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Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage.

Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Hotter G, Capasso C, T Supuran C, Roselló-Catafau J, Rosselló-Catafau J - PLoS ONE (2015)

Bottom Line: In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined.In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation.Interestingly, CA II supplementation was not associated with enhanced CO2 hydration.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain.

ABSTRACT
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. CAs are involved in numerous physiological and pathological processes, including acid-base homeostasis, electrolyte balance, oxygen delivery to tissues and nitric oxide generation. Given that these processes are found to be dysregulated during ischemia reperfusion injury (IRI), and taking into account the high vulnerability of steatotic livers to preservation injury, we hypothesized a new role for CA as a pharmacological agent able to protect against ischemic damage. Two different aspects of the role of CA II in fatty liver grafts preservation were evaluated: 1) the effect of its addition to Institut Georges Lopez (IGL-1) storage solution after cold ischemia; 2) and after 24h of cold storage followed by two hours of normothermic ex-vivo perfusion. In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined. In case of the ex-vivo perfusion, we further assessed liver function (bile production, bromosulfophthalein clearance) and Western blot analysis of phosphorylated adenosine monophosphate activated protein kinase (AMPK), mitogen activated protein kinases family (MAPKs) and endoplasmic reticulum stress (ERS) parameters (GRP78, PERK, IRE, eIF2α and ATF6). We found that CA II was downregulated after cold ischemia. The addition of bovine CA II to IGL-1 preservation solution efficiently protected steatotic liver against cold IRI. In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation. Interestingly, CA II supplementation was not associated with enhanced CO2 hydration. The results suggest that CA II modulation may be a promising target for fatty liver graft preservation.

No MeSH data available.


Related in: MedlinePlus

Effect of CA II addition to IGL-1 solution in hepatic function.Hepatic function expressed as bile output (A) and percentage of bromosulfophthalein (BSP) excretion in bile (B) after 120 min of fatty liver normothermic ex vivoperfusion. CA II supplementation (IGL-1+CAII) significantly enhanced bile production and BSP clearance compared to the IGL-1 group. Ctr 2: Livers flushed and perfused ex-vivo without cold preservation; IGL-1: liver preserved in IGL-1 solution (4°C, 24 h) and subjected to 2h-normothermic ex vivo perfusion. IGL-1+CAII: livers preserved in IGL-1 solution (4°C, 24 h) enriched with CA II (10 ug/ml) and subjected to 2h- normothermic ex vivo perfusion; * p < 0.05 vs Ctr 2; # p < 0.05 vs IGL-1.
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pone.0134499.g003: Effect of CA II addition to IGL-1 solution in hepatic function.Hepatic function expressed as bile output (A) and percentage of bromosulfophthalein (BSP) excretion in bile (B) after 120 min of fatty liver normothermic ex vivoperfusion. CA II supplementation (IGL-1+CAII) significantly enhanced bile production and BSP clearance compared to the IGL-1 group. Ctr 2: Livers flushed and perfused ex-vivo without cold preservation; IGL-1: liver preserved in IGL-1 solution (4°C, 24 h) and subjected to 2h-normothermic ex vivo perfusion. IGL-1+CAII: livers preserved in IGL-1 solution (4°C, 24 h) enriched with CA II (10 ug/ml) and subjected to 2h- normothermic ex vivo perfusion; * p < 0.05 vs Ctr 2; # p < 0.05 vs IGL-1.

Mentions: Furthermore, we evaluated the liver function by measuring bile production and BSP clearance after two hours of reperfusion. Significant reductions in these parameters were observed in fatty livers preserved in IGL-1 solution in comparison with the control group (Fig 3A and 3B respectively). However, both liver function parameters improved significantly when CA II was added to IGL-1 solution (Fig 3).


Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage.

Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Hotter G, Capasso C, T Supuran C, Roselló-Catafau J, Rosselló-Catafau J - PLoS ONE (2015)

Effect of CA II addition to IGL-1 solution in hepatic function.Hepatic function expressed as bile output (A) and percentage of bromosulfophthalein (BSP) excretion in bile (B) after 120 min of fatty liver normothermic ex vivoperfusion. CA II supplementation (IGL-1+CAII) significantly enhanced bile production and BSP clearance compared to the IGL-1 group. Ctr 2: Livers flushed and perfused ex-vivo without cold preservation; IGL-1: liver preserved in IGL-1 solution (4°C, 24 h) and subjected to 2h-normothermic ex vivo perfusion. IGL-1+CAII: livers preserved in IGL-1 solution (4°C, 24 h) enriched with CA II (10 ug/ml) and subjected to 2h- normothermic ex vivo perfusion; * p < 0.05 vs Ctr 2; # p < 0.05 vs IGL-1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520486&req=5

pone.0134499.g003: Effect of CA II addition to IGL-1 solution in hepatic function.Hepatic function expressed as bile output (A) and percentage of bromosulfophthalein (BSP) excretion in bile (B) after 120 min of fatty liver normothermic ex vivoperfusion. CA II supplementation (IGL-1+CAII) significantly enhanced bile production and BSP clearance compared to the IGL-1 group. Ctr 2: Livers flushed and perfused ex-vivo without cold preservation; IGL-1: liver preserved in IGL-1 solution (4°C, 24 h) and subjected to 2h-normothermic ex vivo perfusion. IGL-1+CAII: livers preserved in IGL-1 solution (4°C, 24 h) enriched with CA II (10 ug/ml) and subjected to 2h- normothermic ex vivo perfusion; * p < 0.05 vs Ctr 2; # p < 0.05 vs IGL-1.
Mentions: Furthermore, we evaluated the liver function by measuring bile production and BSP clearance after two hours of reperfusion. Significant reductions in these parameters were observed in fatty livers preserved in IGL-1 solution in comparison with the control group (Fig 3A and 3B respectively). However, both liver function parameters improved significantly when CA II was added to IGL-1 solution (Fig 3).

Bottom Line: In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined.In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation.Interestingly, CA II supplementation was not associated with enhanced CO2 hydration.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain.

ABSTRACT
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. CAs are involved in numerous physiological and pathological processes, including acid-base homeostasis, electrolyte balance, oxygen delivery to tissues and nitric oxide generation. Given that these processes are found to be dysregulated during ischemia reperfusion injury (IRI), and taking into account the high vulnerability of steatotic livers to preservation injury, we hypothesized a new role for CA as a pharmacological agent able to protect against ischemic damage. Two different aspects of the role of CA II in fatty liver grafts preservation were evaluated: 1) the effect of its addition to Institut Georges Lopez (IGL-1) storage solution after cold ischemia; 2) and after 24h of cold storage followed by two hours of normothermic ex-vivo perfusion. In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined. In case of the ex-vivo perfusion, we further assessed liver function (bile production, bromosulfophthalein clearance) and Western blot analysis of phosphorylated adenosine monophosphate activated protein kinase (AMPK), mitogen activated protein kinases family (MAPKs) and endoplasmic reticulum stress (ERS) parameters (GRP78, PERK, IRE, eIF2α and ATF6). We found that CA II was downregulated after cold ischemia. The addition of bovine CA II to IGL-1 preservation solution efficiently protected steatotic liver against cold IRI. In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation. Interestingly, CA II supplementation was not associated with enhanced CO2 hydration. The results suggest that CA II modulation may be a promising target for fatty liver graft preservation.

No MeSH data available.


Related in: MedlinePlus