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Peplomycin, a bleomycin derivative, induces myofibroblasts in pulmonary fibrosis
Author(s) -
Osaki Tokio,
Yoneda Kazunori,
Tatemoto Yukihiro,
Yamamoto Tetsuya,
Yokoyama Takeshi,
Enzan Hideaki
Publication year - 2001
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.1365-2613.2001.iep193.x
Subject(s) - myofibroblast , bleomycin , pulmonary fibrosis , basic fibroblast growth factor , transforming growth factor , desmin , fibrosis , fibroblast , growth factor , vimentin , chemistry , biology , endocrinology , medicine , immunohistochemistry , cell culture , receptor , chemotherapy , genetics
To analyse the mechanism by which a bleomycin derivative, peplomycin (PLM) induces pulmonary fibrosis, we investigated differentiation of rat pulmonary fibroblasts to myofibroblasts (MF). In intraperitoneally PLM (5 mg/kg/day)‐injected rats, the peripheries of lungs adjacent to the pleura revealed advanced fibrosis with a small number of α‐smooth muscle actin (α‐SMA)‐positive MF, which ultrastructurally possessed abundant microfilaments and cellular organelles. In the fibrotic tissue, the expression of α‐SMA‐mRNA was detected by in situ reverse transcription‐polymerase (RT‐PCR). The message was strong just after a 2‐week administration of PLM then decreased thereafter, although fibrosis advanced. When pulmonary fibroblasts were separated from saline‐injected rats (N‐Fib) and cultivated for 7 days in the presence of 5 mg/mL PLM, α‐SMA protein was weakly expressed, while the majority of pulmonary fibroblasts separated from PLM‐injected rats (P‐Fib) became positive for α‐SMA in 7‐day cultivation and the expression of α‐SMA in P‐Fib was strongly increased by cultivation in the presence of PLM and transforming growth factor‐β (TGF‐β), but not basic fibroblast growth factor (bFGF) or platelet‐derived growth factor (PDGF), although the cell proliferation was most strongly enhanced by bFGF and only slightly by PLM and TGF‐β. The α‐SMA‐positive cells expressed vimentin, but only weakly expressed desmin. Additionally, P‐Fib generated larger amounts of TGF‐β and bFGF than were generated by N‐Fib. These results indicate that PLM induces pulmonary fibrosis by differentiating fibroblasts to α‐SMA‐positive MF, and that bFGF and TGF‐β play each critical role in the different phases of PLM‐induced pulmonary fibrosis by inducing fibroblast proliferation and transformation, respectively.