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

Area of Science:

• Environmental Health
• Cell Biology
• Pulmonary Medicine

Background:

• Lactate, a byproduct of glycolysis, is linked to fibrosis.
• Transforming growth factor-beta 1 (TGF-β1) is central to fibrosis development.
• Particulate matter (PM2.5) air pollution is a risk factor for pulmonary fibrosis, but lactate's role is unclear.

Purpose of the Study:

• Identify cells causing lactate accumulation in PM2.5-induced pulmonary fibrosis.
• Elucidate how lactate influences TGF-β1 in this context.

Main Methods:

• Fluorescence-activated cell sorting to isolate lung cells from PM2.5-exposed mice.
• Immunoprecipitation and immunoblotting to assess lactate's effect on TGF-β1 stability.
• Chromatin immunoprecipitation to investigate histone lactylation's impact on Stub1 gene expression.

Main Results:

• Macrophages showed increased lactate production in PM2.5-induced pulmonary fibrosis.
• Lactate suppressed carboxyl terminus of Hsc70-interacting protein (CHIP) expression via histone lactylation.
• Reduced CHIP impaired TGF-β1 degradation, increasing its secretion and worsening fibrosis.

Conclusions:

• PM2.5-induced macrophage lactate accumulation inhibits TGF-β1 ubiquitination and degradation by suppressing CHIP.
• This leads to increased TGF-β1 secretion and exacerbated pulmonary fibrosis.
• Inhibiting lactate production ameliorated pulmonary fibrosis in mice.