Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice.
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-11(C3H), 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 Blmpf1 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.
Haston
Christina K
CK
Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Min
M
Dejournett
Robert E
RE
Zhou
Xinhui
X
Ni
Dan
D
Gu
Xiangjun
X
King
Terri M
TM
Weil
Michael M
MM
Newman
Robert A
RA
Amos
Christopher I
CI
Travis
Elizabeth L
EL
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002874:Chromosome Mapping; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012307:Risk Factors; D012727:Sex Characteristics
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase