Examination of endocannabinoids metabolism inhibition as a new target in the treatment of allergic airway inflammation

Endocannabinoids are biologically active endogeneous substances with a cannabinoid structure. Their degradation is primarily carried out by two enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). It is suggested that endocannabinoids could be important targets for inflammatory airway diseases associated with bronchial hyperreactivity. In this thesis, the effects of FAAH and MAGL inhibitor treatments were investigated in experimental allergic airway inflammation in guinea pigs. For this purpose, guinea pigs were sensitized to ovalbumin and then exposed to ovalbumin inhalation. The effects of the FAAH inhibitor URB597, the MAGL inhibitor JZL184, and the dual FAAH/MAGL inhibitor JZL195 were evaluated in these guinea pigs. Ovalbumin administration led to eosinophilic pulmonary inflammation and airway hyperreactivity, characterized by increased reactivity in tracheal preparations isolated from the guinea pigs, elevated levels of IL-4, IL-13, and eosinophils in bronchoalveolar lavage (BAL) fluid, and increased serum IgE levels. This protocol also caused changes in the metabolomic profile in the lungs. URB597 treatment prevented markers of inflammation such as cytokine production and inflammatory cell infiltration but did not affect airway hyperreactivity. JZL184 and JZL195 treatments reduced both inflammatory markers and hyperreactivity. Allergen exposure specifically led to an increase in metabolites associated with glycolytic metabolism in the lungs, which may be linked to the increase in the number and activation of immune system cells. Our findings suggest that inhibition of endocannabinoid metabolism via FAAH and MAGL inhibitors could be considered for the treatment of allergic inflammatory airway diseases, and further studies are needed for more selective effects.