A micropeptide MSTRG.1695.1-aa alleviates inflammatory-fibrosis pathological injury of lung tissue in COPD mice by suppressing EMT via targeting p38-MAPK

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Background: Small open reading frames (smORFs) in long noncoding RNA (lncRNA) have been demonstrated to encode small peptides. However, it has yet to be investigated whether the engendering peptides correlate directly with inflammatory-fibrosis in COPD. Methods: A combined CS exposure and LPS intratracheal instillation mice model was established and typeⅡ alveolar epithelial (ATⅡ) cells was isolated. Gene expression was analyzed via transcriptome sequencing, and the smORF embedded the lncRNA was identified through preliminary bioinformatics analysis. We named the smORF as peptide MSTRG.1695.1-aa. The morphologic changes, fibrosis injury, cytokines, lung function, EMT proteins in COPD mice and peptide MSTRG.1695.1-treated mice were measured. MSTRG.1695.1-aa in the serum of COPD patients were detected. Results: We identify a key lncRNA-MSTRG.1695.1, with a reduction in ATⅡ cells, and discover a negative correlation between the p38-MAPK pathway and MSTRG.1695.1 in ATII cells. We report that the smORF embedded in MSTRG.1695.1 encodes a micropeptide MSTRG.1695.1-aa. MSTRG.1695.1-aa suppresses the progression of EMT via the p38-MAPK pathway in ATⅡ cells. Exogenous MSTRG.1695.1-aa dramatically mitigates inflammatory cytokine production, fibrosis injury, and EMT proteins expression on the lung tissue in COPD mice. High homologously peptides of MSTRG.1695.1-aa in the serum of COPD patients are detected, which are positive correlated with lung function. Conclusions: MSTRG.1695.1-aa represents a compelling therapeutic target for lung injury in COPD and a putative serum marker for evaluation of early pulmonary fibrosis in COPD patients.

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