Reshaping the lung microenvironment: MSCs attenuate Cr(VI)-induced pulmonary fibrosis associated with metabolic and microbial modulation

As a common environmental and occupational pollutant, hexavalent chromium [Cr(VI)] has been proved to induce pulmonary fibrosis. In recent years, mesenchymal stem cells (MSCs) have become a promising therapeutic strategy for pulmonary fibrosis. However, whether they can mitigate Cr(VI)-induced pulmonary fibrosis specifically through regulating the lung microenvironment and microbial homeostasis remains an open and critical question. This study aims to establish a Cr(VI)-induced lung fibrosis model in rats and investigate the protective mechanisms of MSCs through integrated metabolomic and microbiome analyses. MSCs attenuated lung structural destruction, reduced abnormal collagen fiber deposition, decreased the levels of TNF-α, IL6, MDA and 8-OHdG and increased T-AOC and T-SOD. In addition, Cr(VI) caused metabolic disorders in lung tissue, which was evidenced by the up-regulation or down-regulation of multiple phospholipid metabolites, down-regulation of immune-related pathways and up-regulation of arachidonic acid metabolism and glycerophospholipid metabolism pathways. Microbiome analysis revealed that Cr(VI) exposure significantly increased both the diversity and abundance of microbial communities in alveolar lavage fluid, promoting the enrichment of opportunistic pathogens and ultimately leading to microbial dysbiosis. After MSCs intervention, lipid metabolism disorder was alleviated, immune-related pathway was up-regulated, opportunistic bacteria was reduced, and dysbiosis was alleviated. Correlation analysis revealed that lung chromium and lipid-related metabolites were closely associated with microbial communities, suggesting that the pulmonary metabolism may interact with the lung microbiota to jointly maintain the homeostasis of the pulmonary microenvironment. Our study provides a new perspective on elucidating the role of MSCs in treating Cr(VI)-induced pulmonary fibrosis from the perspective of lung metabolism and microbiota.