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 currently available therapies that act as pulmonary vasodilators have failed to be beneficial 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 plays a protective role in tissue damage by ameliorating epithelial cell death, and a pro-fibrotic role via its ability to stimulate alternative (M2) macrophage activation, fibroblast proliferation and matrix deposition. These divergent responses are mediated by distinct receptor systems in various cell types. However, despite its importance as a regulator of injury/repair responses in pulmonary fibrosis, the interrelationship between CHI3L1 and vascular repair/remodeling associated with pulmonary fibrosis has never been investigated, and the receptor complexes through which CHI3L1 mediates different effector responses in vascular cells have not been characterized. In preliminary studies, we found that pulmonary hypertensive responses during the development of pulmonary fibrosis were mitigated in CHI3L1 null mice and accentuated in transgenic mice that overexpress CHI3L1. We hypothesize that the CHI3L1 and its receptors modulate abnormal pulmonary vascular remodeling and the development of PH in pulmonary fibrosis. We propose to 1) define the cellular effects of CHI3L1 and its receptors on vascular endothelial cells and smooth muscle cells; 2) determine the role of CHI3L1 and its receptors in vascular remodeling and PH in the well-characterized bleomycin mouse model of pulmonary fibrosis; 3) develop CHI3L1-based therapeutics to treat vascular remodeling and PH associated with pulmonary fibrosis. The proposed studies will determine the role of CHI3L1 signaling in pulmonary vascular cells, and may reveal new therapeutic options to slow the development of PH in IPF.
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