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INVITED EDITORIAL
Department of Physiology
University of Kentucky
Lexington, Kentucky
e-mail: michael.reid{at}uky.edu
The truth is balance. However the opposite of truth, which is unbalance, may not be a lie. Susan Sontag, US author and critic (1933–xxxx).
If balance is truth, homeostasis is its biological expression. Students learn the importance of homeostatic regulation in the first few lectures of any physiology course. Research scientists may spend their entire careers defining the mechanisms that underlie homeostasis. However, despite the ubiquity of this concept, our traditional roster of regulated variables (temperature, pH, osmotic pressure, and so on) is not immutable. It may need expanding. Redox homeostasis is a new kid on the block and appears to be a serious player.
Free radicals and their derivatives are continually generated by eukaryotic cells and are buffered by an array of endogenous antioxidants. These two processes represent the yin and yang of redox biology, the ongoing push and pull by which electron flux proceeds. This electromotive pas de deux determines redox status and appears to be closely regulated in a variety of cell types (2). Redox homeostasis remains a novel concept. It is all but invisible in most physiology textbooks. However, the balance between free radical production and antioxidant buffering, illustrated in Fig 1, is fundamental to our discipline as are moments of subtle "unbalance," the transient shifts in redox state that regulate physiological processes. Examples include penile erection, muscle fatigue, immune competence, airway resistance, and blood pressure; at the cellular level, development, growth, metabolism, and adaptation are also modulated via redox mechanisms (2).
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To better define cellular mechanism, Falk and colleagues (3) tested the impact of unloading on redox homeostasis in muscle fibers. The investigators found that muscle fibers respond to unloading by increasing cytosolic oxidant activity. The rise in oxidant activity is accompanied by a drop in total antioxidant capacity. Tissue levels of several individual antioxidants showed similar decreases. Total glutathione was diminished in unloaded muscle as were two antioxidant enzymes, glutathione peroxidase and CuZn-superoxide dismutase. However, antioxidants did not undergo a simple across-the-board drop. Some antioxidant enzymes were unaffected by unloading (catalase, Mn-superoxide dismutase, thioredoxin reductase-1), whereas another increased markedly (heme oxygenase-1). mRNA data suggest that these changes were regulated at the transcriptional level, at least in part. Muscle fibers adjusted their antioxidant portfolio by selectively upregulating expression of some genes and not others.
One strength of the study by Falk et al. (3) is its integrative approach to this adaptive response. Changes in redox homeostasis were assessed at the functional level using global indexes of both oxidant activity and antioxidant capacity. This strategy enabled the investigators to define net changes in redox processes that have multiple inputs and outputs. The use of global assays was essential because the sources and sinks of muscle-derived oxidants are interdependent and are not fully defined. It is not possible to monitor each individually. Plus, any individual marker may not accurately represent overall changes. This is nicely illustrated by the divergent responses of individual antioxidants documented by Falk et al.
Another strength of the report by Falk and associates (3) is their utilization of the 2',7'-dichlorofluorescin (DCFH) oxidation assay. Two common pitfalls were avoided. The first relates to experimental design. Homogenization of tissue or cultured cells before the assay profoundly alters oxidant regulation by disrupting cell compartmentalization, cofactor availability, and membrane potential. Accordingly, subsequent measurements of DCFH oxidation are difficult to interpret. It is rather like using an oxygen-sensitive dye to measure oxygen tension in mitochondria that have been homogenized. One may get a signal, but its relevance to the intact system is enigmatic. Falk and associates dodged this bullet by studying isolated muscle tissue under near-physiological conditions. The DCFH-loaded fibers remained intact, and oxidant regulation was preserved. A second potential pitfall is interpretation of the assay. Contrary to some assertions, DCFH is not selectively oxidized by hydrogen peroxide or other reactive oxygen species. The dye is delightfully promiscuous. It can be oxidized by nitric oxide derivatives, lipid hydroperoxides, direct electron exchange with oxidoreductases, and other redox reactions (4). Falk and associates took advantage of this property, using DCFH to assess overall oxidant activity. This end point could not have been measured using a more selective assay that detects specific oxidant species.
There are unavoidable limitations to the study of Falk and associates (3). For example, the rise in oxidant activity was consistent with the observed drop in antioxidant capacity. The latter could have caused the former, a simple and appealing thesis. However, this neglects the possibility that oxidant production was altered in response to unloading. An unrecognized change in overall synthesis rate, either an increase or a decrease, could have modulated the observed increase in net oxidant activity. Any influence of altered synthesis cannot be evaluated, however; overall rates of oxidant production are not measurable in cellular systems. This conundrum illustrates the limitations that still exist in redox biology. Another example? There is no standard unit for measuring "redox state" or "oxidant activity" at the whole cell level. Imagine trying to study acid-base physiology without being able to measure pH! Such scientific gaps pose considerable challenges for investigators in the field.
Despite these challenges, the rationale for pushing ahead is compelling. Redox biology remains a young field, largely unexplored. It is clear that free radicals and their derivatives play key roles in signal transduction, adaptation, and cell-cell communication, but we still have much to learn about their regulation. Such knowledge will provide a springboard for studies of oxidant-mediated pathology. Free radicals work mischief in conditions as varied as aging and acquired immunodeficiency syndrome, cancer and heart failure, and rheumatoid arthritis and emphysema (2). Better understanding of oxidant regulation will help identify rational therapies for these diseases, reversing the redox imbalances, and promoting homeostasis.
In truth, after all, homeostasis is about balance.
GRANTS
Our research in this field is supported by the National Institutes of Health (HL-45721) and the National Space Biomedical Research Institute (through NASA NCC 9-58).
ACKNOWLEDGMENTS
The author thanks Dr. Jennifer Moylan for creating Figure 1.
REFERENCES
This article has been cited by other articles:
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  E. Spinelli Oliveira, J. T. Hancock, M. Hermes-Lima, D. A. Isola, M. Ochs, J. Yu, and D. Wilhem Filho Implications of dealing with airborne substances and reactive oxygen species: what mammalian lungs, animals, and plants have to say? Integr. Comp. Biol., October 1, 2007; 47(4): 578 - 591. [Abstract] [Full Text] [PDF]
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