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• W2083383152 abstract "EDITORIAL FOCUSIGF-I: mediator of fibrosis or carcinogenesis?Carol A. Feghali-BostwickCarol A. Feghali-BostwickDivision of Pulmonary, Allergy, and Critical Care Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PennsylvaniaPublished Online:01 May 2005https://doi.org/10.1152/ajplung.00012.2005MoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat in 1998, rosenfeld and oh (9) likened insulin-like growth factors (IGFs) in endocrinology to the elephant in the parable of the blind men and the elephant. Since then, IGFs, and especially IGF-I, may have well become the elephant in other disciplines as well due to the numerous effects IGFs can exert in different tissues and cells.IGF-I is a pleiotropic peptide with tissue- and cell-specific effects. IGF-I exhibits mitogenic, antiapoptotic, and profibrotic effects in a cell-specific manner. Secreted IGF binding proteins (IGFBPs) exert their effects in an IGF-dependent manner via modulation of IGF function and in an IGF-independent manner. Several cell types secrete IGF-I in health and disease. In normal lung tissues, IGF-I is detected in macrophages. However, in idiopathic pulmonary fibrosis, IGF-I is expressed by alveolar and interstitial macrophages, alveolar epithelial cells, and interstitial mesenchymal cells (1, 10), suggesting that IGF-I may contribute to the initiation or propagation of fibrosis.Interestingly, the report from Frankel et al., one of the current articles in focus (Ref. 3a, see p. L805 in this issue), provides evidence that overexpression of human IGF-I in alveolar type II epithelial cells of mice results in pulmonary adenomatous hyperplasia and spontaneous pulmonary adenoma formation in older animals. The authors also demonstrate that increased IGF-I production neither alters collagen content nor promotes the development of pulmonary fibrosis. Although IGF-I levels are increased in lung tissues of bleomycin-treated mice (7), Frankel et al. show that transgenic pulmonary expression of human IGF-I neither exacerbates nor ameliorates bleomycin-induced lung inflammation or fibrosis. The findings of the authors raise important questions about the role of IGF-I in fibrosis.Frankel et al. (3a) thoroughly discuss several possible explanations for the inability of IGF-I to cause lung fibrosis in their model: IGFBP-2 or -3 may be masking the effects of IGF in the bleomycin-treated mice; IGF-IB, rather than IGF-IA, may be responsible for fibrogenic activity; delivery of IGF-I into airways does not trigger lung fibrosis and thus expression of IGF-I in macrophages may be necessary; and fibrogenesis may well be a multigenic process. The absence of a fibrotic phenotype in transgenic mice may be due to several additional reasons. First, IGF-I may require cofactor(s), such as one or more IGFBPs, to be expressed concomitantly. Second, IGF-I localization to the appropriate compartment may be required. IGF-I induces collagen production and reduces collagenase levels in fibroblasts (4, 5). Thus, targeting IGF-I expression to mesenchymal cells may elicit a fibrotic phenotype, whereas epithelial secretion fails to induce fibrosis. Third, the levels of IGFBPs may not be sufficient for the development of phenotypic differences or the ratio of IGF to IGFBPs may not be optimal. Finally, the profibrotic effects of IGF-I may actually be a function of IGFBPs. This latter possibility is supported by our recent findings on IGFBP-3 and -5 in idiopathic pulmonary fibrosis (8). We have recently demonstrated that IGFBPs (IGFBP-3 and -5) are overexpressed in fibroblasts cultured from explanted lung tissues of idiopathic pulmonary fibrosis patients and that IGFBP-3 and -5 induce a profibrotic phenotype in normal primary adult lung fibroblasts (8).The tumor growth-promoting properties of IGF-I are likely due to its mitogenic and antiapoptotic effects. The findings of Frankel et al. (3a) are supported by reports of tumors developing in mice overexpressing IGF-I in different organs. In transgenic mice with targeted expression of IGF-I in the mammary glands, 50% of transgenics developed adenocarcinomas at 23 mo of age (6). Targeting of IGF-I to basal epithelial cells of the prostate resulted in hyperplasia at 2–3 mo of age and a 50% incidence of well-differentiated adenocarcinomas at >6 mo of age (3). Expression of IGF-I in interfollicular epidermis increased the propensity for the development of papillomas (2). Together, these studies confirm the role of IGF-I as a tumor progression factor in multistage carcinogenesis. The findings of Frankel et al. emphasize the complexity of the IGF system and raise valid concerns about the risks of growth hormone (an inducer of IGF-I) and/or IGF-I administration in adults. Further studies are necessary to determine the role, if any, of IGF-I in the development of pulmonary fibrosis.REFERENCES1 Aston C, Jagirdir J, Lee TC, Hur T, Hintz RL, and Rom WN. Enhanced insulin-like growth factor molecules in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 151: 1597–1603, 1995.Crossref | PubMed | ISI | Google Scholar2 Bol DK, Kiguchi K, Gimenez-Conti I, Rupp T, and DiGiovanni J. Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice. Oncogene 14: 1725–1734, 1997.Crossref | PubMed | ISI | Google Scholar3 DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, Moats S, Ramirez A, Jorcano J, and Conti C. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA 97: 3455–3460, 2000.Crossref | PubMed | ISI | Google Scholar3a Frankel SK, Moats-Staats BM, Cool CD, Wynes MW, Stiles AD, and Riches DWH. Human insulin-like growth factor-IA expression in transgenic mice promotes adenomatous hyperplasia but not pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 288: L805–L812, 2005.Link | ISI | Google Scholar4 Ghahary A, Shen YJ, Nedelec B, Wang R, Scott PG, and Tredget EE. Collagenase production is lower in post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-like growth factor-1. J Invest Dermatol 106: 476–481, 1996.Crossref | PubMed | ISI | Google Scholar5 Goldstein RH, Poliks CF, Pilch PF, Smith BD, and Fine A. Stimulation of collagen formation by insulin and insulin-like growth factor I in cultures of human lung fibroblasts. Endocrinology 124: 964–970, 1989.Crossref | PubMed | ISI | Google Scholar6 Hadsell DL and Abdel-Fattah G. Regulation of cell apoptosis by insulin-like growth factor I. Adv Exp Med Biol 501: 79–85, 2001.Crossref | PubMed | ISI | Google Scholar7 Maeda A, Hiyama K, Yamakido H, Ishioka S, and Yamakido M. Increased expression of platelet-derived growth factor A and insulin-like growth factor-I in BAL cells during the development of bleomycin-induced pulmonary fibrosis in mice. Chest 109: 780–786, 1996.Crossref | PubMed | ISI | Google Scholar8 Pilewski JM, Liu L, Henry AC, Knauer AV, and Feghali-Bostwick CA. Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition. Am J Pathol. In press.Google Scholar9 Rosenfeld RG and Oh Y. The blind men and the elephant—a parable for the study of insulin-like growth factor binding proteins. Endocrinology 139: 5–7, 1998.Crossref | PubMed | ISI | Google Scholar10 Uh ST, Inoue Y, King TE Jr, Chan ED, Newman LS, and Riches DWH. Morphometric analysis of insulin-like growth factor-I localization in lung tissues of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 158: 1626–1635, 1998.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: C. A. Feghali-Bostwick, Division of Pulmonary, Allergy, and Critical Care Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Univ. of Pittsburgh 628 NW MUH, 3459 Fifth Ave., Pittsburgh, PA 15213 (E-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited BySmall intestinal neuroendocrine tumours and fibrosis: an entangled conundrumEndocrine-Related Cancer, Vol. 25, No. 3Hallmarks of the ageing lung5 February 2015 | European Respiratory Journal, Vol. 45, No. 3Effects of low-level laser therapy on ROS homeostasis and expression of IGF-1 and TGF-β1 in skeletal muscle during the repair process20 June 2012 | Lasers in Medical Science, Vol. 28, No. 3IL-13 Signaling via IL-13Rα2 Induces Major Downstream Fibrogenic Factors Mediating Fibrosis in Chronic TNBS ColitisGastroenterology, Vol. 135, No. 6Is there a relationship between ELF free-IGF-1 levels and fibrotic process enhancement characterizing CLD development in neutropenic premature babies?1 January 2006 | Pediatric Pulmonology, Vol. 41, No. 3Authors' reply1 January 2006 | Pediatric Pulmonology, Vol. 41, No. 3 More from this issue > Volume 288Issue 5May 2005Pages L803-L804 Copyright & PermissionsCopyright © 2005 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00012.2005PubMed15821020History Published online 1 May 2005 Published in print 1 May 2005 Metrics" @default.
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