| Grant number: | 14/02130-1 |
| Support Opportunities: | Regular Research Grants |
| Duration: | February 01, 2015 - July 31, 2017 |
| Field of knowledge: | Biological Sciences - Pharmacology - General Pharmacology |
| Principal Investigator: | Edson Antunes |
| Grantee: | Edson Antunes |
| Host 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)
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