Synergistic protection in lung ischemia-reperfusion injury with calcineurin and thrombin inhibition
| Autor: | Heather E. Merry, Anton S. McCourtie, Elizabeth FitzSullivan, Patrick S. Wolf, Alexander S. Farivar, John Keech, Michael S. Mulligan |
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| Rok vydání: | 2009 |
| Předmět: |
Pulmonary and Respiratory Medicine
Calcineurin Inhibitors Hirudin Pharmacology Lung injury Tacrolimus Transactivation Thrombin Hirudin Therapy medicine Animals Rats Long-Evans Lung medicine.diagnostic_test Activator (genetics) business.industry Drug Synergism medicine.disease Rats Calcineurin Bronchoalveolar lavage Reperfusion Injury Immunology Surgery Drug Therapy Combination Cardiology and Cardiovascular Medicine business Reperfusion injury medicine.drug |
| Zdroj: | The Annals of thoracic surgery. 89(6) |
| ISSN: | 1552-6259 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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