Pulmonary leukostasis and the inhibition of airway neutrophil recruitment are early events in the endotoxemic rat.

Neutrophil (polymorphonuclear leukocyte [PMN]) migration into pulmonary airspaces is a prerequisite for clearance of bacteria commonly found in nosocomial pneumonia. Patients at risk for nosocomial pneumonia often experience endotoxemia, and neutrophil dysfunction is associated with endotoxemia in both humans and animals. Using a rodent model of endotoxemia-associated pneumonia, we characterized the altered kinetics of pulmonary PMN trafficking and addressed the roles of platelets, tumor necrosis factor (TNF), and products of complement activation as potential mediators in the modulation of PMN migratory function. In male Sprague-Dawley rats made endotoxemic with intravenously (i.v.) administered endotoxin (lipopolysaccharide [LPS]), recruitment of PMNs into the lung airspaces in response to intratracheally (i.t.) instilled LPS was inhibited. In animals given IT LPS alone (0.5 mg/rat), numbers of airway PMNs were significantly elevated by 2 h, and immunohistochemical evaluation revealed PMNs in alveolar airspaces, alveolar walls, and in interstitium surrounding large airways. LPS (2 mg/kg i.v.) caused neutropenia and pulmonary PMN sequestration within 15 min of administration. Inhibition of airway PMN accumulation occurred by 30 min and lasted for at least 6 h after i.v. LPS. Factors present or activated after 30 min of endotoxemia were hypothesized to mediate the inhibitory effect of i.v. LPS. We found that pretreatment of rats with cobra venom factor to deplete complement (and C5a production) or immunodepletion of platelets or TNF did not affect the ability of i.v. LPS to inhibit pulmonary PMN recruitment or to cause pulmonary leukostasis. In summary, our results show that the inhibitory effects of i.v. LPS on PMN trafficking are rapid and persist for several hours and suggest that neither TNF, C5a, nor platelets are sufficient to mediate the inhibitory response.