Bleomycin is an important cause of pulmonary interstitial fibrosis. Moreover, because the histopathology of bleomycin induced lung disease resembles that which occurs in response to reactive oxygen species or which occurs in idiopathic pulmonary fibrosis, bleomycin is a useful model for the study of fibrosing lung diseases. Bleomycin exposure results in injury to lung cell types such as endothelial cells yet is followed by the proliferation of fibroblasts. To examine this paradox, we have conducted a number of preliminary studies using cell culture techniques which reveal that fibroblasts are not only more resistant to bleomycin injury but undergo an augmented growth response. At a molecular level, we have pursued the paradox of injury and growth by studying the response of the heat shock genes, a family of genes which are critical to stress tolerance and cell growth. Our preliminary studies reveal that bleomycin induces the promoter of the hsp 70 heat shock gene and that bleomycin exposures which induce this promoter cause the production of the hsp 70 but not the hsp 83 heat shock proteins. The studies described in this proposal are designed to characterize the nature of the heat shock response to bleomycin and to determine how this response is regulated. Through these studies, we hope to learn about the molecular mechanisms of growth induction and response to injury as applied to the clinical problem of pulmonary fibrosis. Further, since our preliminary results reveal that bleomycin exposure causes selective production of the hsp 70 but not the hsp 83 heat shock proteins, our studies may help us better understand the nature and function of the heat shock gene system.
