End-stage left ventricular failure or chronic heart failure (CHF) causes severe lung inflammation, vascular remodeling, WHO type-2 pulmonary hypertension, and right ventricular hypertrophy. However, the molecular mechanism of CHF-induced lung inflammation and remodeling is largely unknown. CD44 is a member of the hyaluronate receptor family of cell adhesion molecules, which has been shown to play a selective role in controlling macrophage and lymphocyte migration. Here we demonstrated that end-stage CHF causes a dramatic increase of CD44 expression in heart and lung in human and mice. Histological staining shows that CD44 is predominantly expressed in leukocytes such as macrophages. Flow cytometry analysis further demonstrates that CD44 is predominantly expressed in F4/80 positive macrophages, CD4+, and CD8+ T cells. CD44 expression is dramatically increased in activated T cell subsets. To further determine the physiological role of CD44 in CHF-induced lung remodeling and type-2 pulmonary hypertension, we studied the effect of CD44 blockade on type-2 pulmonary hypertension development in a group of mice with existing moderate left ventricular failure without apparent lung remodeling. Interestingly, we found that blockade CD44 with blocking antibodies (Abs) significantly attenuate the development of lung vascular and interstitial leukocyte infiltration, lung vascular remodeling, fibrosis, and increase of right ventricular hypertrophy. Blockade CD44 signaling also significantly attenuated further decline of left ventricular ejection fraction in mice with existing LV failure. In addition, we demonstrated that induction of T regulatory cells with IL-2 and IL-2 Abs complex significantly attenuated the infiltration of CD44 positive leukocytes in lung tissue, lung vascular remodeling, lung fibrosis, and right ventricular hypertrophy in mice with existing moderate left ventricular failure. Together, these data indicate an important role of CD44 in left ventricular failure-induced lung inflammation, and type-2 pulmonary hypertension, suggesting that inhibition of CD44 may attenuate heart failure progression and type-2 pulmonary hypertension.
Left Ventricular Failure after Surgery to Correct Right Ventricular Pressure Overload in Pulmonary Hypertension Patients
