Endotoxin-induced Suppression of Pulmonary Antibacterial Defenses against Staphylococcus aureus

In order to evaluate the effect of endotoxin on lung host defenses, Sprague-Dawley rats were intravenously injected with either placebo or 5 mg/kg of Escherichia coli lipopolysaccharide B. Two hours after treatment, animals were challenged with Staphylococcus aureus by either low dose aerosol inhalation or high dose intratracheal instillation of the bacteria into the lungs. Quantitative lung bacteriologic examination and bronchoalveolar lavage (BAL) for total and differential cell counts were performed immediately (zero hour) and at 4 h after bacterial challenge. Lung phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage (AM) in the absence of inflammation. In aerosol-challenged control rats, 20.6 ± 2.0% of the initial deposited bacterial challenge remained viable in the lung at 4 h. Animals pretreated with endotoxin, however, showed a significant decrease in pulmonary bactericidal activity (31.3 ± 3.4% bacteria remaining at 4 h), indicating a defect in alveolar macrophage (AM) function. Further assessment of the bactericidal oxidative metabolism of endotoxin-treated AM by luminol-enhanced chemiluminescence indicated an increased production of free radical oxygen species when compared with control nontreated cells in both the unstimulated (66 ± 4 versus 38 ± 7 × 103 cpm in control) and stimulated (250.5 ± 17.1 versus 147.1 ± 6.2 × 103 cpm in control) states. Total and differential cell counts in both control and endotoxin-treated aerosol-challenged rats were similar. In contrast, after an intratracheal challenge of S. aureus, endotoxin-pretreated rats demonstrated a marked reduction in total cell count (2.6 ± 0.2 × 106 versus 3.1 ± 0.5 × 107) and in polymorphonuclear leukocytes (PMN) (14.0 ± 3.8% versus 85.3 ± 1.9%) recovered in BAL when compared with control animals, resulting in a failure of antibacterial defenses at 4 h (109.4 ± 11.2% versus 71.2 ± 5.1% bacteria remaining) and bacteremia. Histopathologic examination demonstrated few intraalveolar neutrophils and sequestration of PMN within the pulmonary vasculature in endotoxin-pretreated rats subsequently challenged by intratracheal S. aureus. These data suggest that endotoxin may play a central role in contributing to the development of pneumonia by impairing AM bactericidal activity and inhibiting the normal recruitment of PMN into the lung in response to bacteria, which in turn markedly suppresses pulmonary host defenses.