Carbon monoxide-Releasing Molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats

Autor: Edwin Bremer, Marco de Bruyn, Ping Chen, Weihui Zhang, Wijnand Helfrich, Yunwei Wei
Přispěvatelé: Stem Cell Aging Leukemia and Lymphoma (SALL), Targeted Gynaecologic Oncology (TARGON)
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
Pathology
MITOCHONDRIAL CALCIUM-UPTAKE
Apoptosis
Pharmacology
PROTECTS
Ischemia
Mitochondrial calcium uptake
Liver injury
chemistry.chemical_classification
NF-kappa B
Gastroenterology
General Medicine
Treatment Outcome
Liver
Reperfusion Injury
Acute Disease
KINASE PATHWAY
Cytokines
LIVER-INJURY
medicine.symptom
HEME OXYGENASE-1
Research Article
medicine.medical_specialty
Blotting
Western
HYDROGEN-SULFIDE
ISCHEMIA/REPERFUSION INJURY
Ruthenium
ADHESION MOLECULES
medicine
In Situ Nick-End Labeling
Organometallic Compounds
Animals
lcsh:RC799-869
Rats
Wistar
Reactive oxygen species
business.industry
Organ dysfunction
INFLAMMATORY RESPONSE
DNA
medicine.disease
NFKB1
COLD PRESERVATION
Rats
Disease Models
Animal
chemistry
lcsh:Diseases of the digestive system. Gastroenterology
business
Reperfusion injury
Zdroj: Bmc gastroenterology, 10:42. BMC
BMC Gastroenterology
BMC Gastroenterology, Vol 10, Iss 1, p 42 (2010)
ISSN: 1471-230X
Popis: Background Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model. Methods Forty male Wistar rats were randomly assigned into four groups (n = 10). Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg), which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration. Results A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in nuclear extracts of liver homogenates. Moreover, CORM-2 treatment resulted in reduced serum levels of pro-inflammatory cytokines TNF-α and IL-6 and down-regulation of the adhesion molecule ICAM-1 in the endothelial cells of liver. In line with these findings, CORM-2 treatment reduced the accumulation of neutrophils in the liver upon I/Ri. Similar treatment with an inactive variant of CORM-2 (iCORM-2) did not have any beneficial effect on the extent of liver I/Ri. Conclusions CORM-2 treatment at the time of reperfusion had several distinct beneficial effects on severity of hepatic I/Ri that may be of therapeutic value for the prevention of tissue damage as a result of I/Ri during hepatic surgery.
Databáze: OpenAIRE
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