Lung pathology in platelet-derived growth factor transgenic mice: effects of genetic background and fibrogenic agents.
We previously developed transgenic mice expressing human platelet-derived growth factor B chain (PDGF-B) from the lung-specific surfactant protein C (SPC) promoter. These mice developed enlarged airspaces, inflammation, and fibrosis of varying severity. In the present study we examined potential causes of this phenotypic variation and tested whether constitutive PDGF-B expression exacerbated fibrosis induced by bleomycin and silica. The SPC-PDGFB transgene construct was modified by replacement of the PDGF-B 3' UTR, which contains motifs known to mediate instability in other cytokine genes, with SV40 sequences containing an intron and polyadenylation signal. This modification resulted in an increase in the efficiency with which the construct was expressed, but no difference in lung pathology was observed compared to the original construct. Backcrossing of mice carrying the original SPC-PDGFB construct to C57BL/6 and SJL inbred strains resulted in a more severe phenotype in SJL-bred mice compared to C57BL/6-bred mice after 4 generations. To determine whether SPC-PDGFB transgenic mice had increased susceptibility to fibrogenic agents, the mice were treated with bleomycin or silica. No significant differences were detected in lung weight, hydroxyproline content, or histopathologic changes between transgenic and wild-type mice after bleomycin or silica treatment. These results demonstrate that the amount of PDGF-BB produced in wild-type mice is not a limiting factor in the development of bleomycin- or silica-induced pulmonary fibrosis.
Li
Jian
J
Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine and Interdisciplinary Graduate Program in Molecular and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Ortiz
Luis A
LA
Hoyle
Gary W
GW
D000818:Animals; D001761:Bleomycin; D004357:Drug Synergism; D006801:Humans; D008168:Lung / Q000473:pathology / Q000502:physiology; D008171:Lung Diseases / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011510:Proteolipids / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology; D011663:Pulmonary Surfactants / Q000235:genetics; D012822:Silicon Dioxide; D013539:Simian virus 40 / Q000235:genetics
D010982:Platelet-Derived Growth Factor; D011510:Proteolipids; D020574:Proto-Oncogene Proteins c-sis; D011663:Pulmonary Surfactants; D001761:Bleomycin; D012822:Silicon Dioxide