Abnormality in Gene Expression of Key Mediators of Vitamin A Action in COPD

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DESCRIPTION (provided by applicant): Chronic bronchitis and emphysema are two kinds of chronic obstructive pulmonary disease (COPD), which are important causes of morbidity and mortality in the United States. Death rates from COPD are higher among cigarette smokers and numerous findings suggest a possible association of vitamin A nutritional status with COPD and lifetime cigarette smoking. Vitamin A and its active metabolite retinoic acid (RA) are important for growth and differentiation of many tissues/organs, including lung. RA is known to be effective in promoting alveolization in papain-induced emphysema in dogs and elastase-induced emphysema in adult rats. We have reported earlier that cigarette smoke exposure in our guinea pig model caused an accumulation of retinol and a decrease in RA in lung, suggesting an abnormality in retinoid metabolism and signaling had occurred. We have recently obtained preliminary data on the protein levels and expression of some of the mediators of retinoid action of COPD lung specimens from Lung Tissue Research Consortium (LTRC). Western blot data reveal a difference in the protein levels of LRAT, CRBP-I, CRABP-II, CYP26A1, RAR1, RAR2, RAR3, and RXR1 between mild, moderate and severe emphysema. Immunohistochemical data indicate a difference on LRAT, CRBP-1, CRABP-II and RAR2 staining between these samples. Microarray data also reveal a differential expression of RDH10, RDH12, RDH13, RALDH1, RALDH2, CRABP-II, CYP26A1, RAR-1, RAR-2, RAR3, and RXR-1 between these specimens. Mining of existing GEO datasets with microarray data from human COPD studies revealed expression differences for CRBP-1 and RAR-3 with disease state. Based on the above studies, we hypothesize that in some types of COPD, there is an abnormality in the expression of genes for some of the key mediators of vitamin A action that might inhibit normal repair. The objective of this study is to establish a relationship between the severity of emphysema and levels of expression of the above referred genes as well as STRA6 (recently shown to be responsible for internalization of retinol by the cells) and RAR2 subtypes, particularly RAR22 since its expression inversely correlates with lung cancer development associated with COPD. CRBP, LRAT, STRA6, CRABP-II (human), RAR-2, and CYP26A1 are directly induced by RA. Fixed and frozen lung tissues from COPD patients with mild, moderate and severe emphysema have been obtained from LTRC for preliminary studies. For the proposed studies, specimens from the COPD patients will be age-matched and divided into two groups: smokers and non-smokers. We have developed all of the tools required for this study, including immunohistochemistry, Western blot analysis, Real-Time PCR and microarray. If successful in establishing that there is a relationship between expression of the genes of the mediators of vitamin A action and COPD, it will help us in designing potentially therapeutic drugs targeting some of these genes or in providing/restoring appropriate levels of RA. PUBLIC HEALTH RELEVANCE: The objective of this study is to elucidate the relationship between severity of emphysema in COPD patients and abnormality in the expression of key mediators of retinoid action in lung. (End of Abstract)