Inibição da Fosfodiesterase 4 em um modelo murino de pneumonia por Streptococcus pneumoniae

Abstract

Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection but the permanence and excessive activation of neutrophils in the lungs may cause tissue damage. Phosphodiesterase-4 (PDE4) inhibitors, such as rolipram (ROL), effectively reduce inflammation. This study examined the impact of rolipram in a model pneumococcal pneumonia in mice. Balb/C mice were infected intranasally with 103-106CFU of Streptococcus pneumoniae and the kinects of inflammation were evaluated. 104-104 CFU mice were then treated with ROL in a prophylactic or therapeutic schedule in combination or not with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed and ex vivo phagocytosis assays were performed. Rolipram treatment during S. pneumoniae infection decreased neutrophil recruitment into the lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine levels and lung injury. Combined ROL and ceftriaxone treatment was more efficient in reducing inflammation, by increasing pro-resolving protein Annexin A1 expression, and reducing bacteria burden, by enhancing phagocytosis. Furthermore, annexin A1 deficient mice are more susceptible to pneumococcal pneumonia. These data show that immunomodulatory effects of PDE4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases