|Sartin, J. - AUBURN U., AUBURN, AL|
|Martinex, A. - NIH, NCI, ROCKVILLE, MD|
|Montuenga, L. - NIH, NCI, ROCKVILLE, MD|
|Miller, M. - NIH, NCI|
|Cuttitta, F. - NIH, NCI|
Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 16, 1998
Publication Date: N/A
Interpretive Summary: Endotoxin, the extract of bacterial cell walls, is often used to study disease and infection in experimental animals because many of the effects of infection can be mimicked without the need to infect animals with live bacteria. Disease stress caused by bacteria escalates human health care costs as well an animal producer costs by billions of dollars annually in association with lost time at work, incurred medical treatment costs and losses in production efficiency of farm animals. Often times disease situations are encountered where animals or people are much sicker than expected and for significantly longer time periods than should be expected. Our research investigated the effects of low-leve responses to the known additional challenge of bacterial endotoxin. Because calves are particularly sensitive to bacterial infection, they were used as the target species. We infected some of the calves with very low levels of a systemic parasite to scarcely produce observable clinical signs of infection. In addition some of the calves were injected with endotoxin. The data demonstrated that the parasitized calves had much worse responses to the endotoxin challenge that the noninfected calves. A significant point of impact of the combined challenges was the pancreas. The implications of the research are that the pancreas needs to be considered a major target for disease stress. The production of toxic nitrogen free radicals during disease stress in the pancreas of young animals may establish conditions for the development of prolonged diabetes-like diseases.
Technical Abstract: Our objective was to determine whether organ and plasma adrenomedullin (AM) and inducible nitric oxide synthase (iNOS) responses to a mild endotoxin challenge (EC) were affected by the underlying presence of a chronic, occult to low-level systemic protozoan infection. We assigned 20, 3- to 4- mo. old male calves to one of four treatments: noninfected/no EC (C); infected (50,000 oocysts, Sarcocystis cruzi per os, I); 0.45 #g/kg E. coli, 055:B5, iv bolus (EC); and the combination, I+EC. Saline control or endotoxin challenges were administered to all calves on day 30 relative to date of infection. Following the 24 h sample, all calves were euthanized and lung, liver, and pancreas harvested into Bouin's fixative for immunohistochemical localization of AM and iNOS. Hypoglycemia and hypoinsulinemia were temporally correlated and prolonged in I+EC compared to EC alone. EC increased plasma AM concentrations (P<0.001); mean plasma AM response area under the curve was 30% greater in I+EC than EC (P<0.005). Plasma NO2/NO3 concentrations were increased only in I+EC. Lung and liver showed no immunostaining for iNOS; in pancreatic islets, % iNOS immunopositive cells was 1.7, 21, 6.7 and 24, for C, I, EC and I+EC, respectively. AM was present, but not differentially affected by treatments, in the lung epithelium; percent AM immunopositive cells in islets were 8, 25, 17, & 33, for C, I, EC and I+EC, respectively. In serial sections of pancreas, AM was co-localized in peripheral islet cells with INOS and PP. The datat suggest that accentualted pancreatic AM and INOS responses underlying clinically occult infections may potentiate metabolic perturbations.