Obesity and asthma: role of methylglyoxal and advanced glycation end products in allergic pulmonary inflammatory response in genetically obese mice

• Grant number: 24/03508-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): August 01, 2024
• Effective date (End): July 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Edson Antunes
• Grantee: Matheus Leite de Medeiros
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Asthma is a chronic inflammatory disease of the airways that affects more than 300 million people worldwide, thus posing a major threat to global health. In Brazil, asthma is the fourth most common disease in adults and the third in children and young people, resulting in around 160,000 hospitalizations annually and five deaths daily. Asthma is triggered by a complex interaction of genetic and environmental factors, which results in a process of sensitization of the individual. When an allergen comes into contact with the respiratory mucosa, Th2 type T lymphocytes are activated, resulting in the production of pro-inflammatory cytokines, such as IL-4, IL-5 and IL-13. These cytokines recruit other inflammatory cells to the airways, including eosinophils, which play a crucial role in the pathophysiology of the disease. Several genetic and environmental factors, including obesity and type 2 Diabetes Mellitus (T2DM), can worsen asthma. Obesity is closely related to DM2, a chronic condition characterized by high blood glucose levels. Although obesity can make it difficult to control asthma and increase its severity, the mechanisms underlying this association are not yet completely understood. Studies carried out in murine models of obesity and insulin resistance induced by a high-fat diet confirm the association between obesity and increased pulmonary eosinophilic inflammation. During states of hyperglycemia in obese/diabetic individuals, there is a significant increase in plasma levels of dicarbonyl compounds, mainly methylglyoxal (MGO), a highly reactive molecule generated during glycolysis. MGO has the ability to react with amino acid residues in proteins, leading to the formation of advanced glycation end products (AGEs), which interact with a specific receptor, called RAGE (receptor for AGEs), triggering a cascade of intracellular events, including increased production of reactive oxygen species (ROS), among other effects. Methylglyoxal is degraded into D-lactic acid by the glyoxalase (GLO) system, which comprises the GLO1 and GLO2 enzymes. Prolonged administration of MGO in normoglycemic mice significantly exacerbates pulmonary eosinophilic inflammation in response to ovalbumin (OVA) challenge, increasing levels of inflammatory cytokines and ROS. However, there are many gaps in the literature regarding understanding the role of the MGO-AGEs-RAGE and GLO axis in allergic lung inflammation in obese/diabetic individuals. Therefore, in this study, we will employ genetically obese and DM2 mice (ob/ob model) to investigate the contribution of the MGO-AGEs-RAGE pathway and the GLO system to asthma exacerbation in these individuals. Our objective is to elucidate the role of this axis in allergic lung inflammation, using functional and molecular strategies in bronchoalveolar lavage, lung tissue and circulating blood of animals. We will use pharmacological blockers of the MGO-AGEs-RAGE pathway, such as (i) alagebrium (ALT-711), a drug with the ability to "break" already formed AGEs; (ii) transresveratrol/hesperidin (tRES-HESP), polyphenols capable of increasing the activity of GLO1, a critical enzyme in MGO detoxification; (iii) HY-15167A, a selective GLO1 inhibitor devoid of antioxidant activity; and (iv) FPS-ZM1, a selective RAGE inhibitor. We hope that these approaches will help us better understand the contribution of the MGO-AGEs-RAGE axis to asthma exacerbation in obese/diabetic individuals, as well as identify potential therapeutic targets for this pathological condition.