Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China.
Microvasc Res. 2012 Mar;83(2):205-12. doi: 10.1016/j.mvr.2011.09.014. Epub 2011 Oct 8.
Hypoxic pulmonary vasoconstriction may lead to pulmonary hypertension, but the underlying mechanisms of persistent vasoconstriction are still unclear. There is evidence that pulmonary inflammation contributes to the abnormalities of function in the pulmonary artery (PA) following chronic hypoxia exposure. Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine, and we found that expression of MIF was increased in the smooth muscle of PA from hypoxic pulmonary hypertensive rats. Therefore, the aim of the study was to investigate the role of MIF in modulating vasoreactivity of isolated PA rings.
Sprague-Dawley rats were challenged by intermittent chronic hypoxia exposure for 4 weeks to establish hypoxic pulmonary hypertension models. Subsequently, immunohistochemistry and western blot assay were used to examine the MIF expression in pulmonary artery. Moreover, isometric force displacement was measured in isolated intrapulmonary artery.
In the isolated PA, our results showed that MIF mediated the enhanced pulmonary arterial vasoconstriction in response to chronic hypoxia, and the delayed hypoxic constriction in a biphasic pattern of constriction occurs in response to acute hypoxia. We also present the finding that MIF had no effect on force on its own, but concentration-dependently potentiated constrictions pre-evoked by phenylephrine under normoxic condition. The potentiation was independent of the endothelium. MIF-induced potentiation of phenylephrine-evoked constriction was partially inhibited by PKC inhibitor chelerythrine, p38 inhibitor SB 203580, ERK1/2 inhibitor U0126, respectively.
Our results suggested that MIF enhanced vasoconstriction of pulmonary artery elicited by agonist through PKC, p38 and ERK1/2 signal pathways, which may contributes to hypoxic pulmonary vasoconstriction.
低氧性肺血管收缩可能导致肺动脉高压，但持续性血管收缩的潜在机制仍不清楚。有证据表明，慢性低氧暴露后，肺炎症导致肺动脉功能异常。巨噬细胞移动抑制因子（MIF）是一种重要的促炎细胞因子，我们发现低氧性肺动脉高压大鼠肺动脉平滑肌中 MIF 的表达增加。因此，本研究旨在探讨 MIF 在调节离体肺动脉环血管反应性中的作用。
Sprague-Dawley 大鼠接受间歇性慢性低氧暴露 4 周，建立低氧性肺动脉高压模型。随后，采用免疫组织化学和 Western blot 检测肺动脉中 MIF 的表达。此外，还在离体肺内动脉中测量等长力位移。
在离体肺动脉中，我们的结果表明 MIF 介导了慢性低氧引起的肺动脉强烈收缩反应，并且在急性低氧时以双相收缩模式发生延迟性低氧收缩。我们还发现 MIF 本身对力没有影响，但在常氧条件下，浓度依赖性地增强了去甲肾上腺素预先引起的收缩。这种增强作用与内皮无关。MIF 诱导的去甲肾上腺素引起的收缩增强部分被 PKC 抑制剂 chelerythrine、p38 抑制剂 SB 203580 和 ERK1/2 抑制剂 U0126 抑制。
我们的结果表明，MIF 通过 PKC、p38 和 ERK1/2 信号通路增强了激动剂引起的肺动脉收缩，这可能有助于低氧性肺血管收缩。
