COX-2 inhibition and hypoxia-induced pulmonary hypertension: effects on pulmonary vascular remodeling and contractility

摘要

Pulmonary arterial hypertension (PAH) is a significant disease process characterized by elevated pulmonary vascular resistance leading to increased right ventricular afterload and ultimately progressing to right ventricular dysfunction and often death. Irreversible remodeling of the pulmonary vasculature is the hallmark of pulmonary hypertension and frequently leads to progressive functional decline in patients with PAH despite treatment with currently available therapies. Metabolites of the arachidonic acid cascade play an important homeostatic role in the pulmonary vasculature and dysregulation of pathways downstream of arachidonic acid play a central role in the pathobiology of PAH. Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMC) and inflammatory cells during hypoxia and plays a protective role in the lung’s response to hypoxia. We recently demonstrated that absence of COX-2 was detrimental in a mouse model of hypoxia-induced pulmonary hypertension. Exposure of COX-2 null mice to hypoxia resulted in severe pulmonary hypertension characterized by enhanced pulmonary vascular remodeling and significant upregulation of the ET-1 receptor (ETAR) in the lung following hypoxia. Absence of COX-2 in vitro led to enhanced contractility of PASMC following exposure to hypoxia that could be attenuated by iloprost, a prostaglandin I2 analog. These findings suggest that selective inhibition of COX-2 may have detrimental pulmonary vascular consequences in patients with pre-existing pulmonary hypertension or underlying hypoxemic lung diseases. Here we discuss our recent data demonstrating the adverse consequences of COX-2 inhibition on pulmonary vascular remodeling and PASMC contractility.