title: Caspase inhibition improves ischemia-reperfusion injury after lung transplantation.
abstract: Ischemia-reperfusion injury is associated with cell death in many organ systems. The role of programmed cell death (PCD) pathways and the ultimate clinical relevance of PCD in the context of lung transplantation (LTx) are unknown. In randomized and blinded studies, rat single LTx was performed in the presence of caspase inhibitors after 'short' (6 h) and 'long' (18 h) periods of cold ischemic storage. Lung function, electron microscopic morphology, caspase 3, 8 and 9 activities and TUNEL assays were evaluated. Endothelial cells and lymphocytes were observed undergoing apoptotic cell death with electron microscopy. Caspase activities were significantly up-regulated immediately after the initial flush and increased further during short periods of cold ischemic storage. A significant amount of apoptotic cell death was observed after LTx and reperfusion. Caspase inhibition virtually eliminated apoptotic cell death and led to improved lung function after LTx and reperfusion. Activation of caspases during cold ischemia contributes significantly to cell death in LTx. Suppression of caspase activity appears to decrease apoptosis and improve lung function. Clearly, this needs to be investigated further with more experiments to validate the potential role of caspase inhibition as a therapeutic modality in ischemia-reperfusion-induced lung injury.
authors.affiliation: Thoracic Surgery Research Laboratory, Toronto General Research Institute, University Health Network - Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Quadri
authors.forename: Lorne
authors.initials: L
authors.lastname: Segall
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Vernon
authors.initials: V
authors.lastname: Edwards
authors.forename: Nicola
authors.initials: N
authors.lastname: Jones
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D016040:Lung Transplantation; D008854:Microscopy, Electron; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids