Contribution of neutrophil‐derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection

Abstract

Because the pathogenesis of acute respiratory distress syndrome (ARDS) induced by influenza virus infection remains unknown, we can only improve on existing therapeutic interventions. To approach the subject, we investigated immunological etiology focused on cytokines and an acute lung damage factor in influenza-induced ARDS by using a PR-8 (A/H1N1)-infected mouse model. The infected mouse showed fulminant severe pneumonia with leukocyte infiltration, claudin alteration on tight junctions, and formation of hyaline membranes. In addition to interferon (IFN)-α, plenty of keratinocyte-derived chemokines (KC), macrophage inflammatory protein 2 (MIP-2), regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were significantly released into bronchoalveolar lavage fluid (BALF) of the model. We focused on neutrophil myeloperoxidase (MPO) as a potent tissue damage factor and examined its contribution in influenza pneumonia by using mice genetically lacking in MPO. The absence of MPO reduced inflammatory damage with suppression of leakage of total BALF proteins associated with alteration of claudins in the lung. MPO −/− mice also suppressed viral load in the lung. The present study suggests that MPO-mediated OCl − generation affects claudin molecules and leads to protein leakage and viral spread as a damage factor in influenza-induced ARDS.

Protective Immunity and Safety of a Genetically Modified Influenza Virus Vaccine

“…However, the inflammatory mediators released by this cell type also relate to the immunopathology in experimental and natural influenza infection [29], [30]. Although monocytes play an important role in controlling viral infection by release of proinflammatory cytokines, they are also involved in tissue injuries triggered by influenza infection [18], [31], [32]. Importantly, vNA-Δ infection only induced low level of type I interferons and chemokines CXCL1/KC and CCL2/MCP-1 in epithelial cells, leading to a reduced influx of leukocytes and pulmonary injury.…”

Advances in Understanding of the Pathogenesis of Acute Respiratory Distress Syndrome

“…Other components of these vesicles, especially through the generation of ROS have also been implicated; a murine model of influenza-induced ARDS in mice lacking myeloperoxidase showed attenuated inflammatory damage and reduction in leakage of other proteins as detected in BAL fluid [100]. Further studies in animal models of ARDS show that neutrophil-derived ROS, in addition to reactive nitrogen species cause histological lung injury and increased permeability [101].…”

Neutrophils: Neglected Players in Viral Diseases

“…This has been illustrated in influenza virus infection where a reduction of neutrophil infiltration into the lungs was associated with attenuation of tissue damage (Sakai et al, 2000;Seki et al, 2010;Bradley et al, 2012;Sugamata et al, 2012). Moreover, neutrophil-derived proteins, such as MPO (Seki et al, 2010;Sugamata et al, 2012) and elastase, (Seki et al, 2010) are involved in tissue injury.…”

“…Excessive migration or overactivation of neutrophils to the sites of infection could worsen the severity of disease manifestations (Sakai et al, 2000;Seki et al, 2010;Narasaraju et al, 2011;Bradley et al, 2012;Sugamata et al, 2012). This has been illustrated in influenza virus infection where a reduction of neutrophil infiltration into the lungs was associated with attenuation of tissue damage (Sakai et al, 2000;Seki et al, 2010;Bradley et al, 2012;Sugamata et al, 2012).…”