马凡氏综合征
医学
发病机制
肺
弹性蛋白
病理
细胞外基质
肺纤维化
炎症
纤维化
基因剔除小鼠
免疫学
细胞生物学
生物
受体
内科学
作者
Benjamin Ng,Chen Xie,Liping Su,Fathima F. Kuthubudeen,Xiu-Yi Kwek,Daryl Yeong,Sebastian Schäfer,Stuart A. Cook,Wei‐Wen Lim
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2022-11-08
卷期号:146 (Suppl_1)
标识
DOI:10.1161/circ.146.suppl_1.13708
摘要
Introduction: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by fibrillin-1 (FBN1) mutations that is associated with aortic disease. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. Here we studied IL11 in a mouse model of MFS (mMFS). Methods: We studied histological and molecular phenotypes in the lungs of Fbn1 C1041G/+ (mMFS) mice, an established model of MFS. To identify IL11-expressing lung cell types, we studied 4- and 16-week-old Fbn1 C1041G/+ : Il11 EGFP/+ reporter mice lungs by immunohistochemistry. We studied the protective effects of IL11 inhibition in the lung by RT-qPCR, immunoblots and histopathology in two models: 1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice ( Fbn1 C1041G/+ : Il11ra1 -/- ) and 2) administered IgG isotype control or anti-IL11RA (X209; 20mg/kg) antibodies twice weekly in mMFS mice between 4 to 24 weeks of age. Results: IL11 was upregulated in the lungs of mMFS mice, which exhibited progressive loss and enlargement of distal airspaces and increased extracellular matrix production. In the distal airways of young mMFS mice (4 weeks old), IL11 was specifically expressed in smooth muscle cells. In the older (16 weeks old) mMFS lungs, IL11 was expressed in smooth muscle cells, fibroblasts and type II alveolar epithelial cells. In mMFS mice, genetic ( Fbn1 C1041G/+ : Il11ra1 -/- mice) or pharmacologic (anti-IL11RA) inhibition of IL11 protected against emphysematous changes, pulmonary fibrosis and inflammation and was associated with reduced pulmonary ERK1/2 signaling and matrix metalloproteinase (MMP2 and MMP9) expression. Conclusions: IL11 causes pulmonary disease in mMFS. This adds to the recent finding that IL11 underlies aortic pathology in mMFS and provides a common disease mechanism across affected tissues in MFS. This has potential implications for treating multi-organ disease in MFS.
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