Acetazolamide protects steatotic liver grafts against cold ischemia reperfusion injury.
Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Mohamed
http://orcid.org/0000-0003-1075-6170
M
Bejaoui
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Eirini
E
Pantazi
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Viviana
V
De Luca
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Arnau
A
Panisello
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Emma
E
Folch-Puy
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Anna
A
Serafin
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Clemente
C
Capasso
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Supuran
S
C T
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.) jrcbam@iibb.csic.es.
Joan
J
Rosselló-Catafau
D000086:Acetazolamide / Q000627:therapeutic use*; D000818:Animals; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use*; D003080:Cold Temperature; D004789:Enzyme Activation; D004921:Erythropoietin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D016031:Liver Transplantation; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009926:Organ Preservation; D010766:Phosphorylation; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D014655:Vascular Resistance
D002257:Carbonic Anhydrase Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D024402:Carbonic Anhydrase II; D000086:Acetazolamide