Karoor Vijaya, Swindle Delaney, Pak David I, Strassheim Derek, Fini Mehdi A, Dempsey Edward, Stenmark Kurt R, Hassell Kathryn, Nuss Rachelle, Buehler Paul W, Irwin David C
Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Pulm Circ. 2021 Nov 5;11(4):20458940211056806. doi: 10.1177/20458940211056806. eCollection 2021 Oct-Dec.
Macrophages are a heterogeneous population with both pro- and anti-inflammatory functions play an essential role in maintaining tissue homeostasis, promoting inflammation under pathological conditions, and tissue repair after injury. In pulmonary hypertension, the M1 phenotype is more pro-inflammatory compared to the M2 phenotype, which is involved in tissue repair. The role of macrophages in the initiation and progression of pulmonary hypertension is well studied. However, their role in the regression of established pulmonary hypertension is not well known. Rats chronically exposed to hemoglobin (Hb) plus hypoxia (HX) share similarities to humans with pulmonary hypertension associated with hemolytic disease, including the presence of a unique macrophage phenotype surrounding distal vessels that are associated with vascular remodeling. These lung macrophages are characterized by high iron content, HO-1, ET-1, and IL-6, and are recruited from the circulation. Depletion of macrophages in this model prevents the development of pulmonary hypertension and vascular remodeling. In this study, we specifically investigate the regression of pulmonary hypertension over a four-week duration after rats were removed from Hb + HX exposure with and without gadolinium chloride administration. Withdrawal of Hb + HX reversed systolic pressures and right ventricular function after Hb + Hx exposure in four weeks. Our data show that depleting circulating monocytes/macrophages during reversal prevents complete recovery of right ventricular systolic pressure and vascular remodeling in this rat model of pulmonary hypertension at four weeks post exposure. The data presented offer a novel insight into the role of macrophages in the processes of pulmonary hypertension regression in a rodent model of Hb + Hx-driven disease.
巨噬细胞是一类具有促炎和抗炎功能的异质性细胞群体，在维持组织稳态、在病理条件下促进炎症反应以及损伤后的组织修复中发挥着至关重要的作用。在肺动脉高压中，与参与组织修复的M2表型相比，M1表型具有更强的促炎作用。巨噬细胞在肺动脉高压的发生和发展中的作用已得到充分研究。然而，它们在已建立的肺动脉高压消退过程中的作用尚不清楚。长期暴露于血红蛋白（Hb）加缺氧（HX）的大鼠与患有与溶血性疾病相关的肺动脉高压的人类有相似之处，包括在与血管重塑相关的远端血管周围存在独特的巨噬细胞表型。这些肺巨噬细胞的特征是高铁含量、血红素加氧酶-1（HO-1）、内皮素-1（ET-1）和白细胞介素-6（IL-6），并且是从循环中募集而来的。在该模型中巨噬细胞的耗竭可预防肺动脉高压和血管重塑的发展。在本研究中，我们专门研究了在给予或不给予氯化钆的情况下，大鼠从Hb + HX暴露中移除后四周内肺动脉高压的消退情况。在四周内，撤除Hb + HX可使Hb + Hx暴露后的收缩压和右心室功能恢复正常。我们的数据表明，在逆转过程中消耗循环中的单核细胞/巨噬细胞会阻止该大鼠肺动脉高压模型在暴露后四周时右心室收缩压的完全恢复和血管重塑。所呈现的数据为巨噬细胞在Hb + Hx驱动疾病的啮齿动物模型中肺动脉高压消退过程中的作用提供了新的见解。
