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Adverse Mechanical Ventilation and Pneumococcal Pneumonia Induce Immune and Mitochondrial Dysfunctions Mitigated by
Mathieu Blot1, Marine Jacquier2, Laure-Anne Pauchard3
1From INSERM (Institut National de la Santé et de la Recherche Médicale), LabEx LipSTIC, Université de Bourgogne Franche-Comté, LNC Mixed Research Unit 1231, Dijon, France; the Infectious Diseases Department.
Background:
Mechanical ventilation for pneumonia may contribute to lung injury due to factors that include mitochondrial dysfunction, and mesenchymal stem cells may attenuate injury. This study hypothesized that mechanical ventilation induces immune and mitochondrial dysfunction, with or without pneumococcal pneumonia, that could be mitigated by mesenchymal stem cells alone or combined with antibiotics.
Methods:
Male rabbits underwent protective mechanical ventilation (8 ml/kg tidal volume, 5 cm H2O end-expiratory pressure) or adverse mechanical ventilation (20 ml/kg tidal-volume, zero end-expiratory pressure) or were allowed to breathe spontaneously. The same settings were then repeated during pneumococcal pneumonia. Finally, infected animals during adverse mechanical ventilation received human umbilical cord-derived mesenchymal stem cells (3 × 106/kg, intravenous) and/or ceftaroline (20 mg/kg, intramuscular) or sodium chloride, 4 h after pneumococcal challenge. Twenty-four-hour survival (primary outcome), lung injury, bacterial burden, immune and mitochondrial dysfunction, and lung transcriptomes (secondary outcomes) were assessed.
Results:
High-pressure adverse mechanical ventilation reduced the survival of infected animals (0%; 0 of 7) compared with spontaneous breathing (100%; 7 of 7) and protective mechanical ventilation (86%; 6 of 7; both P < 0.001), with higher lung pathology scores (median [interquartile ranges], 5.5 [4.5 to 7.0] vs. 12.6 [12.0 to 14.0]; P = 0.046), interleukin-8 lung concentrations (106 [54 to 316] vs. 804 [753 to 868] pg/g of lung; P = 0.012), and alveolar mitochondrial DNA release (0.33 [0.28 to 0.36] vs. 0.98 [0.76 to 1.21] ng/μl; P < 0.001) compared with infected spontaneously breathing animals. Survival (0%; 0 of 7; control group) was improved by mesenchymal stem cells (57%; 4 of 7; P = 0.001) or ceftaroline alone (57%; 4 of 7; P < 0.001) and improved even more with a combination treatment (86%; 6 of 7; P < 0.001). Mesenchymal stem cells reduced lung pathology score (8.5 [7.0 to 10.5] vs. 12.6 [12.0 to 14.0]; P = 0.043) and alveolar mitochondrial DNA release (0.39 (0.34 to 0.65) vs. 0.98 (0.76 to 1.21) ng/μl; P = 0.025). Mesenchymal stem cells combined with ceftaroline reduced interleukin-8 lung concentrations (665 [595 to 795] vs. 804 [753 to 868] pg/g of lung; P = 0.007) compared to ceftaroline alone.
Conclusions:
In this preclinical study, mesenchymal stem cells improved the outcome of rabbits with pneumonia and high-pressure mechanical ventilation by correcting immune and mitochondrial dysfunction and when combined with the antibiotic ceftaroline was synergistic in mitigating lung inflammation.
Insights
Mesenchymal stem cells (MSCs) improved survival in rabbits with pneumonia under mechanical ventilation by reducing lung injury and mitochondrial dysfunction. Combining MSCs with the antibiotic ceftaroline demonstrated synergistic effects in mitigating inflammation.
Area of Science:
- Critical Care Medicine
- Regenerative Medicine
- Pulmonology
Background:
- Mechanical ventilation, particularly high-pressure settings, can exacerbate lung injury in pneumonia.
- Mitochondrial dysfunction and immune dysregulation are key factors contributing to ventilator-induced lung injury (VILI).
- Mesenchymal stem cells (MSCs) show potential in attenuating various forms of lung injury.
Purpose of the Study:
- To investigate if MSCs can mitigate immune and mitochondrial dysfunction induced by mechanical ventilation in pneumococcal pneumonia.
- To evaluate the efficacy of MSCs alone or in combination with antibiotics in improving outcomes for pneumonia patients on mechanical ventilation.
Main Methods:
- Male rabbits were subjected to protective, adverse, or spontaneous mechanical ventilation during pneumococcal pneumonia.
- Adversely ventilated, infected rabbits received human umbilical cord-derived MSCs and/or ceftaroline.
- Outcomes assessed included 24-hour survival, lung injury scores, bacterial burden, immune markers, mitochondrial dysfunction, and lung transcriptomes.
Main Results:
- Adverse mechanical ventilation led to 0% survival in infected rabbits, whereas spontaneous breathing and protective ventilation showed 100% and 86% survival, respectively.
- MSCs alone improved survival to 57% and reduced lung pathology and mitochondrial DNA release.
- Combination therapy with MSCs and ceftaroline improved survival to 86% and synergistically reduced lung inflammation.
Conclusions:
- MSCs can improve outcomes in rabbits with pneumonia and mechanical ventilation-induced lung injury by addressing immune and mitochondrial dysfunction.
- Combination therapy of MSCs and ceftaroline offers a synergistic approach to mitigate lung inflammation and improve survival.
- This preclinical study supports the therapeutic potential of MSCs in managing severe pneumonia complicated by mechanical ventilation.
