New Omega-3 Derivatives Reduce Airway Inflammation and Prevent Rho-Kinase Activation in an Allergic Model of Asthma

Abstract

Asthma is a chronic inflammatory airways disease characterized by early and late asthmatic reactions that are associated with infiltration and activation of inflammatory cells in the airways. Bronchial hyperresponsiveness to a variety of stimuli is part of the symptomology which include neurotransmitters and inflammatory mediators. Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation in the lung. In the present study, we synthesized new omega-3 polyunsaturated fatty acid (n3-PUFA) derivatives, namely DHA monoglyceride (MAG-DHA) and EPA monoglyceride (MAG-EPA), and investigated their effects on lung inflammation and RhoA activation in an in vivo guinea pig model of allergic asthma. Histological analyses and leukocyte count in bronchoalveolar lavages revealed that oral MAG-DHA and MAG-EPA treatments led to less inflammatory cell recruitment in the lung of ovalbumine (OVA)-sensitized guinea pigs when compared to lung from control animals. Results also revealed a reduction in mucus production in OVA-sensitized animals treated with either MAG-DHA or MAG-EPA. Moreover, per os n-3 PUFA administrations prevented NF k B activation and COX2 over-expression in OVA-sensitized animals. Mechanical tension measurements revealed that oral MAG-DHA and MAG-EPA treatments prevented U-46619-induced bronchial hyperresponsiveness in OVA-sensitized guinea pigs. MAG-DHA and MAG-EPA also prevented U-46619-induced Ca 2+ hypersensitivity of bronchial smooth muscle through a decrease in RhoA activation. Together, these findings provide key evidences regarding the mode of action of MAG-DHA and MAG-EPA in the lung and point to new potential therapeutic strategies for modulating inflammation and airway hyperresponsiveness in asthma.