PMID- 38377392 OWN - NLM STAT- Publisher LR - 20240220 IS - 1535-4989 (Electronic) IS - 1044-1549 (Linking) DP - 2024 Feb 20 TI - Lysophospholipid Acyltransferase 9 Promotes Emphysema Formation via Platelet-activating Factor. LID - 10.1165/rcmb.2023-0253OC [doi] AB - Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases, such as bronchial asthma or COPD. We focused on lysophospholipid acyltransferase 9 (LPLAT9), 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 macrophage (AM). LPLAT9 was predominant and upregulated in AM, particularly monocyte-derived AM, in patients with COPD. To identify the function of LPLAT9/PAF in AM on the pathogenesis of COPD, we exposed cigarette smoke (CS) to systemic LPLAT9 knockout (LPALT9(-/-)) mice. CS increased the number of AM, especially monocyte-derived fraction, which secreted matrix metalloprotease 12 (MMP12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophage and, subsequently, PAF synthesis in mice lung. LPLAT9(-/-) mice lung reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AM by increasing monocyte chemoattractant protein-1 (MCP1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9(-/-) mice than in LPLAT9(+/+) mice. Notably, these phenotypes got worsened again by LPLAT9(+/+) bone marrow transplantation in LPALT9(-/-) mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AM aggravated pulmonary emphysema via PAF-induced further AM accumulation. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD. FAU - Murano, Hiroaki AU - Murano H AD - Yamagata University, 13149, Faculty of Medicine, Department of Cardiology, Pulmonology, and Nephrology, Yamagata, Japan. AD - National Center for Global Health and Medicine, 13805, Department of Lipid Life Science, Shinjuku-ku, Tokyo, Japan. FAU - Inoue, Sumito AU - Inoue S AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan; sinoue@med.id.yamagata-u.ac.jp. FAU - Hashidate-Yoshida, Tomomi AU - Hashidate-Yoshida T AD - National Center for Global Health and Medicine, 13805, Department of Lipid Life Science, Shinjuku-ku, Tokyo, Japan. FAU - Shindou, Hideo AU - Shindou H AD - National Center for Global Health and Medicine, 13805, Department of Lipid Life Science, Shinjuku-ku, Tokyo, Japan. AD - The University of Tokyo Graduate School of Medicine Faculty of Medicine, 38551, Department of Medical Lipid Science, Bunkyo-ku, Tokyo, Japan. FAU - Shimizu, Takao AU - Shimizu T AD - National Center for Global Health and Medicine, 13805, Department of Lipid Signaling Project, Shinjuku-ku, Tokyo, Japan. AD - Institute of Microbial Chemistry, 242076, Shinagawa-ku, Tokyo, Japan. FAU - Otaki, Yoichiro AU - Otaki Y AD - Yamagata University, 13149, Faculty of Medicine, Department of Cardiology, Pulmonology, and Nephrology, Yamagata, Japan. FAU - Minegishi, Yukihiro AU - Minegishi Y AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Kitaoka, Takumi AU - Kitaoka T AD - Yamagata University, 13149, Faculty of Medicine, Department of Pathology, Yamagata, Japan. FAU - Futakuchi, Mitsuru AU - Futakuchi M AD - Yamagata University, 13149, Department of Pathology, Yamagata, Japan. FAU - Igarashi, Akira AU - Igarashi A AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Nishiwaki, Michiko AU - Nishiwaki M AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Nemoto, Takako AU - Nemoto T AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Sato, Masamichi AU - Sato M AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Kobayashi, Maki AU - Kobayashi M AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Sato, Kento AU - Sato K AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Hanawa, Toshinari AU - Hanawa T AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Miyazaki, Osamu AU - Miyazaki O AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. FAU - Watanabe, Masafumi AU - Watanabe M AD - Yamagata University Faculty of Medicine Department of Cardiology Pulmonology and Nephrology, 625053, Yamagata, Japan. LA - eng PT - Journal Article DEP - 20240220 PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 SB - IM OTO - NOTNLM OT - chronic obstructive pulmonary disease OT - cigarette smoke OT - lysophospholipid acyltransferase 9 OT - monocyte-derived macrophage OT - platelet-activating factor EDAT- 2024/02/20 18:42 MHDA- 2024/02/20 18:42 CRDT- 2024/02/20 15:33 PHST- 2024/02/20 18:42 [medline] PHST- 2024/02/20 18:42 [pubmed] PHST- 2024/02/20 15:33 [entrez] AID - 10.1165/rcmb.2023-0253OC [doi] PST - aheadofprint SO - Am J Respir Cell Mol Biol. 2024 Feb 20. doi: 10.1165/rcmb.2023-0253OC.