Identification of mechanisms involved in the acute airway toxicity induced by parathion

Abstract

Organophosphates are still widely used worldwide and cause thousands of intoxications every year. In this work we investigated the mechanisms of parathion (Pth) airway toxicity, using biochemical and functional approaches. A plethysmographic technique for unrestrained guinea pigs was used to analyze Pth-induced modifications of airway mechanics and responsiveness to acetylcholine (ACh: 0.1-3.2 mg/ml, 2-min inhalation each dose). The isolated perfused rabbit lung preparation was used to study the acute effects of Pth on airway responsiveness to ACh (10(-8)-10(-3) M), histamine (10(-8)-10(-3) M) and substance P (10(-10)-10(-6) M), pulmonary acetylcholinesterase inhibition and cytochrome P450 (P450) activity, and their modifications with previous administration of Pth (1 mg/kg s.c. daily, 7 days). We found that: (1) In guinea pigs Pth (3.2-17 mg/kg i.p.) produced a dose-dependent increase in a lung resistance index (iRL), which was greatly reverted (approximately 50%) by salbutamol (2 mg/ml, 2-min inhalation, or 10 microg/kg i.p.). This salbutamol effect was transient (5-10 min), suggesting that this bronchodilator triggered additional obstructive mechanisms. (2) Pth increased the water content in lung parenchyma samples, but not in trachea or bronchi, and augmented the respiratory secretions measured through monosaccharide content in bronchoalveolar lavage. (3) The increase in iRL was greater in female animals, probably due to a higher P450 basal activity, and completely blocked by pharmacological inhibition of P450 with piperonyl butoxide (500 mg/kg i.p.). (4) In male guinea pigs a subclinical dose of Pth (10 mg/kg i.p.) induced airway hyperresponsiveness to ACh. In isolated perfused rabbit lung Pth (10(-6) M) produced airway hyperresponsiveness to ACh and histamine, the latter prevented by atropine (10(-5) M). (5) Repetitive exposure to subclinical doses (1 mg/kg s.c.) of Pth during 1 week caused approximately 80% inhibition of P450 activity in rabbits, which was not enough, however, to prevent the functional manifestation of Pth toxicity in the airways.

Pesticides and Atopic and Nonatopic Asthma among Farm Women in the Agricultural Health Study

“…Recent animal studies have demonstrated that organophosphates induce airway hyperreactivity, potentially at doses below those causing acetylcholinesterase inhibition (6,7,21). Pesticides may also modulate inflammatory responses to other farm exposures, such as endotoxin and allergens.…”

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release

“…In a previous study using an in vivo model of organophosphate poisoning, we (35) found that guinea pigs with an ongoing parathion-induced bronchoobstruction responded to salbutamol administration with a transient bronchodilation, which was followed by a returning of the bronchoobstruction. Those results allowed us to speculate that salbutamol triggered some obstructive mechanism that rapidly counteracted its relaxing action.…”

Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model

“…Mechanical ventilation supplies a constant V I so a reduction in this ratio is a result of decreased V E possibly due to severe loss of pulmonary compliance or outright obstruction of the lower airways resulting in a rupture of the tracheal seal, thereby causing a reduction in expired volume compared to inspired volume. Future studies using this animal model could benefit from measurement of airway pressure, which we would expect to increase due to pulmonary toxicity of OP [10,18].…”

“…Acute effects of poisoning include central apnea [1][2][3][4], seizures [5,6], bronchorrhea, bronchoconstriction, muscle weakness, myosis, urination, and salivation [7][8][9][10]. The morbidity and mortality from acute OP poisoning is attributed to respiratory failure [11] but the relative contributions of the central and peripheral effects in producing collapse of the respiratory system [12] is unclear.…”