Objective: Cytomegalovirus (CMV) is a ubiquitous herpes virus that persists in the host in a latent state following primary infection. We have recently observed that CMV reactivates in lungs of critically ill surgical patients and that this reactivation can be triggered by bacterial sepsis. Although CMV is a known pathogen in immunosuppressed transplant patients, it is unknown whether reactivated CMV is a pathogen in immunocompetent hosts. Using an animal model of latency/reactivation, we studied the pathobiology of CMV reactivation in the immunocompetent host.
Design: Laboratory study.
Setting: University laboratory.
Subjects: Cohorts of immunocompetent BALB/c mice with or without latent murine CMV (MCMV+/MCMV-).
Interventions: Mice underwent cecal ligation and puncture. Lung tissue homogenates were evaluated after cecal ligation and puncture for tumor necrosis factor-alpha, interleukin-1beta, neutrophil chemokine KC, and macrophage inflammatory protein-2 messenger RNA by polymerase chain reaction and real-time quantitative reverse transcription-polymerase chain reaction. Because pulmonary tumor necrosis factor-alpha expression is known to cause pulmonary fibrosis, trichrome-stained sections of lung tissues were analyzed using image analysis to quantitate pulmonary fibrosis. In a second experiment, a cohort of MCMV+ mice received ganciclovir (10 mg/kg/day subcutaneously) following cecal ligation and puncture. Tumor necrosis factor-alpha messenger RNA and pulmonary fibrosis were evaluated as described previously.
Measurements and main results: All MCMV+ mice had CMV reactivation beginning 2 wks after cecal ligation and puncture. Following reactivation, these mice had abnormal tumor necrosis factor-alpha, interleukin-1beta, neutrophil chemokine KC, and macrophage inflammatory protein-2 messenger RNA expression compared with controls. Image analysis showed that MCMV+ mice had significantly increased pulmonary fibrosis compared with MCMV- mice 3 wks after cecal ligation and puncture. Ganciclovir treatment following cecal ligation and puncture prevented MCMV reactivation. Furthermore, ganciclovir-treated mice did not demonstrate abnormal pulmonary expression of tumor necrosis factor-alpha messenger RNA. Finally, ganciclovir treatment prevented pulmonary fibrosis following MCMV reactivation.
Conclusions: This study shows that CMV reactivation causes abnormal tumor necrosis factor-alpha expression, and that following CMV reactivation, immunocompetent mice have abnormal pulmonary fibrosis. Ganciclovir blocks MCMV reactivation, thus preventing abnormal tumor necrosis factor-alpha expression and pulmonary fibrosis. These data may explain a mechanism by which critically ill surgical patients develop fibroproliferative acute respiratory distress syndrome. These data suggest that human studies using antiviral agents during critical illness are warranted.