Role of the MGO-AGE-RAGE Axis in Allergic Lung Inflammation in a Type 1 Diabetes Mellitus Models in Mice

• Grant number: 24/03974-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2024
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Edson Antunes
• Grantee: Kamila Hadassa Geremias
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Overview: Asthma is a chronic inflammatory condition of the airways, influenced by genetic and environmental factors. Diabetes Mellitus presents two main categories: Type 1 (DM1) and Type 2 (DM2). In DM2, insulin loses the ability to regulate glucose in muscle cells, resulting in hyperinsulinemia. On the other hand, DM1 is an autoimmune disease characterized by the progressive destruction of pancreatic ² cells responsible for insulin secretion. Study fundamentals, objectives, and main questions to be addressed: Preclinical and clinical studies clearly show that DM2 exacerbates asthma, possibly due to underlying obesity, hyperglycemia, and insulin resistance. Conversely, in DM1, pulmonary inflammatory response is significantly lower than in the control group (normoglycemic), suggesting that DM1 "protects" the individual from asthma. Recent studies suggest that asthma exacerbation in the DM2 model is due to elevated serum levels of glucose and consequently methylglyoxal (MGO), leading to excess formation of advanced glycation end products (AGEs), which activate the receptor for AGEs (RAGE), culminating in pulmonary inflammatory response. However, there are no studies investigating the involvement of the MGO-AGEs-RAGE pathway in asthma in individuals with DM1. Therefore, this project will investigate the relationship between asthma, DM1, and the MGO-AGEs-RAGE pathway in lung tissue, filling a gap in the scientific understanding of this complex interaction. The central question to be addressed is how the MGO-AGEs-RAGE axis influences asthma in the DM1 model. General methods: Female C57BL/6JUnib mice will be distributed into 4 groups: control (normoglycemic, instilled with saline); OVA (normoglycemic, challenged with ovalbumin; OVA); STZ (DM1 diabetes model induced by streptozotocin [STZ], instilled with saline); and STZ + OVA (DM1 induced by STZ, challenged with OVA). We will evaluate the allergic inflammatory response by quantifying the influx of inflammatory cells in bronchoalveolar lavage and lung tissue, as well as by quantifying levels of MGO, AGEs, and RAGE in serum and/or lung tissue, using microscopic techniques, pulmonary morphometry, immunohistochemistry, and immunoassays (ELISA).