期刊
JOURNAL OF TRAUMA AND ACUTE CARE SURGERY
卷 82, 期 1, 页码 120-125出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TA.0000000000001269
关键词
Mitochondrial DNA; DAMPs; Ventilator-associated pneumonia; DNase; dornase alpha
资金
- American Heart Association [14CRP19010032]
- American College of Surgeons
- American Association for the Surgery of Trauma
- National Institutes of Health [R01 HL58234, R01 HL113614, K08 GM109113]
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. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.)
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