Reata’s AIM molecules inhibit innate and adaptive immune-mediated inflammation by restoring redox (reductive/oxidative) homeostasis in inflamed tissues. They mimic the activities of a class of endogenous lipid mediators called cyclopentenone prostaglandins (cyPGs) that play a key role in the resolution of inflammation. The cyPGs and the AIMs initiate a pro-resolution program in which the activity of the antioxidant and cytoprotective transcription factor Nrf2 is potently induced. This increases the production of antioxidant and reductive molecules (NQO1, HO-1, SOD1, γ-GCS), decreases oxidative stress, and inhibits the production of pro-oxidant and pro-inflammatory molecules (iNOS, COX2, TNF-α). Restoration of redox homeostasis directly reduces inflammation and cellular damage from pro-oxidant species and also inhibits pro-inflammatory signal transduction that would otherwise result from a variety of inflammatory stimuli. Through this mechanism, AIMs cause the cells that host the inflammatory event to revert to a non-inflammatory state. This promotes the resolution of acute inflammation and limits excessive tissue damage to the host.
Nrf2 and its downstream targets are key protective molecules in a variety of inflammation-based diseases. Human and animal studies have demonstrated that the loss of Nrf2 exacerbates, and activation of Nrf2 attenuates, inflammation and oxidative stress in multiple tissue types. The AIMs are active in preclinical models of many inflammation-related diseases including, cardiovascular and renal diseases, autoimmune diseases, transplants, major respiratory diseases, neurodegenerative diseases, and cancer.
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