We have published papers demonstrating that organophosphates (OPs) induce airway hyperreactivity that is dose related, associated with loss of inhibitory neuronal M2 receptor function that normally limit acetylcholine release, and occurs at doses significantly lower than those that inhibit acetylcholinesterase. Here we show that sensitized animals (sensitized to an antigen but never challenged with antigen) are significantly more sensitive to OPs than non sensitized controls. 0.001mg/kg of the OP parathion did not cause hyperreactivity in non-sensitized guinea pigs but it doubled vagally-induced bronchoconstriction in sensitized animals. Higher doses of OPs, that did affect non sensitized animals, had a significantly greater effect in sensitized animals. In addition, we show that the mechanism for OP induced hyperreactivity does not depend on eosinophils in non sensitized animals, but is switched to require eosinophils after sensitization. We have developed a model for eosinophil-nerve interactions that includes active recruitment and adhesion of eosinophils to parasymapthetic nerves followed by activation and release of eosinophil major basic protein that is an endogenous antagonist for the M2 receptors. It is our hypothesis that OP-induced hyperreactivity in sensitized animals is mediated by OPs affecting chemotactic factors and adhesion molecules that enhance eosinophil recruitement to nerves, and also OP induced eosinophil activation. We will test this in vitro inhuman and guinea pig parasympathetic nerves and in vivo in guinea pigs. There are 4 specific aims: We will test whether increased sensitivity to OPs extends to the OP class and will include other non OP insecticides as controls (aim1).
Aim 2 will examine the ability of OPs to alter expression of chemotactic factors, their receptors and adhesion molecules and alter eosinophil-nerve interactions at a cellular level.
Aim 3 will examine how OPs activate eosinophils and aim 4 will determine the physiological relevance pathways identified in aims 2 and 3 in vivo. Human exposures to OPs is great in the United States and worldwide, given that more than 80% of children with asthma are also sensitized to antigen, these studies could directly impact levels of OP exposure considered safe and provide targets for intervention after exposure.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Nadadur, Srikanth
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Oregon Health and Science University
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Shaffo, Frances C; Grodzki, Ana Cristina; Fryer, Allison D et al. (2018) Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma. Am J Physiol Lung Cell Mol Physiol 315:L485-L501
Proskocil, Becky J; Bruun, Donald A; Garg, Jasmine A et al. (2015) The influence of sensitization on mechanisms of organophosphorus pesticide-induced airway hyperreactivity. Am J Respir Cell Mol Biol 53:738-47
Lee, James J; Protheroe, Cheryl A; Luo, Huijun et al. (2015) Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice. J Allergy Clin Immunol 135:477-87
Scott, Gregory D; Blum, Emily D; Fryer, Allison D et al. (2014) Tissue optical clearing, three-dimensional imaging, and computer morphometry in whole mouse lungs and human airways. Am J Respir Cell Mol Biol 51:43-55
Nie, Zhenying; Jacoby, David B; Fryer, Allison D (2014) Hyperinsulinemia potentiates airway responsiveness to parasympathetic nerve stimulation in obese rats. Am J Respir Cell Mol Biol 51:251-61
Drake, Matthew G; Evans, Scott E; Dickey, Burton F et al. (2013) Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs. Am J Respir Cell Mol Biol 48:790-6
Verhein, Kirsten C; Salituro, Francesco G; Ledeboer, Mark W et al. (2013) Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs. PLoS One 8:e75351
Scott, Gregory D; Fryer, Allison D; Jacoby, David B (2013) Quantifying nerve architecture in murine and human airways using three-dimensional computational mapping. Am J Respir Cell Mol Biol 48:10-6
Proskocil, Becky J; Bruun, Donald A; Jacoby, David B et al. (2013) Macrophage TNF-ýý mediates parathion-induced airway hyperreactivity in guinea pigs. Am J Physiol Lung Cell Mol Physiol 304:L519-29
Drake, Matthew G; Kaufman, Elad H; Fryer, Allison D et al. (2012) The therapeutic potential of Toll-like receptor 7 stimulation in asthma. Inflamm Allergy Drug Targets 11:484-91

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