Resolvin D5 limits inflammatory lung injury and enhances antibacterial host defense in severe pneumococcal pneumonia

Streptococcus pneumoniae remains a leading cause of lower respiratory tract infections and pneumonia-related mortality worldwide. Although neutrophil recruitment is essential for pneumococcal containment, excessive and dysregulated neutrophilic inflammation can drive severe lung injury and acute respiratory distress syndrome. Specialized pro-resolving mediators, such as Resolvin D5 (7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid; RvD5), are produced in the lungs and have the potential to promote pathogen clearance and limit inflammatory injury. Using a mouse model of severe pneumococcal pneumonia, we investigated the actions of RvD5 on disease progression. Exogenous RvD5 was administered either at the time of infection or post-infection together with the antibiotic ceftriaxone. Outcomes measured included lung neutrophil accumulation, bacterial burden, neutrophil activation markers, and indices of alveolar barrier integrity. Complementary in vitro assays were performed to assess the effects of RvD5 on human neutrophil phagocytosis and activation by LTB4. When administered at the time of infection, RvD5 reduced neutrophil accumulation in bronchoalveolar lavage (BAL) and lung tissue and enhanced clearance of S. pneumoniae. RvD5 decreased neutrophil activation marker expression and lowered total protein levels in BAL fluid, consistent with reduced inflammatory lung injury. When administered post-infection together with ceftriaxone, RvD5 significantly reduced lung neutrophil numbers and barrier disruption compared with antibiotic treatment alone. In vitro, RvD5 enhanced phagocytic uptake and intracellular killing of bacteria by human neutrophils, and blunted secondary calcium mobilization responses to LTB4. In summary, these findings indicate that RvD5 can initiate pro-resolving mechanisms adjunctive to antibiotics to enhance bacterial clearance and limit inflammation-driven lung injury in severe pneumococcal pneumonia.