4-hydroxy-2-nonenal and Shock

Tumor necrosis factor (TNF) is involved in pathologies like septic shock, inflammatory bowel disease and rheumatoid arthritis. TNF and lipopolysaccharide can incite lethal shock, in which cardiovascular collapse is centrally orchestrated by the vasodilating free radical nitric oxide (NO). However, NO synthase (NOS) inhibition causes increased morbidity and/or mortality, suggesting a dual role for NO. To investigate the potential protective role of NO during TNF shock, we treated mice with TNF with or without NOS inhibition. Experiments in endothelial- NOS- and inducible NOS-deficient mice identified inducible NOS as the source of protective NO. Distinctive TNF-induced lipid peroxidation, especially in liver and kidney, was aggravated by NOS inhibition. In addition, various antioxidant treatments and a phospholipase A2 (PLA2) inhibitor prevented sensitization by NOS inhibition. Together, these in vivo results indicate that induced NO not only causes hemodynamic collapse, but is also essential for curbing TNF-induced oxidative stress, which appears to hinge on PLA2-dependent mechanisms.

Topics: Aldehydes; Animals; Antioxidants; Butylated Hydroxyanisole; Catalase; Cyclic N-Oxides; Enzyme Inhibitors; Female; Immunohistochemistry; Injections, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Phospholipases A; Phospholipases A2; Reactive Oxygen Species; Shock; Spin Labels; Superoxide Dismutase; Survival Rate; Tumor Necrosis Factors

Immunohistochemical analysis of the distribution of the lipid peroxidation product 4-hydroxynonenal (HNE) in the brain of baboons exposed to experimental hemorrhagic traumatic shock or sepsis showed that systemic oxidative stress and the thereby generated HNE affect the blood:brain barrier and the regulation of cerebral blood flow determining secondary brain damage. Similarly, HNE was determined during ischemia in the brain blood vessels of rats exposed to ischemia/reperfusion injury of the brain. After reperfusion, HNE disappeared from the blood vessels but remained in neurones and in glial cells. Since HNE modulates cell proliferation and differentiation (including proto-oncogene expression), it is postulated that HNE might have prominent local and systemic effects that are not only harmful but beneficial, too, determining the outcome of various pathophysiological conditions based on oxidative stress.

Topics: Aldehydes; Animals; Antibodies, Monoclonal; Brain; Cell Division; Cerebral Hemorrhage; Free Radicals; HeLa Cells; Humans; Immunohistochemistry; Ischemic Attack, Transient; Muscle, Smooth, Vascular; Papio; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Second Messenger Systems; Sepsis; Shock; Thymidine

Erythrocytes obtained from human patients with circulatory shock of different aetiology consistently showed a strong increase in lipid peroxidation-derived aldehydes in comparison with red cells of normal adults. The highly toxic compound 4-hydroxynonenal has been recovered exclusively in the erythrocytes of the patients.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Chromatography, High Pressure Liquid; Erythrocytes; Female; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Shock; Shock, Cardiogenic; Spectrophotometry