Source: Annual Congress 2003 - Molecular biology of chronic lung disease and lung cancer
Disease area: Airway diseases

Abstract

Introduction. Thioredoxin (Trx) is a ubiquitous intracellular protein which together with its associated enzyme thioredoxin reductase (TrxR) functions as a major determinant of cellular redox status. The thioredoxin system (Trx with TrxR) regulates intracellular proteins (eg p38 MAPK and NF-κB) by reducing critical cysteine residues. DNCB is an alkylating agent which potently inhibits TrxR. AW-464 is a novel quinone compound which binds to and inhibits intracellular Trx. We sought to establish the role of the Trx system in the inflammatory activation of human lung microvascular endothelial cells (ECs) by measuring cell surface expression of an adhesion molecule for neutrophils (ICAM-1) and release of a neutrophil chemoattractant (IL-8). Results. Pre-incubation of EC with DNCB reduced ICAM-1 expression and IL-8 release induced by LPS and IL-1β (both p<0.01) without affecting cell viability. Likewise AW-464 reduced ICAM-1 expression and IL-8 release induced by the same inflammatory mediators (both p<0.01) without affecting cell viability. These effects were associated with a reduction in respective mRNA transcription measured by RT-PCR. Adhesion of neutrophils to IL-1β-stimulated EC was reduced by pre-incubation of endothelial cells with either DNCB (p<0.05) and AW-464 (p<0.05) indicating functional significance of the above results. Discussion. These data suggest that the Trx system plays a critical role in the inflammatory activation of EC and thus pulmonary neutrophil recruitment, and may represent a novel therapeutic target in inflammatory lung disease.

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M. E. Callister, G. J. Quinlan, T. W. Evans, A. C. Burke-Gaffney (London, United Kingdom). The intracellular thioredoxin system mediates inflammatory activation of human lung microvascular endothelial cells. Eur Respir J 2003; 22: Suppl. 45, 1500

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