Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine (B.B.G., J.C., L.G., J.P., E.D., L.D., T.T., L.S., N.D., R.W.V.) and Department of Pathology (X.-J.W.), Anschutz Medical Campus, Aurora, CO; Pulmonary Vascular Research Institute (B.B.G., A.B., H.C.C., G.B., R.M.T.); Memorial S. Jose Hospital, Universidade de Pernambuco in Recife, Recife, Brazil (A.B.); Division of Cardiology, University of Pittsburgh, Pittsburgh, PA (H.C.C.); School of Pharmacy, University of Kent, Kent, UK (G.B.); and Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (T.A.W.).
Circulation. 2013 Sep 17;128(12):1354-64. doi: 10.1161/CIRCULATIONAHA.113.003072. Epub 2013 Aug 19.
The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.
Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries.
Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
血吸虫病是全球最常见的肺动脉高压病因之一，但其导致肺动脉高压的发病机制尚不清楚。我们假设，Th2 炎症引起的转化生长因子-β（TGF-β）信号通路对于这种疾病的发病机制至关重要。
用曼氏血吸虫卵致敏并随后进行攻卵的小鼠发生了肺动脉高压，伴有右心室收缩压升高、肺动脉中层增厚和右心室肥厚。Rho 激酶依赖性血管收缩约占右心室收缩压升高的 60%。肺血管重构和肺动脉高压依赖于 TGF-β信号的增加，因为 TGF-β配体和受体的药理学阻断以及缺乏 Smad3 的小鼠对血吸虫引起的肺动脉高压有显著的保护作用。TGF-β 信号通路的阻断也导致了白细胞介素-4 和白细胞介素-13 浓度的降低，这两种细胞因子驱动了血吸虫病肺部病理学特征性的 Th2 反应。与血吸虫病相关的肺动脉高压患者的肺部有证据表明，其重构的肺血管中存在 TGF-β 信号。
实验性曼氏血吸虫诱导的肺血管疾病依赖于经典的 TGF-β 信号通路。
