TY - JOUR
T1 - Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice
AU - Haston, Christina K.
AU - Wang, Min
AU - Dejournett, Robert E.
AU - Zhou, Xinhui
AU - Ni, Dan
AU - Gu, Xiangjun
AU - King, Terri M.
AU - Weil, Michael M.
AU - Newman, Robert A.
AU - Amos, Christopher I.
AU - Travis, Elizabeth L.
N1 - Funding Information:
The authors thank Drs Michael Seldin and Kirsten Fischer Lindahl for helpful discussion. We thank Mr Kuriakose Abraham for preparation of the histological sections. Bleomycin (clinical grade Blenoxane) was the kind gift of Mr Sal Lucania, Dr Terry Dugan and Ms Mary Springer, Bristol Myers Squibb Company. Authentic BLM A2 and dBLM were kindly provided by Nippon Kayaku (Tokyo, Japan). This work was supported by the National Institutes of Health, 5RO1 CA 64193 (E.L.T.) and RO1 HG 02275 (C.I.A.).
PY - 2002/8/1
Y1 - 2002/8/1
N2 - Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11C3H, and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpfl as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.
AB - Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11C3H, and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpfl as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.
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U2 - 10.1093/hmg/11.16.1855
DO - 10.1093/hmg/11.16.1855
M3 - Article
C2 - 12140188
AN - SCOPUS:0036667985
SN - 0964-6906
VL - 11
SP - 1855
EP - 1863
JO - Human molecular genetics
JF - Human molecular genetics
IS - 16
ER -