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Retinoid Induction of Alveolar Regeneration: from Mice to Man?

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Retinoid Induction of Alveolar Regeneration: from Mice to Man? Review Retinoid induction of alveolar regeneration: from Thorax: first published as 10.1136/thx.2008.105437 on 28 April 2009. Downloaded from mice to man? M Hind,1,2 A˚ Gilthorpe,2 S Stinchcombe,2 M Maden2 1 Department of Respiratory ABSTRACT other words, the gas exchanging regions of the lung Medicine, Royal Brompton The use of retinoids to induce human lung regeneration is must have a degree of plasticity. That this plasticity Hospital and National Heart and Lung Institute, Imperial College under investigation in a number of studies in patients with exists has been demonstrated, at least in rodents, by London, London, UK; 2 MRC chronic obstructive pulmonary disease (COPD). Retinoic a body of work by Massaro and colleagues and Centre for Developmental acid (RA) has complex pleiotropic functions during others in a number of different experimental Neurobiology, King’s College vertebrate patterning and development and can induce paradigms including re-feeding after calorie restric- London, London, UK regeneration in a number of different organ systems. tion6 and oestrogen replacement in oestrogen- 7 Correspondence to: Studies of retinoid signalling during lung development might deficient mice, and is exemplified by experiments Dr M Hind, Department of provide a molecular basis to explain pharmacological showing that exogenous all-trans retinoic acid Respiratory Medicine, Royal induction of alveolar regeneration in adult models of lung (atRA) can induce alveolar regeneration in adult Brompton Hospital and National disease. In this review the role of endogenous RA signalling rats with elastase-induced emphysema,8 partially Heart and Lung Institute, 9 Imperial College London, London during alveologenesis is explored and data suggesting that rescue emphysema in the tight-skin mouse mutant SW3 6NP, UK; m.hind@ a number of exogenous retinoids can induce regeneration in and rescue dexamethasone (Dex)-impaired alveolo- imperial.ac.uk the adult lung are discussed. Current controversies in this genesis in adult mouse lung.10–12 area are highlighted and a hypothesis of lung regeneration The ability to pharmacologically induce alveolar Received 1 August 2008 regeneration is a novel and attractive therapeutic Accepted 16 October 2008 is put forward. Understanding the cellular and molecular mechanisms of induction of regeneration will be central for approach for patients with too few alveoli and a effective translation into patients with lung disease and reduced gas exchanging surface area and might be may reveal novel insights into the pathogenesis of alveolar applied to infants with developmental lung arrest, disease and senescence. adults with emphysema or adults with age-related loss of alveoli.13 The restoration of functional gas exchanging tissue in humans with alveolar insuffi- The lung is the primary organ for gas exchange ciency would be a significant step forward in the across mammalian species, providing an interface treatment of respiratory diseases that have major public health implications where little in the way between blood and air in a structurally stable http://thorax.bmj.com/ 14 environment. As gas exchange is a passive process, of disease-modifying therapy exists. Whether it is a large thin surface area is required for efficient possible to induce regeneration in the human lung supply of oxygen and removal of carbon dioxide. Gas is not yet known. Currently, specific retinoic acid exchange occurs in alveolar saccules, alveoli and receptor (RAR) c agonists are in phase II clinical alveolar ducts. Alveolar formation (or alveologen- trials in adults with emphysema secondary to a1- esis) occurs predominantly during a developmental antitrypsin deficiency and in patients with smok- restricted early postnatal period in rats, mice and ing-related emphysema. 1–5 In this review we discuss the potential mechan- humans. The cellular and molecular regulation of on September 29, 2021 by guest. Protected copyright. this complex developmental event is not well isms by which atRA can induce alveolar regenera- understood. Here we discuss a growing body of tion in animal models by examining data evidence highlighting the role of endogenous retinoic highlighting the role of endogenous RA signalling acid (RA) signalling in the regulation of mammalian that occurs during normal alveolar formation. alveologenesis, and interpret findings suggesting Deciphering the complex cellular, molecular and that pharmacological dosing with RA can induce genetic signals that regulate development and alveolar regeneration in adult animals outside the regeneration provides not only an insight into the temporally restricted period of alveologenesis. As pathogenesis of diseases where homeostatic repair fundamental developmental mechanisms are widely processes are disrupted, but should also identify conserved across species, these findings open up the rational targets for the development of future regenerative therapies. In other biological systems, possibility of human lung regeneration as a potential regeneration—at least in part—recapitulates devel- therapeutic approach for patients with lung disease. opment so, to understand lung regeneration, we The gas exchanging tissues of the pulmonary must first consider lung development. alveoli are lined with epithelial cells (type I and type II cells) which are in direct contact with air and therefore vulnerable to injury following the inhala- LUNG DEVELOPMENT tion of toxins, infections or reactive oxygen species. Until recently, most studies of mammalian lung The remarkable ability of the lung to maintain development have been performed in rats,2315 but function through the life of the organism must, in the recent explosion in mouse genetics offers a highly part, reflect the ability of epithelial, interstitial and manipulated genome which allows specific questions endothelial cell populations—together with extra- to be asked about the role of candidate develop- cellular matrix—to undergo renewal, repair or mental genes. These studies, coupled with lineage regeneration over the lifetime of the animal. In tracing experiments, should enable progress to be Thorax 2009;64:451–457. doi:10.1136/thx.2008.105437 451 Review made in deciphering the complex patterning mechanisms that Interestingly, morphometric studies suggest that septation Thorax: first published as 10.1136/thx.2008.105437 on 28 April 2009. Downloaded from underpin lung development. Current knowledge of these mechan- alone does not account for the entire increase in alveolar tissue isms is, at best, sketchy. Normal function of the lung requires the that occurs in the postnatal period, and that alveoli might be correct temporal and spatial sequence of developmental mechan- generated by the transformation of distal bronchioles into alveoli, isms. Understanding how these fundamental signalling pathways called retrograde alveolisation.25 Recently, a subpopulation of cells that appear to be active—rather like switching lights on and off at known as bronchoalveolar stem cells (BASCs) has been identified different times in different places—are regulated and interact will that are located at the interface between the terminal bronchiole be central to understanding not only mechanisms of alveolar and the alveolar epithelium—the bronchioalveolar duct junction. development, but also alveolar disease and senescence. These cells co-express Clara cell markers (CC10) typical of distal The lung arises from foregut endoderm during early develop- bronchiolar epithelium and type II cell markers (SP-C) seen in the ment of the embryo. Paracrine signalling between the extending alveolar epithelium. Isolated BASC populations in vitro have been epithelium and surrounding mesenchyme is involved in pattern- shown to self-renew—a requirement for a stem cell population— ing the developing lung bud.16 Lung development proceeds and can differentiate into cells that express markers characteristic through four morphologically distinct but continuous embryonic of bronchial epithelium, alveolar type I cells or alveolar type II phases that include branching morphogenesis (embryonic day, cells.26 The role of these cells in alveolar formation has not yet E9–E12 in mice), the pseudoglandular stage (E12–E15 in mice), been defined, but the location and multilineage potential of this canalicular stage (E15–E17 in mice) and saccular stages (E17–birth population suggests that, under the right developmental cues, in mice). In rats and mice, pups are born with no true alveoli but these cells might contribute to alveologenesis. thick-walled alveolar saccules and alveolar formation occurs There is some evidence that matrix turnover is higher in entirely as a postnatal event.1–3 Human alveologenesis occurs subpleural regions of the lung outside the period of septation, from around 24 weeks, the current limit of premature survival, and this is accompanied by a shift in the location of the majority of human alveolar formation occurring during the lipofibroblasts from central regions during septation to the early postnatal period, certainly up to 18 months5 and possibly periphery after septation ceases.27 In studies of alveolar wall cell into later childhood even early adulthood. proliferation during murine alveologenesis, two discrete pat- terns of proliferating cells have been identified: a central pattern A DISTAL LUNG SIGNALLING CENTRE AND INDUCTION OF that is temporally associated with septation and a peripheral 28 ALVEOLOGENESIS subpleural pattern that extends into adulthood. Alveoli are generated
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