Investigating the role of vitamin A intake and retinoic acid signalling in lung homeostasis and repair-A multidisciplinary approach

Abstract

Retinoic acid (RA), obtained wholly from dietary sources, is essential for lung development and can induce alveolar regeneration in a number of animal models of alveolar insufficiency. The mechanisms by which RA mediates lung repair however remain unclear. To assess the role of vitamin (vit) A and RA signalling in the lung we used a multi-disciplinary, epidemiological and lab-based approach. Linear regression analysis of the UK Biobank population (n=500,000) to assess the effect of dietary vit A on adult lung function identified a positive association between increased vit A intake and Forced vital capacity (FVC) and a protective effect on FVC in smokers. In addition, analysis of RA pathway genes identified multiple SNPs which significantly modulate FVC. To determine the cell and molecular mechanisms of how RA might modulate lung repair, we developed a novel model using precision cut lung slices (PCLS) and HCl to generate a restricted area of damage to study cellular responses in both injured and uninjured regions of lung tissue. Following injury, inhibition of RA signalling with Diethylaminobenzaldehyde, an inhibitor of RA synthesis and BMS493, a pan-RAR inverse agonist, reduced proliferation in PCLS. Interestingly exposure to increased exogenous RA also abrogated proliferation in addition to increasing progenitor cell number. We believe this may be an indication that RA promotes proliferation within a narrow concentration window which is then prevented when levels of RA production and signalling are decreased with inhibitors or increased with exogenous RA. These data support a role for vit A and RA in lung homeostasis and provide further insight into mechanisms that contribute to regeneration of the lung.