The goal of this Program Project is to investigate the mechanisms through which pre-exposure of the lung to ozone modifies specific pulmonary physiologic and pathophysiologic processes and to evaluate the manner in which inherent susceptibility to ozone influences this modification. The normal functions of the lung encompass a wide variety of cellular and biochemical processes including mediator synthesis and release, inflammatory cell influx, modulation of allergic responsiveness and the regulation of central and peripheral lung function. Each of these processes may be influenced by exposure to environmental oxidants, such as ozone, depending upon the nature of the interaction of ozone with the mechanisms involved with the process and upon the inherent susceptibility of its component mechanisms to ozone-induced modification. Thus, apparently subtle effects of ozone on cellular activity can lead to substantial alterations in many aspects of normal lung function. This program consists of three projects proposed by investigators and co-investigators with expertise in pulmonary cellular metabolism, physiology, immunology, pharmacology, biochemistry, pathology, cell and molecular biology and genetics. The specific objectives of the projects are: Project 1 - Kleeberger: To investigate the molecular basis of gene-linked resistance and susceptibility to ozone-induced inflammation in the airways. Project 2 - Spannhake: To determine the cellular and humoral loci of ozone-induced attenuation of antigenic responsiveness in the airways. Project 3 - Weinmann: To investigate the relationship between ozone-induced changes in spirometry and specific indices of peripheral airway function in human subjects. Each project represents an independent research effort; however each is based upon rationales, experimental approaches and defined end-points which are shared with one or more of the others. The resulting interactions and exchange of information and scientific insight between investigators will enhance productivity and promise to facilitate progress in the proposed research. The result should be a more complete understanding of the impact of environmental oxidants, such as ozone, on lung function in healthy individuals and those with lung disease.
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