Fibrosis animal models

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

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. 

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 routes of delivery of rAAV in animal models have been largely based upon the specific needs dictated by the disease process to be treated. For example, rAAV-cystic fibrosis transmembrane conductance regulator (CFTR) vectors that have been developed for treatment of cystic fibrosis (CF) were tested in New Zealand white rabbits and in rhesus macaques by the endobronchial route (Flotte et al., 1993 Afione et al., 1996 Conrad et al., 1996). In each instance aliquots of vector were instilled directly into the lumen of a bronchus through a fiberoptic bronchoscope. Vector DNA transfer and mRNA expression were detectable (albeit at low levels) for more than 6 months in each instance, without any indication of inflammation or any other toxicity. Studies in rhesus monkeys also indicated that the likelihood of rescue of rAAV by concomitant wild-type AAV and adenovirus infection was low. These studies... 

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. 

Much of our understanding of the pathogenesis of lung fibrosis comes from studies in animal models as well as from patients with lung fibrosis. 

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). 

---