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Obesity, sex hormones and asthma Th1 and Th2

Grant number: 17/12108-1
Support type:Regular Research Grants
Duration: November 01, 2017 - October 31, 2019
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Wothan Tavares de Lima
Grantee:Wothan Tavares de Lima
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Cristoforo Scavone ; Henrique Takachi Moriya ; Niels Olsen Saraiva Câmara

Abstract

Asthma and obesity are the two fastest growing conditions in the western world. Asthma is a chronic inflammatory disease of the airways that is commonly treated with steroidal and brochodilators. However, there is a portion of obese asthmatic patients who present resistance to steroid treatment and in this case the disease is classified as steroid-resistant asthma. These patients develop a predominantly neutrophilic lung inflammation instead of eosinophilic and release Th1 inflammatory mediators instead of Th2, originating the terms Th1 asthma (neutrophilic) or Th2 asthma (eosinophilic).The interaction of sex hormones and asthma is complex and the effect of these hormones on the worsening or amelioration of the disease has been extensively debated in the literature. Interestingly, it has been reported that female asthmatic patients present a worsening of the symptoms after menopause and the incidence of the disease seems to increase among post-menopausal women, particularly steroid-resistant asthma. More importantly, some studies have shown that a significant percentage of patients with steroid-resistant asthma are obese women. Obesity as an important factor in asthma incidence and development has been widely demonstrated in the literature however, the mechanisms underlying this interaction are yet to be clarified. Considering that the changes in women physiology after menopause are related to weight gain and fat mobilization, it is reasonable to propose a connection between the interruption of the production of sex hormones after menopause, steroid-resistant asthma and obesity. The aim of this project is to compare the role of reduction of female sex hormones in the Th1 and Th2 pre-established asthma in obese mice. To this end we will use a high calorie diet-induced model of obesity and once asthma Th1 and Th2 had been established, the post-menopause will be emulated by the removal of the ovaries and subsequently the ovariectomized obese asthmatic (10 days) mice will be re-challenged. Using these tools, we will investigate the activation and expression of the cell signalling molecule NFkB, the Th1 and Th2 profile of biomarkers release, in vivo lung mechanics, ex-vivo tracheal reactivity, systemic inflammation, morphologic lung changes. In order to identify new therapeutic targets we will compare in both models of asthma the effectiveness of drugs such as corticosteroid, bronchodilator, anti-cholinergic, leukotrienes-receptors antagonist (C4 and B4), estradiol, progesterone, sinvastatin. Asthma and obesity significantly alter the patient's quality of life and also self-esteem. Moreover, the cost of treatment in asthmatic obese patients is higher than in normal-weight patients due the low effectiveness of most drugs, particularly steroids. Very often, there is the need of the use of additional drugs in order to achieve an acceptable level of control of the disease, increasing the cost to the public health system. From this perspective, this study comes in an important moment when the understanding of the mechanism of asthma, both Th1 and Th2 in post-menopausal obese patients is critical (AU)