The natural immune responses that are elicited after an insult to the body as a result of injury or infection from a pathogen, is both rapid and powerful. Initially inflammatory cells are mobilized to the site of the trauma. The predominant cell types that are recruited are macrophages and neutrophils that release free radical reactive oxygen and nitrogen species (RONS) that are lethal to invading organisms. However, these chemical moieties are so powerful that they can also kill and mutate the surrounding normal tissue. Although there are naturally induced anti-inflammatory responses that are also initiated, the optimum balance is difficult to achieve. In some diseases, such as ulcerative colitis and rheumatoid arthritis, such anti-inflammatory responses are unavailable. Therefore, for this reason medical intervention in the form of medication becomes appropriate.
There are, of course, many different anti-inflammatory medications currently available. Recently Dr. Torkild Visnes and his colleagues from the Karolinska Institutet in Sweden in collaboration with the University of Texas Medical Branch, Uppsala University and Stockholm University have discovered a new methodology for enhancing the anti-inflammatory response. In order to understand the investigator’s approach, we need to examine the rationale for this research in greater detail.
Normally the enzyme 8-oxyguanine DNA glycosylase 1 (OGG1) functions as a DNA repair enzyme that both recognizes and repairs the nucleotide base excision repair of 7,8 dihydro-8-oxoguanine (8-oxoG) that represents one of the major types of DNA damage produced by RONS. Paradoxically, the binding of OGG1 to 8-oxoG, facilitates the action of the NF-kB transcription factor that promotes the activation of quiescent chemokine and cytokine genes that subsequently leads to the inflammatory response and the subsequent release of RONS at the site of trauma.
Visnes and his group have identified a small molecule (TH5487) that binds to the active site of OGG1 and effectively blocks its repair capabilities on account of the fact that inhibited OGG1 cannot bind to that G-rich region of the DNA leads to the activation of the NF-kB transcription factor that promotes proinflammatory genes. In fact, TH5487 has been shown to inhibit this process in mouse and human lung epithelial cells in vitro and the TNF-induced neutrophil inflammation in the in vivo mouse model.
This research is of value since it elucidates a molecular mechanism that demonstrates a connection between the normal DNA repair function of OGG1 and the inflammatory response and has discovered a small molecule inhibitor of this process.
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