Drug induced injury of the lung parenchyma is an important cause of interstitial lung disease because of the wide use of agents such as paraquat in nitrofurantoin and the efficacy of other agents such as bleomycin in the treatment of various malignancies. Although all three agents are capable of directly injuring lung parencghyma, they have also been shown to induce an inflammatory response in the lung characterized by the presence of neutrophils. The neutrophil alveolitis precedes the development of interstitial fibrosis. The proposed studies will examine the mechanisms of lung injury by bleomycin, nitrofurantoin and paraquat. In preliminary studies (see preliminary data), it has been shown that bleomycin can directly injure lung tissue, that exposure of lung tissue to bleomycin results in the release of chemotactic factor for granulocytes, and that granulocytes can augment bleomycin induced lung injury. The goals of the present studies are: to complete the preliminary studies of bleomycin noted above and extend these studies to nitrofurantoin and paraquat. The chemotactic factor released by the lung parenchyma following exposure to these drugs and also the types of cells which produce the factor will also be characterized. The research model for the initial studies will be the rat lung explant system, a system which has been used extensively in the evaluation of high dose paraquat toxicity. Once these studies have been completed, the injurious effects of the drugs and granulocytes on isolated cell lines (endothelial cells, lung fibroblasts, and type II pneumocytes) will be done. I will also use isolated cells to determine if they release chemotactic factors for granulocytes and/or growth factors for fibroblasts when exposed to the toxic agents. The latter studies are designed to determine if there is a relationship between the inflammation and the fibrosis which develops in the lung. The proposed program of research is designed to evaluate the direct effects of some commonly used drugs on lung parenchyma. The studies will also evaluate the role of the body's inflammatory response in augmenting this direct lung injury. The use of specific lung cell lines will allow determination of cell types which are most susceptible to injury. Finally, the relationship between injury and fibrosis will be addressed by examining the release of fibroblast growth factors. These studies should provide insights into the pathogenesis and, possibly, the evaluation and treatment of these disorders.
| Peterson, M W; Geist, L J; Schwartz, D A et al. (1991) Outcome after cardiopulmonary resuscitation in a medical intensive care unit. Chest 100:168-74 |
| Solomon, L R; Beerelli, R D; Moseley, P L (1989) Bleomycin-iron can degrade DNA in the presence of excess ethylenediaminetetraacetic acid in vitro. Biochemistry 28:9932-7 |
