SESSION TYPE: Occupational/ Environmental Lung Disease
PRESENTED ON: Tuesday, October 23, 2012 at 04:30 PM - 05:45 PM
PURPOSE: Our group has studied toxicant-induced constrictive bronchiolitis obliterans (CBO) since the popcorn oil-related incident earlier in the decade, and have established a toxicant-induced animal model to study mechanisms. Lung homogenates consistently demonstrated elevated transforming growth factor beta (TGFβ) and matrix metalloproteinase 9 (MMP9). We tested three inhibitors of specific phosphorylation pathways leading to MMP9, and found that a JUN kinase inhibitor SP600125 showed MMP9 inhibition, in vitro, at a nontoxic level. An endogenous tissue inhibitor of metalloproteinases (TIMP) appeared to be much more effective with the toxicant-induced model of CBO than with a transplantation model. This report details early studies and active hypotheses for our CBO models.
METHODS: Toxicant induced CBO was induced by slow intratracheal infusion of a Papaverine HCl -saline solution using implanted Alzet pumps as described by our group earlier (Lung 182: 119-34,2004). This drug, the main alkaloid in edible (Sauropus) plants, was responsible for several cases of human CBO. The exact mechanism by which Papaverine produces CBO is unknown, and our investigation of Papaverine metabolism in the rat shows mainly nonreactive metabolites with no propensity to bond covalently to tissue protein or induce an immune process. We considered, based on only the simplest three dimensional structural analysis, that Papaverine would be an operational candidate to hinder steric docking of agonist-inhibitor pairs involved in cartilage remodeling (TIMP-MMP).
RESULTS: Recent, elegant structural biology studies (Nature Med 18:143-7, 2012) have produced an antibody that imitates the inhibitory molecular mechanisms of TIMPs, generated against the catalytic domain of MMPs. Their work strengthens our published suggestion that Papaverine -TIMP binding has a key role in regulating the pathological CBO process in this model.
CONCLUSIONS: Inhibition work in vivo on CBO models continues, evaluating inhibitors of MMP with emphasis on Papaverine -like congeners and TIMP, measuring histological and physiological outcome.
CLINICAL IMPLICATIONS: Our toxicant-induced CBO model is progressing to clarify the roles of the MMPs and their endogenous inhibitors (TIMPs) in an infrequent but important pulmonary pathology.
DISCLOSURE: The following authors have nothing to disclose: Ammar Alkhazna, Anwaar Saeed, Jennifer Svetlecic, Agostino Molteni, Betty Herndon
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