EXPERIMENTAL EMPHYSEMA--STUDIES ON REMEDIATION

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DESCRIPTION (Applicant's abstract): Our long range goal is to achieve a molecular and cellular explanation for the formation of an alveolus and to use this information for therapeutic purposes in diseases such as pulmonary emphysema. The latter, characterized by alveolar destruction, is among the leading causes of disability and death in U.S., in part, because the lung fails to replace destroyed alveoli. A central unmet challenge of lung research - the induction and formation of alveoli for therapeutic purposes - has led to lung transplantation being the only remediation for emphysema. However, a paradigm - the possibility of non-surgical inexpensive remediation of emphysema - is offered by three recent observations: 1) treatment of newborn rats with all trans retinoic acid (RA) causes a 50 percent increase in alveolar number without increasing lung volume; 2) identical treatment prevents the inhibition of alveolar formation and low body mass specific alveolar surface area caused by corticosteroid treatment; 3) treatment with RA of adult rats previously made emphysematous by elastase administration abrogates the structural features of human emphysema (larger and fewer alveoli, increased lung volume, and diminished volume corrected surface area) providing the first non-surgical remediation of emphysema and the possibility of a similar effect in humans. Our specific aims are 1) to use unbiased morphometric methods to test the hypothesis that treatment with RA will abrogate key findings of elastase induced emphysema in a non-human primate; 2) to use molecular biology techniques to initiate a systematic approach to the identification of genes responsible for the formation of alveoli in a non-human primate; 3) to use morphometric methods to test the hypothesis that, in a non-human primate, the cellular composition of the alveolar wall, and the balance between alveolar epithelial surface area and alveolar capillary surface area are changes in elastase-induced emphysema and are returned to normal by treatment with RA. We believe that we can achieve these specific aims because we have 1) considerable experience with morphometry, 2) produced and reversed emphysema in rats, 3) successful experience with all the necessary molecular biology procedures, and 4) produced emphysema in a non-human primate.