Mechanistic Studies Investigating the Role of Organophosphate Insecticide Exposure in the Development and Exacerbation of Asthma
Abstract
This grant proposed to determine whether organophosphate insecticides act upon the cholinergic system in the lungs increasing cholinergic neurotransmission and causing airway hyperresponsiveness, a key characteristic of asthma. Guinea pigs were treated with the organophosphate insecticides, chlorpyrifos, diazinon and parathion. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was used to assess the state of reactivity of the airways. Pharmacologic agents were used to define the roles that specific muscarinic receptors played in the changes in airway reactivity caused by the exposures. In summary, the results of the project demonstrate that organophosphates cause airway hyperreactivity at doses lower than those that inhibit acetylcholinesterase. Thus, inhibition of acetylcholinesterase is not a good biomarker of lung toxicity. Organophosphate induced hyperreactivity is linked to loss of neuronal M2 muscarinic receptor function. Decreased M2 function leads to increased release of acetylcholine and increased bronchoconstriction. Unlike other models of hyperreactivity, loss of M2 receptor function is not mediated by eosinophils in non-sensitized guinea pigs. Furthermore, preliminary data demonstrate that atopic, sensitized, guinea pigs are sensitive to organophosphates at a 10-fold lower dose than non-sensitized animals. Thus, doses of organophosphates that have no effect in non-sensitized guinea pigs, cause hyperreactivity in sensitized guinea pigs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA443663
Entities
People
- Ernst W. Spannhake
Organizations
- Johns Hopkins University