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Date of Award

1987

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Andrew W. Stadnyk

Abstract

The acute inflammatory response is an organism's immediate reaction to injury. In mammals the response is facilitated by an abundance of molecules circulating in the plasma. These molecules are responsible for clotting the blood and chemotaxis of inflammatory cells. Polymorphonuclear leukocytes and monocytes usually comprise the cell infiltrate during acute inflammation.

Within several hours of a localised injury and the start of the acute inflammatory response, systemic indications of the response are detectable. A number of plasma glycoproteins, collectively referred to as the Acute Phase Proteins, change in concentration during acute inflammation. Acute Phase Proteins are synthesized primarily by the liver parenchymal cells, the hepatocytes. The molecules which induce hepatocytes to adopt Acute Phase Protein synthesis (hepatocyte-stimulating factors) arise from the inflammatory macrophages at the site of inflammation. The phenomena of the Acute Phase Protein changes constitutes the Acute Phase Protein Response. The predictable nature of the Acute Phase Protein Response, during inflammation caused by noxious agents, has led to the speculation that the response may serve as a manifestion of infectious diseases.

Certain intestinal-dwelling nematodes elicit an inflammatory response in the small bowel of their host. Nippostrongylus brasiliensis and Trichinella spiralis are two such parasites of rodents. It was important for an understanding of the nature of intestinal inflammation, to establish whether the Acute Phase Protein Response occurred in animals harboring the parasites.

Following a subcutaneous injection, N. brasiliensis larvae pass through the rat host's lungs before reaching and maturing in the intestine. Acute Phase Protein changes were detected in infected rats at the time at which the worms were passing through the lungs and following the establishment of the adults in the intestine. Infective T. spiralis must be ingested and subsequently mature in the small intestine. Adults live, and give birth to larvae, while living in an intracellular compartment comprised of intestinal epithelial cells. No Acute Phase Protein Response was detected during infection of rats by T. spiralis.

An infection by T. spiralis did not inhibit the Acute Phase Protein Response due to a second stimuli, and macrophage secretion of factors relevant to the Acute Phase Protein Response, from sites other than the intestine, was normal. An Acute Phase Protein Response was detected in animals which harbored concurrent N. brasiliensis and T. spiralis infections. No Acute Phase Protein Response was detected in rats into which mature N. brasiliensis larvae were transferred, in order to eliminate the lung stage of infection. It was concluded that the lung phase of an infection by N. brasiliensis was important in the genesis of the Acute Phase Protein Response during intestinal inflammation. Furthermore, it was concluded from these studies that inflammation in the rat intestine does not lead to the Acute Phase Protein Response.

When the intestinal cells of normal rats were examined for the production of factors which may induce the Acute Phase. Protein Response, it was shown that constitutive secretion of the relevant molecules occurred. Secretion of these factors increased during infection of rats by N. brasiliensis but declined during infection by T. spiralis. A rat intestinal epithelial cell line was used to demonstrate that these cells, in addition to macrophages, secrete molecules important in the regulation of the Acute Phase Protein Response. It was concluded that T. spiralis likely inhibited the constitutive hepatocyte-stimulating factor activity by infecting epithelial cells of the intestine.

The pathology that the rodent infections elicit are good models of inflammation for the study of mechanisms of the acute inflammatory response of the intestine.

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