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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 271-274, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F263

Perspective

Retinoids, Alveolus Formation, and Alveolar Deficiency

Clinical Implications

Donald Massaro and Gloria De Carlo Massaro

Departments of Medicine and Pediatrics, Lung Biology Laboratory, Georgetown University School of Medicine, Washington, District of Columbia

Address correspondence to: Donald Massaro, M.D., Lung Biology Laboratory, Box 571481, Georgetown University School of Medicine, Preclinical Science Building, GM-12, 3900 Reservoir Road, N.W., Washington, D.C. 20057-1481. Email: massarod{at}georgetown.edu

Abbreviations: all-trans retinoic acid, ATRA • chronic obstructive pulmonary disease, COPD • cellular retinol binding protein-I, CRBP-I • lipid interstitial cells, LICs • retinoic acid receptor, RAR • retinoid

In this issue of the Journal, Nakajoh and colleagues demonstrate all-trans retinoic acid (ATRA) protects a human lung cell line against injury by elastase (1). This reveals yet another action of a retinoid that may have therapeutic importance for major human conditions in which individuals have too few alveoli and too little alveolar surface area for adequate gas exchange. These conditions include premature birth in which there is impaired formation of alveoli (2–5), chronic obstructive pulmonary disease (COPD), in which small conducting airways, alveoli, and alveolar surface area are lost (6, 7), and the age-related loss of alveoli (8, 9), alveolar surface area (8, 9), and lung function (10, 11) that, even in otherwise healthy people, begins in the third decade. This Perspective provides background findings that led to a study that showed ATRA induces the formation of alveoli in rats, and reviews the rapidly increasing number of reports indicating that retinoids may or may not be useful to induce the formation of alveoli, or slow loss of alveoli, for therapeutic purposes in humans.

Several lines of evidence, in a guilt-by-association manner, suggested retinoids might induce the formation of alveoli. Brody and colleagues (12–16), in a series of seminal papers, showed in the young of the species examined (rat, mouse, and hamster) that the alveolar wall is rich in fibroblasts that contain lipid storage granules; they called these cells "lipid interstitial cells" (LICs). Importantly, retinol (vitamin A) is among the contents of these granules (17–19). In studies of the early postnatal period, when alveoli are being formed in part by subdivision (septation) of the large saccules of the immature lung, Burri found LICs especially concentrated at "septal junctions" (i.e., sites from which several septa emanate) (20). McGowan and colleagues added important information on retinoid receptors in LICs and on the ability of LICs to synthesize elastin (21, 22). Beyond the early neonatal period, when septation of the saccules present at birth is over, LICs lose their generalized distribution but remain densely present in the subpleural region (18), the putative site of alveolus formation that continues after the early postnatal period (23). Thus, retinol storage cells and sites of alveolus formation coincide temporarily and geographically. Important papers by Ong and Chytil (24) and Geevarghese and Chytil (25) also suggested a link between retinoids and alveolus formation by demonstrating a high level of retinoid metabolic activity in lung at the time alveoli are being formed at an especially fast rate (20). They also demonstrated ATRA increases expression in lung of cellular retinol binding protein-I (CRBP-I) (26), a key molecule in the formation of ATRA (27, 28), and reported the opposing actions of ATRA and dexamethasone, a glucocorticosteriod hormone, on CRBP-I expression (29). These opposing actions seemed important because dexamethasone had already been identified as a potent inhibitor of alveolus formation (30). Thaller and Eichele (31) provided evidence that ATRA is a morphogen, i.e., a molecule released by a cell to which other cells respond based on the concentration of the molecule they "see" (32). The latter, in turn, depends upon the distance the molecule has diffused from the cell that released it as well as on the amount released.

In essence, the observations on lung by Brody (12–16), Ong and Chytil (24), Geevarghese and Chytil (25), Riaz-Ul-Haq and Chytil (26), Rush and coworkers (29), and McGowan (21, 22), and those by Thaller and Eichele on chicken limb buds (31), combined with general knowledge of the properties of retinoids (32), led to the hypothesis that retinoids are importantly involved in the regulation and induction of alveolus formation. A series of experiments in several laboratories has confirmed this hypothesis, extended the findings, and expanded the actions of retinoids on the lung, providing additional support for the possibility that retinoids may have therapeutic value in humans with too few alveoli for adequate gas exchange. More specifically, experiments (Figure 1) , mainly in rodents, showed that exogenous ATRA: induces the formation of extra alveoli in newborn rats (33), but not in otherwise unmanipulated fetal lambs (34); maintains alveolar forming ability under inhibiting conditions (33–38); partially rescues pharmacologic and genetically impaired alveolus formation (39, 40) without, however, a demonstrable improvement of lung function in the former (not reported in the latter) (41); induces alveolus formation and increases elastic recoil in lung of adult rats with elastase-induced emphysema (42–44); and that a retinoic acid receptor (RAR) {gamma} agonist diminishes the distance between alveolar walls (Lm), decreases destruction, and improves expiratory flow in mice with cigarette smoke-induced emphysema (45, 46). However, ATRA does not affect cigarette smoke-induced emphysema in guinea pigs (47). It diminishes the extent to which emphysema is produced in mice by cigarette smoke (48, 49), increases the size of the remaining lung after pneumonectomy in rats (50), but impairs the recovery of lung function after pneumonectomy in dogs (51). Retinol is required in adult rats to maintain alveolar architectural stability (52).



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  		Figure 1. Actions of retinoids on the lung.

 
Retinoids act through RARs and retinoid X receptors (RXRs), which are ligand-activated transcription factors. The genetic analysis of RARs and RXRs has confirmed a role for retinoids in the endogenous formation of alveoli. Of particular importance was the demonstration by McGowan and colleagues (53) that RAR{gamma}–RXR{alpha}-null mice display a marked failure of septation of the alveolar saccules that constitute the gas-exchange region of the architecturally immature lung. The work of McGowan and colleagues (53), and the report that a RAR{gamma} agonist reverses emphysema in rats (45), strongly suggest RAR{gamma}, most likely heterodimerized with RXR{alpha} (53), are the key nuclear receptors through which ATRA induces the formation of alveoli (33, 39, 42). However, in keeping with the evidence that multiplicity of receptors generates diversity in retinoid signaling pathways (54), and demonstrating different retinoid regulation of alveolus formation during and after the early perinatal period, RARß is an endogenous inhibitor of alveolus formation during but not after the first three postnatal weeks in mice (55). Indeed, it is likely that it inhibits the premature onset of alveolus formation in the fetus (55). Therefore, when an inhibitor of RARß is made available, it might allow the early onset of alveolus formation when used alone or with ATRA or a RAR{gamma} agonist. In contrast to RARß, RAR{alpha} does not influence alveolus formation during the first two postnatal weeks, but its absence slows the formation of alveoli from age 14 to at least 50 d (56).

Aside from the requirement of retinoid receptors for alveolus formation (53, 56) and the ability of exogenous ATRA to induce alveolus formation (33, 39, 40, 42–44), recent findings (Figure 1) indicate that ATRA slows the development of alveolar destruction by cigarette smoke (48, 49). This slowing might be related to: the protection of alveolar type 2 cells against elastase-induced injury (1); ATRA's attenuation of cytokine-induced degradation of extracellular matrix by fibroblasts (57); the ability of ATRA to down-regulate matrix metalloprotease-9 and upregulate tissue inhibitor of matrix proteinase-1 (58); the stimulation by ATRA of proliferation of alveolar type 2 cells (59, 60); its protection of alveolar type 2 cells from the antiproliferative effect of tumor necrosis factor alpha (61), a key agent in cigarette smoke-induced pulmonary inflammation and extracellular matrix destruction (62); and the action of ATRA to diminish intrapulmonary inflammation (63, 64).

An especially interesting observation is related to the effect of exogenous ATRA given to newborn rat pups exposed to hyperoxia (38). Such exposure markedly diminishes formation of alveoli (65). ATRA administered to O2-exposed rat pups does not protect against the O2 inhibition of alveolus formation. However, ATRA administered while rat pups are exposed to hyperoxia results in post hoc catch-up alveolus formation several weeks after removal from hyperoxia, without the pups having received ATRA after removal from O2. Thus, ATRA in O2-exposed rat pups does not prevent the inhibition of alveolus formation by hyperoxia, but protects the lung's ability to form alveoli in a post hoc manner upon removal from hyperoxia. The mechanism by which this occurs is completely unclear.

Clearly, there are three important negative findings regarding the ability of retinoids to return alveolar architecture and gas exchange function to normal or near-normal values. First, ATRA did not affect the production of emphysema in guinea pigs treated with cigarette smoke (47). Some would, perhaps correctly, ascribe the success of ATRA in rats and mice to the continual growth of these species through most of their life; the implication being that they also continue to form alveoli and hence may already have the functioning molecular machinery for alveolus formation as rat and mouse pups, and are thus responsive to the stimulating effect of ATRA. In fact, the evidence is that male rats and mice (information not yet available in females) stop increasing the number of alveoli at about age 6–7 wk (66, 67) and indeed begin to lose alveoli (9, 67). A difference in the effect cigarette smoke has on the retinol content of the lung in guinea pigs and mice may be relevant. Cigarette smoke increases the concentration of retinol in the lung of guinea pigs 8- to 9-fold (68) but does not alter the retinol concentration of mouse lung (69). Thus, while cigarette smoke clearly causes emphysema in guinea pigs (47), we have wondered if the 8- to 9-fold elevation of retinol by cigarette smoking alone may have obscured, or diminished, an effect of ATRA.

As with ATRA and guinea pigs, we don't have any insights that bear on the inhibitory effect ATRA has on recovery of lung function after pneumonectomy in dogs (51). The report of a failure to find improvement of lung function (41) in association with ATRA-produced partial rescue of dexamethasone-impaired alveolus formation (39) is an important negative observation. However, because the functional studies were on anesthetized animals, we have some slight reservations about their meaning. Nevertheless, the study was carefully done and ATRA did not rescue lung function. This suggests that more attention needs to be paid to an analysis of the anatomic effect of ATRA on the gas-exchange region. This might be best approached by an anatomic assessment of diffusion capacity, which would allow assessment of the individual components of the alveolar wall involved in O2 transfer.

Finally, it is worth recalling that there is a clear relationship between an organism's need for O2 as reflected by its oxygen consumption and the size of its alveoli and alveolar surface area (67). This relationship indicates that the duration of the period in which alveoli are formed, the rate of their formation, and the spacing and length of septa are key factors to optimal gas exchange. Unfortunately, we know very little about the endogenous signals responsible for the onset and cessation of alveolus formation. However, the LICs, so presciently studied by various workers (12–16, 21, 22), seem to be key cells. They release retinoids in culture that can increase the expression of CRBP-I messenger RNA in a second lung cell, the pulmonary microvascular cell (70). The amount of retinoid released seems to reflect the LICs concentration of retinol storage granules, and the release of ATRA, but not of retinol, is halved in the presence of a potent inhibitor of alveolus formation (i.e., dexamethasone) (70). It is completely unclear what determines the presence of retinol in these cells during development, what determines their location in the lung (i.e. diffuse as in the neonate or subpleural as in the older animal [14, 16, 18, 23]), and what regulates the release of retinoids by these cells. In the same vein, is it the onset and cessation of the release of retinoids or of a particular retinoid by LICs that determine the onset and end of alveolus formation? If so, what signals these actions? Is the signal hard-wired in the lung, perhaps in the LIC itself or, as is our preference, is there a systemic agent that might induce (signal) the sequential maturation of several organs? We have in mind, for example, that the species active corticosteroid seems to be low when septation of the saccules, which constitute the gas-exchange region of the architecturally immature lung, takes place (71, 72). Prevention of the trough inhibits alveolus formation (30). By contrast, a post-septation rise in corticosteroids is associated with accelerated alveolar wall thinning, diminishing retinol storing granules in LICs (73) but stimulating maturation of pancreatic hormones that, in rodents, is in time for a switch from milk to a more diverse diet (74). Is there a single signal that initiates the onset or end of alveolus formation (a dictatorship), or is there a complex of signals (a junta) (75)? All this absent information will have biological relevance, and may have therapeutic relevance. Obviously, and excitingly, much remains to be discovered, tested, and hopefully put to therapeutic use.


   Acknowledgments
 
The authors thank Drs. Linda B. Clerch, Ghenima Dirami, and Sandra Jensen-Taubman for reviewing this manuscript. Supported in part by NHLBI grants HL-20366 and HL-37666. D. M. is Cohen Professor at Georgetown University.


   Footnotes
 
D.M. and G.D.M. hold a patent for the use of retinoids in lung diseases.

Received in original form January 8, 2003


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