Pretreatment of nafithromycin attenuates inflammatory response in murine lipopolysaccharide induced acute lung injury

Acute respiratory distress syndrome following an acute lung injury (ALI) is a life threatening inflammatory condition predominantly characterized by vascular protein leakage, neutrophil recruitment and overexpression of proinflammatory cytokines. Pulmonary and systemic bacterial infections are the major cause of ALI wherein the bacterial cell components play a crucial role. Macrolide/ketolide antibiotics are reported to possess immunomodulatory activity; as a result improved survival has been noted in pneumonia patients. Hence immunomodulatory activity of nafithromycin, a novel lactone ketolide antibacterial agent was assessed in the murine LPS induced ALI model. Vehicle, nafithromycin (100 mg/kg), azithromycin (600 mg/kg) and dexamethasone (20 mg/kg) were administered orally, 1 h prior to LPS challenge and bronchoalveolar lavage (BAL) fluid was collected thereafter at 18, 24 and 48 h to determine the total cell count, total protein, myeloperoxidase (MPO), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Results from the current study showed that pretreatment with nafithromycin significantly reduced the total cell count, total protein, MPO, TNF-alpha and IL-6 levels in BAL fluid compared to LPS control group. Histopathological evaluations also suggest significant reduction in neutrophil infiltration by nafithromycin. Dexamethasone, a positive reference standard as expected exhibited potent anti-inflammatory activity. The immunomodulatory effect of nafithromycin at dose of 100 mg/kg was comparable to azithromycin dosed at 600 mg/kg. As a result of immunomodulatory activity, nafithromycin is expected to provide additional clinical benefits by resolving the secondary complications associated with severe pneumonia and thereby improving survival in such patients.