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An IFN-gamma/mast cell axis in THS-exacerbated allergic airw

Institution: Stanford University
Investigator(s): Stephen Galli, M.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IR-0012 Award: $478,312
Subject Area: Environmental Exposure/Toxicology
Award Type: High Impact Research Project Award
Abstracts

Initial Award Abstract

Asthma is one of the most prevalent chronic respiratory disorders of children and adults, with enormous impact on the health of individual patients and high annual costs in health care resources and time lost from school and work. Third hand smoke (THS), which represents the accumulation of secondhand smoke (SHS) both on indoor surfaces and in dust, can, with time, become progressively more toxic than SHS. It is well known that the children of smokers are at increased risk for developing asthma and for exacerbations of that disease if they already have it. However, unfortunately, the influence on human health of exposure to THS through involuntary inhalation, digestion, or dermal uptake, remain unknown. Cockroach allergen (CRA) was found to be the most important risk factor for asthma in inner-city households. The National Cooperative Inner-City Asthma Study found that asthma morbidity was highest in children with both a positive skin-test response and a high level of exposure in the bedroom to the cockroach allergens. This suggests that children in low-income urban homes are more likely to be at risk of exposure to CRA, in addition to the risk of exposure to SHS and THS. Supported by a prior TRDRP award (Grant # 21RT-0147), we developed a new mouse model of CRA-induced allergic asthma and, using that model, we found that an important component of THS, namely 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), through contact with the skin, could increase the severity of airway inflammation and airway hyperreactivity (AHR), the two characteristic features of asthma, in such “asthmatic” mice. We further found that NNK worsened airway inflammation and AHR in that asthma model by binding to the NNK receptor (namely the alpha 7 nicotinic acetylcholinergic receptor [alpha7 nAChR]) expressed on mast cells (MCs), immune cells that are normally present in the lungs. Our previous research also showed that interferon-gamma (IFN-g), a key molecule in inflammation, can worsen asthma pathology in mouse models by binding to IFN-g receptors (IFN-gRs) on MCs. There is evidence that IFN-g can worsen asthma in humans as well. We therefore studied whether IFN-g could influence our model of CRA-induced asthma. Our preliminary findings suggest that IFN-g can stimulate activated MCs to release higher amounts of asthma-inducing products, and this can be enhanced further when IFN-g is used together with the THS component, NNK. Moreover, in our mouse model of asthma, the ability of dermal NNK exposure to worsen airway inflammation and AHR was decreased in “asthmatic mice” treated with antibodies that neutralized IFN-g, and we found that this antibody treatment was more effective in male than female mice. Our proposed project will employ state-of-the-art approaches to test our hypothesis that IFN-g can exacerbate the effects of THS components on asthma pathology and will define mechanisms that can account for this effect, such as effects of IFN-g on airway mast cells. We will be able to define: 1) to what extent IFN-g, acting via IFN-gRs expressed on MCs, can influence the ability of epicutaneous exposure to NNK to exacerbate AHR and airway inflammation in a clinically relevant asthma model in mice; 2) whether and to what extent gender can influence the ability of IFN-g to exacerbate this asthma model. If our proposed work were to confirm and extend our preliminary results, this will reveal an entirely new (and unexpected) mechanism by which IFN-g, through stimulating MCs, can influence the ability of THS to worsen airway pathology. Our proposed research, if successful, will enhance our knowledge of previously unknown mechanisms through which THS can increase the severity of asthma, and may suggest novel approaches to reduce pathology in individuals exposed to THS.