Combined effects of mesenchymal stromal cells and antibiotic therapy on Enterobacter ventilator-associated pneumonia in rabbits.

Abstract

BACKGROUND: Although mesenchymal stromal cells (MSCs) have shown promising effects in preclinical pneumonia models, their ability to improve outcomes in ventilator-associated pneumonia (VAP) remains poorly explored, despite VAP being a frequent and severe complication in critically ill patients. This study investigated whether MSCs could enhance outcomes in a rabbit VAP model. METHODS: Male rabbits were ventilated and received lipopolysaccharide (LPS, 3 ng/kg) to mimic sepsis-induced immune dysfunction. After 24 h, animals were inoculated intratracheally with Enterobacter aerogenes to induce VAP. In experiment 1, rabbits (n = 10/group) were randomized to receive human umbilical cord-derived MSCs (3 × 10^6/kg, intravenous) or saline, 4 h after bacterial challenge. In experiment 2, all rabbits received cefepime, with or without MSCs. Outcomes included lung bacterial load (primary), systemic dissemination, 24 h survival, lung injury, and markers of immune and mitochondrial dysfunction. RESULTS: MSC infusion alone did not improve survival (8/10 vs. 9/10; p = .46), lung bacterial load (median [IQR] 6.67 [5.64-7.60] vs. 6.08 [5.72-6.82] log10 CFU/ml; p = .37), systemic dissemination, or lung inflammation. Similarly, lung pathology scores, alveolar neutrophils, and systemic cytokines were unaffected. In contrast, when combined with cefepime, MSCs showed a non-significant trend toward improved survival (10/10 vs. 7/10; p = .067), significantly reduced lung bacterial burden (5.23 [5.05-5.56] vs. 5.47 [5.18-7.01] log10 CFU/ml; p = .049), improved macroscopic lung scores (p = .008), and lowered IL-6 levels (p = .037). However, MSCs did not correct systemic immune dysfunction. CONCLUSION: MSCs alone did not improve lung bacterial clearance or inflammation resolution in this rabbit VAP model. However, the combination of MSCs with cefepime enhanced lung bacterial clearance and reduced lung IL-6 concentrations, compared with cefepime alone. Further studies are required to elucidate the mechanisms underlying the combined effects of antibiotics and MSCs.