From the Department of Surgery (E.M.B., R.S.C., C.P.S., D.J.H., T.R.B., P.M.B.), University of Pittsburgh Cancer Institute (E.M.B.), Division of Pediatric Surgery, Children's Hospital Pittsburgh (C.P.S., D.J.H.), Department of Pharmacology and Chemical Biology (P.M.B.), and Vascular Medicine Institute (P.M.B.), University of Pittsburgh School of Medicine, PA.
Circ Res. 2014 May 9;114(10):1596-600. doi: 10.1161/CIRCRESAHA.114.303662. Epub 2014 Mar 17.
Recent studies demonstrate a role for toll-like receptor 4 (TLR4) in the pathogenesis of pulmonary hypertension (PH); however, the cell types involved in mediating the effects of TLR4 remain unknown.
The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH.
TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular (RV) systolic pressure and RV hypertrophy. However, the deletion of TLR4 from myeloid lineage cells had no effect on the development of PH because we found no difference in RV systolic pressure or RV hypertrophy in wild-type versus LysM-TLR4(-/-) mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet-specific TLR4(-/-) mice were generated (PF4-TLR4(-/-) mice). TLR4(-/-) platelets from either global TLR4(-/-) or PF4-TLR4(-/-) mice were functional but failed to respond to lipopolysaccharide, demonstrating a lack of TLR4. PF4-TLR4(-/-) mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RV systolic pressure and RV hypertrophy, decreased platelet activation, and less pulmonary vascular remodeling. The deletion of TLR4 from platelets attenuated serotonin release after chronic hypoxia, and lipopolysaccharide-stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner.
Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.
最近的研究表明，Toll 样受体 4（TLR4）在肺动脉高压（PH）的发病机制中起作用；然而，介导 TLR4 作用的细胞类型尚不清楚。
本研究旨在确定非实质细胞表达的 TLR4 对 PH 发病机制的贡献。
TLR4 骨髓嵌合体小鼠通过测量右心室（RV）收缩压和 RV 肥大来确定 TLR4 在非实质细胞和实质细胞发病机制中的同等作用。然而，骨髓细胞中 TLR4 的缺失对 PH 的发展没有影响，因为我们在野生型与 LysM-TLR4（-/-）小鼠之间没有发现 RV 收缩压或 RV 肥大的差异。为了探讨血小板 TLR4 在 PH 发病机制中的潜在作用，生成了血小板特异性 TLR4（-/-）小鼠（PF4-TLR4（-/-）小鼠）。来自全身性 TLR4（-/-）或 PF4-TLR4（-/-）小鼠的 TLR4（-/-）血小板具有功能，但对脂多糖无反应，表明缺乏 TLR4。PF4-TLR4（-/-）小鼠对低氧诱导的 PH 有明显的保护作用，包括 RV 收缩压和 RV 肥大的增加减少、血小板活化减少和肺血管重构减少。血小板 TLR4 的缺失减轻了慢性低氧后 5-羟色胺的释放，脂多糖刺激的血小板以 5-羟色胺依赖的方式释放 5-羟色胺并促进肺动脉平滑肌细胞增殖。
我们的数据表明，血小板上的 TLR4 有助于 PH 的发病机制，并进一步强调了血小板在 PH 中的作用。
