H2-Ea deficiency is a risk factor for bleomycin-induced lung fibrosis in mice.
Pulmonary fibrosis is a significant complication in cancer patients when treated by radiation, e.g., thoracic malignant diseases, or chemotherapeutic agents. Bleomycin is one of the primary drugs used to treat testicular cancer, but the incidence of significant pulmonary fibrosis limits the dose. It is known that susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait controlled by multiple genes, none of which, however, are yet known. In this study, we used expression profiling and genetic analysis in mouse models of bleomycin-induced pulmonary fibrosis and identified MHC class II antigen Ealpha (H2-Ea) as a risk factor for this disease. We found that a loss-of-function deletion in the H2-Ea gene was linked to susceptibility. A functional test of H2-Ea in transgenic mice showed 100% survival in the transgenic mice compared with 53% in C57BL/10J mice and significantly decreased pulmonary fibrosis from 16.42% (C57BL/10J) to 5.76% (transgenic; P = 1.20e(-8)). These results show that H2-Ea expression protects mice from bleomycin-induced pulmonary fibrosis, which implicates H2-Ea as a candidate susceptibility gene for pulmonary fibrosis.
Du
Min
M
Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Irani
Roxanna A
RA
Stivers
David N
DN
Lee
Sang-Joon
SJ
Travis
Elizabeth L
EL
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D005260:Female; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000235:genetics*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics* / Q000276:immunology
D006183:H-2 Antigens; D001761:Bleomycin