Redox signaling and oxidative stress in wound healing responses

Redox

Reduction-Oxidation (Redox) Reactions and Signaling at Wound Sites: Implications for Healing

Wounds are a natural if not especially pleasant feature of life. All living organisms will experience some sort of unwanted damage to their outer layers potentially due to no more than some wind blown debris, or to their inner workings through the inhalation or uptake of some microscopic infectious agent. In order to combat such instances, all organisms have developed certain methods for reacting to wounds and infections that include the development of special cells whose sole purpose is the destruction of foreign cells, and others that are meant to promote healing and to reinforce protection by providing necessary chemical enhancements. Though the mechanisms by which these processes are carried out are still a matter of a great deal of research and debate, redox signaling is believed to play a major role in the identification of target areas for these cells and the triggering of other biological reactions.

Redox signaling is essentially the triggering of a cascade of reactions to identify wound and/or infection areas and promote healing/infection destruction at the site (Forman et. al., 2010; Forman & Dickinson, 2003; Forman & Torres 2001). This type of redox signaling acts fundamentally like a chemical beacon, causing chemical chain reactions that "notify" or signal for the triggering of other biological reactions related to a healing of the identified or signaling area. Though only discovered relatively recently, knowledge in the area has grown immensely and it appears the redox signaling is a major physiological process (Forman et. al., 2010).

Redox signaling occurs because of redox reactions, those involving a change in the oxidation number of various molecules in a chemical reaction and that drive many aspects of metabolism and thus all cellular activities (Sies & Dimmeler, 2006). It is through redox reactions that many different necessary covalent bonds are formed from organic elements, and by which organic compounds are broken down into useful components by living organisms and then (most often) reconstituted as waste products through later processes. From this, it is clear that redox reactions are highly important in a wide variety of biological functions at a very basic level, but there are also more subtle and more complex ways in which redox reactions allow for the continuing functionality of individual cells and organisms as a whole.

Despite the usefulness of redox reactions and redox signaling in biological processes generally and wound response specifically, these processes must be carefully controlled or else they can actually become harmful in and of themselves. A failure to properly regulate redox signaling can create an overabundance of compounds like peroxides that, while themselves somewhat useful in fighting of infectious agents, are harmful to all components of living tissue (Chiarugi, 2008). This is a state known as oxidative stress, where the ongoing reodx reactions cannot be controlled or mitigated by the other biological functions and so the body is left without the necessary resources to truly promote healing (Chiarugi, 2008). Controlling the rate of redox signaling by controlling oxygen levels has been recommended to promote healing and eliminate oxidative stress (Sen 2008).

Redox Reaction Enzymes

There are a number of complex and highly specific chemical reactions that take place between various enzymes during redox signaling and the creation of reactive oxygen species that prove harmful when their numbers are not properly controlled. One study found that the enzyme glutathione was essential in controlling the rate of redox signaling and reactions, and that insufficient levels of this commonly produced enzyme were positively associated with a lack of healing in specific wounds and negatively associated with lifespan in diabetic mice (Mudge et. al., 2002). By donating an electron to reactive oxygen species, glutathione can essentially "deactivate" them and reduce further signaling, drawing this mechanism of the healing response to a close when necessary (Mudge et. al., 2002).

Several other highly important enzymes in the redox signaling process are found in the NADPH oxidases, which in combination with other compounds and in the correct situations can result in the ongoing synthesis of H2O2, or hydrogen peroxide (Forman et. al., 2010). Though this peroxide is believed to be a secondary messenger in the redox signaling process, causing a cascade reaction that ultimately draws the redox signaling to a close, peroxides are also one form of the potentially dangerous reactive oxygen species and their unregulated promotion is dangerous to healing and has also been indicated as a possible link to cancer growth (Forman et. al., 2010; Chiarugi, 2008). Though NADPH is still not firmly placed in the chain of redox signaling reactions, it seems likely that it plays a major role.

Further study into the role and influences of glutathione has also found some potential reasons for its failure to properly fulfill its function and deactivate the production of peroxides. Different environmental enzymes and potential toxins can affect the metabolism of a glutathione component known as GSH, and this can both lead to problems in the synthesis of glutathione and trigger the use of varying signaling pathways that lead to interruptions of the cascade reactions that are supposed to occurred during a normal and non-toxified healing response (Forman & Dickinson, 2003). Specifically, the presence of nitric oxide (NO) has been found to be a major inhibitor to the proper metabolism of GSH and triggers signaling pathways for the ongoing production of peroxides, causing harm from both ends by producing the reactive oxygen species and inhibiting their control (Forman & Dickinson, 2003).

Regulation of Redox-Related Enzymes

Both NADPH and glutathione obviously play major roles in the control of redox signaling, and there are other enzymes that can play a major role in regulating these enzymes. Rac-1 is a compound in the Rho family (Ras superfamily) that binds to several sites on the NADPH molecule and renders it effectively inoperable in its redox signaling functions (Chiarugi, 2008). The positive correlation that has been observed to exist between Rac-1 presence and cell survival is a major indicator that the substance is effective at reducing peroxide levels so that they are no longer fatal to cells by disabling the signaling properties of NADPH (Chiarugi, 2008). Other regulatory mechanisms are still under scrutiny.

Conclusion

Research into the complexities of redox signaling in wound response and its implications for the healing process remains ongoing, and many current findings are still the product of a great deal of conjecture. Still, enormous advancements have been made in this area of biochemical knowledge. As redox signaling and other aspects of wound healing are better understood, more effective methods for dealing with infections and slow healing times can be developed, and many in the world will truly experience better living through chemistry in a very direct way.