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(American Journal of Pathology. 2002;160:2111-2122.)
© 2002 American Society for Investigative Pathology

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The Combination of Ischemic Preconditioning and Liver Bcl-2 Overexpression Is a Suitable Strategy to Prevent Liver and Lung Damage after Hepatic Ischemia-Reperfusion

Carmen Peralta^*, José Carlos Perales, Ramón Bartrons, Claudia Mitchell, Hélène Gilgenkrantz, Carme Xaus, Neus Prats, Leticia Fernández^*, Emilio Gelpí^*, Julia Panés^¶ and Juan Roselló-Catafau^*

From the Department of Medical Bioanalysis,^*Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d’Investigacions Biomèdiques August Pi i Sunyer, CSIC-IDIBAPS, Barcelona, Spain; Unitat de Bioquímica,Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain; U.129 INSERM,Paris, France; the Department of Animal Pathology,Veterinary School, Universitat Autònoma de Barcelona, Barcelona, Spain; and the Department of Gastroenterology,^¶Hospital Clinic, Barcelona, Spain

The present study evaluates the effectiveness of ischemic preconditioning and Bcl-2 overexpression against the liver and lung damage that follow hepatic ischemia-reperfusion and investigates the underlying protective mechanisms. Preconditioning and Bcl-2, respectively, reduced the increased tumor necrosis factor (TNF) and macrophage inflammatory protein-2 (MIP)-2 levels observed after hepatic reperfusion. Bcl-2 overexpression or anti-MIP-2 pretreatment seems to be more effective than preconditioning or anti-TNF pretreatment against inflammatory response, microcirculatory disorders, and subsequent hepatic ischemia-reperfusion injury. Furthermore, each one of these strategies individually was unable to completely inhibit hepatic injury. The combination of preconditioning and Bcl-2 overexpression as well as the combined anti-TNF and anti-MIP-2 pretreatment totally prevented hepatic injury, whereas the benefits of preconditioning and Bcl-2 were abolished by TNF and MIP-2. In contrast to preconditioning, Bcl-2 did not modify lung damage induced by hepatic reperfusion. This could be explained by the differential effect of both treatments on TNF release. Anti-TNF therapy or preconditioning, by reducing TNF release, reduced pulmonary inflammatory response, whereas the benefits of preconditioning on lung damage were abolished by TNF. Thus, the induction of both Bcl-2 overexpression in liver and preconditioning, as well as pharmacological strategies that simulated their benefits, such as anti-TNF and anti-MIP-2 therapies, could be new strategies aimed to reduce lung damage and inhibit the hepatic injury associated with hepatic ischemia-reperfusion.

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