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Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice
Erjian Wang1, Marie Simard, Nathalie Ouellet
1Infectious Diseases Research Center, Laval University, Quebec City, Canada G1V 4G2.
Abstract:
Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.
Insights
Leukopenic mice with Streptococcus pneumoniae pneumonia show severe lung injury without neutrophil infiltration. This suggests bacterial virulence factors, not neutrophils, drive lung damage in these high-risk patients.
Area of Science:
- Immunology
- Pathology
- Microbiology
Background:
- Streptococcus pneumoniae pneumonia is common in leukopenic patients, often leading to lung injury and septicemia.
- Limited understanding exists on the interplay between microbial growth, inflammation, and lung pathology in specific leukopenic conditions.
Purpose of the Study:
- To investigate the pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenic mice.
- To correlate microbial proliferation, inflammatory responses, and histopathological changes in leukopenic hosts.
Main Methods:
- Induction of leukopenia using cyclophosphamide in a mouse model of pneumococcal pneumonia.
- Assessment of inflammatory mediator secretion (IL-1, IL-6, MIP-1, MIP-2, MCP-1).
- Evaluation of bacterial dissemination, lung permeability, edema, and histopathology via electron microscopy.
Main Results:
- Leukopenia did not impede inflammatory cytokine secretion but enhanced bacterial proliferation in lungs.
- Pulmonary capillary permeability, edema, and lung injury were increased in leukopenic mice.
- Despite lack of neutrophil infiltration, extensive alveolar epithelial damage, surfactant defects, and diffuse alveolar damage were observed.
Conclusions:
- Neutrophils are not essential for lung injury development in this pneumococcal pneumonia model.
- Bacterial virulence factors play a significant role in driving lung pathology in leukopenic hosts.
- Leukopenic individuals with pneumococcal pneumonia face an elevated risk of developing diffuse alveolar damage.