Published ahead of print on June 19, 2003, doi:10.1164/rccm.200209-982OC Am. J. Respir. Crit. Care Med., Volume 168, Number 9, November 2003, 1075-1083 A more recent version of this article appeared on November 1, 2003
Submitted on September 5, 2002 Redox-Active Protein Thioredoxin Prevents Proinflammatory Cytokine- or Bleomycin-Induced Lung InjuryHajime Nakamura1,1 Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan, 2 Internal Medicine 1, Kurume University, Kurume, Fukuoka, Japan, 3 Pathology, Kurume University, Kurume, Fukuoka, Japan, 4 Laboratory of Experimental Immunology, DBS, National Cancer Institute at Frederick, Frederick, MD, USA * To whom correspondence should be addressed. E-mail: hoshino{at}med.kurume-u.ac.jp.
Thioredoxin (TRX) is a multifunctional redox (reduction/oxidation)-active protein that scavenges reactive oxygen species by itself or together with TRX-dependent peroxiredoxin. TRX also has chemotaxis-modulating functions and suppresses leukocyte infiltration into sites of inflammation. Leukocyte infiltration and oxidative stress may be involved in the pathogenesis of several diseases, including interstitial lung diseases (ILD). We examined the effects of TRX in two mouse models of human ILD. Recently, we established a new mouse model for human ILD in which daily administration of proinflammatory cytokine IL-18 with IL-2 induces lethal lung injury accompanied by acute interstitial inflammatory responses. Administration of recombinant TRX suppressed IL-18/IL-2-induced interstitial infiltration of cells and prevented death and lung tissue damage. TRX-transgenic mice also showed resistance to lethal lung injury caused by IL-18/IL-2. Administration of bleomycin induces the infiltration of polymorphonuclear and mononuclear leukocytes in the pulmonary interstitium, followed by progressive fibrosis. Wild type mice given recombinant TRX treatment and TRX-transgenic mice demonstrated a decrease in bleomycin-induced cellular infiltrates and fibrotic changes in the lung tissue. These results suggest TRX modulates pulmonary inflammatory responses and acts to prevent lung injury. TRX may have clinical benefits in human ILD, including lung fibrosis, for which no effective therapeutic strategy currently exists. Key words: thioredoxin (TRX), redox, interstitial lung diseases, cytokine, bleomycin
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