Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Nat Commun. 2024 Aug 22;15(1):7241. doi: 10.1038/s41467-024-51683-1.
Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.
2 型肺泡上皮 (AT2) 细胞在调节肺对损伤的肺泡炎症中起着重要作用。假设 AT2 细胞中线粒体长链脂肪酸 β-氧化 (mtLCFAO) 的受损会加重急性肺损伤 (ALI) 中的肺泡炎症，但 mtLCFAO 对 AT2 细胞功能的重要性仍需确定。本文中我们发现，在急性呼吸窘迫综合征 (ARDS) 中，AT2 细胞中肉毒碱棕榈酰转移酶 1a (CPT1a) 的表达，即 mtLCFAO 的限速酶，显著降低。在小鼠中，AT2 细胞中 Cpt1a 的缺失不会减少 ATP 产生，但会改变肺泡中表面活性剂磷脂的丰度。通过删除 Cpt1a 或 Acadl（长链酰基辅酶 A 脱氢酶）均可在 AT2 细胞中损害 mtLCFAO，从而抑制 AT2 细胞中中性粒细胞趋化因子 CXCL2 的产生，从而限制 ALI 中的肺泡炎症。因此，本研究强调了 mtLCFAO 作为 AT2 细胞损伤的免疫代谢，并提示 ARDS 中 AT2 细胞中受损的 mtLCFAO 作为抗炎反应。
