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Role of insulin resistance in the pulmonary eosinophil recruitment in obese mice: anti-inflammatory and antioxidant actions of resveratrol

Grant number: 14/02130-1
Support type:Regular Research Grants
Duration: February 01, 2015 - July 31, 2017
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Edson Antunes
Grantee:Edson Antunes
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Obesity and asthma are prevalent and increasing diseases, and both have significant impact on global public health. Obesity may be an important factor for asthma development, and can even worse a pre-existing asthma. However, studies aiming to examine the mechanisms involved in exacerbation of asthma in obese animals are still scarce, and most have only focused on bronchial hyperresponsiveness. There are about five years we designed a study to standardize a model of obesity in C57BL6/J mice by a high-fat diet (HFD), given for 10 weeks. We observed that HDF fed mice become obese and insulin resistant, and exhibit exacerbation of lung eosinophil infiltration upon challenge with ovalbumin (OVA), a phenomenon accompanied by marked eosinopoese in bone marrow. Another important finding was that the anti-hyperglycemic, metformin, normalizes both the insulin resistance and pulmonary eosinophilic inflammation in the obese mice. Metformin also decreases the elevated levels of TNF-a, eotaxin and NOx, as well as the enhanced expression of iNOS in the lung tissue. Nitric oxide (NO) plays important modulatory role both in the development of obesity and insulin resistance. NO is also considered a key mediator in asthmatic inflammation, and levels of this mediator are elevated in bronchoalveolar lavage (BAL) of obese mice. Therefore, it seems relevant to examine if the excessive NO production is directly related to insulin resistance in the lungs of obese animals, which may take place by nitration and nitrosylation of proteins essential for glucose uptake. Reactive species of oxygen and nitrogen (ROS and RNS) have been implicated in asthma and obesity; in addition, the antioxidant resveratrol attenuates the insulin resistance in HFD-fed animals, as evaluated by measurements of phosphorylated AMP-activated protein kinase (AMPK), via PDE4 and sirtuin-1 (SIRT-1). Therefore, in obese mice previously sensitized and challenged with OVA (and respective control groups), we designed protocols to elucidade the importance of insulin resistance to the exacerbation of the pulmonary eosinophil recruitment, giving particular attention to the expression of protein involved in the insulin signaling pathways such as p-IR, p-IRS-1, p-AKT e GLUT4 in the lung tissue. We also aim to evaluate the role of NO in the insulin resistance in the lungs of obese and sensitized mice, by performing nitrosylation and nitration assays of proteins involved in the insulin signaling, as well as by quantifying the production of ROS (H2O2, O2-) and RNS (ONOO-) in the lung tissue and BAL fluid of the animals. We will also examine the effects of the antioxidant resveratrol on the allergic pulmonary inflammation by examining the cell counts and measuring the expression of SIRT1, PDE4 and p-AMPK in BAL fluid and/or lung tissue. In bone marrow (treated or not with resveratrol) we will evaluate the cell adhesion to VCAM-1 and ICAM-1-coated cells, and the expression of the adhesion molecules VLA-4, Mac-1 and CCR3. (AU)

Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ANDRE, DIANA MAJOLLI; HORIMOTO, CRISTINA MAKI; CALIXTO, MARINA CIARALLO; ALEXANDRE, EDUARDO COSTA; ANTUNES, EDSON. Epigallocatechin-3-gallate protects against the exacerbation of allergic eosinophilic inflammation associated with obesity in mice. International Immunopharmacology, v. 62, p. 212-219, SEP 2018. Web of Science Citations: 4.
MENDES-SILVERIO, CAMILA B.; LESCANO, CAROLINE H.; ZAMINELLI, TIAGO; SOLLON, CAROLINA; ANHE, GABRIEL F.; ANTUNES, EDSON; MONICA, FABIOLA Z. Activation of soluble guanylyl cyclase with inhibition of multidrug resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy. Biochemical Pharmacology, v. 152, p. 165-173, JUN 2018. Web of Science Citations: 3.
ANDRE, DIANA M.; CALIXTO, MARINA C.; SOLLON, CAROLINA; ALEXANDRE, EDUARDO C.; TAVARES, EDITH B. G.; NAIME, ANA C. A.; ANHE, GABRIEL F.; ANTUNES, EDSON. High-fat diet-induced obesity impairs insulin signaling in lungs of allergen-challenged mice: Improvement by resveratrol. SCIENTIFIC REPORTS, v. 7, DEC 11 2017. Web of Science Citations: 3.
ANDRE, DIANA MAJOLLI; CALIXTO, MARINA CIARALLO; SOLLON, CAROLINA; ALEXANDRE, EDUARDO COSTA; LEIRIA, LUIZ O.; TOBAR, NATALIA; ANHE, GABRIEL FORATO; ANTUNES, EDSON. Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice. International Immunopharmacology, v. 38, p. 298-305, SEP 2016. Web of Science Citations: 18.

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