Immunologic alterations in bleomycin-treated mice: role of pulmonary fibrosis in the modulation of immune responses.

Abstract

Among the side effects of bleomycin (BLM), a drug frequently used in the treatment of lymphomas and squamous-cell carcinomas, is pneumonitis with pulmonary fibrosis. The most prominent biochemical lesion associated with pulmonary fibrosis, a chronic debilitating and sometimes fatal disease, is an increase in the levels of collagen in the lung parenchyma. The mechanisms involved in the induction of this disease are still unclear, although results have suggested that the development of fibrosis may be immunologically mediated. There have, however, been no reports in the literature on the frequency and function of lymphocytes in the regional and systemic lymphoid tissues in BLM-induced pulmonary fibrosis. We therefore conducted a study, in which we inoculated C57Bl/6 mice intratracheally with BLM or saline, and tested the animals' lymphoid cells for various cell-mediated and humoral immune responses. The results indicated an increase in the number of lymphocytes in the lung-associated hilar lymph nodes, whereas the number of splenic lymphocytes was reduced as compared with control mice. Moreover, there was a significant inhibition of the antibody response to sheep erythrocytes in both the spleen and hilar lymph nodes of BLM-treated mice. Inhibition of the immune system appeared to be associated with the development of pulmonary fibrosis, and not to result from BLM toxicity, since the immune response of mice was not inhibited when they were injected with an identical dose of BLM under conditions that did not cause pulmonary fibrosis. Moreover, inhibition of splenic antibody responses was also observed in a hapten-induced model of pulmonary fibrosis, providing additional evidence that the induction of fibrosis and not the chemical toxicity of BLM was responsible for the modulation of immune responses.

Host predisposition by endogenous Transforming Growth Factor-β1 overexpression promotes pulmonary fibrosis following bleomycin injury

“…By using Gene Ontology database, Bleomycin TR+ vs TR+ altered transcripts were classified and grouped in functional families in correlation with their significant role in fibrosis development. Altered fibrosis-associated genes, which drive angiogenesis, inflammatory response, immune response and apoptosis, in response to bleomycin in TR+ mice were found dysregulated, as also previously reported [ 28 - 30 ]. In addition, we found a large number of significantly altered genes that function in the regulation of cellular morphogenesis, development and gene transcription.…”

Expression of Yeast Apurinic/Apyrimidinic Endonuclease (APN1) Protects Lung Epithelial Cells From Bleomycin Toxicity

“…Bleomycin pulmonary toxicity in vivo is more complicated than in vitro studies. It is associated with an intense inflammatory or immune reaction in the lung (23,31). In addition, other factors, such as the level of bleomycin hydrolase, have been shown to influence bleomycin toxicity (23,32).…”

Bone Marrow–Derived Mesenchymal Stem Cells in Repair of the Injured Lung

“…Lung expression of IFN-␥, IL-2, IL-1␤, and IL-4 was increased at 14 d after bleomycin and stem cell transplant resulted in return of expression of these cytokines toward normal. This suppression of the prolonged inflammatory response in the lungs (19) may provide an environment more favorable to normal repair.…”