Role of obesity in pulmonary endothelial glycocalyx sheeding and asthma exacerbations: in vitro approaches

• Grant number: 23/12573-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2023
• End date: October 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vânia Luiza Deperon Bonato
• Grantee: Carolina de Lima Esquisatto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Obesity is a risk factor for asthma worsening, a lung chronic inflammatory disease that affects about 334 million people worldwide. Comorbidity asthma and obesity is characterized by neutrophil infiltration in the airways, which is associated with a severe asthma phenotype with low responsiveness to corticosteroids. The mechanisms involved in the asthma exacerbation that occurs with obesity are poorly understood. Our research group has been investigating the participation of endothelial cells (EC), specifically the endothelial glycocalyx, as a mechanism for obesity-induced asthma exacerbation. Endothelial cells directly contribute to tissue inflammation by expression of adhesion molecules that interact with circulating leukocytes, favoring their transmigration to tissues. The endothelial glycocalyx, a network of proteoglycans and glycoproteins anchored to the EC membrane, plays a direct role in the regulation of transendothelial migration and inflammation. Endothelial glycocalyx shedding promotes an increase of exposure of adhesion molecules by EC, favoring leukocyte trafficking. Recent observations by our research group show that both asthma and obesity promote endothelial glycocalyx shedding in an experimental model of comorbidity. However, the trigger that leads to this process is not well established and comprises one of the objectives of this project. Our hypothesis is that the association of asthma with obesity promotes exacerbation of inflammation when compared to isolated inflammatory conditions (asthma or obesity) due to the loss of integrity of the endothelial glycocalyx, triggered by concomitant exposure to the allergen and the presence of a hyperglycemic microenvironment, characteristic of obesity. To test our hypothesis, we will work with in vitro approaches, seeking to mimic the comorbidity of asthma and obesity, using immortalized endothelial cells lineage (EA.hy 926) to be stimulated with house dust mite (HDM) in the presence or absence of a hyperglycemic environment. Our aim is to elucidate the mechanisms involved in the endothelial glycocalyx shedding in these two experimental conditions, allowing to analyze the machinery involved in the evolution of the pathophysiological pattern of asthma integrated with obesity. Also, we seek to propose host-directed therapies, aiming at the reduction of pulmonary inflammation associated with increased quality of life in obese and asthmatic patients.