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J Clin Invest. 1994 Apr; 93(4): 1691–1699.
PMCID: PMC294218

Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice.


Increased production of EGF or TGF-alpha by the respiratory epithelial cells has been associated with the pathogenesis of various forms of lung injury. Growth factors and cytokines are thought to act locally, via paracrine and autocrine mechanisms, to stimulate cell proliferation and matrix deposition by interstitial lung cells resulting in pulmonary fibrosis. To test whether TGF-alpha mediates pulmonary fibrotic responses, we have generated transgenic mice expressing human TGF-alpha under control of regulatory regions of the human surfactant protein C (SP-C) gene. Human TGF-alpha mRNA was expressed in pulmonary epithelial cells in the lungs of the transgenic mice. Adult mice bearing the SP-C-TGF-alpha transgene developed severe pulmonary fibrosis. Fibrotic lesions were observed in peribronchial, peribronchiolar, and perivascular regions, as well as subjacent to pleural surfaces. Lesions consisted of fibrous tissue that included groups of epithelial cells expressing endogenous SP-C mRNA, consistent with their identification as distal respiratory epithelial cells. Peripheral fibrotic regions consisted of thickened pleura associated with extensive collagen deposition. Alveolar architecture was disrupted in the transgenic mice with loss of alveoli in the lung parenchyma. Pulmonary epithelial cell expression of TGF-alpha in transgenic mice disrupts alveolar morphogenesis and produces fibrotic lesions mediated by paracrine signaling between respiratory epithelial and interstitial cells of the lung.

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Selected References

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  • Carpenter G, Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193–216. [PubMed]
  • Das M, Fox CF. Molecular mechanism of mitogen action: processing of receptor induced by epidermal growth factor. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2644–2648. [PMC free article] [PubMed]
  • Cohen S, Carpenter G. Human epidermal growth factor: isolation and chemical and biological properties. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1317–1321. [PMC free article] [PubMed]
  • Marquardt H, Hunkapiller MW, Hood LE, Todaro GJ. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science. 1984 Mar 9;223(4640):1079–1082. [PubMed]
  • Derynck R, Roberts AB, Winkler ME, Chen EY, Goeddel DV. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. [PubMed]
  • Fox CF, Das M. Internalization and processing of the EGF receptor in the induction of DNA synthesis in cultured fibroblasts: the endocytic activation hypothesis. J Supramol Struct. 1979;10(2):199–214. [PubMed]
  • Reynolds FH, Jr, Todaro GJ, Fryling C, Stephenson JR. Human transforming growth factors induce tyrosine phosphorylation of EGF receptors. Nature. 1981 Jul 16;292(5820):259–262. [PubMed]
  • Warburton D, Seth R, Shum L, Horcher PG, Hall FL, Werb Z, Slavkin HC. Epigenetic role of epidermal growth factor expression and signalling in embryonic mouse lung morphogenesis. Dev Biol. 1992 Jan;149(1):123–133. [PubMed]
  • Stahlman MT, Orth DN, Gray ME. Immunocytochemical localization of epidermal growth factor in the developing human respiratory system and in acute and chronic lung disease in the neonate. Lab Invest. 1989 Apr;60(4):539–547. [PubMed]
  • Raaberg L, Nexø E, Damsgaard Mikkelsen J, Seier Poulsen S. Immunohistochemical localisation and developmental aspects of epidermal growth factor in the rat. Histochemistry. 1988;89(4):351–356. [PubMed]
  • Raaberg L, Poulsen SS, Nexø E. Epidermal growth factor in the rat lung. Histochemistry. 1991;95(5):471–475. [PubMed]
  • Sannes PL, Burch KK, Khosla J. Immunohistochemical localization of epidermal growth factor and acidic and basic fibroblast growth factors in postnatal developing and adult rat lungs. Am J Respir Cell Mol Biol. 1992 Aug;7(2):230–237. [PubMed]
  • Strandjord TP, Clark JG, Hodson WA, Schmidt RA, Madtes DK. Expression of transforming growth factor-alpha in mid-gestation human fetal lung. Am J Respir Cell Mol Biol. 1993 Mar;8(3):266–272. [PubMed]
  • Lee DC, Rochford R, Todaro GJ, Villarreal LP. Developmental expression of rat transforming growth factor-alpha mRNA. Mol Cell Biol. 1985 Dec;5(12):3644–3646. [PMC free article] [PubMed]
  • Kubiak J, Mitra MM, Steve AR, Hunt JD, Davies P, Pitt BR. Transforming growth factor-alpha gene expression in late-gestation fetal rat lung. Pediatr Res. 1992 Mar;31(3):286–290. [PubMed]
  • Johnson MD, Gray ME, Carpenter G, Pepinsky RB, Sundell H, Stahlman MT. Ontogeny of epidermal growth factor receptor/kinase and of lipocortin-1 in the ovine lung. Pediatr Res. 1989 May;25(5):535–541. [PubMed]
  • Snead ML, Luo W, Oliver P, Nakamura M, Don-Wheeler G, Bessem C, Bell GI, Rall LB, Slavkin HC. Localization of epidermal growth factor precursor in tooth and lung during embryonic mouse development. Dev Biol. 1989 Aug;134(2):420–429. [PubMed]
  • Ganser GL, Stricklin GP, Matrisian LM. EGF and TGF alpha influence in vitro lung development by the induction of matrix-degrading metalloproteinases. Int J Dev Biol. 1991 Dec;35(4):453–461. [PubMed]
  • Sundell HW, Gray ME, Serenius FS, Escobedo MB, Stahlman MT. Effects of epidermal growth factor on lung maturation in fetal lambs. Am J Pathol. 1980 Sep;100(3):707–726. [PMC free article] [PubMed]
  • Catterton WZ, Escobedo MB, Sexson WR, Gray ME, Sundell HW, Stahlman MT. Effect of epidermal growth factor on lung maturation in fetal rabbits. Pediatr Res. 1979 Feb;13(2):104–108. [PubMed]
  • Plopper CG, St George JA, Read LC, Nishio SJ, Weir AJ, Edwards L, Tarantal AF, Pinkerton KE, Merritt TA, Whitsett JA, et al. Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF. Am J Physiol. 1992 Mar;262(3 Pt 1):L313–L321. [PubMed]
  • Whitsett JA, Weaver TE, Lieberman MA, Clark JC, Daugherty C. Differential effects of epidermal growth factor and transforming growth factor-beta on synthesis of Mr = 35,000 surfactant-associated protein in fetal lung. J Biol Chem. 1987 Jun 5;262(16):7908–7913. [PubMed]
  • Madtes DK, Raines EW, Sakariassen KS, Assoian RK, Sporn MB, Bell GI, Ross R. Induction of transforming growth factor-alpha in activated human alveolar macrophages. Cell. 1988 Apr 22;53(2):285–293. [PubMed]
  • Wispé JR, Warner BB, Clark JC, Dey CR, Neuman J, Glasser SW, Crapo JD, Chang LY, Whitsett JA. Human Mn-superoxide dismutase in pulmonary epithelial cells of transgenic mice confers protection from oxygen injury. J Biol Chem. 1992 Nov 25;267(33):23937–23941. [PubMed]
  • Wert SE, Glasser SW, Korfhagen TR, Whitsett JA. Transcriptional elements from the human SP-C gene direct expression in the primordial respiratory epithelium of transgenic mice. Dev Biol. 1993 Apr;156(2):426–443. [PubMed]
  • Brinster RL, Allen JM, Behringer RR, Gelinas RE, Palmiter RD. Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci U S A. 1988 Feb;85(3):836–840. [PMC free article] [PubMed]
  • Bruce MC, Schuyler M, Martin RJ, Starcher BC, Tomashefski JF, Jr, Wedig KE. Risk factors for the degradation of lung elastic fibers in the ventilated neonate. Implications for impaired lung development in bronchopulmonary dysplasia. Am Rev Respir Dis. 1992 Jul;146(1):204–212. [PubMed]
  • Whitsett JA, Dey CR, Stripp BR, Wikenheiser KA, Clark JC, Wert SE, Gregory RJ, Smith AE, Cohn JA, Wilson JM, et al. Human cystic fibrosis transmembrane conductance regulator directed to respiratory epithelial cells of transgenic mice. Nat Genet. 1992 Sep;2(1):13–20. [PubMed]
  • Wikenheiser KA, Clark JC, Linnoila RI, Stahlman MT, Whitsett JA. Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice. Cancer Res. 1992 Oct 1;52(19):5342–5352. [PubMed]
  • Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990 Jun 15;61(6):1137–1146. [PubMed]
  • Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990 Jun 15;61(6):1121–1135. [PubMed]
  • Glasser SW, Korfhagen TR, Bruno MD, Dey C, Whitsett JA. Structure and expression of the pulmonary surfactant protein SP-C gene in the mouse. J Biol Chem. 1990 Dec 15;265(35):21986–21991. [PubMed]

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