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.
Bronchiolitis obliterans (BO) is a rare disease characterized by fibrotic airway obstruction and for which there are no effective treatments. We have now developed a novel rodent model that enables the prioritization of therapeutic interventions for immediate translation to first in human trials. Successful completion of the proposed studies will enable first in human trials and the development of effective therapies for this rare disease.
