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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (508)	6/18/2001 7:53:10 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 1169

J Clin Invest, June 2001, Volume 107, Number 12, 1529-1536 Copyright ©2001 by the American Society for Clinical Investigation -------------------------------------------------------------------------------- Article Transient expression of IL-1ß induces acute lung injury and chronic repair leading to pulmonary fibrosis Martin Kolb1,2, Peter J. Margetts1, Daniel C. Anthony3, Fernando Pitossi4 and Jack Gauldie1 1 Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada 2 Medizinische Klinik, Julius-Maximilians-Universität Würzburg, Germany 3 CNS Inflammation Group, University of Southampton, United Kingdom 4 Gene Therapy Laboratory, Institute for Biochemical Research, Campomar Foundation, Buenos Aires, Argentina Address correspondence to: Jack Gauldie, Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. Phone: (905) 521-2100 ext. 76332; Fax: (905) 577-0198; E-mail: gauldie@mcmaster.ca. Received for publication February 20, 2001, and accepted in revised form May 8, 2001. IL-1ß is one of a family of proinflammatory cytokines thought to be involved in many acute and chronic diseases. Although it is considered to participate in wound repair, no major role has been attributed to IL-1ß in tissue fibrosis. We used adenoviral gene transfer to transiently overexpress IL-1ß in rat lungs after intratracheal administration. The high expression of IL-1ß in the first week after injection was accompanied by local increase of the proinflammatory cytokines IL-6 and TNF- and a vigorous acute inflammatory tissue response with evidence of tissue injury. The profibrotic cytokines PDGF and TGF-ß1 were increased in lung fluid samples 1 week after peak expression of IL-1ß. Although PDGF returned to baseline in the third week, TGF-ß1 showed increased concentrations in bronchoalveolar lavage fluid for up to 60 days. This was associated with severe progressive tissue fibrosis in the lung, as shown by the presence of myofibroblasts, fibroblast foci, and significant extracellular accumulations of collagen and fibronectin. These data directly demonstrate how acute tissue injury in the lung, initiated by a highly proinflammatory cytokine, IL-1ß, converts to progressive fibrotic changes. IL-1ß should be considered a valid target for therapeutic intervention in diseases associated with fibrosis and tissue remodeling.