Immunomodulatory Activity of Omadacycline In Vitro and in a Murine Model of Acute Lung Injury

Objective and Design: Omadacycline, a tetracycline antibiotic, demonstrates in vitro activity against key cystic fibrosis (CF) pathogens, effective lung penetration, and increasing clinical evidence for treatment of lung infections in people with CF (PwCF). This study evaluates its anti-inflammatory effects in vitro and in a murine model of lipopolysaccharide (LPS)-induced lung neutrophilia. Methods In vitro , THP-1-derived macrophages were pretreated with omadacycline (20–100µg/mL) 30min before LPS stimulation. Pro-inflammatory cytokine (TNF-α, IL-1β/6/18), chemokine (CXCL-1/2), and MMP-9 levels were analyzed after 24h by ELISA. Effects on IL-8-induced human neutrophil chemotaxis were also investigated. In vivo , omadacycline (2.5–30mg/kg) was administered to male BALB/c mice 1h before and 6h after intranasal LPS challenge, respectively. Leukocyte counts and differentials in bronchoalveolar lavage fluid (BALF), inflammatory mediator levels in BALF and lung homogenates, pulmonary edema markers, and lung injury severity were evaluated 24h or 48h post-challenge. Results Omadacycline treatment resulted in significant, dose-dependent reductions in IL-6, CXCL-1, and MMP-9 expression and inhibition of IL-8-induced neutrophil chemotaxis in vitro . In vivo , omadacycline yielded protective and therapeutic effects by reducing production of proinflammatory cytokines/chemokines and neutrophil infiltration into the lungs, along with modestly improving lung injury severity. Conclusions Omadacycline may provide dual anti-bacterial and anti-inflammatory activities relevant to treatment of chronic lung infections in PwCF.