title: Transforming growth factor-alpha deficiency reduces pulmonary fibrosis in transgenic mice.
abstract: Despite evidence that implicates transforming growth factor-alpha (TGF-alpha) in the pathogenesis of acute lung injury, the contribution of TGF-alpha to the fibroproliferative response is unknown. To determine whether the development of pulmonary fibrosis depends on TGF-alpha, we induced lung injury with bleomycin in TGF-alpha null-mutation transgenic mice and wild-type mice. Lung hydroxyproline content was 1.3, 1.2, and 1.6 times greater in wild-genotype mice than in TGF-alpha-deficient animals at Days 10, 21, and 28, respectively, after a single intratracheal injection of bleomycin. At Days 7 and 10 after bleomycin treatment, lung total RNA content was 1.5 times greater in wild-genotype mice than in TGF-alpha-deficient animals. There was no significant difference between mice of the two genotypes in lung total DNA content or nuclear labeling indices after bleomycin administration. Wild-genotype mice had significantly higher lung fibrosis scores at Days 7 and 14 after bleomycin treatment than did TGF-alpha-deficient animals. There was no significant difference between TGF-alpha-deficient mice and wild-genotype mice in lung inflammation scores after bleomycin administration. To determine whether expression of other members of the epidermal growth factor (EGF) family is increased after bleomycin-induced injury, we measured lung EGF and heparin-binding- epidermal growth factor (HB-EGF) mRNA levels. Steady-state HB-EGF mRNA levels were 321% and 478% of control values in bleomycin-treated lungs at Days 7 and 10, respectively, but were not significantly different in TGF-alpha-deficient and in wild-genotype mice. EGF mRNA was not detected in normal or bleomycin-treated lungs of mice of either genotype. These results show that TGF-alpha contributes significantly to the pathogenesis of pulmonary fibrosis after bleomycin-induced injury, and that compensatory increases in other EGF family members do not occur in TGF-alpha-deficient mice.
authors.affiliation: Sections of Pulmonary and Critical Care Medicine and Pathology, Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA. dmadtes@fhcrc.org
authors.forename: D K
authors.initials: DK
authors.lastname: Madtes
authors.forename: A L
authors.initials: AL
authors.lastname: Elston
authors.forename: R C
authors.initials: RC
authors.lastname: Hackman
authors.forename: A R
authors.initials: AR
authors.lastname: Dunn
authors.forename: J G
authors.initials: JG
authors.lastname: Clark
mesh_terms: D000818:Animals; D001483:Base Sequence; D001761:Bleomycin / Q000633:toxicity; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004815:Epidermal Growth Factor / Q000235:genetics; D005838:Genotype; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000172:deficiency* / Q000235:genetics
chemical_list: D017931:DNA Primers; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D001761:Bleomycin; D004815:Epidermal Growth Factor; D012313:RNA; D003094:Collagen; D004247:DNA