Interactions between cytochrome P-450 activities and ozone-induced modulatory effects on endothelial permeability in rabbit lungs: influence of gender.
Delaunois, Annie ; Florquin, Sandra ; et al
in Inhalation Toxicology (1999), 11(11), 999-1014
The effects of rabbit exposure to ozone (O(3)) (0.4 ppm for 4 h) on two different cytochrome P-450 (CYP450)-dependent activities were investigated. In turn, the role of CYP450 in the inhibitory effect of ... [more ▼]
The effects of rabbit exposure to ozone (O(3)) (0.4 ppm for 4 h) on two different cytochrome P-450 (CYP450)-dependent activities were investigated. In turn, the role of CYP450 in the inhibitory effect of O(3) on acetylcholine (ACh)-evoked increase in endothelial permeability was also assessed. Immediately after the period of exposure, rabbits of both sexes were sacrificed and their lungs were extracted. Some lungs were used for preparation of microsomes and measurement of 7-ethoxyresorufin O-deethylase (EROD) and parathion oxidase activities. Other rabbit lungs were isolated and recirculatingly blood-free perfused. Arterial, venous pressures, and lung weight were continuously recorded. Capillary pressure was measured by applying the double occlusion method. Capillary filtration coefficient (K(f,c)) was evaluated by measuring the amount of fluid filtering through the endothelium when vascular pressures were suddenly increased. Dose-response curves to ACh were constructed in air- or O(3)-exposed rabbits. Some animals were pretreated with piperonyl butoxide (PBO), a well-known inhibitor of CYP450. O(3) significantly reduced both EROD and parathion oxidase lung microsomal activities in females, while it had no effect in males. Exposure to O(3) strongly inhibited the ACh-induced increase in K(f,c). Pretreatment with PBO reversed the modulatory effect of O(3) on endothelial permeability in male rabbits, but not in females. It was concluded (1) that inhibition of 2 different CYP450-dependent activities after exposure to 0.4 ppm O(3) for 4 h appears to be a gender-dependent phenomenon, and (2) that CYP450 is probably involved in the O(3)-evoked inhibitory mechanism against ACh-induced increase in endothelial permeability, but only in males. [less ▲]Detailed reference viewed: 26 (2 ULg)
Identification of mechanisms involved in the acute airway toxicity induced by parathion.
; ; et al
in Naunyn-Schmiedeberg's Archives of Pharmacology (1999), 360(6), 699-710
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 ... [more ▼]
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. [less ▲]Detailed reference viewed: 20 (0 ULg)
Comparison of ozone-induced effects on lung mechanics and hemodynamics in the rabbit.
Delaunois, Annie ; ; et al
in Toxicology and Applied Pharmacology (1998), 150(1), 58-67
The effects of rabbit exposure to ozone (O3)(0.4 ppm for 4 h) on pulmonary mechanical properties and hemodynamics have been investigated on the isolated perfused lung model. Tracheal pressure, airflow ... [more ▼]
The effects of rabbit exposure to ozone (O3)(0.4 ppm for 4 h) on pulmonary mechanical properties and hemodynamics have been investigated on the isolated perfused lung model. Tracheal pressure, airflow, and tidal volume were measured in order to calculate lung resistance (RL) and dynamic compliance (Cdyn). Using the arterial/venous/double occlusion method, the total pressure gradient (deltaPT) was partitioned into four components (arterial, pre-, postcapillary and venous). Dose-response curves to acetylcholine (ACh), substance P (SP), and histamine were constructed in lungs isolated from rabbits immediately or 48 h after air or O3 exposure O3 induced a significant increase in the baseline value of deltaPt, more markedly 48 h after the exposure. Immediately after the exposure, O3 partly inhibited the ACh-, SP-, and histamine-induced decreases in Cdyn and increases in RL. This inhibitory effect was still in part present 48 h after O3 treatment. In the groups studied immediately after exposure, O3 did not significantly modify the ACh-, SP-, and histamine-induced vasoconstriction. Forty-eight hours after exposure, O3 induced a contractile response to ACh and SP in the arterial segment but decreased the response to histamine. We conclude that O3 can induce direct vascular constriction. Directly, but also 48 h after exposure, O3 can inhibit the ACh-, SP-, and histamine-induced changes in lung mechanical properties. Ozone can also induce some changes in the intensity and in the location of the vascular responses to ACh, SP, and histamine. [less ▲]Detailed reference viewed: 29 (0 ULg)
Ozone-induced increase in microvascular permeability and hyperactivity to acetyl-choline in isolated perfused rabbit lungs
; ; et al
Poster (1997)Detailed reference viewed: 2 (0 ULg)
Ozone-Induced Stimulation of Pulmonary Sympathetic Fibers: A Protective Mechanism against Edema
Delaunois, Annie ; ; Dessy, Cécile et al
in Toxicology and Applied Pharmacology (1997), 147(1), 71-82
Tropospheric ozone exerts well-described toxic effects on the respiratory tract. Less documented, by contrast, is the ability of ozone to induce protective mechanisms against agents that are toxic to the ... [more ▼]
Tropospheric ozone exerts well-described toxic effects on the respiratory tract. Less documented, by contrast, is the ability of ozone to induce protective mechanisms against agents that are toxic to the lungs. In particular, interactions between ozone and the sympathetic nervous system have never been considered. Using a model of permeability edema in isolated perfused rabbit lungs, we report here that, immediately after exposure of rabbits to 0.4 ppm ozone for 4 hr, the pulmonary microvascular responses to acetylcholine and substance P are completely blocked. Several lines of evidence, including partial inhibition of the ozone-induced protective effect by several drugs (alpha2- and beta-adrenergic antagonists, neuropeptide Y antagonist, guanethidine), measured levels of released catecholamines in blood and urine and the in vitro response of isolated lungs exposed to 0.4 ppm ozone all seem to suggest that ozone can stimulate pulmonary adrenergic fibers and induce the local release of catecholamines and neuropeptide Y, this resulting in transient protection against pulmonary edema. We also showed that, 48 hr after the exposure, ozone increased the baseline microvascular permeability and the response to low concentrations of acetylcholine [less ▲]Detailed reference viewed: 46 (0 ULg)
Interactions between acetylcholine and substance P effects on lung mechanics in the rabbit.
Delaunois, Annie ; Gustin, Pascal ; et al
in Fundamental & Clinical Pharmacology (1996), 10(3), 278-88
The pharmacological mechanisms involved in the acetylcholine (ACh)- and substance P (SP)-induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and ... [more ▼]
The pharmacological mechanisms involved in the acetylcholine (ACh)- and substance P (SP)-induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and airflow were measured by a Fleisch pneumotachograph and pressure transducers. Air volume, lung resistance (RL) and dynamic compliance (Cdyn) were calculated. ACh induced a dose-dependent increase in Ptr and RL, and a decrease in Cdyn. These effects were strongly prevented by atropine, and partly by SR140333, a neurokinin NK1 receptor antagonist; SR48968, a neurokinin NK2 receptor antagonist; indomethacin and antihistaminics. Ketanserin had no significant protective effect against ACh. SP also induced concentration-dependent increases in RL and decreases in Cdyn. SR140333 and atropine strongly inhibited the effects of SP, while ketanserin, SR48968, antihistaminics and indomethacin did not protect the lungs against this drug. 5-hydroxytryptamine induced no significant change in lung mechanic parameters. Cumulative concentrations of histamine increased RL and decreased Cdyn. We conclude that ACh-induced changes in lung resistance and compliance are in part mediated by a direct effect on airway smooth muscle and in part by the stimulation of C fibers, by the release of histamine from mast cells and by the synthesis of arachidonic acid metabolites. In turn, the effects of SP on lung mechanics are partly due to cholinergic activation. [less ▲]Detailed reference viewed: 68 (0 ULg)