Department of Internal Medicine (Pulmonology), University of Giessen Lung Center, Justus Liebig University, Giessen, Germany.
Am J Respir Crit Care Med. 2010 Sep 15;182(6):805-18. doi: 10.1164/rccm.200909-1367OC. Epub 2010 Jun 3.
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed.
The objective of this study was to assess the possible contribution of the IL-13 system to IPAH.
Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC.
Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects.
The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.
特发性肺动脉高压（IPAH）的特征是肺动脉平滑肌细胞（paSMC）增生导致中膜肥厚。炎症被认为在与 IPAH 相关的血管重构中起作用。IL-13 作为组织重构的调节剂而出现；然而，IL-13 系统对 IPAH 的贡献尚未得到评估。
本研究旨在评估 IL-13 系统对 IPAH 的可能贡献。
通过实时逆转录-聚合酶链反应、免疫组织化学和流式细胞术，评估 IL-13、IL-13 受体 IL-4R、IL-13Rα1 和 IL-13Rα2 在 IPAH 患者肺组织、paSMC 和微血管病变以及缺氧或单克隆鼠尾草诱导的肺动脉高压啮齿动物肺组织中的表达和定位。全基因组微阵列分析用于研究 paSMC 中 IL-13 调节的基因。
与 IPAH 患者和两种 IPAH 动物模型中的 IL-13 信号传导受体 IL-4R 和 IL-13Rα1 相比，IL-13 诱饵受体 IL-13Rα2 在肺中的表达上调。IL-13 通过 STAT3 和 STAT6 信号通路抑制 paSMC 增殖，促进 G0/G1 期阻滞。全基因组微阵列显示，IL-13 抑制 paSMC 内皮素-1 的产生，提示 IL-13 通过调节内皮素的产生来控制 paSMC 的生长。IL-13ra2 基因的异位表达导致 IL-13 对 paSMC 生长控制的部分丧失，并减弱了 IL-13 对 paSMC 内皮素-1 产生的抑制作用，而 il13ra2 基因表达的小干扰 RNA 敲低则产生了相反的效果。
IL-13 系统是 paSMC 生长的一种新的调节剂。在 IPAH 中，IL-13 受体表达的失调可能部分是 IPAH 中与病理性血管重构相关的平滑肌肥大的基础。
