Effect of alkylating agents on the clearance of Staphylococcus aureus from murine lungs

Alkylating agents have several effects on cellular host defense responses which could increase either the frequency or the severity of pulmonary infections. In addition, some of these agents directly injure lung parenchyma and could have effects on intrapulmonary killing processes independent of any effect on phagocyte number and function. We have used a murine model for staphylococcal clearance to evaluate the effect of cyclophosphamide and mechlorethamine on intrinsic lung defenses. Single doses of mechlorethamine (40 micrograms IV) or of cyclophosphamide (150 mg/kg IP) reduce peripheral blood neutrophil counts and spleen weights on day 3 after injection; with the exception of neutrophil counts in mechlorethamine-treated mice, these parameters returned to normal by days 10-12. Both drugs reduced the number of alveolar macrophages recoverable by bronchoalveolar lavage on days 10-12 but not day 3. Mechlorethamine delayed the clearance of Staphylococcus aureus 502A from the lung on both days 3 and 12, but cyclophosphamide did not alter clearance on either day 3 or 10. The defect in clearance in mechlorenthamine-treated mice resolved by 3 wk after drug administration. These results demonstrate that alkylating agents do not have uniform effects on antibacterial processes in the murine lung. Since the mechlorethamine effect on staphylococcal elimination appears independent of its effect on macrophage numbers, these results suggest that staphylococcal clearance also depends on nonphagocytic host defense factors.