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Lysophospholipid Acyltransferase 9 Promotes Emphysema Formation via Platelet-activating Factor.

Hiroaki MuranoSumito InoueTomomi Hashidate-YoshidaHideo ShindouTakao ShimizuYoichiro OtakiYukihiro MinegishiTakumi KitaokaMitsuru FutakuchiAkira IgarashiMichiko NishiwakiTakako NemotoMasamichi SatoMaki KobayashiKento SatoToshinari HanawaOsamu MiyazakiMasafumi Watanabe
Published in: American journal of respiratory cell and molecular biology (2024)
Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9 -/- ) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9 -/- mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9 -/- mice compared with LPLAT9 +/+ mice. Notably, these phenotypes were again worsened by LPLAT9 +/+ bone marrow transplantation in LPALT9 -/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.
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