Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice.

Abstract

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.

• Authors: Christina K Haston, Min Wang, Robert E Dejournett, Xinhui Zhou, Dan Ni, Xiangjun Gu, Terri M King, Michael M Weil, Robert A Newman, Christopher I Amos, Elizabeth L Travis
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 11 Issue 16 Pg. 1855-63 (Aug 01 2002) ISSN: 0964-6906 [Print] England
• PMID: 12140188 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Bleomycin
• Cysteine Endopeptidases
• bleomycin hydrolase

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Bleomycin (toxicity)
• Chromosome Mapping
• Cysteine Endopeptidases (genetics, metabolism)
• Female
• Humans
• Major Histocompatibility Complex
• Male
• Mice
• Mice, Congenic
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Models, Biological
• Phenotype
• Pulmonary Fibrosis (enzymology, genetics, immunology, pathology)
• Risk Factors
• Sex Characteristics