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Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans

在罕见疾病闭塞性细支气管炎的啮齿动物模型中进行概念治疗干预的验证

基本信息

批准号：
10040120
负责人：
Scott M Palmer
金额：
$ 24.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040120
关键词：
Acute Address Air Animal Disease Models Attenuated Biological Biological Models Bolus Infusion Bronchiolitis Obliterans Butter Cells Chemicals Chronic Clinical Data Development Diacetyl Disease Disease Progression Dose ERBB2 gene Epidermal Growth Factor Receptor Epithelial Cells Exposure to FDA approved Female Fibrosis Flavoring Food Gender Goals Health Care Costs Histologic Human Human Characteristics Hyaluronan Industry Inflammation Inhalation Interleukin-8 Intervention Lead Life Expectancy Light Link Liquid substance Literature Lung MMP9 gene Metalloproteases Modeling Occupational Occupational Exposure Phosphorylation Physiological Play Pre-Clinical Model Prevention Production Proteomics Publishing Pulmonary Fibrosis Quality of life Rare Diseases Rattus Receptor Signaling Reporting Respiratory physiology Rodent Model Role Signal Transduction Testing Therapeutic Intervention Translating Translations Trastuzumab Treatment Efficacy airway epithelium airway obstruction clinically relevant drug candidate effective therapy epithelial injury erbB-2 Receptor erythritol anhydride exposed human population first-in-human gender difference in vitro Model inhibitor/antagonist insight male neutrophil novel pre-clinical preclinical study prevent prophylactic response small molecule inhibitor therapeutic candidate therapy development treatment response vapor

项目摘要

Bronchiolitis obliterans (BO) is a poorly understood rare disease. Inhalation of flavoring chemicals used in the food manufacturing industry directly contributes to the development and progression of the occupational form of BO known as ‘popcorn lung’. BO is characterized by neutrophilic inflammation, altered lung function and persistent airway fibrosis that can lead to reduced quality of life, increased health care costs and reduced life expectancy. Because of its rarity, there have been no effective therapies developed for any form of BO. Critical impediments to the advancement of effective therapies for BO have been: 1) the lack of an appropriate pre-clinical model for hypothesis driven proof of concept testing of candidate therapeutics; and, 2) a poor understanding of basic disease mechanisms to guide hypothesis driven targeted interventions. We have directly addressed these impediments as follows. First, we have recapitulated in rats the clinical observation that workplace exposure to the artificial butter flavoring compound diacetyl (2-,3-butanedione; DA) causes BO in humans1. Second, because epithelial injury is central to the development of other forms of fibrosis, we have modeled DA vapor exposure of the human airway using primary human airway epithelial cells. Taken together these represent the enabling advances by virtue of which this proposal was developed. Preliminary data from our in vitro model system shows that DA exposure induces persistent selective phosphorylation of the epidermal growth factor receptor (EGFR) and the closely related co-receptor ErbB2. Similarly, we show that the DA exposed airway epithelium secretes significantly increased quantities of interleukin (IL) 8, hyaluronan (HA) and matrix metalloprotease (MMP) 9 in an EGFR dependent manner. IL-8, HA and MMP9 are all pathognomonic of BO and have been plausibly linked with the development of airway fibrosis in other animal models of disease. Consistent with this, we show significant increases in IL-8, HA, and MMP9 in the DA-induced rodent model as BO develops and progresses. Therefore our hypothesis is that blocking EGFR or ErbB2 using FDA approved small molecule inhibitors will prevent disease development and progression in our rodent model of DA-induced occupational BO. To test our hypothesis we have developed the following Specific Aims: Aim 1: Determine the efficacy of prophylactic inhibition of the EGFR with the FDA approved specific inhibitor Icotinib, or ErbB2 with the FDA approved specific inhibitor Trastuzumab in attenuating the development of neutrophilic inflammation, altered lung function and persistent airway fibrosis observed in DA-induced BO both in male and female rats. Aim 2: Determine the efficacy of therapeutic intervention of the EGFR with Icotinib, or ErbB2 with Trastuzumab in preventing the progression of previously established neutrophilic inflammation, altered lung function and persistent airway fibrosis observed in DA induced BO in both male and female rats.

闭塞性细支气管炎（BO）是一种人们知之甚少的罕见疾病。吸入使用的调味化学品食品制造业直接促进了职业的发展和进步 BO 的形式被称为“爆米花肺”。 BO 的特点是中性粒细胞炎症、肺功能改变和持续性气道纤维化，可能导致生活质量下降、医疗保健费用增加和减少预期寿命。由于其罕见，目前还没有针对任何形式的 BO 开发出有效的疗法。阻碍 BO 有效治疗的主要障碍是：1）缺乏有效的治疗方法。用于候选疗法的假设驱动概念验证测试的适当临床前模型；以及，2) 对基本疾病机制的了解不足，无法指导假设驱动的有针对性的干预措施。我们有直接解决这些障碍如下。首先，我们回顾了大鼠的临床观察工作场所接触人造黄油调味化合物二乙酰（2-,3-丁二酮；DA）会导致 BO 在人类1.其次，由于上皮损伤是其他形式纤维化发展的核心，我们有使用原代人气道上皮细胞模拟人气道的 DA 蒸气暴露。合在一起这些代表了促成本提案得以制定的进展。我们的体外模型系统的初步数据表明，DA 暴露会诱导持续选择性表皮生长因子受体 (EGFR) 和密切相关的辅助受体 ErbB2 的磷酸化。同样，我们发现暴露于 DA 的气道上皮分泌的白细胞介素 (IL) 8、透明质酸 (HA) 和基质金属蛋白酶 (MMP) 9 以 EGFR 依赖性方式发挥作用。白细胞介素-8, HA 和 MMP9 都是 BO 的特征，并且似乎与气道的发育有关其他疾病动物模型中的纤维化。与此一致的是，我们发现 IL-8、HA 和 DA 诱导的啮齿动物模型中 MMP9 作为 BO 的发育和进展。因此我们的假设是使用 FDA 批准的小分子抑制剂阻断 EGFR 或 ErbB2 将预防疾病 DA 诱导的职业性 BO 啮齿动物模型的发育和进展。来测试我们的假设我们制定了以下具体目标：目标 1：确定 FDA 批准的特定抑制剂预防性抑制 EGFR 的功效埃克替尼 (Icotinib) 或 ErbB2 与 FDA 批准的特异性抑制剂曲妥珠单抗 (Trastuzumab) 一起减缓疾病的发展 DA 诱导的 BO 中观察到中性粒细胞炎症、肺功能改变和持续性气道纤维化在雄性和雌性大鼠中。目标 2：确定使用埃克替尼治疗 EGFR 或使用曲妥珠单抗治疗 ErbB2 的疗效预防先前已形成的中性粒细胞炎症的进展、肺功能的改变以及在雄性和雌性大鼠中，在 DA 诱导的 BO 中观察到持续性气道纤维化。