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Updated: Mar 13, 2026
Murine Oropharyngeal Aspiration Model of Ventilator-associated and Hospital-acquired Bacterial Pneumonia
Published on: June 28, 2018
Mitochondrial DNA damage associated molecular patterns in ventilator-associated pneumonia: Prevention and reversal by
Jon D Simmons1, Daniel R Freno, C Annie Muscat
1From the Departments of Surgery (J.D.S., D.R.F., Y.L.L., S.B.B.) and Pharmacology (B.O., V.M.P., M.N.G.), and Center for Lung Biology (J.D.S., C.A.M., B.O., V.M.P., M.N.G.), University of South Alabama School of Medicine, Mobile, AL.
Background:
Previous studies in isolated perfused rat lungs have revealed that endothelial barrier disruption after intratracheal administration of Pseudomonas aeruginosa (strain 103; PA103) only occurs after accumulation of extracellular mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs) in the perfusate and is suppressed by addition of DNase to the perfusion medium. Herein, we tested the hypothesis that intratracheal DNase-a route of administration readily translatable to patient with ventilator-associated pneumonia (VAP)-also enhances degradation of mtDNA and prevents bacteria-induced lung injury.
Methods:
Intratracheal DNase was administered to isolated rat lungs either before or after intratracheal challenge with PA103 to determine if bacteria-induced mtDNA DAMP-dependent lung injury could be prevented or reversed by enhanced mtDNA degradation. To explore whether this concept is translatable to patients with VAP, consecutive patients suspected of VAP were prospectively enrolled. All patients suspected of VAP received a bronchoalveolar lavage (BAL) with quantitative culture for the diagnosis of VAP. Mitochondrial and nuclear DNAs were measured from the BAL. MtDNA DAMPs (i.e., ND6) were measured from serum at time of suspected diagnosis and at 24 to 48 hours afterward.
Results:
Intratracheal PA103 caused significantly increased the vascular filtration coefficient (Kf) and perfusate mtDNA DAMPs. In contrast, lungs pretreated or posttreated with intratracheal DNase were protected from increases in Kf and mtDNA DAMPs. Patients with the diagnosis of VAP had significantly higher mtDNA DAMPs in the BAL (248.70 ± 109.7 vs. 43.91 ± 16.61, p < 0.05, respectively) and in the serum at 24 hours (159.60 ± 77.37 vs. 10.43 ± 4.36, p < 0.05; respectively) when compared with patients that did not have VAP.
Conclusion:
These findings in isolated perfused rat lungs and a cohort of severely injured patients reveal an association between bacterial pneumonia and accumulation of mtDNA DAMPs in the lung and serum. Furthermore, administration of intratracheal DNase I prevented and reversed pulmonary endothelial dysfunction evoked by PA103.
Insights
Intratracheal DNase prevents and reverses lung injury caused by Pseudomonas aeruginosa by degrading mitochondrial DNA damage-associated molecular patterns. This approach shows promise for treating ventilator-associated pneumonia.
Area of Science:
- Pulmonary Medicine
- Microbiology
- Molecular Biology
Background:
- Endothelial barrier disruption in rat lungs after Pseudomonas aeruginosa (PA103) infection is linked to extracellular mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs).
- DNase administration suppressed this injury in isolated perfused rat lungs.
- Intratracheal DNase is a potential treatment for ventilator-associated pneumonia (VAP).
Purpose of the Study:
- To test if intratracheal DNase degrades mtDNA DAMPs and prevents or reverses bacteria-induced lung injury.
- To assess the translatability of this approach to patients with VAP.
Main Methods:
- Isolated rat lungs were treated with DNase before or after PA103 challenge.
- Vascular filtration coefficient (Kf) and perfusate mtDNA DAMPs were measured.
- Patients with suspected VAP underwent bronchoalveolar lavage (BAL) for diagnosis and DNA analysis.
- Serum mtDNA DAMPs were measured at diagnosis and 24-48 hours later.
Main Results:
- PA103 increased Kf and mtDNA DAMPs in rat lungs, but DNase treatment protected against these effects.
- Patients diagnosed with VAP had significantly higher levels of mtDNA DAMPs in BAL fluid and serum compared to non-VAP patients.
- DNase administration prevented and reversed PA103-induced pulmonary endothelial dysfunction.
Conclusions:
- Bacterial pneumonia is associated with increased mtDNA DAMPs in the lung and serum.
- Intratracheal DNase I is effective in preventing and reversing bacterial pneumonia-induced pulmonary endothelial dysfunction.
- This suggests a potential therapeutic role for DNase in managing VAP.
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