LATE-BREAKING ABSTRACT: Organophosphorus pesticides induce airway hyperreactivity via stimulation of alveolar macrophage Mac-1

Abstract

Background: Billions of people are exposed to chlorpyrifos (CPF), an organophosphorus pesticide (OP) used in agriculture worldwide, during its application or in their diet. Although safe levels of OP exposure are based on acetylcholinesterase (AChE) inhibition, we found OPs cause airway hyperreactivity at concentrations below this threshold and are associated with asthma. Objective: To characterize the mechanism of CPF-induced airway hyperreactivity. Methods: Guinea pigs were pretreated with clodronate i.n. to deplete macrophages and exposed to CPF s.c. Physiology was measured 24h later in anesthetized animals. OP effects were also evaluated in differentiated THP1 monocytes. THP1 cells were pretreated with either heparin 10 U/ml or antibody to Mac-1 10 µg/ml to antagonize Mac-1 receptors, then exposed to CPF (100 µM). RNA expression was quantified by real time PCR 24h later. Results: CPF caused airway hyperreactivity that was prevented by depleting macrophages and was independent of AChE inhibition. Blocking Mac-1 attenuated a CPF-induced increase in pro-inflammatory cytokine IL1β RNA expression in THP1 cells. Conclusions: OPs cause AChE-independent airway hyperreactivity by activating alveolar macrophages via Mac-1 receptor. Our results demonstrate a potential mechanism linking OP exposure to asthma pathogenesis and question the safety of current OP exposure level limits.