Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke

Rationale Impaired endothelial cell-dependent vasodilation, inflammation, apoptosis, and proliferation are manifestations of endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Prostacyclin (PGI(2)) is a major product of the cyclooxygenase pathway with potent vasoclilatory and antimitogenic properties and may be relevant to endothelial dysfunction in COPID. Objectives: To determine if PGI(2) expression is altered in smokingrelated lung disease and if it may be protective in COPD-associated endothelial dysfunction. Methods: We evaluated, by immunohistochemistry, Western blotting, and polymerase chain reaction, human emphysema tissue compared with normal tissue for expression of prostacyclin synthase (PGI(2)S)- We examined the effects of cigarette smoke extract (CSE) and aldehyde components on eicosanoid expression in primary human pulmonary microvascular endothelial cells. Finally, we used a murine model of lung-specific PGI(2)S overexpression and in vitro studies to determine if PGI(2) expression has protective effects on cigarette smoke-induced enclothelial apoptosis. Measurements and Main Results: Human emphysema lung tissue exhibited lower PGI(2)S expression within the pulmonary endothelium than in normal lung. In vitro studies demonstrated that CSE, and in particular the alpha,beta unsaturated alclehyde acrolein, suppressed PGi(2)S gene expression, whereas CSE significantly induced the upstream mediators COX-2 and cytosolic phospholipase A2 in human pulmonary microvascular endothelial cells. Mice with lung-specific PG12S overexpression exhibited less enclothelial apoptosis after chronic smoke exposure. In vitro, iloprost exhibited protective effects on CSE-incluced apoptosis. Conclusions: PGI(2)has protective effects in the pulmonary vasculature after acute and chronic cigarette smoke exposure. An imbalance in eicosanoid expression may be important to COPID-associated enclothelial dysfunction.