Published online before print May 8, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.071021v1 172/6/1580    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hsu, E. Articles by Feghali-Bostwick, C. A. Search for Related Content PubMed PubMed Citation Articles by Hsu, E. Articles by Feghali-Bostwick, C. A.

(American Journal of Pathology. 2008;172:1580-1590.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071021

Insulin-Like Growth Factor-II Is Increased in Systemic Sclerosis-Associated Pulmonary Fibrosis and Contributes to the Fibrotic Process via Jun N-Terminal Kinase- and Phosphatidylinositol-3 Kinase-Dependent Pathways

Eileen Hsu^* and Carol A. Feghali-Bostwick^*

From the Department of Medicine,^* Division of Pulmonary, Allergy, and Critical Care Medicine, and the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Systemic sclerosis (SSc)-related pulmonary fibrosis, for which there are few effective therapies, is the most common cause of SSc-related mortality. We examined insulin-like growth factor (IGF)-II expression in explanted lung tissues from control and SSc patients to determine its role in the pathogenesis of fibrosis. IGF-II levels in vivo were detected using immunohistochemistry. Primary lung fibroblasts were cultured from lung tissues, and IGF-II mRNA was measured using reverse transcriptase-polymerase chain reaction. Western blot analysis measured extracellular matrix (ECM) production and phosphorylated signaling molecules. Immunostaining revealed increased IGF-II expression in fibroblastic foci of SSc lungs. Furthermore, primary SSc lung fibroblasts had a fourfold increase in IGF-II mRNA and a twofold increase in IGF-II protein compared with normal lung fibroblasts. IGF-II mRNA in SSc lung fibroblasts was expressed primarily from the P3 promoter of the IGF-II gene, and IGF-II induced both a dose- and time-dependent increase in collagen type I and fibronectin production. IGF-II triggered the activation of both phosphatidylinositol-3 kinase and Jun N-terminal kinase signaling cascades, the inhibition of which diminished IGF-II-induced ECM production. Our study demonstrates increased local IGF-II expression in SSc-associated pulmonary fibrosis both in vitro and in vivo as well as IGF-II-induced ECM production through both phosphatidylinositol-3 kinase- and Jun N-terminal kinase-dependent pathways. Our results provide novel insights into the role of IGF-II in the pathogenesis of SSc-associated pulmonary fibrosis.

This article has been cited by other articles:

				R. M. Strieter and B. Mehrad New Mechanisms of Pulmonary Fibrosis Chest, November 1, 2009; 136(5): 1364 - 1370. [Abstract] [Full Text] [PDF]

				H. Yasuoka, E. Hsu, X. D. Ruiz, R. A. Steinman, A. M.K. Choi, and C. A. Feghali-Bostwick The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms Am. J. Pathol., August 1, 2009; 175(2): 605 - 615. [Abstract] [Full Text] [PDF]