Aldehyde dehydrogenase ALDH3A1 rescues cigarette smoke-induced emphysema by conferring alveolar type 2 to type 1 cell...

Cigarette smoke (CS) is one of the major risk factors of emphysema, which is characterized by alveolar destruction. Alveolar type 2 (AT2) cells enable regeneration of alveoli after injury by transiting into alveolar type 1 (AT1) cells; however, the mechanisms regulating AT2 to AT1 transition during the CS-induced emphysema remain unclear. Primary human alveolar cells exposed to commercially available cigarette smoke extract (CSE) were subjected to single-cell RNA sequencing, and data showed an imbalance in the ratio of AT1 to AT2 cells, with decreased expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1) in alveolar epithelial cells. Subsequently, a CS-induced emphysema mouse model was established using a nasal-oral exposure system. Compared to the control, the pulmonary function of CS-exposed mice was significantly reduced, and the alveolar structure was severely damaged with a significantly increased mean linear intercept. The ratio of aquaporin 5⁺ AT1 cells to surfactant protein C⁺ AT2 cells was significantly decreased, accompanied by the decreased expression of ALDH3A1. Additionally, in vitro models of CSE-induced emphysema and ALDH3A1 overexpression were established using alveolar organoids. Gene expression levels of ALDH3A1 in the organoids decreased with CSE exposure in a dose-dependent manner, and this decrease was transcriptionally regulated by aryl hydrocarbon receptor (AHR)/AHR nuclear transporter (ARNT). More critically, overexpression of ALDH3A1 or the AHR agonist, indole-3-pyruvic acid, effectively restored the ratio of NAD⁺/NADH and protected alveolar organoids against CSE-induced imbalance between AT1 and AT2 cells. This study confirms the crucial role of AHR/ARNT/ALDH3A1 signaling in maintaining alveolar structure during alveoli repair in CS-induced emphysema. The murine alveolar organoid successfully resembles the alteration in human lungs, providing a useful in vitro model to study the mechanism of emphysema.