Interstitial pulmonary fibrosis (IPF) may result from a wide range of processes. Some of these processes are of known and some of unknown origin. The formation of reactive oxygen species (ROS) in the lung is known to cause significant, acute lung damage that eventuates into IPF. Thus, it is possible that the free radicals derived from molecular oxygen represent a common etiology for lung fibrosis caused by a diversified group of chemicals including exposure to toxic levels of O2, air pollutants, some anti-neoplastic drugs, herbicides and lung toxins. There is a wide gap in our knowledge regarding the generation of ROS and increased collagen synthesis and deposition. It is known that ROS stimulate the synthesis of prostaglandins and related compounds and it is becoming apparent that the members of the prostanoid family play an important role in the regulation of collagen metabolism. The major goal of the proposed study is to test the hypothesis that the formation of prostaglandins (PGs) and thromboxane A2 (TxA2) constitute a link between ROS and increased collagen synthesis and accumulation following intratracheal administration of a variety of mixtures known to generate ROS in the lung. In this regard, experiments will be carried out to assess the effects of different oxidants on the circulating and lung levels of PGs and TxA2 and total lung collagen content following intratracheal administration. Morphometric and electron microscopic techniques will be employed to evaluate the derangement in lung structure by characterizing the influx of inflammatory cells by type and fibroblasts in lesions, volume of stainable collagen in lesions and volume of reactive lesions per lung. Biochemical tests will be employed to assess collagen and prostaglandin synthesizing and degrading abilities of the lung. If it can be demonstrated that the members of the prostanoid family act as mediators of oxidant-induced increased collagen synthesis and accumulation, then the effectiveness of drugs that inhibit PGs and TxA2 synthesis against lung fibrosis will also be evaluated. The criteria for evaluation of effectiveness for each compound will be at both the morphometric and biochemical levels. We believed that a multidisciplinary approach, as proposed in this project, will provide a better understanding of the pathophysiological mechanisms responsible for the genesis of IPF as well as in controlling the inflammatory sequelae frequently associated with IPF.
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