Lung defenses against viral and bacterial challenges during immunosuppression with cyclophosphamide in mice.
Pulmonary virus infections predispose to secondary bacterial pneumonias by suppressing the antibacterial defenses of the lung. Cyclophosphamide (CY) treatment interferes with antiviral defenses and also impairs pulmonary bactericidal activity. To determine whether CY aggravates secondary bacterial pneumonias, mice were infected by aerosol inhalation with para-influenza 1 (Sendai) virus and injected intraperitoneally with either 0.5, 1.0, 2.5, and 5.0 mg of CY on Days 1 and 5 of the infection. On Day 7, the lungs of control (CY-treated but not infected) and virus-infected mice were lavaged and the total and differential number of free pulmonary cells quantitated. At the same time, other groups of mice were challenged aerogenically with Staphylococcus aureus and the number of initially viable bacteria remaining in their lungs quantitated at 4 and 24 h thereafter. The CY treatment induced a dose-dependent neutropenia, which was paralleled by the number of free pulmonary cells recovered from the lungs. Pulmonary bactericidal activity was also suppressed by CY treatment, with the percentage of staphylococci remaining at 24 h in the lungs of control animals being 0.5 +/- 0.2% and 1.5 +/- 0.5%, 4.0 +/- 1.5%, 8.5 +/- 2%, and 36 +/- 5%, respectively, for the increasing doses of CY. In virus-infected animals, CY treatment suppressed the inflammatory response in a dose-dependent manner, with the total number of free lung cells recovered from the highest dose group being only 5% of that recovered from untreated animals. Virus infection depressed the antibacterial defenses of the lung so that in untreated animals, 80 +/- 9% of the staphylococcal remained at 24 h. Treatment with the 2 higher doses of CY caused the bacteria to proliferate extensively in the lungs to 280 +/- 53% and 792 +/- 112%, respectively, for the 2.5 mg and 5.0 mg CY doses. In contrast, treatment with 0.5 mg and 1.0 mg of CY significantly enhanced the intrapulmonary killing of S. aureus in virus-infected lungs so that the bactericidal values at 24 h were 28 +/- 3% and 21 +/- 2%, respectively. These data demonstrated that immunosuppression modulates virus-induced suppression of pulmonary antibacterial defenses with high doses of CY aggravating and low doses ameliorating the defect.
D000336:Aerosols; D000818:Animals; D003520:Cyclophosphamide / Q000009:adverse effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007165:Immunosuppression Therapy; D007274:Injections, Intraperitoneal; D008168:Lung / Q000276:immunology*; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced; D010222:Parainfluenza Virus 1, Human / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology
D000336:Aerosols; D003520:Cyclophosphamide