Characterization of the pulmonary extracellular matrix in the asthma associated obesity and study of inhibitors of metalloproteinases as a possible therapeutic target

Abstract

The increase in the prevalence of both asthma and obesity has prompted researchers to suggest that obesity may have an important role in the development of asthma, or even worsen the pre-existing asthma. About a decade ago we began a study to understand the pathophysiological mechanisms involved in the exacerbation of allergic lung inflammation in ovalbumin (OVA)-sensitized and challenged animals and its relationship with obesity.We showed that obese mice fed with a high-fat diet for 10-12 weeks become insulin resistant, and exhibit exacerbation of pulmonary eosinophilic infiltrate and marked bone marrow eosinophil accumulation. Treatment with metformin corrected both the insulin resistance and eosinophilic lung inflammation in these animals. Recent advances in understanding the pathogenesis of asthma have revealed that remodeling of the airway is due, at least in part, to deposition of excess of extracellular matrix (ECM) in the airway walls, which may play a significant role in airway obstruction. The metalloproteinases of extracellular matrix (MMPs) are key proteolytic enzymes responsible for the remodeling of the airways and / or severity of asthma. MMP-1, 2, 8, 9 and 12 are the main enzymes involved in obesity and asthma, being mainly regulated by its inhibitor TIMP I and II. Obesity and asthma individually elevate the levels of TNF-±, a pro-inflammatory cytokine that lead to induction of MMP-1, 2 and 9. There is also an excessive deposition of fibronectin, tenascin and collagen I, III and IV in the asthmatic lung.Based on these findings, we find relevant to study the imbalance between MMPs / TIMPs and consequently the elements of MEC in obese-asthmatics. Thus, in this project we propose to: (1) Elucidate the pathophysiological profile of the lung ECM of obese animals challenged with OVA, with particular attention to the presence and expression of MMP-1, 2, 8, 9 and 12, TIMP-1 and 2, as well as the enzymatic activity MMPs; (2) Evaluate how the high levels of TNF-± found in obese-asthmatics animals may be related to the induction of MMPs and TIMPs, and deposition of collagens, fibronectin and tenascin; (3) Investigate the effect of synthetic MMP inhibitors such as R-94138 and MMP408 on allergic inflammation by functional and molecular analysis of the lung of asthmatic obese animals (this objective is assumed that the partial inhibition of MMPs, especially of MMP-9 and MMP-12. may be a new pharmacological target for the control of asthma in obese individuals).