Divergent Immune Resolution Pathways in Murine Models of Pneumonia and Acute Lung Injury: Pathogen-specific Mechanisms of Inflammation and Repair

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Abstract Rationale: Pneumonia, a primary cause of acute respiratory distress syndrome (ARDS), drives diverse immune responses based on the infecting agent. Understanding how different pathogens modulate lung inflammation and injury resolution is crucial for developing targeted therapies. Aim: To assess the immunological cell landscape after intratracheal challenge with lipopolysaccharides (LPS), S. pneumoniae (SPN) and K. pneumoniae (KPN) during the resolution of pneumonia. Methods: Ten- to twelve-week-old C57BL6J mice were challenged intratracheally with either LPS (3 mg/kg), SPN (5x10^6 CFU), or KPN (300 CFU). Mice were closely monitored for 15 days with sequential body weight measurements. Bronchoalveolar lavage (BAL) and lung samples were collected on days 3, 7, and 15 post-infections for cell count differentials, protein quantification, histology, BAL bacterial counts, and spectral flow cytometry. Results: LPS and SPN models exhibited signs of lung injury on days 3 and 7 but resolved by day 15, with reduced inflammatory markers and increased regulatory T cells (Tregs; CD4+, CD25+, FoxP3+). The SPN challenge uniquely recruited the highest Treg numbers, suggesting enhanced immune regulation in bacterial clearance and tissue repair (ANOVA, p<0.05). Conversely, the KPN model showed sustained inflammation on day 15, with high BAL cellularity and a pro-inflammatory macrophage phenotype (elevated MHC-II, iNOS, CD36), indicating delayed resolution and chronic inflammation. Conclusion: These findings reveal pathogen-specific immune resolution pathways, with SPN and LPS inducing recovery through Treg recruitment and macrophage modulation, whereas KPN elicits persistent inflammation and macrophage activation. Targeting these differential immune mechanisms could offer new therapeutic avenues for pathogen-specific management of pneumonia-induced lung injury.

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