Rationale: Impaired endothelial cell dependent vasodilation, inflammation, apoptosis and proliferation are manifestations of endothelial dysfunction in COPD. Prostacyclin (PGI₂) is a major product of the cyclooxygenase pathway with both potent vasodilatory and anti-mitogenic properties and may be relevant to endothelial dysfunction in COPD Objectives: To determine if PGI₂ expression is altered in smoking related lung disease and if it may be protective in COPD associated endothelial dysfunction. Methods: We evaluated by immunohistochemistry, western blotting and PCR, human emphysema tissue compared to normal tissue for expression of Prostacyclin Synthase (PGI₂S). We examined the effects of both cigarette smoke extract (CSE) and aldehyde components on eicosanoid expression in primary human pulmonary microvascular endothelial cells (HPMVEC). Lastly, we utilized a murine model of lung specific PGI₂S over-expression and in-vitro studies to determine if PGI₂ expression has protective effects on cigarette smoke induced endothelial apoptosis. Measurements and Main Results: Human emphysema lung tissue exhibited lower PGI₂S expression within the pulmonary endothelium than normal lung. In-vitro studies demonstrated that cigarette smoke extract (CSE) and in particular the , unsaturated aldehyde acrolein suppressed PGI₂S gene expression while CSE significantly inducing upstream mediators COX-2 and cPLA₂ in HPMVEC. Mice with lung specific PGI₂S over-expression exhibited less endothelial apoptosis following chronic smoke exposure. In-vitro, Iloprost exhibited protective effects on CSE-induced apoptosis. Conclusions: PGI₂ has protective effects in the pulmonary vasculature following both acute and chronic cigarette smoke exposure. An imbalance in eicosanoid expression may be important to COPD associated endothelial dysfunction.