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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）是一种罕见的疾病。吸入用于调味的化学物质