Mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection
Reinout A Bem1, Job B M van Woensel, Albert P Bos
1Pediatric Intensive Care Unit, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
Abstract:
Severe infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury (ALI). Accumulating evidence suggests that mechanical ventilation (MV) is an important cofactor in the development of ALI by modulating the host immune responses to bacteria. This study investigates whether MV enhances the host response to pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for RSV infection in humans. BALB/c mice were inoculated intranasally with diluted clarified lung homogenates from mice infected with PVM strain J3666 or uninfected controls. Four days after inoculation, the mice were subjected to 4 h of MV (tidal volume, 10 ml/kg) or allowed to breathe spontaneously. When compared with that of mice inoculated with PVM only, the administration of MV to PVM-infected mice resulted in increased bronchoalveolar lavage fluid concentrations of the cytokines macrophage inflammatory protein (MIP)-2, MIP-1alpha (CCL3), and IL-6; increased alveolar-capillary permeability to high molecular weight proteins; and increased caspase-3 activity in lung homogenates. We conclude that MV enhances the activation of inflammatory and caspase cell death pathways in response to pneumovirus infection. We speculate that MV potentially contributes to the development of lung injury in patients with RSV infection.
Insights
Mechanical ventilation (MV) worsens lung injury in mice infected with pneumonia virus of mice (PVM), a model for human respiratory syncytial virus (RSV). MV increases inflammation and cell death, suggesting it may contribute to acute lung injury in RSV patients.
Area of Science:
- Pulmonary Medicine
- Virology
- Critical Care
Background:
- Severe respiratory syncytial virus (RSV) infection in children can lead to acute lung injury (ALI).
- Mechanical ventilation (MV) is suspected to exacerbate ALI by altering immune responses, particularly in bacterial pneumonia.
- Pneumonia virus of mice (PVM) serves as a relevant animal model for human RSV infections.
Purpose of the Study:
- To investigate if MV exacerbates the host response to PVM infection in mice.
- To determine the impact of MV on inflammatory pathways and lung injury markers during pneumovirus infection.
Main Methods:
- BALB/c mice were intranasally inoculated with PVM or controls.
- Four days post-inoculation, mice underwent 4 hours of MV or spontaneous breathing.
- Bronchoalveolar lavage fluid and lung homogenates were analyzed for cytokine concentrations, protein permeability, and caspase activity.
Main Results:
- MV in PVM-infected mice significantly increased bronchoalveolar lavage fluid concentrations of MIP-2, MIP-1alpha (CCL3), and IL-6.
- MV administration led to increased alveolar-capillary permeability to high molecular weight proteins.
- Caspase-3 activity in lung homogenates was elevated in PVM-infected mice subjected to MV.
Conclusions:
- Mechanical ventilation enhances inflammatory and caspase-mediated cell death pathways during pneumovirus infection.
- These findings suggest MV may contribute to lung injury development in patients with RSV infections.
- Further research is warranted to elucidate the precise mechanisms by which MV affects viral pneumonia outcomes.
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