Mechanisms of Fibrosis in Asthma and Other Fibroproliferative Diseases

哮喘和其他纤维增殖性疾病中纤维化的机制

• 批准号: 9161599
• 负责人: Thomas Wynn
• 金额: $ 84.93万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161599
• 关键词: Adrenal Cortex Hormones; Affect; Allergens; Allergic; Allergic inflammation; Anti-Inflammatory Agents; Anti-inflammatory; Area; Aspergillus; Asthma; Attention; Autoimmune Process; Automobile Driving; Biological Markers; Breeding; CSF3 gene; Cardiovascular system; Cessation of life; Chemicals; Chronic; Chronic Disease; Cicatrix; Clinical; Clinical Research; Collagen; Complex; Deposition; Development; Disease; Drug Targeting; Excision; Extracellular Matrix; Fibrosis; Functional disorder; Gene Expression Profile; Genetic; Gland; Goals; Hamman-Rich syndrome; Health Care Costs; Hyperplasia; Immunity; In Vitro; Inbred BALB C Mice; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interleukin-17; Intestines; Investigation; Kidney Diseases; Lead; Liver; Liver Cirrhosis; Lung; Lung diseases; MUC5AC gene; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucins; Mucous body substance; Mus; Muscle Contraction; Nature; Obesity; Obstruction; Organ; Ovalbumin; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Production; Radiation; Reaction; Residual state; Resistance; Rhinovirus; Role; Signal Pathway; Skin; Smooth Muscle; Stimulus; Systemic Scleroderma; TNF gene; Therapeutic; Tissues; Up-Regulation; Whole-Body Irradiation; airway hyperresponsiveness; airway inflammation; allergic response; asthmatic airway; asthmatic patient; body system; chemokine; cytokine; eosinophilic inflammation; fibrogenesis; in vivo; in vivo Model; interest; methacholine; mortality; mouse model; novel; patient population; respiratory smooth muscle; response; targeted treatment; therapeutic target; treatment response

We are investigating the role of Type-2 immunity in several models of fibrosis that affect the lung, liver, and intestine to determine whether there are common as well as distinct mechanisms of fibrosis in various organ systems and/or fibrotic diseases. Several distinct in vivo models of organ fibrosis are employed, including mouse models of chronic asthma, inflammatory bowel disease, and obesity induced steatosis. Progress was made in following areas over the past year. 1. In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced. 2. Asthma is a chronic disorder, characterised by episodic airway hyperresponsiveness (AHR), and remodelling with variable degrees of eosinophilic and neutrophilic inflammation. Asthma causes significant morbidity and mortality, and approximately 10% of patients have disease that is resistant to current therapies. This group consumes 50 to 60% of health care costs attributed to asthma, underscoring the necessity to discover new therapies. The clinical expression of asthma is heterogeneous with several distinct phenotypes identified. Identifying the molecular mechanisms driving subtypes of asthma has the potential to reveal drug targets, biomarkers to predict treatment response, and appropriately target therapy, as evidenced by recent clinical studies of Th2 cytokine antagonists. In addition to the Th2 pathway, attention has focused on Th17 cytokines as candidate alternative drivers of severe asthma pathophysiology. IL-17A and F can amplify selected NF-κB dependent signalling pathways such as those induced by TNFα, a cytokine upregulated in asthmatic airways, and are further upregulated following allergen challenge and experimental rhinovirus infection. In particular, IL-17A may contribute to neutrophilic airway inflammation via upregulation of CSF3 and CXCL chemokines, mucus gland hyperplasia, AHR and corticosteroid resistance. Therapeutic strategies targeting Th2 and Th17 inflammatory pathways are currently under active investigation in asthma. However, the nature and extent of the activity of these two pathways in individual patients is unclear. Th2 cytokines can negatively regulate Th17 cytokine expression, and inhibiting Th2 cytokines in vitro or in vivo has the potential to increase IL-17A production and IL-17A-dependent airway inflammation. The cross-talk between Th2 and Th17 pathways is therefore complex, and it has been proposed that targeting Th2 cytokines might promote corticosteroid resistant IL-17-dependent neutrophilic airway inflammation. In this project, we showed that Th2 and Th17-related gene expression signatures are mutually exclusive in the airways of asthma patients, but both are associated with eosinophilic inflammation. Also, using an in vivo preclinical model of HDM-induced asthma, we show that therapeutic targeting of Th2 and Th17 cytokines, respectively, can lead to amplification of activity of the opposing pathway. Thus, therapeutics that disrupt both pathways simultaneously may show increased efficacy across a diverse patient population.

我们正在研究影响肺，肝脏和肠道的几种纤维化模型中2型免疫力的作用，以确定各种器官系统和/或纤维化疾病中是否存在常见和纤维化的不同机制。采用了几种不同的器官纤维化体内模型，包括慢性哮喘，炎症性肠病和肥胖诱导的脂肪变性的小鼠模型。 在过去的一年中，以下领域取得了进展。 1。在哮喘中，认为气流阻塞主要是由于炎症触发的气道平滑肌（ASM）收缩而导致的。然而，抗炎和平滑肌浮肿的处理通常是暂时的或无效的。粘蛋白MUC5AC的过量生产是一种附加的疾病特征，尽管在病理上密切相关，但在功能上却很少理解。在这里，我们表明MUC5AC是气道高反应性（AHR）对甲酸酯（MCH）所需的过敏性炎症的中心效应。在两种特征良好的应变背景（C57BL/6和BALB/C）上繁殖的小鼠中，暴露于两个单独的过敏刺激（卵形蛋白和曲霉提取物）中，遗传去除MUC5AC废除了AHR。残留的MCH反应与无挑战的对照相同，尽管炎症仍然完好无损，但异质性粘液闭塞却降低了74％。因此，尽管仅对ASM的炎症作用对于AHR不足，但MUC5AC介导的堵塞是一种基本机制。抑制MUC5AC可能有效治疗哮喘和其他肺部疾病，在该疾病中也被过量生产。 2。哮喘是一种慢性疾病，其特征是情节性气道高反应性（AHR），并具有可变程度的嗜酸性和嗜中性粒细胞炎症的重塑。哮喘会引起明显的发病率和死亡率，并且大约10％的患者患有对当前疗法具有抗性的疾病。该小组消耗的50％至60％的医疗保健费用归因于哮喘，强调了发现新疗法的必要性。哮喘的临床表达是异质的，并且发现了几种不同的表型。鉴定驱动哮喘亚型的分子机制具有揭示药物靶标，生物标志物预测治疗反应并适当靶向治疗的潜力，这是Th2细胞因子拮抗剂的临床研究所证明的。除TH2途径外，注意力集中在Th17细胞因子作为严重哮喘病生理学的候选驱动因子上。 IL-17a和F可以扩增选定的NF-κB依赖性信号传导途径，例如TNFα诱导的NF-κB，这是哮喘气道中上调的细胞因子，并在过敏原挑战和实验性鼻病毒感染后进一步上调。特别是，IL-17A可能通过上调CSF3和CXCL趋化因子，粘液腺增生，AHR和皮质类固醇耐药而导致嗜中性粒细胞气道炎症。针对TH2和TH17炎症途径的治疗策略目前正在哮喘中积极研究。但是，这两种途径在个别患者中的活动性质和程度尚不清楚。 Th2细胞因子可以负调节Th17细胞因子的表达，并在体外或体内抑制Th2细胞因子具有增加IL-17A产生和IL-17A依赖性气道炎症的潜力。因此，Th2和Th17途径之间的串扰是复杂的，并且已经提出，靶向Th2细胞因子可能促进皮质类固醇抗皮质激素的IL-17依赖性嗜中性粒细胞性气道炎症。在这个项目中，我们表明TH2和TH17相关的基因表达特征在哮喘患者的气道中互斥，但两者都与嗜酸性粒细胞炎症有关。 同样，使用HDM诱导的哮喘的体内临床前模型，我们表明，Th2和Th17细胞因子的治疗靶向可以导致相对途径的活性扩增。因此，同时破坏这两种途径的治疗剂可能会显示出多种患者人群的疗效。