Mitochondrial DNA damage associated molecular patterns in ventilator-associated pneumonia: Prevention and reversal by intratracheal DNase i

Jon D. Simmons, Daniel R. Freno, C. Annie Muscat, Boniface Obiako, Yann-Leei Lee, Viktor M. Pastukh, Sidney B. Brevard, Mark N. Gillespie

Research output: Contribution to journalArticle

Abstract

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 DNasewas administered to isolated rat lungs either before or after intratracheal challengewith PA103 to determine if bacteriainduced mtDNA DAMP-dependent lung injury could be prevented or reversed by enhanced mtDNAdegradation. To explorewhether 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. (J Trauma Acute Care Surg. 2017;82: 120-125.

Original languageEnglish (US)
Pages (from-to)120-125
Number of pages6
JournalJournal of Trauma and Acute Care Surgery
Volume82
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Ventilator-Associated Pneumonia
Deoxyribonucleases
Mitochondrial DNA
DNA Damage
Lung
Bronchoalveolar Lavage
Lung Injury
Serum
Bacterial Pneumonia
Deoxyribonuclease I
Pseudomonas aeruginosa
Blood Vessels
Perfusion
Bacteria
Wounds and Injuries

Keywords

  • DAMPs
  • DNase
  • Dornase α
  • Mitochondrial DNA
  • Ventilator-associated pneumonia

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

Cite this

Mitochondrial DNA damage associated molecular patterns in ventilator-associated pneumonia : Prevention and reversal by intratracheal DNase i. / Simmons, Jon D.; Freno, Daniel R.; Muscat, C. Annie; Obiako, Boniface; Lee, Yann-Leei; Pastukh, Viktor M.; Brevard, Sidney B.; Gillespie, Mark N.

In: Journal of Trauma and Acute Care Surgery, Vol. 82, No. 1, 01.01.2017, p. 120-125.

Research output: Contribution to journalArticle

Simmons, Jon D. ; Freno, Daniel R. ; Muscat, C. Annie ; Obiako, Boniface ; Lee, Yann-Leei ; Pastukh, Viktor M. ; Brevard, Sidney B. ; Gillespie, Mark N. / Mitochondrial DNA damage associated molecular patterns in ventilator-associated pneumonia : Prevention and reversal by intratracheal DNase i. In: Journal of Trauma and Acute Care Surgery. 2017 ; Vol. 82, No. 1. pp. 120-125.
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abstract = "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 DNasewas administered to isolated rat lungs either before or after intratracheal challengewith PA103 to determine if bacteriainduced mtDNA DAMP-dependent lung injury could be prevented or reversed by enhanced mtDNAdegradation. To explorewhether 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. (J Trauma Acute Care Surg. 2017;82: 120-125.",
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T2 - Prevention and reversal by intratracheal DNase i

AU - Simmons, Jon D.

AU - Freno, Daniel R.

AU - Muscat, C. Annie

AU - Obiako, Boniface

AU - Lee, Yann-Leei

AU - Pastukh, Viktor M.

AU - Brevard, Sidney B.

AU - Gillespie, Mark N.

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N2 - 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 DNasewas administered to isolated rat lungs either before or after intratracheal challengewith PA103 to determine if bacteriainduced mtDNA DAMP-dependent lung injury could be prevented or reversed by enhanced mtDNAdegradation. To explorewhether 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. (J Trauma Acute Care Surg. 2017;82: 120-125.

AB - 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 DNasewas administered to isolated rat lungs either before or after intratracheal challengewith PA103 to determine if bacteriainduced mtDNA DAMP-dependent lung injury could be prevented or reversed by enhanced mtDNAdegradation. To explorewhether 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. (J Trauma Acute Care Surg. 2017;82: 120-125.

KW - DAMPs

KW - DNase

KW - Dornase α

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