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Combined effects of mesenchymal stromal cells and antibiotic therapy on Enterobacter ventilator-associated pneumonia
Marine Jacquier1,2,3, Caroline Laroye4, Danièle Bensoussan4
1Department of Intensive Care, François Mitterrand, University Hospital, Dijon, France. marine.jacquier@chu-dijon.fr.
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.
Insights
Mesenchymal stromal cells (MSCs) alone did not improve outcomes for ventilator-associated pneumonia (VAP) in rabbits. However, combining MSCs with cefepime enhanced bacterial clearance and reduced lung inflammation.
Area of Science:
- Regenerative Medicine
- Pulmonary Medicine
- Critical Care Medicine
Background:
- Ventilator-associated pneumonia (VAP) is a severe complication in critically ill patients.
- Mesenchymal stromal cells (MSCs) show promise in preclinical pneumonia models but are underexplored in VAP.
- This study aimed to evaluate MSC efficacy in a rabbit VAP model.
Purpose of the Study:
- To investigate the therapeutic potential of mesenchymal stromal cells (MSCs) in a rabbit model of ventilator-associated pneumonia (VAP).
- To assess the impact of MSCs, alone and in combination with cefepime, on VAP outcomes.
Main Methods:
- Rabbits were subjected to mechanical ventilation and lipopolysaccharide (LPS) to induce immune dysfunction, followed by intratracheal inoculation with Enterobacter aerogenes to induce VAP.
- Experiment 1: Rabbits received intravenous MSCs or saline.
- Experiment 2: Rabbits received cefepime with or without MSCs. Outcomes included bacterial load, survival, lung injury, and immune markers.
Main Results:
- MSC infusion alone did not improve survival, lung bacterial load, or inflammation.
- In combination with cefepime, MSCs showed a trend toward improved survival (p=0.067) and significantly reduced lung bacterial burden (p=0.049).
- The combination therapy also improved lung pathology scores and reduced IL-6 levels, but did not correct systemic immune dysfunction.
Conclusions:
- Mesenchymal stromal cells (MSCs) alone were ineffective in clearing lung bacteria or resolving inflammation in this VAP model.
- Combining MSCs with cefepime enhanced bacterial clearance and reduced lung IL-6 levels compared to cefepime alone.
- Further research is needed to understand the synergistic mechanisms between MSCs and antibiotics in VAP treatment.
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