We studied lung clearance of technetium-labeled diethylenetriamine pentaacetic acid [( 99mTc]DTPA), plasma and bronchoalveolar lavage fluid (BALF) concentrations of 6-keto-PGF1 alpha (stable metabolite of prostacyclin, prostaglandin I2, PGI2), TxB2 (stable metabolite of thromboxane A2, TxA2), and leukotriene B4 (LTB4), and inflammatory cells as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Thirty-one rabbits were randomly assigned to four groups: control sham exposure (SS, n = 6), sham smoke ibuprofen-pretreated (SS-I, n = 7), CSE (n = 6), and CSE ibuprofen-pretreated (CSE-I, n = 12). Ibuprofen, a cyclooxygenase eicosanoid inhibitor, was administered as a single daily intramuscular injection (25 mg/kg) for 7 d before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine [99mTc]DTPA biological half-life (T1/2). The CSE-I group was retrospectively divided into rabbits who survived the 30-breath subset (CSE-IL, n = 6) and those who died during the 30-breath CSE (CSE-ID, n = 6). In the CSE, CSE-IL, and CSE-ID groups, [99mTc]DTPA T1/2 as well as BALF LTB4 levels were significantly decreased. Plasma and BALF 6-keto-PGF1 alpha increased in CSE rabbits compared to the other groups. Alveolar macrophages were lower in the CSE-ID rabbits than in the CSE-IL group. CSE and CSE-IL BALF lymphocyte levels were decreased compared to SS values. Our data indicate that acute CSE is associated with significant increases in 6-keto-PGF1 alpha and decreases in LTB4 as well as a significant reduction in lymphocytes. Furthermore, pretreatment with ibuprofen before CSE was associated with severe lung injury in half of the rabbits. The severity of lung injury may be related to a combination of a lower number of alveolar macrophages and blockade of lung PGI2.