Antimicrobial and immunologic activities of clarithromycin in a murine model of Mycoplasma pneumoniae-induced pneumonia

Abstract

Because macrolide antibiotics are hypothesized to possess immunomodulatory activity independent of their antimicrobial activity, we evaluated the immunomodulatory effect of clarithromycin in a murine model of lung inflammation induced by either live or UV-killed Mycoplasma pneumoniae. BALB/c mice were intranasally inoculated once with live or UV-killed M. pneumoniae. Clarithromycin (25 mg/kg of body weight) or placebo was subcutaneously administered once daily in both groups of mice. In mice infected with live M. pneumoniae, clarithromycin treatment significantly reduced quantitative M. pneumoniae bronchoalveolar lavage (BAL) culture, pulmonary histopathologic scores (HPS), and airway resistance-obstruction (as measured by plethysmography) compared with placebo. Concentrations of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), mouse KC (functional IL-8), JE/MCP-1, and MIP-1alpha in BAL fluid were also significantly decreased in mice infected with live M. pneumoniae given clarithromycin. In contrast, mice inoculated with UV-killed M. pneumoniae had no significant reduction in HPS, airway resistance-obstruction, or BAL cytokine or chemokine concentrations in response to clarithromycin administration. Clarithromycin therapy demonstrated beneficial effects (microbiologic, histologic, respiratory, and immunologic) on pneumonia in the mice infected with live M. pneumoniae; this was not observed in the mice inoculated with UV-killed M. pneumoniae.

FIG. 1.

BAL M. pneumoniae (Mp) cultures, HPS, and Penh for mice inoculated with live M. pneumoniae and treated with clarithromycin versus placebo for 1 to 4 days. Treatment began 12 h after inoculation (0.5 day on the x axis). For each pair of bars, placebo treatment is shown on the left and clarithromycin (Clari) treatment is shown on the right. Values shown are the means ± standard errors (error bars) (n = 5 to 7 for clarithromycin data; n = 4 or 5 for placebo data). Values for the clarithromycin and placebo treatments that are significantly different from each other (P ≤ 0.05) are indicated by an asterisk. PMG, plethysmography.

FIG. 2.

BAL M. pneumoniae (Mp) cultures, HPS, and Penh for mice inoculated with live M. pneumoniae and treated with clarithromycin or placebo for 1 to 13 days. Treatment began 1 day after inoculation. Values shown are the means ± standard errors (error bars) (n = 5 for clarithromycin data; n = 7 for placebo data). PMG, plethysmography; Post Rx 8 Days, 8 days after completion of treatment.

FIG. 3.

Cytokine and chemokine concentrations in BAL specimens from mice inoculated with live M. pneumoniae (Mp) and treated with clarithromycin or placebo for 1 to 4 days. Treatment began 12 h after inoculation (0.5 day on the x axis). For each pair of bars, placebo treatment is shown on the left and clarithromycin (Clari) treatment is shown on the right. Values shown are the means ± standard errors (error bars) (n = 5 to 7 for clarithromycin data; n = 5 for placebo data). Values for the clarithromycin and placebo treatments that are significantly different from each other (P ≤ 0.05) are indicated by an asterisk.

FIG. 4.

Cytokine and chemokine concentrations in BAL specimens from mice inoculated with dead M. pneumoniae (Mp) and treated with clarithromycin or placebo for 1 to 4 days. Treatment began 12 h after inoculation (0.5 day on the x axis). For each pair of bars, placebo treatment is shown on the left and clarithromycin (Clari) treatment is shown on the right. Values shown are the means ± standard errors (error bars) (n = 7 or 8 for clarithromycin data; n = 5 for placebo data). Values for the clarithromycin and placebo treatments that are significantly different from each other (P ≤ 0.05) are indicated by an asterisk.