RESUMO
Secondary bacterial pneumonia is a frequent complication of influenza, associated with high morbidity and mortality. We hypothesized that treatment with neutralizing influenza A antibody AT10_002 protects against severe secondary pneumococcal infection in a mouse model of influenza A infection. Influenza A (H3N2) virus-infected male C57Bl6 mice were treated intravenously with either AT10_002 or a control 2 days postinfection. Seven days later, both groups were infected with Streptococcus pneumoniae and killed 18 hours later. Mice receiving AT10_002 showed less loss of bodyweight compared with controls (+1% vs -12%, P < .001), lower viral loads in bronchoalveolar lavage fluids (BALFs) (7 vs 194 RNA copies per µL; P < .001), and reduced bacterial outgrowth in lung homogenates (3.3 × 101 vs 2.5 × 105 colony-forming units per mg; P < .001). The treatment group showed lower pulmonary wet weights, lower cell counts, and lower protein levels in BALF compared with controls. Treatment with AT10_002 was associated with lower levels of tumor necrosis factor-α, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (KC), and interferon-γ in BALF and lower IL-6 and KC in lung homogenates. Treatment with anti-influenza antibody AT10_002 is associated with reduced weight loss, viral load, bacterial outgrowth, and lung injury in a murine model of secondary pneumococcal pneumonia following influenza infection.
Assuntos
Anticorpos Antivirais/administração & dosagem , Imunização Passiva/métodos , Fatores Imunológicos/administração & dosagem , Influenza Humana/complicações , Influenza Humana/terapia , Pneumonia Pneumocócica/patologia , Pneumonia Pneumocócica/prevenção & controle , Animais , Carga Bacteriana , Peso Corporal , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/virologia , Citocinas/análise , Modelos Animais de Doenças , Humanos , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Masculino , Camundongos Endogâmicos C57BL , Streptococcus pneumoniae/isolamento & purificação , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: The incidence of transfusion-related acute lung injury (TRALI) in cardiac surgery patients is high and this condition contributes to an adverse outcome. Damage-associated molecular pattern (DAMP) molecules, HMGB1 and S100A12, are thought to mediate inflammatory changes in acute respiratory distress syndrome. We aimed to determine whether DAMP are involved in the pathogenesis of TRALI in cardiac surgery patients. MATERIALS AND METHODS: This was a secondary analysis of a prospective observational trial in cardiac surgery patients admitted to the Intensive Care Unit of a university hospital in the Netherlands. Fourteen TRALI cases were randomly matched with 32 transfused and non-transfused controls. Pulmonary levels of HMGB1, S100A12 and inflammatory cytokines (interleukins-1ß, -6, and -8 and tumour necrosis factor-α) were determined when TRALI evolved. In addition, systemic and pulmonary levels of soluble receptor for advanced glycation end products (sRAGE) were determined. RESULTS: HMGB1 expression and levels of sRAGE in TRALI patients did not differ from those in controls. There was a trend towards higher S100A12 levels in TRALI patients compared to the controls. Furthermore, S100A12 levels were associated with increased levels of markers of pulmonary inflammation, prolonged cardiopulmonary bypass, hypoxemia and duration of mechanical ventilation. CONCLUSION: No evidence was found that HMGB1 and sRAGE contribute to the development of TRALI. S100A12 is associated with duration of cardiopulmonary bypass, pulmonary inflammation, hypoxia and prolonged mechanical ventilation and may contribute to acute lung injury in cardiac surgery patients.