Elevated lactate production exacerbates PM2.5-induced pulmonary fibrosis by stabilizing TGF-β1

Lactate, a glycolysis byproduct, has been implicated in the fibrotic process, while transforming growth factor-beta 1 (TGF-β1) plays a central role in promoting fibrosis. Air pollution, particularly fine particulate matter (PM2.5), represents a significant environmental risk factor for the development of pulmonary fibrosis. However, the role of lactate and the underlying mechanisms by which it acts in PM2.5-induced pulmonary fibrosis remain poorly understood.

This study aimed to identify the cell types contributing to lactate accumulation in lung tissue during PM2.5-induced pulmonary fibrosis and elucidate the mechanism by which lactate regulates TGF-β1.

Seven types of lung cells from PM2.5-exposed mice were isolated using fluorescence-activated cell sorting to determine their lactate production. Immunoprecipitation and immunoblotting were performed to assess the impact of lactate on TGF-β1 stability. The effect of histone lactylation on Stub1 gene expression was investigated by chromatin immunoprecipitation assays.

Macrophages exhibited elevated lactate production during PM2.5-induced pulmonary fibrosis. Elevated intracellular lactate levels in macrophages suppressed the expression of carboxyl terminus of Hsc70-interacting protein (CHIP, encoded by Stub1) via the enrichment of lactylated H3K18 at the Stub1 promoter locus. Consequently, reduced CHIP expression impeded TGF-β1 degradation, promoted enhanced TGF-β1 secretion by macrophages, and exacerbated pulmonary fibrosis symptoms. Moreover, the inhibition of lactate production significantly alleviated the pulmonary fibrosis phenotype in PM2.5-exposed mice.

Elevated lactate production in macrophages induced by PM2.5 inhibits the ubiquitination and degradation of TGF-β1 through the suppression of CHIP expression, thereby enhancing TGF-β1 secretion and exacerbating pulmonary fibrosis.