Inflammation/inflammatory response animal models

A number of animal diseases caused by viruses involve primary demyelination and often are associated with inflammation. These diseases are studied as animal models, which may provide clues about how a viral infection could lead to immune-mediated demyelination in humans [1, 5, 6]. Canine distemper virus causes a demyelinating disease, and the lesions in dog brain show a strong inflammatory response with some similarities to acute disseminated encephalomyelitis in man [ 1 ]. Visna is a slowly progressive demyelinating disease of sheep caused by a retrovirus [ 1 ]. 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

The anti-inflammatory and antihypoproliferative activities of this compound were compared to those of other compounds in several animal models. The compound was 1300-fold more potent than hydrocortisone, and 11-fold more potent than clobetasol propionate, respectively, in suppressing the erythemal responses in a guinea pig model of UV-induced inflammation, and it was 10-fold more potent than clobetasol in the cotton pellet granuloma assay in rats. 

In humans, chronic inflammation of the liver is associated with hepatitis B virus (HBV) infections, and this inflammation is considered an important contributing event in HBV-induced liver cancer. In animal models, there is evidence that inflammation contributes to tumor promotion. Treatment of mouse skin with TPA produces an inflammatory response and increases the expression of proinflammatory mediators such as TNF-a, IL-la GM-CSF, and cyclooxygenase-2 (COX-2). Genetically modified mice deficient in TNFa or COX-2 are resistant to TPA-induced tumor promotion. These results indicate that the inflammatory effects of TPA are important in tumor promotion. 

The molecular mechanism linking the inflammatory response to redox equilibria and modification of nitric oxide production will be explored in an animal model system of septic shock, a generalized inflammation induced by bacterial lipopolisaccharide (LPS). It is known that endotoxemia induces a complex interplay between the activation of nuclear transcription factors such as nuclear factor kappa B (NFkB) and a cascade-activation of various enzymatic activities, mostly mediators of the inflammatory response with particular attention to the variation of the inducible form of nitric oxide synthase (iNOS). 

Finally, routine animal models for inflammatory diseases can be used for testing the in vivo efficacy of selectin antagonists the murine peritonitis model and the ear edema model are the most common. In the murine peritonitis model [200], the migration of leukocytes in response to an acute inflammatory stimulus is assessed by intraperitoneal injection of thioglycolate. In the arachidonic acid- or croton oil-induced ear edema model [131,201], inflammation is measured as neutrophil infiltration, represented by myeloperoxidase activity in ear biopsy samples. 

Taken together, the identification of mast cell hyperplasia and mediator release at sites of tissue fibrosis and wound healing, observations in animal models, and study of the actions of mast cell products, has provided much circumstantial evidence that mast cells are involved in tissue remodelling, healing and fibrosis. It is unlikely that mast cells are essential in these responses, but more likely that they augment them. Complex interactions between different connective tissue components, mast cells and other inflammatory cells are likely to operate, and are unlikely to be fully delineated in humans in vivo. It seems reasonable to hypothesize however that initial mast cell mediator release has the potential to activate fibroblasts, which may then promote the recruitment at d proliferation of further mast cells, explaining the mast cell hyperplasia often witnessed at sites of chronic inflammation. 

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