their subdivision into smaller units (alveoli) septation, and the period in which septation occurs the period of septation. The formation of alveoli other than by septation of alveolar saccules is referred to as "other," but the architectural mechanism by which the other occurs is unclear (see below). We discuss evidence that, at least in part, the regulation of septation and other means of forming alveoli may differ.
In all mammals of which we are aware, pulmonary alveoli are formed, in part, by septation of alveolar saccules (3, 5, 17, 25, 26, 28, 33, 41, 43, 44, 46, 83, 154, 156, 157). However, the time in development during which septation occurs varies considerably among species in a manner that greatly reflects the newborn's activity lifestyle. For example, guinea pigs (33) and range mammals (3, 28, 154), which have great locomotive capacity at birth, septate in utero; others, e.g., rats (25, 26) and mice (5), with little locomotive capacity at birth, septate after birth. Humans septate during the last month of gestation and during the postnatal period (83, 156, 157). Precisely when septation ends in humans is uncertain, but it seems to continue for at least a few months after birth (83, 156, 157).
Burri et al. (25, 26) published some of the first and most
useful modern era studies on septation. Among many important observations, they showed that the distance between alveolar walls (Lm) diminishes during the period of septation
(5, 26). In rats, ~70% of this diminution occurs by
postnatal (PN) day 7 (26), suggesting that
septation is almost complete by then. This interpretation of the 70%
fall in Lm was supported and extended by the use
of procedures that allow estimation of the volume of individual
alveoli. Thus the average volume of individual alveoli in rats falls
sixfold between PN days 1 and 6 (125), but only little more over a period twice as long,
i.e., between PN days 2 and 14 (95)
(Fig. 4). Because the rate at which lung
volume increases does not change during the period of septation
(24), the virtually identical fold fall in volume over 6 days and 12 days indicates septation is complete, or almost complete,
by PN day 7, as was gleaned from the data of Burri et al.
(26).
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Based on the number and volume of individual alveolar saccules present in 1-day-old rats (before septation) and the number of alveoli in 6-day-old rats (after the onset of septation), Randell et al. (125) calculated septation of alveolar saccules to account for only about one-third of the alveoli formed between PN days 1 and 6. Calculations from similar measurements on rats on PN day 2 and PN day 14 indicate that ~25% of alveoli formed during the period of septation result from septation of the original alveolar saccules (95). These observations support the notion (93) that during the period of septation, alveoli are formed by septation of the original saccules present at birth and by other as yet poorly identified architectural events, which probably occur at the periphery of the lung.
Beginning in the second PN week and accelerating in the third, alveolar walls become thinner (25, 26) due, at least in part, to apoptosis of interstitial cells of the alveolus (7, 22, 136). This timing is stressed to encourage consideration of the role in these processes, e.g., ending septation, alveolar capillary remodeling, and apoptosis, of several molecules, already identified, whose expression peaks in rat lung at approximately PN day 7-9. These molecules include galectin-1 (30, 124), cellular retinoic acid binding protein-I (CRABP-I) (120), rA5D3, a recently cloned gene (15), and cGMP phosphodiesterase (57). Bioinformatic and experimental molecular searches for additional genes whose expression is briefly elevated or depressed around PN day 7-10 and that share similar molecular binding sites in their promoter regions should be fruitful.
In rat (13, 95) and mouse (75), species whose gas-exchange region has been studied most completely, alveoli continue to form after PN day 14 until about age 40 days (Fig. 4). However, little about the anatomical process or sites of the postseptation formation of alveoli has been directly shown. Reports (18, 46) that the number of generations of conducting airways diminishes after birth in dogs have suggested these airways may have been remodeled into gas-exchange airways, thereby increasing the number of alveoli (so-called retrograde alveolarization). However, because there are so few terminal airways compared with the number of alveoli, it is unlikely retrograde alveolarization, if in fact it occurs, would produce many alveoli. More importantly, using rigorous sampling techniques and morphometric procedures, Randell et al. (125) did not detect a change in the number of terminal bronchioles in rats during the early PN period. Many additional questions about other means of forming alveoli remain. For example, after the period of septation has ended, are alveoli formed throughout the lung among already formed alveoli, or are they generated, as the thorax enlarges, in a more peripheral location, i.e., in the subpleural zone, much as a tree increases in length and crown size by growth from the peripheral tips of its branches? Reason and indirect evidence support the periphery as the site of postseptation formation of alveoli. Thus if after septation of alveolar saccules is complete and alveoli continue to form throughout the lung by production of septa among alveoli already formed, alveoli should become smaller, not larger, after age 14 days (Fig. 4) unless lung volume increases more rapidly than alveoli are formed, which does not occur (24). The presence of a uniform turnover throughout the lung of extracellular matrix after age 14 days would support the notion of alveolus formation throughout the lung. However, within the limits of the methods used to assess it, matrix turnover is more rapid among subpleural alveoli than among more central alveoli (96). This supports the notion the periphery is the site of the postseptation formation of alveoli. Finally, analysis of changes in alveolar septal border lengths during PN development of ferrets suggests septation of already formed alveoli is not a prominent mechanism for an increase in the number of alveoli and size of alveolar surface area after the period of septation (155). From these findings and considerations, we propose that after the period of septation, alveoli are formed predominantly in the peripheral subpleural region. We extrapolate from these same considerations that during the period of septation, the other means of alveolus formation takes place in the subpleural region.
The cellular and molecular bases for the putative shift in the location of alveolus formation from throughout the lung, including the subpleural region, to only the subpleural region, are unclear. The architectural mechanism(s) for the peripheral formation of alveoli is also unknown. However, if the lung's gas-exchange region is considered to be a series of branching tubes, continued branching of the distal alveoli and septation of the blunt ends of the branches to generate appropriately sized alveoli as the thorax enlarges are to us, an attractive possibility as a mechanism of alveolus formation after the period of septation (93). Supporting this possibility, cells that store retinol, a precursor of all-trans retinoic acid (ATRA), which can induce alveolus formation (see below), are diffusely distributed in the lung during the period of septation (147) but become concentrated in the subpleural region after that period has ended (81, 96, 119). It will be of interest to test whether treatment with ATRA, which induces alveolus formation in adult rodents (12, 98, 99), causes the in vivo appearance of lipid interstitial cells throughout the lung.
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THE "CALL FOR OXYGEN" |
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Hyperoxia. The clear relationship among O2 need, alveolar size, and the magnitude of alveolar Sa from the smallest to the largest mammals (Figs. 1 and 2) (143) suggests that hyperoxia (excess O2) and hypoxia (or other causes of cellular O2 shortfall) have opposing regulatory effects on the size of the alveolar Sa. Experimental work supports this notion but must be considered in light of the fact that most of it has been carried out in rats and with consideration of the potential harmful effects on cellular function exerted by hyperoxia and hypoxia through the production of O2 radicals (50). For example, among several studies that show hyperoxia diminishes septation (9, 23, 48, 137, 151), those of Randell et al. (125) in which newborn rats were exposed to 95% O2 from PN day 1 to PN day 6 provide the most quantitative information, including the demonstration that hyperoxia depresses other means of forming alveoli as well as septation (125). However, 95% oxygen severely damages the lung (23, 48, 137, 151) and slows body growth (139); it is, therefore, uncertain whether the decreased rate of alveolus formation reflects a need for less gas-exchange surface in an O2-rich environment, the toxic effect of O2 directly on the lung, an effect on the lung of systemic O2 toxicity, or a combination of these possibilities.
The issue of O2 toxicity was somewhat diminished by Burri and Weibel (27), who began much of the early work on the relationship between O2 need and lung architecture. They exposed rats that had already septated but were still growing rapidly to 40% O2, which is much less damaging than 95% O2. A key feature of their experiments is that the rats exposed to 40% O2 increased body mass at the same rate as air-breathing rats of the same age. In spite of identical rates of body growth, which suggests the absence of systemic damage due to hyperoxia, lung growth in O2 rats, as evidenced by total lung volume, alveolar capillary volume, lung tissue volume, alveolar Sa, and alveolar capillary Sa, was ~16% less than in air-breathing rats (27). However, pulmonary oxygen toxicity must still be considered because at any concentration of inspired O2, the lung is exposed to a higher PO2 than other tissues. Nevertheless, our operational conclusion regarding the Burri and Weibel data (27) is that a diminished rate of increase of gas-exchange surface, without a concomitant inhibition of increase of body mass, reflects a need for less alveolar Sa due to a greater delivery of O2 to tissues in an O2-enriched environment. One of the anonymous reviewers of this manuscript pointed out that the arterial O2 content at 40% O2 is only about 2% higher than at 21% O2 and asks, "Why should that tiny increase in O2 content cause the degree of difference in alveolar architecture reported by Burri and Weibel (27)?" This is a good, thought-provoking question for which we lack an equally good answer. Perhaps the most obvious answer is that our operational conclusion about the Burri and Weibel work is wrong, and the difference between alveolar and peripheral tissue O2 tension at these concentrations of O2 is sufficient to cause alveolar O2 toxicity without O2 toxicity in the peripheral tissues. Conversely, however, if it is peripheral tissue(s) that sounds the call for oxygen, the difference in peripheral tissue PO2 at 20.9% and 40% inspired O2 may be sufficient to signal the need for less lung. Such putative tight regulation would be consistent with the notion of symmorphosis, i.e., sufficient but not excess tissue for functional need (152). The molecular basis for sensing O2 need, the location of the sensor(s), and the signaling path(s) constitute a challenging and exciting area of research.Hypoxia. The relationship between lung function and a chronically low inspired PO2 has been intensively studied for many years (for a range of reviews, see Refs. 8, 34, 51, 67, 76, 82, 110, and 111), mainly because of people native to high altitude whose forbearers lived for generations at high altitude. We refer to those individuals as highlanders, and we refer to those of the same race, native to sea level, as lowlanders. It is important to point out that among highlander populations in different parts of the world, e.g., South America, the U.S. Rockies, Tibet, and Ethiopia, those populations that have established high altitude residence earliest in evolutionary time seem to be most adapted, perhaps reflecting more time for genetic adaptation (111).
Andean highlanders have a 38% larger residual lung volume (67), larger, more numerous alveoli (134), lower maximum expiratory flow rate per lung volume, and lower upstream airway conductance than lowlanders (20). The last two characteristics contributed to the notion that gestation and PN maturation of humans at high altitude results in dysanaptic lung growth, more specifically, excess growth of the gas-exchange region compared with the conducting airways (20). Also contributing to the notion of dysanapsis in this context is the clear evidence that the adaptive response of healthy pregnant humans and animals (38, 87, 111), while not complete (54, 64, 111), partially protects the fetus from the low PO2 of high altitude, which is, therefore, first fully felt at birth (110, 127). Thus the lung's conducting zone, which in all mammalian species reported develops mainly during gestation (21), would be less affected by a low atmospheric PO2 than the gas-exchange region of organisms that septate after birth, e.g., rats (25, 26), or mainly after birth, e.g., humans (83, 156, 157). Tenney and Remmers (142) compared alveolar dimensions of guinea pigs bred and raised for many generations at 4,530 m and third-generation sheep resident at 4,390 m with guinea pigs and sheep native to Hanover, NH (altitude 160 m). Both species septate in utero (3, 33). They failed to find intraspecific differences in alveolar dimensions between sea level and highlander animals (Table 1), supporting the notion that atmospheric hypoxia does not have a large effect on alveolar dimensions in organisms that septate in utero.
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Alveolar plasticity in response to the endogenous call for oxygen.
The use of an altered inspired PO2 to study the
effect the availability of O2 has on alveolar dimensions
has, as discussed above, provided very useful information. However, as
also mentioned, tissue toxicity due to oxygen radicals as a determinant
of the alveolar response to an altered inspired O2 is
difficult to exclude. Treatment with thyroid hormone, or blocking
conversion of thyroxine to triiodothyronine, to alter
O2, is confounded by the action of
thyroid hormone beyond its effect on
O2
(6). We believe that a more physiological means of
altering
O2, one that occurs in nature
(66) and represents an endogenous alteration in the call
for oxygen, is calorie restriction (CR) and CR followed by refeeding
(CR-RF). CR lowers
O2; refeeding after
CR returns
O2 to values present before
CR (47, 53).
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HORMONAL REGULATION OF ALVEOLUS FORMATION DURING THE PERIOD OF SEPTATION |
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Glucocorticosteroid hormones. In contrast to the detailed information about architectural processes of alveolus formation during the period of septation, due mainly to work in Bern (24-27, 156, 157) and which now includes many species (3, 5, 28, 83, 140, 154), little is known about the regulation of septation. Our early thinking was greatly influenced by a consideration of the architectural events needed to form a septum and by the notion that changes in the concentration of systemic hormones (59, 60) might regulate the sequence in which organs, e.g., PN lung and pancreas, attain adult anatomical or functional characteristics (5, 25, 26, 60). We should bear in mind that little work on regulation of alveolus formation has been done other than in rodents.
From the available systemic hormones, we tested the possibility that glucocorticosteroids might affect (inhibit) the formation of septa for three main reasons. First, eruption and elongation of alveolar septa are brought about by forming ridges in epithelial sheets, which in part requires epithelial cell division. In addition, new septa must be filled with capillaries and fibroblasts, which also requires cell replication. Because glucocorticosteroids inhibit cell division in several tissues (86), including the lung (93, 112), they might prevent septation. This idea was strengthened because there is a trough in the serum concentration of the species' active glucocorticosteroid hormone during the period of septation, whether septation occurs in utero or postnatally (59, 70). Furthermore, the serum concentration of glucorticosteroid hormones begins to increase as septation ends and as there is acceleration of the thinning of the alveolar wall (25, 26). This suggests the elevated concentration of the hormone initiates the end of septation, the onset of accelerated alveolar wall thinning, and the remodeling of alveolar vessels from a double capillary to a single capillary system (25, 26). Treatment of rat pups with dexamethasone, a synthetic glucocorticosteroid hormone, during the period of septation prevents septation (14, 93) and diminishes the rate of DNA synthesis and accumulation in the lung (93). The mechanism(s) by which dexamethasone inhibits septation is unknown, and, in view of the many genomic (1) and nongenomic (29) actions of corticosteroid hormones, there is a myriad of possibilities. Nevertheless, in the spirit of guilt by association (Ref. 4 and later in this paper), the PN time course of activity in lung of ornithine decarboxylase (ODC) offers two possible, not mutually exclusive, mechanisms. The activity of ODC peaks in lungs of rats during septation (PN days 4-6) but not in liver, heart, brain, or kidney (146) and is depressed in lung, but not in liver, by corticosteroid treatment (10) during the period of septation (26). ODC, whose activity correlates with DNA synthesis (123), catalyzes the synthesis of polyamines, which are involved in cell replication. Thus to the extent that proliferation of alveolar wall cells is essential to, but not sufficient for, the formation of a septum, the impairment of septation by dexamethasone could reflect its depression of proliferation of alveolar wall cells by its inhibition of ODC activity. Because polyamines can regulate communication through gap junctions (138), the inhibition of septation by dexamethasone could involve more than depression of cell replication. Dexamethasone might block septation by interfering with intercellular communication through gap junctions. This notion is supported by studies on other organs showing that the expression of gap junction protein is developmentally regulated (19, 71) and that gap junction channels regulate epithelial-mesenchymal transformation during heart development (118). To extend this line of thinking, oxidative stress diminishes the function of gap junctions (78, 90, 116); hypoxia (37), hyperoxia (50), and premature birth (49) cause oxidative stress and impair septation (13, 23, 32, 89, 101, 140). Therefore, if corticosteroids, hyperoxia, hypoxia, and premature birth inhibit septation by diminishing cell-cell communication through gap junctions, it opens the possibility of preventing the inhibition of septation during hypoxia, hyperoxia, or corticosteroid treatment by pharmacologically augmenting communication through gap junctions. In addition to blocking septation, dexamethasone treatment markedly accelerates alveolar wall thinning and changes the cellular composition of the wall (91). Within 2 days of the onset of treatment of 4-day-old rats with diluent or dexamethasone, dexamethasone-treated pups have 20% thinner gas-exchange walls, a 32% lower absolute volume of retinol-storing interstitial fibroblasts, and a 1.5-fold higher volume of alveolar type II cells than diluent-treated rats (91). These experiments also provide evidence that dexamethasone 1) diminishes replication of fibroblasts in the alveolar wall, thereby diminishing the number of retinol storage cells (see below for relevance) and 2) impairs conversion of alveolar type II cells to alveolar type I cells, for which there would be less need if the gas-exchange surface is increasing at a slower rate than in diluent-treated pups. Once septation has been prevented by corticosteroids, discontinuing them is not followed by spontaneous septation, at least not up to age 60 or 95 days, i.e., 47 (93) and 82 (132) days after stopping the administration of corticosteroids. Failed septation is accompanied by the formation of fewer pulmonary arteries and by pulmonary hypertension (84). Because the gas-exchange Sa is also diminished, a restricted alveolar capillary bed could contribute to the pulmonary hypertension. Furthermore, the magnitude of hypoxia-induced pulmonary hypertension is greater in dexamethasone-treated rats than in diluent-treated rats (84). This important paper (84) clearly demonstrates a long-term functional effect of early events. The effects of dexamethasone on septation and the pulmonary vessels have important implications for prematurely born babies treated with corticosteroids for days or weeks. Such treatment might increase the impairment of septation that occurs even in the absence of glucocorticosteroid therapy (68, 89, 140). In addition, because of the anatomy of the lung in bronchopulmonary dysplasia, these infants have areas of alveolar hypoxia that could further increase pulmonary vascular resistance.Thyroid hormones.
Three considerations led us to the hypothesis that thyroid
hormone exerts a regulatory effect on subdivision of the large saccules
that constitute the gas-exchange region of the rat lung at birth.
1) Thyroid hormone concentration in rat serum
(113) and thyroid hormone receptor density in rat lung
(11, 129) begin to increase just before the onset of
septation. 2) Thyroid hormone treatment induces substantial
changes in brain architecture without a detectable effect on
O2 (31, 121). 3)
Thyroid hormone treatment increases DNA synthesis in the lung of
newborn rats (113). Triiodothyronine (T3)
administered to newborn rats at a dose that does alter the
developmental increase in body weight (92) and that at
even higher doses does not increase
O2
(141) accelerates the pace of septation, resulting in
smaller alveoli and a greater Sa without affecting lung volume
(92). The combination of a larger Sa without a large lung
volume indicates T3 induces the formation of additional
alveoli. Injection of propylthiouracil, which blocks conversion of
thyroxine to T3 (35), impairs septation without slowing the developmental increase of body mass or lung volume.
Thyroxine treatment, at a lower dose than is required to increase
O2 (141), overcomes the
inhibitory effect of propylthiouracil on septation (92).
These findings indicate thyroid hormone does not accelerate septation
by increasing
O2 and raise the
possibility that treatment with thyroid analogs that have little effect
on
O2 might induce septation when given
alone, or in combination with, retinoids (see below).
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RETINOID REGULATION OF ALVEOLUS FORMATION: MORE GUILT BY ASSOCIATION |
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Several lines of evidence available in the late 1980s and early 1990s led to the notion that retinoids might play a key role in the formation of pulmonary alveoli during the period of septation. In rats, this evidence included: 1) the high concentration of cellular retinol binding protein-I (CRBP-I) in lung, but not in liver, during the period of septation (120); 2) treatment of adult rats with ATRA upregulates CRBP-I mRNA, whereas treatment with dexamethasone, which inhibits septation (14, 93, 132), downregulates CRBP-I mRNA (130); 3) the lung's concentration of CRABP-I peaks at approximately PN day 9-10 (120) (we now speculate CRABP-I may be an inhibitor of septation or may be involved in conversion of the double to the single capillary system in the alveolus; see below); and 4) fibroblasts rich in vitamin A (retinol) storage granules occupy a large fraction of the alveolar wall throughout the lung during the period of septation (147), a time when alveoli are formed throughout the lung. After the period of septation, these cells become located mainly in the subpleural region (81, 96), the site where, we believe, the postseptation formation of alveoli takes place (96). These observations, as clues that retinoids exert a regulatory effort on septation, were supported by the general knowledge that retinoids play a key role in developmental processes in many tissues (106).
On the supposition of guilt by association, i.e., much lung retinoid
activity during the period of septation, we tested the hypothesis that
treatment of newborn rats with ATRA might prevent the inhibition of
alveolus formation produced by dexamethasone; the hypothesis was not
falsified (97). Furthermore, treatment of rat pups with
ATRA alone causes the formation of more numerous, but smaller, alveoli
without affecting lung volume or alveolar Sa. Briefly (see Ref.
83 for a full discussion of this seeming paradox), the
absence of a higher Sa in rats treated with ATRA alone, compared with
vehicle-treated rats, suggests the presence of a control mechanism that
inhibits the size of alveoli when there is not a
O2-induced need for additional Sa. On
the basis of these findings and the larger alveoli of rats exposed to
hypoxia in the postseptation period (Table 2) (13), we
envision two processes, differently regulated, in the formation of
alveoli: eruption of a septum and subsequent elongation of a septum. We propose that ATRA induces eruption of a septum and determines the
distance between septa; other factors, principally
O2, determine the length of a septum.
Thus with excess eruption of septa in ATRA-treated rats,
without a need for greater Sa, septum length is curtailed. This notion
presupposes a different gradient for the morphogen ATRA among species,
or interspecific differences in cellular sensitivity to ATRA, to
account for the interspecific differences in spacing of septa
(143). Finally, to explain the interspecific differences
in alveolar size, we do not exclude a link between
O2 and alveolar wall ATRA gradients.
Because of the opposing action of ATRA and dexamethasone on CRBP-I in adult rat lung (130), the effect of treatment with ATRA on CRBP-I mRNA and CRABP-I mRNA was examined in rats during the period of septation. ATRA treatment transiently increases the concentration of CRABP-I mRNA but does not prevent the depression of its mRNA by dexamethasone (153). ATRA also increases the concentration of CRBP-I mRNA in the lungs of neonatal rats (153) as it does in lungs of adult rats (130). Of particular interest, ATRA treatment prevents the depression of CRBP-I mRNA induced by dexamethasone (153).
The consequences to septation of the timing of the changes in lung concentration of CRBP-I and CRABP-I and the opposing action of ATRA and dexamethasone on CRBP-I mRNA concentration in lung are unknown, but it may be useful to speculate about this in light of some known and suspected general properties and functions of these proteins. The cellular concentration of retinoid-binding proteins exceeds those of the retinoids to which they bind with high affinity, resulting in exceedingly low intracellular concentrations of free retinoids (117). Binding of retinoids by CRBP and CRABP helps to insure specificity of the interaction of retinoids with cellular dehydrogenases responsible for their metabolism and prevents nonenzymatic isomerization and oxidation of retinoids (117). Indeed, CRBP-null mice exhibit a sixfold faster turnover of retinol than wild-type mice, which is consistent with the notion that retinol is promiscuously metabolized in the absence of CRBP-I (52). CRBP-I increases cell uptake of retinol, decreases its esterification, and increases the generation of ATRA and other biologically active retinoids (117). Therefore, a high concentration of CRBP-I, as occurs in lungs of untreated rats during the period of septation (120), should increase the production of ATRA by lung cells, perhaps in a cell-specific manner. Because we think septation is mainly over by PN day 7-8, the peak of CRABP-I about then could bind ATRA and end septation. Furthermore, the high expression of CRABP-I, if it occurred in only some cell types in the alveolar wall, could determine which cells respond to ATRA as the lung begins to remodel the alveolar wall, converting its double capillary system to a single capillary system.
Recent findings expand the potential therapeutic usefulness of ATRA beyond the prevention of failed septation. ATRA partially rescues septation previously inhibited by treatment of rat pups with dexamethasone and in adult mice with a genetic failure of septation (99). Veness-Meehan et al. (149) found ATRA does not prevent the hyperoxia-induced inhibition of septation in rat pups but confirmed ATRA prevents the inhibition of septation by dexamethasone. Two subsequent studies showed that rat pups exposed to hyperoxia and simultaneously treated with ATRA, but not those treated with vehicle, septate a few weeks after removal from hyperoxia without post-O2 treatment with ATRA (39, 148). This suggests that ATRA, perhaps by an antioxidant action, preserves the lung's ability to septate. Finally, also relevant to potential therapy in humans, ATRA substantially abrogates in adult rats the elastase-induced loss of elastic recoil, increased lung volume, large gas-exchange units, diminished number of alveoli, and low alveolar Sa, i.e., ATRA induces alveolus regeneration (12, 98, 144). The mechanism(s) and downstream changes in gene expression and protein-protein interaction by which ATRA affects alveolus formation are being actively sought in several laboratories.
The induction of alveolus formation by ATRA, of course, led to studies
to identify the retinoid receptors involved. Retinoid receptors are
nuclear receptors of two classes: retinoic acid receptors (RARs) and
retinoid X receptors (RXRs) (88). Three subtypes of RARs
and RXRs have been identified: RAR-, RAR-
, and RAR-
, and
RXR-
, RXR-
, and RXR-
. At physiological concentrations of
ligand, RARs respond to ATRA and 9-cis retinoic acid and
RXRs respond to 9-cis retinoic acid.
Retinoid agonists, antagonists, and mutant mice are being used to
determine which retinoid receptors are involved in septation. RAR-
/
mutant mice have early onset of septation and, during the period
of septation, form alveoli twice as fast as wild-type mice. As expected
from the results from RAR-
mutant mice, a RAR-
agonist blocks
septation (100). Thus RAR-
is an endogenous inhibitor of septation. However, RAR-
/
mice generate alveoli after the period of septation at the same rate as wild-type mice. This supports the notion that alveolus formation, during the period of septation and
after, is regulated, at least in part, by different molecular mechanisms. On the basis of the early induction of septation in RAR-
/
mice, it is possible that treatment of very prematurely born
children with a RAR-
antagonist (85) would allow the
early onset of septation. Further important information has come from analysis of RAR-
mutant mice (104). RAR-
gene
deletion diminishes septation, and the additional deletion of one
RXR-
allele further impairs septation (104). Because
ATRA induces alveolus formation, RAR-
inhibits septation, and
RAR-
mutant mice have impaired septation, combined therapy with
appropriate agonists and antagonists might provide the strongest
therapeutic induction of alveolus formation. RAR-
was recently
reported (56) to induce "alveolar repair and/or
alveolarization in adult rats." The same report states a RAR-
agonist "has been shown to induce alveolar repair in two rodent
models, pancreatic elastase-induced emphysema in rats, and cigarette
smoke-induced emphysema in mice" (56). Alveolar repair,
i.e., the reestablishment of the integrity of the alveolar air-tissue
barrier after it has been injured (45, 103), occurs spontaneously in many conditions (72, 73), including
elastase-induced emphysema (80). Therefore, the
"repair" ascribed to RAR-
must have been induction of the
formation of alveoli.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Drs. Linda B. Clerch, Ghenima Dirami, and Le Ann Blomberg for reviewing the manuscript and for stimulating discussions.
![]() |
FOOTNOTES |
---|
This work was supported, in part, by National Heart, Lung, and Blood Institute Grants HL-20366, HL-59432, HL-60115, and HL-37666.
D. Massaro and G. D. Massaro are Senior Fellows of the Lovelace Respiratory Research Institute, Albuquerque, NM. D. Massaro is Cohen Professor, Georgetown University.
Address for reprint requests and other correspondence: D. Massaro, Lung Biology Laboratory, Georgetown Univ. School of Medicine, 3900 Reservoir Rd. NW, Washington, DC 20007-2197 (E-mail: massarod{at}georgetown.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00374.2001
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