Inflammation is central to the pathogenesis of pulmonary vascular remodeling and pulmonary hypertension (PH). Inflammation precedes remodeling in preclinical models, thus supporting the concept that changes in immunity drive remodeling in PH. Platelets are recognized as mediators of inflammation, but whether platelets contribute to hypoxia-driven inflammation has not been studied. We utilized a murine hypoxia model to test the hypothesis that platelets drive hypoxia-induced inflammation. We evaluated male and female 9-week-old normoxic and hypoxic mice and in selected experiments included hypoxic thrombocytopenic mice. Thrombocytopenic mice were generated with an anti-GP1ba rat IgG antibody. We also performed immunostaining of lung sections from failed donor controls and patients with idiopathic pulmonary arterial hypertension. We found that platelets are increased in the lungs of hypoxic mice and hypoxia induces platelet activation. Platelet depletion prevents hypoxia-driven increases in the pro-inflammatory chemokines CXCL4 and CCL5 and attenuates hypoxia-induced increase in plasma CSF-2. Pulmonary interstitial macrophages are increased in the lungs of hypoxic mice; this increase is prevented in thrombocytopenic mice. To determine the potential relevance to human disease lung sections from donors and patients with advanced iPAH were immunostained for the platelet specific protein CD41. We observed iPAH lungs had a two-fold increase in CD41, compared to controls. Our data provide evidence that platelets are increased in the lungs and activated in mice with hypoxia-induced inflammation and provides rationale for the further study of the potential contribution of platelets to inflammatory mediated vascular remodeling and PH.

中文翻译：

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血小板活化有助于缺氧诱导的炎症

炎症是肺血管重塑和肺动脉高压 (PH) 发病机制的核心。在临床前模型中，炎症先于重塑，因此支持免疫变化驱动 PH 重塑的概念。血小板被认为是炎症的介质，但尚未研究血小板是否会导致缺氧驱动的炎症。我们利用小鼠缺氧模型来检验血小板驱动缺氧引起的炎症的假设。我们评估了雄性和雌性 9 周大的常氧和缺氧小鼠，并在选定的实验中包括缺氧血小板减少小鼠。用抗 GP1ba 大鼠 IgG 抗体产生血小板减少小鼠。我们还对失败的供体对照和特发性肺动脉高压患者的肺切片进行了免疫染色。我们发现缺氧小鼠肺中的血小板增加，并且缺氧诱导血小板活化。血小板耗竭可防止缺氧驱动的促炎趋化因子 CXCL4 和 CCL5 增加，并减弱缺氧诱导的血浆 CSF-2 增加。缺氧小鼠肺间质巨噬细胞增多；这种增加在血小板减少的小鼠中被阻止。为了确定与人类疾病的潜在相关性，来自捐赠者和晚期 iPAH 患者的肺切片对血小板特异性蛋白 CD41 进行了免疫染色。我们观察到与对照组相比，iPAH 肺的 CD41 增加了两倍。