Pulmonary fibrosis affects millions of people worldwide. A common form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The mean survival after diagnosis is only approximately 3 years, which is similar to, if not worse than, the prognosis associated with many types of cancer. IPF is characterized by epithelial and endothelial cell damage, varying degrees of inflammation, abnormal pulmonary vascular remodeling, aberrant fibroblast proliferation, and extracellular matrix deposition that result in distortion of pulmonary architecture and organ dysfunction. The development of pulmonary hypertension (PH) in settings of IPF occurs in 60-80% of patients and predicts mortality from the disease. However, the mechanisms that drive endothelial injury, abnormal vascular remodeling, and the development of PH are poorly understood, and various pulmonary vasoactive agents failed to show positive effects in IPF patients. Therefore, novel therapeutic targets that can be manipulated to control the vascular remodeling and PH in these disorders are in dire need of scientific breakthroughs.

Chitinase 3-like 1(CHI3L1) is the prototypic chitinase-like protein. The levels of circulating CHI3L1 levels are higher in individuals with IPF and other forms of pulmonary fibrosis compared to controls and that they correlate with disease severity. CHI3L1 has multiple effects in the lung where it functions to simultaneously decrease epithelial injury and augment repair. These divergent responses are mediated by distinct receptor systems in various cell types. However, the direct effect of CHI3L1 and the receptor complexes through which CHI3L1 mediates different effector responses in endothelial cells, vascular smooth muscle cells, and vascular remodeling responses in pulmonary fibrosis is poorly understood. We hypothesize that the CHI3L1 and its receptors modulate abnormal pulmonary vascular remodeling and the development of PH in settings of pulmonary fibrosis. The proposed studies will utilize vascular endothelial cells and smooth muscle cells, and innovative mouse models to ascertain the role of CHI3L1 signaling in vascular remodeling associated with pulmonary fibrosis and may reveal new therapeutic options to slow the development of PH in IPF.