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Methylprednisolone inhibits low-flow hypoxia-induced mitochondrial dysfunction in isolated perfused rat liver.

Abstract：

OBJECTIVE:To investigate the mechanism by which methylprednisolone protects the liver from hypoxia-induced injury. DESIGN:Prospective control study using the isolated rat liver. SETTING:Animal research facility. SUBJECTS:Male, fasted, pathogen-free Sprague-Dawley rats. INTERVENTIONS:Low-flow hypoxia was produced by reducing afferent perfusate pressure from 10 to 2.5 cm H(2)O; isolated livers were portally perfused for 2 hrs. MEASUREMENTS AND MAIN RESULTS:We measured mitochondrial membrane potential and hydrogen peroxide production by imaging rhodamine 123 and 2'-7'-dichlorofluorescein fluorescence, respectively. Leakage of mitochondrial enzymes was also monitored by assaying mitochondrial aspartate aminotransferase activity in the outflow perfusate, and the radical-scavenging effect of methylprednisolone was assessed by measuring luminol-dependent hydrogen peroxide chemiluminescence. Apoptosis in liver cells was determined by using terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling. Rhodamine 123 fluorescence was significantly diminished in the hypoxic liver, especially in the region of the terminal hepatic venules, which is indicative of membrane depolarization in the mitochondria in those areas. Hypoxia-induced mitochondrial dysfunction was indicated by leakage of aspartate aminotransferase into the outflow perfusate, and increased 2'-7'-dichlorofluorescein fluorescence indicated increased hydrogen peroxide levels, particularly in the midzone. Pretreatment with 30, 10, or 3 mg/kg of methylprednisolone inhibited the hypoxia-induced mitochondrial membrane depolarization and enzyme leakage, although hydrogen peroxide levels and apoptosis in sinusoidal endothelial cells were unaffected. CONCLUSIONS:Methylprednisolone does not protect the liver from hypoxia-induced injury by suppressing hydrogen peroxide production. Instead, the beneficial effect of methylprednisolone seems to be related to its ability to protect against mitochondrial membrane depolarization under hypoxic conditions.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Motoyama S,Saito S,Minamiya Y,Saito R,Nakamura M,Okuyama M,Imano H,Ogawa J

doi

10.1097/01.CCM.0000066176.49774.CC

subject

Has Abstract

pub_date

2003-05-01 00:00:00

pages

1468-74

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Methylprednisolone inhibits low-flow hypoxia-induced mitochondrial dysfunction in isolated perfused rat liver.