The Role of RAGE and RAGE Ligands in Pulmonary Fibrosis

RAGE 和 RAGE 配体在肺纤维化中的作用

• 批准号: 8055003
• 负责人: TIM D OURY
• 金额: $ 22.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055003
• 关键词: A549; Acute Lung Injury; Adhesions; Advanced Glycosylation End Products; Affinity; Age; Alveolar; Animal Model; Animals; Applications Grants; Asbestos; Basement membrane; Binding; Biochemical; Biological Assay; Cell Line; Cells; Chronic; Collagen; Collagen Type IV; Data; Development; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Epidemiologic Studies; Epithelial; Epithelial Cells; Exposure to; Fibrosis; Grant; HMGB1 gene; Hamman-Rich syndrome; Healed; Hyperglycemia; Injury; Kidney Diseases; Knockout Mice; Laminin; Lead; Ligands; Lung; Lung diseases; Mediating; Membrane Proteins; Modeling; Mus; Myofibroblast; Pathogenesis; Patients; Physiological; Play; Predisposition; Progressive Disease; Proteins; Pulmonary Fibrosis; Risk; Rodent; Role; Side; Signal Transduction; Signaling Molecule; Small Interfering RNA; Testing; Time; Tissues; Vascular Diseases; Wound Healing; cell type; diabetic; diabetic patient; healing; knock-down; lung injury; public health relevance; receptor; receptor for advanced glycation endproducts; research study; response; treatment strategy; wound

DESCRIPTION (provided by applicant): Recent studies have found that the receptor for advanced glycation endproducts (RAGE) plays an important role in the pathogenesis of pulmonary fibrosis and acute lung injury. In contrast to other tissues where RAGE expression is low and increases with disease, RAGE is highly expressed in the normal lung and its expression decreases in response to pulmonary injury. We found that RAGE protects against fibrosis in the lung, which led us to investigate the physiologic role of RAGE. Pulmonary RAGE localizes to the basement membrane side of type I alveolar epithelial cells. We found that RAGE has a very high affinity for components of the basement membrane including: collagen I, collagen IV, and laminin. We also found that RAGE loses this affinity in the presence of its ligand, AGEs (advanced glycation endproducts). This led us to study the effect of chronic exposure to excess RAGE ligand and what role it might have on pulmonary RAGE expression and subsequent predisposition to pulmonary disease. Notably, uncontrolled diabetes with sustained hyperglycemia leads to the overproduction of the RAGE ligand, AGE. This ligand contributes to many systemic complications that occur in diabetic patients including vascular disease, and nephropathy. However, few studies have examined the effects of diabetes and AGEs in lung disease. Elevated levels of the RAGE ligand, AGEs, in diabetics may increase their risks of pulmonary complications. We hypothesize that high levels of RAGE ligands, such as occurs in diabetics, will disrupt normal pulmonary epithelial RAGE/basement membrane interactions. This will lead to enhanced de-epithelialization, impaired re-epithelialization and lead to an augmented fibrotic response. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis is a disease that causes scaring of the lungs. The cause of this disease is not known, but there are about 40 new cases of this disease for every 100.000 people each year. There is no treatment available for patients with this disease and most patients will die from their disease three to five years after being diagnosed. A better understanding of how this disease develops will allow us to develop better treatment strategies for patients with this terrible disease. We have found that a protein called the receptor for advanced glycation endproducts is present in high levels in the lung and that it plays an important role in the progression of pulmonary fibrosis. This grant application will determine how molecules that signal through this receptor may contribute to pulmonary fibrosis and how blocking signaling through this receptor may offer a viable treatment option for patients with this relentlessly progressive disease.

描述（由申请人提供）：最近的研究发现，晚期糖基化最终产物（RAGE）的受体在肺纤维化和急性肺损伤的发病机理中起重要作用。与其他愤怒表达低并且随疾病增加的组织相反，愤怒在正常肺中高度表达，其表达对肺损伤的响应降低。我们发现愤怒可以预防肺中的纤维化，这使我们研究了愤怒的生理作用。肺愤怒位于I型肺泡上皮细胞的基底膜侧。我们发现，愤怒对地下膜的成分具有很高的亲和力，包括：胶原蛋白I，胶原蛋白IV和层粘连蛋白。我们还发现，愤怒在其配体的存在下失去了这种亲和力（高级糖基化终产物）。这使我们研究了长期暴露于过量愤怒配体的影响，以及它对肺部愤怒表达和随后对肺部疾病的倾向的作用。值得注意的是，持续高血糖的不受控制的糖尿病导致愤怒配体的生产过多。这种配体有助于糖尿病患者在内的许多系统并发症，包括血管疾病和肾病。但是，很少有研究检查糖尿病和年龄在肺部疾病中的影响。糖尿病患者的愤怒配体水平升高可能会增加其肺并发症的风险。我们假设高水平的愤怒配体（例如在糖尿病患者中发生）会破坏正常的肺上皮rage/地下膜相互作用。这将导致增强的上皮化，重新上皮化受损并导致增强的纤维化反应。 公共卫生相关性：特发性肺纤维化是一种引起肺部恐惧的疾病。这种疾病的原因尚不清楚，但是每年有40例这种疾病的新病例每年有40例。该疾病患者没有治疗，大多数患者被诊断出三到五年死于他们的疾病。更好地了解这种疾病的发展将使我们能够为这种可怕疾病的患者制定更好的治疗策略。我们发现，一种称为晚期糖基化最终产物受体的蛋白质在肺中以高水平存在，并且在肺纤维化的进展中起着重要作用。该赠款的应用将确定通过该受体信号的分子如何有助于肺纤维化以及通过该受体的阻断信号传导如何为这种无情进行性疾病的患者提供可行的治疗选择。