A Role for Advanced Glycation End-Products in Diabetic Lung Injury

描述(申请人提供)：肺尘埃沉着病是指因吸入石棉和二氧化硅等尘埃纤维/微粒而引起的职业性肺部疾病。石棉肺的实验模型概括了特发性肺纤维化(IPF)的显著特征，由于缺乏有效的治疗方法，IPF是一种发病率和死亡率都很高的衰弱疾病。最近的流行病学研究表明，糖尿病患者患特发性肺纤维化的风险增加。这导致我们的实验室假设，糖尿病患者在环境暴露后患肺部疾病的风险增加。随着糖尿病人口以惊人的速度增长，重要的是确定糖尿病患者更容易受到肺损伤的机制，以便更好地预防和治疗。最近，我们的实验室发现晚期糖基化终末产物受体(RAGE)的缺失是肺纤维化发生的关键致病步骤。该受体还参与了许多其他糖尿病的病理过程，包括神经病变、动脉粥样硬化和肾病。这促使我们研究它在增加糖尿病患者对肺损伤的易感性方面的潜在作用。初步研究表明，老年糖尿病小鼠的肺组织中的愤怒消失。这可能提供了一种潜在的机制，糖尿病患者更有可能通过这种机制发展为肺纤维化。该项目将侧重于RAGE促进伤口愈合和防止脱上皮化和后续疾病的机制。我们还将研究晚期糖基化终末产物(AGEs)增加在疾病发病机制中的作用。最终，我们希望确定通过使用非信号诱骗受体SRAGE清除RAGE配体是否可以防止石棉暴露后的纤维化反应。该项目将调查糖尿病患者在暴露于职业粉尘颗粒后患肺纤维化的风险增加的可能性。它将提供对疾病如何发展的更好了解，这将帮助我们开发更好的方法来预防和治疗疾病及其症状。

DESCRIPTION (provided by applicant): Pneumoconioses are occupational lung diseases caused by the inhalation of dust fibers/particles such as asbestos and silica. Experimental models of asbestosis recapitulate the salient features of idiopathic pulmonary fibrosis (IPF), a debilitating disease with both high morbidity and mortality due to a lack of effective therapies. Recent epidemiological studies have suggested that diabetics are at increased risk of developing idiopathic pulmonary fibrosis. This has led our lab to hypothesize that diabetics are at increased risk of developing pulmonary disease after environmental exposures. As the diabetic population increases at an alarming rate it is important to determine the mechanism by which diabetics are more susceptible to pulmonary injury so that it can be better prevented and treated. Recently our lab has implicated loss of the receptor for advanced glycation end-products (RAGE) as a key pathogenic step in the development of pulmonary fibrosis. This receptor has also been implicated in numerous other diabetic pathologies including neuropathy, atherosclerosis, and nephropathy. This has led us to investigate its potential role in increasing diabetics susceptibility to pulmonary injury. Preliminary studies have shown that aged diabetic mice have a loss of RAGE in their lung tissue. This could provide a potential mechanism by which diabetics are more likely to develop pulmonary fibrosis. This project will focus on the mechanisms by which RAGE promotes wound healing and prevents de-epithelialization and subsequent disease. We will also investigate the role that increased advanced glycation end-products (AGEs) play in the disease pathogenesis. Ultimately, we hope to determine if clearing RAGE ligands by use of a non-signaling decoy receptor, sRAGE, protects against the fibrotic response after asbestos exposure. This project will investigate the possibility that diabetics are at increased risk of developing pulmonary fibrosis after being exposed to occupational dust particles. It will provide a better understanding of how the disease develops which will help us develop better ways to prevent and treat the disease and its symptoms.