TRANSGENIC MICE EXPRESSING THE SH BLE BLEOMYCIN RESISTANCE GENE ARE PROTECTED AGAINST BLEOMYCIN-INDUCED PULMONARY FIBROSIS

Despite the high efficiency of bleomycin (BLM) as a chemotherapeutic a gent against various carcinomas, the potentially lethal and chronic fi brotic response of the lung is a major dose-limiting side effect, Here , we explore the possibility of a direct inhibition of lung tissue inj ury by in vivo expression of the actinomycetes BLM resistance protein Sh ble, Transgenic mice expressing the Sh ble gene under the control o f a composite viral promoter were produced after introduction of the t ransgene into D3 ES cells, The protein was detected at high level in l ungs, spleen, and kidney, We then assessed its ability to modulate the BLM-induced fibrotic response in the transgenic mice in comparison wi th C57BL/6 and 129/Sv parental mice, Cumulative doses of 300, 400, or 500 mg/kg BLM were administered either by i,p, or s,c, repeated inject ions in the different strains, Transgenic mice were shown to be clearl y less sensitive to BLM toxicity, as assessed by lung histology, The p ulmonary hydroxyproline content in the treated transgenic mice was clo se to its baseline level, whereas it was up to 50% higher than the con trol level in C57BL/6 and 129/Sv parental mice, These observations are consistent with the hypothesis that a resistance gene specifically ex pressed in lungs may prevent the BLM-induced inflammation.