Asthma Exacerbation by Organophosphate Pesticides

Summary

Principal Investigator: ALLISON DEBORAH FRYER
Abstract: 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Antigen sensitization influences organophosphorus pesticide-induced airway hyperreactivity
    Becky J Proskocil
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Environ Health Perspect 116:381-8. 2008
  2. pmc IL-1 receptors mediate persistent, but not acute, airway hyperreactivity to ozone in guinea pigs
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Am J Respir Cell Mol Biol 39:730-8. 2008
  3. pmc β2-Agonists inhibit TNF-α-induced ICAM-1 expression in human airway parasympathetic neurons
    Zhenying Nie
    Division of Pulmonary and Critical Care Medicine, Medical School Oregon Health and Science University, Portland, Oregon, USA
    PLoS ONE 7:e44780. 2012
  4. pmc The therapeutic potential of Toll-like receptor 7 stimulation in asthma
    Matthew G Drake
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, USA
    Inflamm Allergy Drug Targets 11:484-91. 2012
  5. pmc Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs
    Becky J Proskocil
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA
    Am J Physiol Lung Cell Mol Physiol 304:L519-29. 2013
  6. pmc Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs
    Matthew G Drake
    Department of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA
    Am J Respir Cell Mol Biol 48:790-6. 2013
  7. pmc Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 8:e75351. 2013
  8. pmc Atropine-enhanced, antigen challenge-induced airway hyperreactivity in guinea pigs is mediated by eosinophils and nerve growth factor
    Norah G Verbout
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, 97239, USA
    Am J Physiol Lung Cell Mol Physiol 297:L228-37. 2009
  9. pmc Organophosphorus pesticides decrease M2 muscarinic receptor function in guinea pig airway nerves via indirect mechanisms
    Becky J Proskocil
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 5:e10562. 2010
  10. pmc Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science Univ, Portland, OR 97239, USA
    Am J Physiol Lung Cell Mol Physiol 300:L176-84. 2011

Scientific Experts

  • David Jacoby
  • Elad H Kaufman
  • Bart C Moulton
  • Allison D Fryer
  • Kirsten C Verhein
  • Becky J Proskocil
  • Matthew G Drake
  • Donald A Bruun
  • Pamela J Lein
  • K S Buels
  • Zhenying Nie
  • Erin L Foster
  • Norah G Verbout
  • Francesco G Salituro
  • Nico Van Rooijen
  • Burton F Dickey
  • Mark W Ledeboer
  • Scott E Evans
  • A D Fryer
  • Isabella W Jacoby
  • Nancy A Lee
  • Mehdi S Hazari
  • Eric L Simpson
  • Lorna J Fredrikson
  • James J Lee
  • Charles M Thompson
  • Gerald J Gleich
  • Jesse K Lorton
  • Kirsten C Blensly

Detail Information

Publications14

  1. pmc Antigen sensitization influences organophosphorus pesticide-induced airway hyperreactivity
    Becky J Proskocil
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Environ Health Perspect 116:381-8. 2008
    ..In support of this hypothesis, we have demonstrated that environmentally relevant concentrations of OPs induce airway hyperreactivity in guinea pigs...
  2. pmc IL-1 receptors mediate persistent, but not acute, airway hyperreactivity to ozone in guinea pigs
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Am J Respir Cell Mol Biol 39:730-8. 2008
    ..Furthermore, preventing hyperreactivity was accompanied by decreased eosinophil major basic protein deposition within the lung, suggesting that IL-1 affects eosinophil activation 3 days after ozone exposure...
  3. pmc β2-Agonists inhibit TNF-α-induced ICAM-1 expression in human airway parasympathetic neurons
    Zhenying Nie
    Division of Pulmonary and Critical Care Medicine, Medical School Oregon Health and Science University, Portland, Oregon, USA
    PLoS ONE 7:e44780. 2012
    ..We have shown that inflammatory cytokines induce eotaxin and ICAM-1 expression in parasympathetic neurons...
  4. pmc The therapeutic potential of Toll-like receptor 7 stimulation in asthma
    Matthew G Drake
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, USA
    Inflamm Allergy Drug Targets 11:484-91. 2012
    ..We examine the current understanding of TLR7 as a therapeutic target and its translation to asthma treatment in humans...
  5. pmc Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs
    Becky J Proskocil
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA
    Am J Physiol Lung Cell Mol Physiol 304:L519-29. 2013
    ..These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures...
  6. pmc Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs
    Matthew G Drake
    Department of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA
    Am J Respir Cell Mol Biol 48:790-6. 2013
    ..Furthermore, TLR agonists independently cause AHR, albeit through a distinctly different mechanism from that of parainfluenza virus...
  7. pmc Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 8:e75351. 2013
    ..Neutrophil influx into bronchoalveolar lavage was not affected by MAPK inhibitors. Thus p38 and JNK MAPK mediate ozone-induced airway hyperreactivity through multiple mechanisms including prevention of neuronal M2 receptor dysfunction...
  8. pmc Atropine-enhanced, antigen challenge-induced airway hyperreactivity in guinea pigs is mediated by eosinophils and nerve growth factor
    Norah G Verbout
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, 97239, USA
    Am J Physiol Lung Cell Mol Physiol 297:L228-37. 2009
    ..Therefore, therapeutic strategies that target both eosinophil activation and NGF-mediated inflammatory processes in allergic asthma are likely to be beneficial...
  9. pmc Organophosphorus pesticides decrease M2 muscarinic receptor function in guinea pig airway nerves via indirect mechanisms
    Becky J Proskocil
    Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 5:e10562. 2010
    ....
  10. pmc Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor
    Kirsten C Verhein
    Department of Physiology and Pharmacology, Oregon Health and Science Univ, Portland, OR 97239, USA
    Am J Physiol Lung Cell Mol Physiol 300:L176-84. 2011
    ....
  11. pmc Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs
    Elad H Kaufman
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA
    J Allergy Clin Immunol 127:462-9. 2011
    ..Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs...
  12. pmc Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD
    Bart C Moulton
    Division Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, 97239, USA
    Br J Pharmacol 163:44-52. 2011
    ..Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease...
  13. pmc Eosinophils increase neuron branching in human and murine skin and in vitro
    Erin L Foster
    Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 6:e22029. 2011
    ....
  14. pmc Non-bronchodilating mechanisms of tiotropium prevent airway hyperreactivity in a guinea-pig model of allergic asthma
    K S Buels
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA
    Br J Pharmacol 165:1501-14. 2012
    ..We tested whether selective blockade of M(3) receptors, at the time of antigen challenge, blocks subsequent development of airway hyperreactivity in antigen-challenged guinea-pigs...