The histone deacetylases are transcriptional repressors which have been implicated buy inhibitor in the resolution of inflammation as well as the regulation of MMP expression. In COPD patients, Inhibitors,Modulators,Libraries reductions in the expression of HDAC2 and HDAC5 correlate with dis ease severity and increased IL 8 expression. Simi larly, the type III HDAC Sirt1, which regulates MMP expression, was also found to be downregulated in COPD. Lipopolysaccharide, a cell wall component of gram negative bacteria, is a potent inflammatory mole cule and is present in appreciable amounts in cigarette smoke. It is also an active component in environmental and occupational exposures associated with the develop ment of COPD. Experimental inhalation of LPS evokes pulmonary and systemic inflammation in healthy human subjects.

Chronic exposure of experimen tal animals causes emphysema, Inhibitors,Modulators,Libraries goblet cell metaplasia, and airway wall thickening. These alterations persist up to four to eight weeks following LPS administration. Recently, we demonstrated that mice exposed to a combination of LPS and elastase once a week for 4 weeks display COPD like features including widespread lung inflammation, goblet cell metaplasia, increased lung volume, emphysema and decreased elastic recoil. These changes persisted up to 8 weeks after cessation of exposure to elastase and LPS. These mice were also found to be more susceptible for rhinovirus infection. Quercetin is a 3,3,4,5,7 pentahydroxyflavone found in many plants. Based on its polyphenol structure, querce tin has potent antioxidant effects, combining with free radical species to form considerably less reactive phe noxy radicals.

Inhibitors,Modulators,Libraries Quercetin also has anti inflamma tory effects, inhibiting lipid, protein tyrosine and serine/ threonine kinases by its capacity to compete with the binding of ATP at the nucleotide binding site. Pre Inhibitors,Modulators,Libraries viously, we demonstrated that quercetin inhibits TNF a stimulated IL 8 expression at the transcriptional level in airway epithelial cells and decreases airways hyperre sponsiveness in cockroach allergen sensitized and chal lenged mice, a model of allergic airways disease, at a dose of 0. 6 mg per day. Quercetin was also shown to suppress eosi nophilic inflammation in ovalbumin sensitized and challenged mice at a dose of 10 mg/kg body weight. Further, quercetin decreases the expression of MMP9 stimulated by TNF a in epidermal cells.

Based on these observations, we hypothesized that quer cetin reverses oxidative stress and inhibit MMP produc tion, perhaps by increasing the expression of the histone deacetylase Sirt 1, thereby preventing the progression of lung disease in COPD. To test this hypothesis, we trea ted elastase/LPS exposed mice with quercetin, Inhibitors,Modulators,Libraries and examined oxidative stress, inflamma tion and expression of MMP9, MMP12 and SIRT 1 in the lungs. We also determined the effect of quercetin on the histone acetylation selleck products of the MMP9 and MMP12 pro moters by chromatin immunoprecipitation assay.