The Virtual Meeting Symposium on “Resolution of Inflammation in Chemical Toxicity/Tissue Injury: What’s Emerging?” was chaired by Kymberly Gowdy, PhD, Associate Professor at the Ohio State University in Columbus, Ohio, and co-chaired by Srikanth Nadadur, PhD, National Institute of Environmental Health Sciences (NIEHS) in Durham, North Carolina. The primary endorser of this session was Comparative Toxicology, Pathology, and Veterinary Specialty Section (CTPVSS).
The inflammatory response is divided into three temporal phases: initiation, amplification and maintenance, and resolution. Classical anti-inflammatory treatments have focused on interference with target pathways involved in the initiation and maintenance of inflammation. Resolution of inflammation was thought to occur because of the lack of inflammatory drive when concentrations of inflammation-initiating and -maintaining mediators are removed or in decline. However, new studies show that the resolution of inflammation is an active mechanism involving the activation of signaling pathways during inflammation initiation, and the later generation of fatty acid–derived specialized pro-resolving mediators (SPMs) that activate resolution mechanisms. These mediators include resolvins, lipoxins, protectins, and maresins. Resolvins and protectins are omega-3 fatty acids derived from docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), the two dietary fatty acids widely consumed for their reported anti-inflammatory and other beneficial effects. SPMs mediate their pro-resolving effects through a range of G-protein-coupled receptors and ion channels such as transient receptor potential (TRP) ion channels. In general, SPMs help injured tissues to return to their original architecture and function by promoting resolution through the recruitment of noninflammatory monocytes. Then, macrophages remove cellular debris, inflammation causative agent(s), and excess neutrophils. The field of resolution biology is expanding rapidly in the last decade and unfolding the therapeutic benefits of SPMs in several preclinical disease models.
Dr. Kymberly Gowdy showed her work on ozone-induced pulmonary inflammation. In the ozone-exposed mice, the precursors of SPMs have significantly decreased compared with control animals. Treatment of mice with SPMs or dietary supplementation of DHA decreased ozone-induced pulmonary inflammation. Debra Laskin, PhD, of Rutgers, The State University of New Jersey, presented her work on macrophage phenotype and inflammation in lung injury and resolution. Dr. Laskin focused on ozone-induced lung injuries and M2 macrophage phenotype switching, with emphasis on the role of lipid-related transcription factors and downstream lipid transport genes. The third speaker, Valerian E. Kagan, PhD, is a renowned scientist in the field of free radical biology and medicine at the University of Pittsburg. Dr. Kagan talked about oxidized lipids and nitric acid as regulators of necro-inflammatory cell death pathways in macrophages, including ferroptosis during the resolution phase of inflammation. The fourth speaker, Diane K. Jorkasky, MD, FACP, presented her talk entitled “The Road from Bench to Bedside: The Clinical Development of Nitro Fatty Acid CXA-10.” Dr. Jorkasky is a retired physician-scientist who actively consults on drug development of a small molecule nitro fatty acid, CXA-10, as a potential treatment for focal segmental glomerulosclerosis (FSGS) and pulmonary arterial hypertension. Nitro fatty acids modulate metabolic and inflammatory gene expression and protein function. Dr. Jorkasky walked through the different steps involved in the drug development process. Nitro fatty acids specifically activate genes responsible for organ protection and inhibit genes otherwise responsible for organ demise.
Dr. Nadadur concluded the meeting with his perspective on resolution biology in chemical toxicity. Dr. Nadadur announced the “RESolution of InflammaTion in EnvirOnmentally Related DiseasE (RESTORE)” program, an effort of NIEHS to advance the field of resolution of inflammation in chemical injuries and toxicity. Although SPMs hold a great promise for therapeutic intervention in several disease models, there are very limited studies in chemical toxicity and resolution of inflammation. Let us hope that the specific RFA from RESTORE program bridges the knowledge gap!
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