Role of ALDH3A1 in Maintaining the Balance between Alveolar Type 1 and Type 2 Cells in Emphysema: From Patient to Organoid Model

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Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction, which is called emphysema. Alveoli are mainly composed of alveolar type 1 (AT1) and alveolar type 2 (AT2) cells; however, the specific mechanisms regulating AT1 and AT2 during the development of emphysema remain unclear. Methods: This study performed single-cell sequencing (scSeq) and pseudo-time analysis on primary human alveolar cells exposed to cigarette smoke extract (CSE). Subsequently, a cigarette smoke (CS)-induced emphysema mouse model was established using a nasal-oral exposure system, and an intervention model was created by intraperitoneal injection of dexamethasone (DEX) solution. Pulmonary function tests, H&E staining, immunochemistry, and immunofluorescence staining were conducted in mice. Additionally, using alveolar organoids, in vitro models of CSE-induced emphysema model, DEX intervention model, and ALDH3A1 overexpression model were established, followed by flow cytometry, RT-qPCR, and western blot assays. Results: Analysis of scSeq data showed that primary human lung cells exposed to CSE exhibited an imbalance in the ratio of AT1 to AT2 cells, with decreased expression of ALDH3A1 in alveolar cells. In the in vivo emphysema model, pulmonary function was significantly reduced, and the alveolar structure was severely damaged with a significantly increased mean linear intercept. The ratio of aquaporin 5 (AQP5) + AT1 cells to surfactant protein C (SFTPC) + AT2 cells was significantly decreased, accompanied with the development of emphysema; further, DEX treatment protected lungs against CS-induced emphysema. Using the alveolar organoid, gene expression levels of ALDH3A1 were decreased with CSE in a dose-dependent manner with decreased AT1 to AT2 ratio. DEX intervention could not rescue ALDH3A1 completely. More critically, overexpression of ALDH3A1 effectively protects alveolar organoids against CSE-induced imbalance between AT1 and AT2 cells. Conclusion: This study confirms the crucial role of ALDH3A1 in maintaining alveolar structure; however, DEX protected alveolar cells in an ALDH3A1-independent manner. More importantly, the murine alveolar organoid successfully resembles the alteration in human lungs, providing a useful in vitro model for the mechanism study of emphysema.

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