We studied the influence of sex on the modulation by acute ethanol intoxication of lung polymorphonuclear leukocyte (PMN) recruitment, production of chemotactic factors, and nuclear factor kappa-B (NF-kappa B) activation in alveolar macrophages (AMs) of rats receiving an intrapulmonary challenge with endotoxin (ET). Male and female Charles River rats were given an intratracheal ET challenge [100 micro g in phosphate-buffered saline (PBS)], followed by an intravenous infusion of ethanol or saline for 2.5 h. At that time, bronchoalveolar lavage (BAL) fluid was obtained, and AMs and recruited PMNs were isolated. Acute ethanol treatment [primed 2.5-h intravenous infusion of ethanol, priming dose of 0.87 ml per 100 grams of body weight of 20% (vol./vol.) ethanol, followed by a continuous infusion of 20% ethanol at 0.15 ml per 100 grams of body weight per hour] suppressed ET-induced lung PMN recruitment equally in female and male rats. However, cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) in BAL fluid were suppressed only in female rats. Polymorphonuclear leukocytes of untreated female rats responded to MIP-2 and formyl-methionyl-leucyl-phenylalanine (fMLP) with lower chemotactic activity than did PMNs of male rats. Activation of NF-kappa B in AMs of female rats treated with ET or with ET plus ethanol was less than that in male rats, supporting the suggestion of transcriptional regulation of chemoattractant production, leading to reduced PMN recruitment. Because excessive PMN recruitment with subsequent release of granular contents is associated with tissue damage, these results indicate a potential protective mechanism against pulmonary damage in female rats.