Synergistic Protection in Lung Ischemia-Reperfusion Injury With Calcineurin and Thrombin Inhibition

Anton S. McCourtie, Heather E. Merry, Patrick S. Wolf, Elizabeth FitzSullivan, John C. Keech, Alexander S. Farivar, Michael S. Mulligan

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Ischemia-reperfusion injury impairs lung transplant outcomes. The transcription factors, activator protein-1, and nuclear factor kappa B, are activated early in reperfusion and drive the development of injury. Thrombin inhibition with hirudin, and calcineurin inhibition with tacrolimus have independently been shown to ameliorate lung ischemia-reperfusion injury by reducing activator protein-1 and nuclear factor kappa B activation, respectively. However, high doses were required to achieve protection using individual agents, raising concerns about potential toxicities. We sought to determine if low-dose combination therapy reduced injury through synergistic inhibition of pretranscriptional signaling events. Methods: Rats were pretreated with either intravenous hirudin or tacrolimus at low doses or high doses, or both at low doses, prior to undergoing left lung ischemia and reperfusion. Lungs were assessed for markers of lung injury, including bronchoalveolar lavage cytokine-chemokine content and transcription factor transactivation of activator protein-1 and nuclear factor kappa B. Results: High-dose monotherapy with hirudin or tacrolimus reduced lung injury and transactivation of activator protein-1 and nuclear factor kappa B activation, respectively, whereas low-dose monotherapy with either agent did not alter transcription factor activation or lung injury compared with positive controls. Low-dose combination therapy was more protective than high-dose monotherapy with either drug, and correlated with a reduction in activation of both transcription factors and their associated cytokines. Conclusions: The significant decrease in lung injury severity and transcription factor activation with combined pathway inhibition suggests pretranscriptional signaling redundancy between the calcineurin and thrombin dependent pathways in lung reperfusion injury.

Original languageEnglish (US)
Pages (from-to)1766-1771
Number of pages6
JournalAnnals of Thoracic Surgery
Volume89
Issue number6
DOIs
StatePublished - Jun 1 2010

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Calcineurin
Lung Injury
Reperfusion Injury
Thrombin
NF-kappa B
Transcription Factor AP-1
Transcription Factors
Hirudins
Transcriptional Activation
Tacrolimus
Lung
Reperfusion
Cytokines
Wounds and Injuries
Bronchoalveolar Lavage
Chemokines
Ischemia
Transplants
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Synergistic Protection in Lung Ischemia-Reperfusion Injury With Calcineurin and Thrombin Inhibition. / McCourtie, Anton S.; Merry, Heather E.; Wolf, Patrick S.; FitzSullivan, Elizabeth; Keech, John C.; Farivar, Alexander S.; Mulligan, Michael S.

In: Annals of Thoracic Surgery, Vol. 89, No. 6, 01.06.2010, p. 1766-1771.

Research output: Contribution to journalArticle

McCourtie, Anton S. ; Merry, Heather E. ; Wolf, Patrick S. ; FitzSullivan, Elizabeth ; Keech, John C. ; Farivar, Alexander S. ; Mulligan, Michael S. / Synergistic Protection in Lung Ischemia-Reperfusion Injury With Calcineurin and Thrombin Inhibition. In: Annals of Thoracic Surgery. 2010 ; Vol. 89, No. 6. pp. 1766-1771.
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