Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma- sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells.
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Endogenous signalling molecules to induce lung regeneration
This approach has roots in developmental biology using factors important in lung development and maintenance and is exemplified by investigation into the role of vitamin A derivatives (retinoids). Retinoids including the biologically active molecule all-trans-RA (atRA) are essential for correct development of a number of organs including the lung. atRA is generated from vitamin A (retinol) through a series of reactions dependent on retinaldehyde dehydrogenase (RALDH1-3) enzymes. The expression of these enzymes correlates with atRA activity in vivo. atRA acts via nuclear retinoic acid receptors (RARs), which are members of the glucocorticoid/thyroid hormone receptor superfamily. There are three RARs (?? and ?) each of which has multiple isoforms. RARs form heterodimers with retinoid X receptors (RXRs) that bind atRA to form a ligand-activated transcription factor complex that regulates downstream gene transcription. atRA and retinol are bound within the cell complexed to cellular retinol binding proteins (CRBP1 and 2) and cellular retinoic acid binding proteins (CRABP1 and 2). Active atRA is oxidized to polar metabolites such as 4-oxo-RA through the CYP26 class of cytochrome P450 enzymes. Precise intracellular levels of atRA are regulated by a balance between synthesizing and degrading enzymes (Duester, 1999). The lung is second only to the liver as the largest store of retinoids in the body and retinoids are stored as retinyl esters in lipid-laden fibroblasts (Okabe et al., 1984) that are abundant in the alveolar wall often in close approximation with type II pneumocytes. Lipid-laden fibroblasts generate biologically active atRA that can regulate gene transcription in pulmonary microvascular endothelial cells (Dirami et al., 2004) and atRA regulates elastin, an essential structural component of lung matrix in perinatal fibroblasts (McGowan et al., 1997). Levels of retinoid synthesizing enzymes RARs and retinoid-binding proteins demonstrate dynamic patterns of regulation in whole lung during alveologenesis in the in rat (McGowan et al., 1995) and mouse (Hind et al., 2002a,b;). In mice mutant for RAR genes alveolar formation is disrupted: RAR? functions as a positive regulator of alveologenesis (McGowan et al., 2000) whereas RAR? is a negative regulator of alveologenesis (Massaro et al., 2000). atRA supplementation during alveolar septation increases the number of alveoli but not total surface area in normal rats and prevents the reduction in both number of alveoli and low surface area corrected for body mass in rats treated with dexamethasone during septation (Massaro and Massaro, 1996). These data provided the first experimental evidence to suggest that pharmacological regenerative therapy might be a potential approach for human diseases characterized by too few alveoli and reduced surface area such as emphysema.
Do retinoids affect lung development in man? It appears that the answer is yes. Mutations in the cell surface receptor for retinol STRA6 have been identified in a screen of children born with anophthalmia (Golzio et al., 2007; Pasutto et al., 2007). Interestingly these infants also had structural lung defects and a failure of normal alveologenesis. Remarkably, vitamin A supplementation during pregnancy in women in areas of endemic dietary retinoid deficiency increases lung function in their offspring (Checkley et al., 2010). This suggests conservation of retinoid signalling between mouse and human lung development and demonstrates gas exchanging surface area can be manipulated by retinoids in man.
It is therefore conceivable that the re-awakening of the retinoid signalling pathway used in alveolar development would induce regeneration of alveoli in the damaged lung. This is indeed the case as the administration of atRA to elastase-induced emphysema in adult rats restored alveoli and reversed the pathologic features of the disease (Massaro and Massaro, 1997). This phenomenon also occurs in several other models of airspace enlargement, for example the dexamethasone treated mouse, where mean chord length and lung surface area were recovered after atRA administration (Hind and Maden, 2004; Stinchcombe and Maden, 2008). Using retinoic acid receptor agonists it was shown that the effect of atRA can be replicated by either a RAR? or a RAR? agonist (Maden, 2006) paving the way for the current clinical trial of one of these compounds (see the following). These positive effects of atRA have now been replicated several times in elastase or dexamethasone models of lung damage (Belloni et al., 2000; Massaro and Massaro, 2000; Tepper et al., 2000; Ishizawa et al., 2004; Garber et al., 2006; Perl & Gale, 2009); in the tight skin mouse mutant (Massaro and Massaro, 2000); in pneumonectomized lungs (Kaza et al., 2001) and it protects from 02 induced damage (Veness-Meehan et al., 2000, 2002; Ozer et al., 2005).
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Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic alveolar formation, and vitamin A deficiency in a mother during pregnancy could have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or beta carotene in women before, during, and after pregnancy on the lung function of their offspring, in a population with chronic vitamin A deficiency.
We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers had participated in a placebo-controlled, double-blind, cluster- randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997.
Of 1894 children who were alive at the end of the original trial, 1658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1371 of the children (83% of those eligible) between October 2006 and March
- Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV(1)) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV(1), 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV(1) and FVC values that were similar to those of children whose mothers had received placebo (FEV(1), 14 ml higher with beta carotene; 95% CI, -24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, -21 to 55).
In a chronically undernourished population, maternal repletion with vitamin A at recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years.