Effects of eugenol and dehidrodieugenol isolated from Nectandra leucantha (Lauraceae) treatments in experimental models of acute and chronic lung disease

Abstract

According to DATASUS data, respiratory diseases, including asthma, emphysema, pneumonia, bronchitis and bronchiolitis, have led to more than 135,000 deaths in 2017. The acute respiratory distress syndrome (ARDS) affects 2% to 26% of all mechanical ventilation hospitalized in intensive care centers is characterized by a diffuse pulmonary inflammatory response that causes acute lung injury (LPA) due to the activation of pro-inflammatory and oxidizing agents from various causes, and has a mortality rate of around 40% despite of studies with new therapeutic and ventilatory strategies. Bronchial asthma, a chronic allergic disease characterized by bronchial hyperresponsiveness, chronic inflammation mainly with a response profile diverted to Th2 and bronchial remodeling with impairment of function, still has a very high morbidity. Still, a portion of the patients present different phenotypes that do not respond to conventional treatment. Pulmonary emphysema, which affects mainly smokers, is the fourth cause of death in the world, and is characterized by the destruction of lung tissue by proteases and oxidants leading to progressive worsening of lung function, which, for the most part, is not reversible with conventional treatments. In common, these diseases have, in addition to pulmonary inflammation, the participation of oxidative stress in their pathophysiology and the lack of a specific and effective treatment for all patients. Our group has sought new therapeutic strategies for these diseases and mainly to understand pathophysiological mechanisms as well as action of new compounds with therapeutic potential. In this sense, eugenol is a substance with anti-inflammatory and antioxidant effects already known, but still controversial, while its dimerized form (dehydrodieugenol), isolated from the vegetal species Nectandra leucantha (Lauraceae), could have a more intense effect in the reduction of inflammation and less toxic. Objective: To evaluate the effects of treatment with eugenol and its dimer (dehydrodieugenol) on changes in pulmonary and histopathological function, characterizing possible mechanisms of action in models of pulmonary inflammatory diseases (model of acute lung injury, experimental asthma with eosinophilic phenotype and phenotype neutrophilic and pulmonary emphysema).Methodology: Mice will be submitted to LPS instillation protocol for induction of LPA, elastase for induction of emphysema and ovalbumin for induction of two different models of asthma. These animals will be treated with eugenol and dehydrodieugenol according to each protocol. Some groups will receive dexamethasone as a positive control of recommended treatment for some of these diseases. In all subprojects will be evaluated the mechanics of the respiratory system, pulmonary inflammation through the bronchoalveolar lavage, the dosage of pro-inflammatory cytokines; the remodeling of the extracellular matrix, oxidative stress and possible signaling pathways such as NF-kB, MAP kinase, JAK-STAT-SOCS and components of the cholinergic anti-inflammatory system. Some in vitro cell culture experiments will be performed to evaluate cytotoxicity and antioxidant capacity of the compounds. Histopathological analysis of the liver of the animals will also be performed to assess toxicity. Statistical analysis will be performed through the SigmaStat program and the tests will be subsequently selected. Due to the constant search for an effective therapeutic measure in the treatment of respiratory diseases and the known anti-inflammatory and antioxidant effect of eugenol and its dimer, animals treated with dehydrodieugenol are expected to show improvement in inflammatory response and pulmonary function and reduction of oxidative stress induced in these models of pulmonary diseases. Additionally, it will be possible to understand some of the mechanisms of action of these compounds. (AU)