6533b824fe1ef96bd127ff53

RESEARCH PRODUCT

Role of JAK2/STAT3 pathway in vascular function of pulmonary fibrosis patients

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Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive lung disease with a life expectancy of 2-5 years. A proportion of IPF patients develop pulmonary hypertension (PH), characterized by vasoconstriction and remodeling of pulmonary arteries. Currently, no therapy can improve survival of patients diagnosed with this disease. JAK2/STAT3 molecular route is overexpressed in proliferative disorders, however, its role in PH- associated IPF is unknown. Objective: To analyze the role of JAK2/STAT3 in vascular function of IPF patients with PH. We hypothesized that inhibition of JAK2, STAT3 or JAK2/STAT3 may improve vascular function. Methods: Human precision cut lung slices and arterial pulmonary rings were obtained from 8 control subjects, 14 IPF and 14 IPF with PH patients. We evaluated the effect of Cucurbitacin I (CuI), a JAK2/STAT3 inhibitor, on pulmonary artery contraction and tissue remodeling. Pulmonary arterial smooth muscular cells (PASMCs) were cultured to evaluate the effect of CuI on cell proliferation and cytoplasmic calcium levels. Results: CuI was able to revert and prevent vasoconstriction in pulmonary arteries by an endothelium independent and potassium BKCa channel dependent mechanism. PASMCs reduced proliferation rates, cytoplasmic calcium levels and consequently expression levels of p-Myosin Light Chain Kinase as consequence of JAK2 inhibition by CuI. Pulmonary artery remodeling induced by TGFβ1 was inhibited by CuI in pulmonary artery explants and PASMCs Conclusions: JAK2/STAT3 molecular route is a key component in the vascular processes of IPF and PH associated. Pharmacologic modulation of this route may be a promising target for the treatment of this disease.