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Title: PARTICIPATION OF GREE-RADICAL PRODUCTION IN THE DOWNREGULATION OF INSULIN-LIKE GROWTH FACTOR-(IGF)-1 IN ENDOTOXIN-SIMULATED DISEASE STRESS

Author
item Elsasser, Theodore
item Kahl, Stanislaw
item SARTIN, J. - DEPT. OF PHYS., AUBURN AL
item Rumsey, Theron

Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/1998
Publication Date: N/A
Citation: N/A

Interpretive Summary: Disease stress in food-producing animals results in significant losses to producers and increased costs to consumers. Many acute diseases result in pathology because highly chemically reactive molecules can be formed inside cells that chemically modify normal proteins and cause altered biochemictry in cells or cell death. One class of these highly reactive molecules produced during disease are nitrogen free radicals and the compound peroxynitrite is one of them. We demonstrated using calves that the production of these free radicals is dependent on the severity of the disease stress to which animals are subjected. Now that we have identified a chemical cause of disease in animals we can pursue strategies to decrease the extent of disease stress by giving animals other compounds that interfere with the generation of the toxic free radicals during disease. Antioxidants are being considered for their role in this regard. Antioxidants can stabilize the internal environment of cells so that the chance of forming peroxynitrite is reduced.

Technical Abstract: The objective of this study was to determine the relative roles of tumor necrosis factor-a (TNF), cortisol (C), and nitrogen free radicals (NFR) in the downregulation of IGF-I in calves after iv endotoxin (LPS) bolus challenge. Nine 4-mo old Holstein bull calves were assigned to LPS (E. coli, 055:B5) at doses of 0.2, 1.0 and 2.5 mg/kg BW. LPS was administered once daily for 3 consecutive days and on the fourth day all calvs received 5.0 mg/kg, iv. Plasma was assayed by RIA for TNF, C and IGF-I. NO production was assessed in terms of measurement of plasma NO3-. Immunohistochemical localization of nitrotyrosine-containing proteins in tissue sections was used as evidence of peroxynitrite (ONOO-) and NFR formation. Plasma TNF increased in response to dose of LPS (P<0.01). Plasma C concentrations increased at all doses of LPS, did not differ by LPS dose, but were significantly depressed after LPS on d-3 relative to d-1 in calves receiving 2.5 mg/kg LPS (P<0.05). Plasma NO3- responses peaked 6 to 8 hors after LPS and were greatest with administration of LPS at 1.0 mg/kg. Plasma IGF-I was depressed at 1.0 and 2.5 mg/kg LPS. Only calves displaying large plasma IGF-I reductions after LPS showed positive immunostaining for NT. While at the present time we cannot distinguish between a generalized free-radical cytotoxic disruption of cell function from specific interruption of somatotropic axis signal transduction pathways, the presence of NFR-modified proteins in lung and liver of IGF-I downregulated calves challenged daily with the high doses of LPS suggests NFRs and ONOO participate in the pathophysiology of the metabolic/somatotropic axis in disease stress.