One of the major life-threatening complication of conventional chemical and radiation therapies of cancer is the development of interstitial pulmonary fibrosis. For bleomycin treatment, a chemotherapeutic agent of choice for cancers of the aged, the incidence of fibrosis has been determined to be as high as 40%, and the incidence of mortality has been estimated at 1-7% of these affected patients. There is strong evidence from animal studies that bleomycin and radiation-induced disease share a common-mechanism. Thus the investigation of the process underlying the development of pulmonary fibrosis via bleomycin administration is likely to be relevant to radiation-induced interstitial disease. The objective of this proposal is to elucidate the mechanism involved in the generation of bleomycin-induced pulmonary fibrosis. The long-term goal is to construct a strategy for the clinical intervention of both drug and radiation-induce fibrosis, and to establish genetic markers for identifying patients most at risk of developing this disorder. Our approach to this problem is based on preliminary studies which have dissected the genetics of pulmonary fibrogenesis and which indicates a key role of interleukin 6 (IL-6) in this process.
The Specific Aims of the proposal are to: 1) map and identify the genes controlling the early or inflammatory stage of bleomycin-induced pulmonary fibrosis. We have determined that susceptibility to the development of bleomycin-induced pulmonary inflammation and fibrosis is dominant over resistance and have identified two markers, the development of cachexia, and the elevation of IL-6 mRNA in the lung, which correlate with the onset and extent of the inflammatory stage of the disease. We will map the genes responsible for controlling these markers using simple sequence repeat polymorphism analysis, with the eventual goal of identifying and isolating these genes; 2) investigate the role of IL-6 in the inflammatory process by altering normal IL-6 expression patterns in bleomycin sensitive and resistant mice. The consequences of ablating IL-6 expression on the development of bleomycin-induced cachexia and lung inflammation will be investigated using mice carrying a targeted IL-67 gene disruption; and 3) determine whether pulmonary inflammatory response is a prerequisite for subsequent fibrogenesis, and which early stage susceptibility genes contribute to the development of late stage fibrosis.
| Thatcher, Thomas H; Sime, Patricia J; Barth, Richard K (2005) Sensitivity to bleomycin-induced lung injury is not moderated by an antigen-limited T-cell repertoire. Exp Lung Res 31:685-700 |
| Barth, Richard K; Hanchett, LeRoy A; Baecher-Allan, Clare M (2002) Mapping susceptibility genes for the induction of pulmonary fibrosis in mice. Chest 121:21S |
