TY - JOUR
T1 - Synergistic Protection in Lung Ischemia-Reperfusion Injury With Calcineurin and Thrombin Inhibition
AU - McCourtie, Anton S.
AU - Merry, Heather E.
AU - Wolf, Patrick S.
AU - FitzSullivan, Elizabeth
AU - Keech, John C.
AU - Farivar, Alexander S.
AU - Mulligan, Michael S.
N1 - Funding Information:
This research was funded by the University of Washington , Department of Surgery , Cardiothoracic Surgery Division . The authors of this research had full control of the design of the study, methods used, outcome parameters, analysis of data, and production of the written report.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77952299227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952299227&partnerID=8YFLogxK
U2 - 10.1016/j.athoracsur.2010.02.068
DO - 10.1016/j.athoracsur.2010.02.068
M3 - Article
C2 - 20494024
AN - SCOPUS:77952299227
SN - 0003-4975
VL - 89
SP - 1766
EP - 1771
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 6
ER -