© 2003 American Thoracic Society
Redox Active Agents in Inflammatory Lung InjuryNational Jewish Medical and Research Center Denver, Colorado The lung is unique in having large, delicate epithelial surfaces exposed to external sources of oxidative stress. The typical adult inhales 10,000 to 20,000 liters of air per day containing a wide variety of oxidants, particulates and infectious agents. Both the airways and the alveolar septa are well designed to handle normal levels of oxidative stress resulting from environmental exposures. The first level of antioxidant defense is in the lung lining fluids and extracellular spaces. These spaces are uniquely rich in antioxidants, particularly the extracellular form of superoxide dismutase (1) that is more highly expressed in lung airways than in most other organs or tissues (2). In addition, levels of glutathione in lung extracellular fluids are 100-fold greater than that in plasma (3). Lung intracellular spaces are protected against oxidative stress by a variety of enzymatic and nonenzymatic antioxidants, many with highly specific intracellular locations such as the manganese superoxide dismutase in mitochondria (4) or catalase in peroxisomes (5). Catalase and glutathione peroxidase are generally considered to be the dominant hydrogen peroxide scavenging enzymes in the lung. In addition to these classic antioxidant enzymes, the lung contains a number of other proteins that have the capacity to consume hydrogen peroxide (6, 7). These include thioredoxin–thioreductase systems, thioredoxin peroxidases (peroxiredoxins) and the glutaredoxins (8). In the lung these enzymes are primarily expressed in the airways and in macrophages (9, 10). The thioredoxins are a recently described class of proteins found in virtually all cells and are redox active due to two cysteines at their active site. These proteins can act as electron donors for a number of reactions and have been shown to play a role in DNA synthesis by donating electrons to ribonucleotide reductase (11). Reduced thioredoxin is regenerated by accepting electrons from NADPH through thioredoxin reductase. Under normal physiologic conditions one would not expect thioredoxins to play a substantial role in regulating the cellular redox state. The high concentrations and high rate constants of enzymes like the superoxide dismutases and glutathione peroxidase make it unlikely that thioredoxins would effectively compete for reactive oxygen species under normal conditions. It is also physiologically inefficient for cells to use thioredoxin as a primary scavenger for reactive oxygen species since the reaction consumes reducing equivalents (NADPH) needed for multiple other critical cell metabolic pathways. The superoxide dismutases and catalase, in contrast, efficiently scavenge superoxide and hydrogen peroxide with no net consumption of other cell resources. While knockout studies of the classic antioxidant enzymes have shown the resultant animals to have increased sensitivity to oxidative stress, such knockout studies have not been reported for the thioredoxins. Under conditions of high oxidative stress multiple antioxidant mechanisms, including the thioredoxins, may become physiologically important. In addition, if a redox active protein such as thioredoxin is pharmacologically or genetically augmented to supraphysiological levels, it could become a dominant antioxidant pathway. In this issue of the Journal (pp. 1075–1083), Hoshino and coworkers (12) show that overexpression of thioredoxin or administration of recombinant human thioredoxin give substantial protection against both inflammatory cytokine- (interleukin-18/interleukin-2) and bleomycin-induced lung injury and fibrosis. Both methods of enhancing lung thioredoxin levels reduce inflammatory cell infiltration and the magnitude and progression of lung injury. Similar results using other antioxidants have been previously achieved in similar models of lung injury (5, 8, 13, 14). The study of Hoshino and coworkers (12), however, raises a number of interesting questions and possible opportunities. It is of interest that both transgenic overexpression of thioredoxin and intraperitoneal injection of recombinant human thioredoxin gave similar results. It should not be assumed that the 12-kD recombinant human protein given systemically will distribute the same as the intracellular, genetically overexpressed protein. It is not unlikely that these two models of thioredoxin administration result in different distributions of the protein with one exclusively overexpressed intracellularly and the other with a large extracellular distribution. The fact that both approaches give substantial protection in these models of lung inflammation suggests that the inflammatory process is mediated by redox stress and/or redox-mediated signaling in both the intracellular and extracellular compartments and that both are critical to the ultimate inflammatory amplification. This conclusion is supported by prior findings with other antioxidants that are selectively increased in lung intracellular or extracellular spaces and that provide protection against inflammatory lung reactions (8, 13, 15). Another tantalizing suggestion supported by the findings of Hoshino and coworkers (12) is that high levels of thioredoxin may block inflammation by a pathway involving reductive biosynthesis rather than reductive scavenging of hydrogen peroxide. Thioredoxin can potentially function as an electron donor in a substantial number of critical metabolic pathways and thereby downregulate inflammatory responses. These include regulation of collagen synthesis (12), inflammatory cell chemotaxis (16), and DNA synthesis (11). Most or all of these processes are likely modulated by thioredoxin acting as an electron donor but may or may not involve electron transfer steps involving partially reduced oxygen species. Thioredoxin modified at its redox active site has been shown to lose both antioxidant and antichemotactic effects (15). This does not, however, prove whether or not overexpression of thioredoxin is acting to reduce inflammation primarily by an antioxidant pathway since electron transfer to any species could be inhibited by modifying the active site of thioredoxin. Experiments using thioredoxin in combination with other powerful antioxidants are necessary to see whether thioredoxin has critical, novel functions as an antiinflammatory that go beyond scavenging reactive oxygen species. Both the reductive biosynthesis and reductive scavenging actions of thioredoxins need to be more fully elucidated and will likely give new insight into the development of novel, specific therapeutic strategies to control inflammatory lung injury. FOOTNOTES Conflict of Interest Statement: J.D.C. is one of the founders of a biotech firm, Incara Pharmaceuticals, Inc., that is focused on developing small molecular weight antioxidant mimetics. These products are not discussed in the editorial. REFERENCES
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