Abstract 399: End-stage Heart Failure Causes Severe Lung Fibrosis and Dysfunction

Abstract

Chronic heart failure (CHF) causes trouble breathing in patients. We recently demonstrated that systolic pressure overload by transverse aortic constriction (TAC) causes severe left ventricular (LV) failure that is associated with massive lung fibrosis and lung vascular remodeling, and right ventricular (RV) dysfunction in mice. Here, we further studied the effect of CHF on lung structure and function in mice, and the effect of CHF on lung fibrosis in patients. We demonstrated that chronic TAC resulted in decrease of LV ejection fraction, and increases LV weight, lung weight, and RV weight, as well as their ratios to bodyweight. Interestingly, the development of LV failure is associated with a significant lung dysfunction as evidenced by a ~2-fold increase of lung resistance and a ~50% dramatic decrease of lung compliance in vivo . Lung compliance was also significantly reduced ~50% in lung isolated from CHF mice, indicating the decrease of lung compliance is due to the structure change of lung. The reduced lung compliance in CHF mice is significantly correlated with the decrease of LV ejection fraction, the increase of lung weight, and RV hypertrophy, suggesting the reduced lung compliance might contribute to the development of RV hypertrophy and failure. Histochemical analyses further demonstrated that CHF causes massive lung vascular, perivascular and interstitial fibrosis, as well as increase of lung myofibroblast proliferation. By using the chimeric mice created by transplantation of Bone Marrow Derived Cells (BMDCs) from GFP mice into wild type mice, we demonstrated that BMDCs contribute to the increased lung myofibroblasts and lung fibrosis. However, BMDCs don’t differentiate into lung smooth muscles cells in CHF mice. Moreover, we demonstrated that inhibition of lung inflammation by a cytokine therapy protocol is effective in attenuating TAC-induced lung fibrosis. Finally, we demonstrated that end-stage CHF causes increase of lung fibrosis in patients, and the increased lung fibrosis is associated with RV hypertrophy and dysfunction in patients. Together, our study demonstrated that end-stage CHF causes lung fibrosis and lung dysfunction, and inhibition of inflammation is effective in attenuating heart failure induced lung fibrosis.