Effects of bifunctional sEH and COX-2 inhibition on airway constriction, inflammation, and smooth muscle function in asthma
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Abstract
The necessity of improving asthma treatment is indisputable. Affecting approximately 300 million people worldwide, this condition is characterized by airway constriction and inflammation that, when left untreated, may lead to death. Currently, the standard treatment of asthma includes symptomatic relief provided by long-acting beta-agonists in coordination with high-dose oral or inhaled corticosteroids. While this overcomes bronchoconstriction in some patients, approximately 55% of those affected by asthma continue to experience episodes of acute bronchospasm. In response to this unmet need, alternative therapeutics such as antibodies targeting immunoglobin E (IgE), interleukin-4 (IL-4), interleukin-5 (IL-5)/IL-5 receptors have been developed. However, these alternative therapies have proven costly and have a multitude of adverse side effects. There has been noteworthy excitement in inflammatory research regarding bifunctional soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibitors and their potential to alleviate inflammation and oxidative stress in acute and chronic pathologies. Beyond anti-inflammatory effects, we hypothesized bifunctional sEH and COX-2 inhibition can serve as a novel therapeutic strategy to inhibit methacholine (MCh)-induced airway constriction and airway smooth muscle (ASM) contraction. Thus, alleviating bronchoconstriction through bifunctional sEH and COX-2 inhibition can inhibit the two hallmarks of asthma: airway inflammation and ASM hyperconstriction.
To test this hypothesis, we utilized bifunctional sEH and COX-2 inhibitor OX-001. Our results showed multiple important findings: (1) OX-001 inhibited key proteins known to potentiate inflammatory and contractile responses, (2) evaluated concentrations of OX-001 did not affect human cell viability, (3) pre-treatment with OX-001 reduced MCh-induced human airway smooth muscle (hASM) cell constriction and murine precision cut lung slices (mPCLS) constriction, respectively, (4) pre-treatment with OX-001 does not inhibit effects of β-agonists or corticosteroids when administered in coordination, (5) pre-treatment with OX-001 lessens desensitization of β-agonists, and (6) OX-001 uniquely inhibits basal hASM cell contraction when compared to non-bifunctional inhibitors. Currently, further studies are being conducted to quantify the effect of OX-001 on inflammatory markers. Future experiments will seek to see if results are reproducible using hPCLS models.
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2024