Abstract 13708: Il11 Causes Pulmonary Tissue Remodeling and Emphysematous Lung Disease in the Fbn1C1041G/+ Mouse Model of Marfan Syndrome

IntroductionMarfan 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). MethodsWe studied histological and molecular phenotypes in the lungs of Fbn1C1041G/+ (mMFS) mice, an established model of MFS. To identify IL11-expressing lung cell types, we studied 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice lungs by immunohistochemistry. We studied the protective effects of IL11 inhibition in the lung by RT-qPCR, immunoblots and histopathology in two models1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+: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. ResultsIL11 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 (Fbn1C1041G/+: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. ConclusionsIL11 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.