O ácido láurico previne as alterações morfofuncionais das vias aéreas de ratos Wistar com asma alérgica

Abstract

Lauric acid (LA) is a medium-chain saturated fatty acid and the major component of virgin coconut oil, which, in turn, has already shown a preventive effect on changes induced by asthma in animals. This study aimed to evaluate morphofunctional effects of LA in an ovalbumin (OVA)-induced asthma model in Wistar rats. Experimental procedures were approved by the Animal Use Ethics Committee of UFPB (No. 9310040522). Rats were randomly divided for toxicological analyses into the control group (CG) and the group treated with 100 mg/kg/day of LA (LA100G), each consisting of 5 males and 5 females. For the other experimental protocols (n = 5-6), the rats were divided into CG, asthmatic group (AG), asthmatic groups treated with LA at 25 mg/kg (ALA25G), 50 mg/kg (ALA50G), and 100 mg/kg (ALA100G), or dexamethasone at 5 mg/kg (ADEXAG). In the evaluation of repeated dose toxicity, LA at 100 mg/kg/day did not promote any signs of toxicity. In the analysis of asthma-induced changes, minute volume was quantified using plethysmography, revealing that LA (25 mg/kg) prevented the reduction of this parameter observed in GA. In the assessment of tracheal responsiveness, AG animals previously sensitized with OVA exhibited increased contractile reactivity to this allergen in vitro, an effect partially prevented by LA (25, 50 and 100 mg/kg) and dexamethasone. Electromechanical pathways of contraction and relaxation do not seem to be involved in airway hyperresponsiveness in this asthma model. Conversely, in the evaluation of pharmacomechanical coupling of contraction, all groups treated with LA and dexamethasone prevented the increase in contractile efficacy to carbachol observed in the AG. In the evaluation of the involvement of pharmacomechanical coupling in relaxation, the groups treated with LA also prevented the reduction in the relaxing capacity of aminophylline in the AG. In silico molecular docking studies also revealed that LA has a good binding affinity for various targets involved in inflammation and airway hyperresponsiveness, as β2-adrenergic receptor, CaV, BKCa, KATP, adenylyl cyclase, PKG, eNOS, iNOS, and COX-2. Furthermore, the characterization of LA’s mechanism of action at 25 mg/kg, the lowest effective dose in reducing tracheal hyperresponsiveness, was pursued. It was observed that LA promotes a probable reduction in the production of contractile prostanoids by cyclooxygenase (COX) pathways, as well as a decrease in excessive nitric oxide (NO) production due to a possible increase in nitric oxide synthase (NOS) activity/expression, was observed, along with a potential decrease in superoxide anion production. Additionally, a probable negative modulation of the RhoA-ROCK and TGF-β pathways was evidenced. In the analysis of oxidative stress imbalance and antioxidant defenses in lung homogenate, LA prevented the increase in lipid peroxidation and nitrite levels, as well as the reduction in superoxide dismutase (SOD) activity observed in AG. However, it did not prevent the reduction in reduced glutathione (GSH) levels. LA at different doses also prevented inflammatory infiltration and excessive extracellular matrix deposition in the lung parenchyma, as well as the increase in smooth muscle α-actin and ROCK1 expression. Therefore, these data suggest that lauric acid exerts a preventive effect on the morphofunctional changes caused by asthma in the airways of Wistar rats by negatively modulating the signaling mediated by COXs, NOS, RhoA-ROCK, TGF-β and reactive oxygen species, and may therefore act as an adjuvant in the treatment of asthma.