Bleomycin sensitivity of mice expressing dominant-negative p53 in the lung epithelium.
The chemotherapeutic drug bleomycin causes DNA damage and apoptosis in the lungs of mice within hours of endotracheal instillation followed by inflammation and fibrosis weeks later. The p53 tumor suppressor protein mediates cellular responses to DNA damage, including induction of apoptosis, but the effects of p53 activation in the various cell types of the lung during bleomycin-induced pulmonary fibrosis remain unclear. We show here that a transgene with a dominant-negative mutant form of human p53 expressed from the surfactant protein C promoter sensitizes mice to bleomycin-induced lung injury. The bleomycin-exposed transgenic animals display more severe lung pathology with associated collagen deposition and more pronounced lung eosinophilia than simultaneously exposed nontransgenic littermates. These observations suggest that compromising p53 function in the alveolar epithelium impairs recovery of the lung from bleomycin-induced injury.
Ghosh
Sushmita
S
Program in Lung Biology, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane/Xavier Center for Bioenvironmental Research and Tualne Cancer Center, New Orleans, LA 70118, USA.
Mendoza
Tamra
T
Ortiz
Luis A
LA
Hoyle
Gary W
GW
Fermin
Cesar D
CD
Brody
Arnold R
AR
Friedman
Mitchell
M
Morris
Gilbert F
GF
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D004249:DNA Damage; D003627:Data Interpretation, Statistical; D004804:Eosinophils; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009154:Mutation; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D012313:RNA / Q000032:analysis
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D012313:RNA