Schistosomiasis-Induced Experimental Pulmonary Hypertension Role of Interleukin-13 Signaling
Schistosomiasis-Induced Experimental Pulmonary Hypertension Role of Interleukin-13 Signaling
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DOI：
10.2353/ajpath.2010.100063
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Tuder, Rubin M.
中科院分区：
文献类型：
--
作者：
Graham, Brian B.;Mentink-Kane, Margaret M.;Tuder, Rubin M.
血吸虫病引起的肺动脉高压(PH)是世界范围内最常见的PH原因之一，其发病机制尚不清楚。我们试图确定曼氏血吸虫是否以白介素13依赖的方式引起实验性肺血管重构相关的肺高压。IL-13Rα1是典型的IL-13信号受体，而IL-13Rα2是一种竞争性的非信号诱骗受体。用野生型IL-13Rα1(-/-)和IL-13Rα2(-/-)C57BL/6J小鼠经皮感染曼氏血吸虫尾蚴。注射卵子。我们通过右室插管、肺血管重塑的组织学评估以及IL-13和转化生长因子-β信号的检测来评估PH。感染的小鼠出现肺部笔卵肉芽肿和动脉重塑，主要累及血管中层。此外，功能增强的IL-13Ra2-/-小鼠加剧了血管重构和PH。IL-13Rα1功能丧失的小鼠没有发生肺高压，肺血管重塑减少。此外，IL-13信号转导靶点抵抗素样分子-a在感染野生型和IL-13Rα2(-/-)的小鼠中表达增加，但不增加IL-13Rα1(-/-)的表达。磷酸化的Smad2/3，转化生长因子-β信号的靶标，在感染这种疾病的小鼠和人类中都增加了。我们的数据表明，实验性血吸虫病导致PH，并可能残留上调的IL-13信号。(Am J Pathol 2014177：1549-1561：DO！：10.2353/ajpath.2010.100063)
The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13R alpha 1 is the canonical IL-13 signaling receptor, whereas IL-13R alpha 2 is a competitive non-signaling decoy receptor. Wild-type, IL-13R alpha 1(-/-), and IL-13R alpha 2(-/-) C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-beta signaling. Infected mice developed pulmonary pen-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Ra2-/- mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13R alpha 1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-a, a target of IL-13 signaling, was increased in infected wild-type and IL-13R alpha 2(-/-) but not IL-13R alpha 1(-/-) mice. Phosphorylated Smad2/3, a target of transforming growth factor-beta signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relics on up-regulated IL-13 signaling. (Am J Pathol 2014 177:1549-1561: DO!: 10.2353/ajpath.2010.100063)