Inhibition of Phosphodiesterase-4 during Pneumococcal Pneumonia Reduces Inflammation and Lung Injury in Mice

Abstract

Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, 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. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into 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 level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.

The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

“…We have established a clinically relevant murine model of pneumococcal pneumonia and showed that decreased intact AnxA1 levels in lungs during pneumococcal pneumonia were associated with a worse disease outcome . This feature also applies to other mammalian species and might be generally related to disease severity during severe pneumonia .…”

“…FPR2 signaling has been linked to the majority of the proresolving actions of AnxA1 . We have shown that AnxA1 is cleaved during severe pneumococcal pneumonia and this might be correlated with disease severity . However, the specific role of the AnxA1/FPR2 pathway during pneumococcal pneumonia remained to be determined.…”

“…Vaccines and antibiotics are not completely effective to prevent or treat serotype 3 pneumococcal pneumonia 2 ; therefore, new therapeutic strategies are urgently needed. 3,4 Neutrophilic inflammation triggered by S pneumoniae is an important feature of pneumococcal pneumonia. 5 Activation of alveolar macrophages and lung epithelial cells leads to the massive production of cytokines and chemokines and consequent neutrophil recruitment, which plays an important role in bacterial clearance in the lungs.…”

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…Respiratory function was measured by invasive spirometry under anesthesia. Briefly, mice were tracheostomized, placed in a body plethysmograph and connected to a computer‐controlled ventilator (Forced Pulmonary Maneuver System; Buxco Research Systems, Wilmington, NC), as previously described . Under mechanical respiration, the dynamic compliance (Cdyn) and lung resistance (Rl) were determined by Rl and compliance test.…”

Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation

“…Rolipram has been shown to inhibit lung injury in animals exposed to bleomycin (Pan et al, 2009), hyperoxia (Mehats et al, 2008), and Streptococcus pneumoniae (Tavares et al, 2015). For chlorine injury, we previously showed in mice inhibition by rolipram of pulmonary edema and airway hyperreactivity, which for the lung function measurements involved three rolipram treatments between chlorine exposure and assessment 24 hr after exposure (Chang et al, 2012).…”