Matrix metalloproteinase inhibition decreases ischemia-reperfusion injury after lung transplantation.
Increased microvascular permeability and extravasation of inflammatory cells are key events of lung ischemia-reperfusion (IR) injury. The purpose of this study was to investigate the role of matrix metalloproteinases (MMP) in IR-induced alveolar capillary membrane disruption after experimental lung transplantation. We used a rat model of lung orthotopic transplantation (n = 86) with a prolonged cold ischemic phase. MMP2 and MMP9 were elevated 4 h after the onset of ischemia and further increased during reperfusion. Compared to sham values, the alveolar-capillary membrane permeability increased by 105% and 82.6% after 4 h of ischemia and 2 h or 24 h of reperfusion, respectively. A 4- and 5-fold increase of the infiltration of ischemic tissue by neutrophils was also observed after 2 h and 24 h of reperfusion. The PO2/FIO2 ratio dropped significantly from 244 to 76.6 after 2 h of reperfusion and from 296.4 to 127.6 after 24 h of reperfusion. A nonselective inhibitor of MMP, administered to the rats and added to the preservation solution, reduced significantly the alveolar-capillary leakage, the transmigration of neutrophils and improved gas exchanges in animals submitted to 4 h of ischemia combined with 2 h or 24 h of reperfusion. We conclude that inhibition of MMP attenuates IR injury after experimental lung transplantation.
Soccal
Paola M
PM
Division of Pulmonary & Critical Care Medicine, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA. paola.soccal@hcuge.ch
Gasche
Yvan
Y
Miniati
Douglas N
DN
Hoyt
Grant
G
Berry
Gerald J
GJ
Doyle
Ramona L
RL
Theodore
James
J
Robbins
Robert C
RC
D000818:Animals; D002196:Capillaries / Q000276:immunology; D004396:Coloring Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005070:Evans Blue / Q000494:pharmacology; D000860:Hypoxia; D007511:Ischemia; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010919:Placebos; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury; D013997:Time Factors
D004396:Coloring Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010919:Placebos; D005070:Evans Blue; D009195:Peroxidase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9