Li Lili, Xu Maojia, Rowan Simon C, Howell Katherine, Russell-Hallinan Adam, Donnelly Seamas C, McLoughlin Paul, Baugh John A
UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland.
Pulm Circ. 2020 Oct 26;10(4):2045894020941352. doi: 10.1177/2045894020941352. eCollection 2020 Oct-Dec.
While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout ( ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice ( ). Following exposure to hypoxia for three weeks, isolated lungs from mice had significantly higher pulmonary vascular resistance than those from mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.
虽然低氧性肺动脉高压的血流动力学原因是肺血管阻力增加已得到充分证实，但阻力增加的分子发病机制仍未完全明确。巨噬细胞移动抑制因子是一种多效性细胞因子，具有内源性互变异构酶活性以及细胞内和细胞外信号传导功能。在几种疾病中，巨噬细胞移动抑制因子具有促炎作用，这些作用依赖于通过细胞表面受体CD74、CXCR2和CXCR4的信号传导。在低氧性肺动脉高压动物模型中，巨噬细胞移动抑制因子的表达增加，巨噬细胞移动抑制因子互变异构酶抑制剂可阻断巨噬细胞移动抑制因子的一些功能，已证明其可减轻小鼠的低氧性肺动脉高压和大鼠的野百合碱诱导的肺动脉高压。然而，由于其作用途径多样，巨噬细胞移动抑制因子在低氧性肺动脉高压发展过程中的综合作用尚不清楚。我们在此报告，在常氧条件下饲养的成年巨噬细胞移动抑制因子基因敲除（）小鼠的离体肺脏，与野生型小鼠（）的肺脏相比，表现出更大的急性低氧性血管收缩。在暴露于低氧环境三周后，小鼠的离体肺脏的肺血管阻力显著高于小鼠的肺脏。低氧MIF小鼠肺血管阻力增加幅度更大的主要机制是由于正常低氧诱导的肺泡毛细血管网络扩张受损，导致肺血管床减少。综上所述，这些结果表明巨噬细胞移动抑制因子在慢性肺泡低氧引起的肺血管反应的发展中起核心作用。
