Ichinose Fumito, Ullrich Roman, Sapirstein Adam, Jones Rosemary C, Bonventre Joseph V, Serhan Charles N, Bloch Kenneth D, Zapol Warren M
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
J Clin Invest. 2002 Jun;109(11):1493-500. doi: 10.1172/JCI14294.
Cytosolic phospholipase A(2) (cPLA(2)) releases arachidonic acid (AA) from phospholipids in cell membranes. To assess the role of cPLA(2) in hypoxic pulmonary vasoconstriction (HPV), we measured the increase in left lung pulmonary vascular resistance (LPVR) before and during hypoxia produced by left main stem bronchus occlusion (LMBO) in mice with and without a targeted deletion of the PLA2g4a gene that encodes cPLA(2alpha). LMBO increased LPVR in cPLA(2alpha)(+/+) mice but not in cPLA(2alpha)(-/-) mice. cPLA(2alpha)(+/+) mice were better able to maintain systemic oxygenation during LMBO than were cPLA(2alpha)(-/-) mice. Administration of a cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone, blocked the LMBO-induced increase in LPVR in wild-type mice, while exogenous AA restored HPV in cPLA(2alpha)(-/-) mice. Intravenous angiotensin II infusion increased PVR similarly in cPLA(2alpha)(+/+) and cPLA(2alpha)(-/-) mice. Inhibitors of cyclooxygenase or nitric oxide synthase restored HPV in cPLA(2alpha)(-/-) mice. Breathing 10% oxygen for 3 weeks produced less right ventricular hypertrophy in cPLA(2alpha)(-/-) than in cPLA(2alpha)(+/+) mice, but restored HPV in cPLA(2alpha)(-/-) mice despite the continued absence of cPLA(2) activity. These results indicate that cPLA(2) contributes to the murine pulmonary vasoconstrictor response to hypoxia. Augmenting pulmonary vascular tone restores HPV in the absence of cPLA(2) activity.
胞质型磷脂酶A2（cPLA2）从细胞膜中的磷脂释放花生四烯酸（AA）。为了评估cPLA2在低氧性肺血管收缩（HPV）中的作用，我们测量了在编码cPLA2α的PLA2g4a基因有或无靶向缺失的小鼠中，左主支气管闭塞（LMBO）诱导的低氧期间及之前左肺肺血管阻力（LPVR）的增加情况。LMBO使cPLA2α（+/+）小鼠的LPVR增加，但对cPLA2α（-/-）小鼠无此作用。与cPLA2α（-/-）小鼠相比，cPLA2α（+/+）小鼠在LMBO期间能更好地维持全身氧合。给予cPLA2抑制剂花生四烯酰三氟甲基酮可阻断野生型小鼠中LMBO诱导的LPVR增加，而外源性AA可恢复cPLA2α（-/-）小鼠的HPV。静脉输注血管紧张素II在cPLA2α（+/+）和cPLA2α（-/-）小鼠中使肺血管阻力（PVR）同样增加。环氧化酶或一氧化氮合酶抑制剂可恢复cPLA2α（-/-）小鼠的HPV。持续3周呼吸10%氧气，cPLA2α（-/-）小鼠的右心室肥厚程度低于cPLA2α（+/+）小鼠，尽管cPLA2活性持续缺失，但仍恢复了cPLA2α（-/-）小鼠的HPV。这些结果表明，cPLA2促成了小鼠对低氧的肺血管收缩反应。在缺乏cPLA2活性的情况下，增强肺血管张力可恢复HPV。
