NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia
| Autor: | Anwar Farhood, Hartmut Jaeschke, Jaspreet S. Gujral, Jack A. Hinson |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Time Factors Necrosis Neutrophils Physiology Apoptosis Galactosamine medicine.disease_cause Mice Onium Compounds Physiology (medical) medicine Animals Enzyme Inhibitors chemistry.chemical_classification Liver injury Mice Inbred C3H Reactive oxygen species Oxidase test NADPH oxidase Hepatology biology Tumor Necrosis Factor-alpha Gastroenterology NADPH Oxidases medicine.disease Molecular biology Endotoxemia Endotoxins Oxidative Stress Liver Biochemistry chemistry Myeloperoxidase biology.protein Tumor necrosis factor alpha medicine.symptom Oxidative stress |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 287:G243-G252 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00287.2003 |
| Popis: | Neutrophils can cause liver injury during endotoxemia through generation of reactive oxygen species. However, the enzymatic source of the oxidant stress and the nature of the oxidants generated remain unclear. Therefore, we investigated the involvement of NADPH oxidase in the pathophysiology by using the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) in the galactosamine/endotoxin (700 mg/kg Gal:100 μg/kg ET) model of liver injury. In addition, we measured chlorotyrosine as indicator for hypochlorous acid formation by myeloperoxidase. Gal/ET treatment of male C3HeB/FeJ mice resulted in sinusoidal neutrophil accumulation and parenchymal cell apoptosis (14 ± 3% of cells) at 6 h. At 7 h, 35% of neutrophils had transmigrated. The number of apoptotic cells increased to 25 ± 2%, and the overall number of dead cells was 48 ± 3%; many of them showed the characteristic morphology of necrosis. Hepatocytes, which colocalized with extravasated neutrophils, stained positive for chlorotyrosine and 4-hydroxynonenal (4-HNE) protein adducts. In contrast, animals pretreated with DPI (2.5 mg/kg) were protected against liver injury at 7 h (necrosis = 20 ± 2%). These livers showed little chlorotyrosine or 4-HNE staining, but apoptosis and neutrophil accumulation and extravasation remained unaffected. However, DPI-treated animals showed serious liver injury at 9 h due to sustained apoptosis. The results indicate that NADPH oxidase is responsible for the neutrophil-derived oxidant stress, which includes formation of hypochlorous acid by myeloperoxidase. Thus NADPH oxidase could be a promising therapeutic target to prevent neutrophil-mediated liver injury. However, the long-term benefit of this approach needs to be investigated in models relevant for human liver disease. |
| Databáze: | OpenAIRE |
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