Animal Models of Fibrosis

The mechanism finking chronic inflammation and tissue fibrosis is poorly understood. Various exposures and conditions are believed to cause pulmonary fibrosis. These include particulate agents, physical agents and infectious agents. To examine the pathogenesis of pulmonary fibrosis different experimental models in animals have been described. The most commonly used method to 

Various studies have also examined animal models of pulmonary inflammation that are representative of primary eosinophil or neutrophil infiltration. Lung inflammation characterized by eosinophil influx has been used as a model of asthma and is not generally associated with lung fibrosis. After several episodes of repeated antigen challange, a subset of Ascaris -sensitive Cynomolgus monkeys developed a persistent eosinophilia and enhanced intercellular adhesion molecule-1 (ICAM-1) expression on pulmonary endothelial and epithelial cells when compared to control animals (Gundel etal., 1991, 1992). 

The role of various cytokines has been studied in chronic lung inflammatory conditions. A mouse model of hypersensitivity pneumonitis which progresses to. 

In this model, IL-6 plays a role in regulating the cellular recruitment in the lungs during an inflammatory response and IL-4 administration partially abrogates the disease process (Ghadirian and Denis, 1992). TNFa has also been shown to play an essential role in determining hypersensitivity pneumonitis in a mouse model (Denis et al., 1991). 

Altered expression of small proteoglycans, collagen and TGF/3 has been shown in bleomycin-induced pulmonary fibrosis in rats (Khalil etal., 1989 Shahzeidi etal., 1993 Denholm and Rollins, 1993 Westergren-Thorsson etal., 

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Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

Chemokines and Chemokine Receptors in Animal Models of Pulmonary Fibrosis... 

One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme s activity, enhanced protein synthesis and cellular regeneration may occur in diseased but not malignant cells. Milk thistle may have a role in hepatic fibrosis. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the profibrogenic cytokine TGF-13. 

The immunosuppressive drug cyclosporine A (CSA) has revolutionized transplant medicine. However, CSA induced-nephrotoxicity still represents a major therapeutic challenge. Chronic CSA nephropathy is characterized by a decrease in glomerular filtration rate (GFR), tubular atrophy, interstitial fibrosis and progressive renal dysfunction. It is difficult to delineate the mechanisms of CSA toxicity from clinical data since the majority of clinical experiences with CSA have been in renal transplant recipients. Animal models of CSA nephropathy have brought some insights, how-... 

Liver Fibrosis Liver fibrosis is a common end result of inflammation and/or necrosis. While the liver does have considerable regenerative capabilities, cytokine release associated with the inflammatory/necrotic process can lead to fibrosis that can have a deleterious effect on hepatic function, not only from the aspect of decreased hepatic functional mass but also from the standpoint of compromising blood supply. Animal models of hepatic fibrosis would be valuable from the standpoint of facilitating the development of noninvasive biomarkers as well as development of interventional agents. 

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