Daley Eleen, Emson Claire, Guignabert Christophe, de Waal Malefyt Rene, Louten Jennifer, Kurup Viswanath P, Hogaboam Cory, Taraseviciene-Stewart Laimute, Voelkel Norbert F, Rabinovitch Marlene, Grunig Ekkehard, Grunig Gabriele
St. Luke's Roosevelt Hospital, New York, NY 10019, USA.
J Exp Med. 2008 Feb 18;205(2):361-72. doi: 10.1084/jem.20071008. Epub 2008 Jan 28.
Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4(+) T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule alpha, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH.
以血管平滑肌密度增加为特征的肺动脉重塑是肺动脉高压（PAH）中常见的病变，PAH是一种致命疾病。临床相关性研究提示肺动脉重塑存在免疫发病机制，但缺乏实验证据。我们发现，用两种不同的可溶性抗原之一经气道进行免疫和长期间歇性激发可诱导中小肺动脉发生严重肌化。CD4(+) T细胞耗竭、抗原特异性2型辅助性T细胞（Th2）反应或致病性Th2细胞因子白细胞介素13可显著改善肺动脉肌化。肺动脉肌化的严重程度与表达平滑肌细胞有丝分裂原抵抗素样分子α的上皮细胞和巨噬细胞数量增加有关，但令人惊讶的是，与肺动脉高压并无关联。我们的数据首次提供了实验证据，表明对可溶性抗原的适应性免疫反应足以导致严重的肺动脉肌化，并支持儿科患者和伴侣动物的临床观察结果，即肌化是可能共同导致PAH的几种肺动脉损伤事件之一。
