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See detailEvaluation of particle translocation across the alveolo-capillary barrier in isolated perfused rabbit lung model
Nemmar, A.; Hamoir, J.; Nemery, B. et al

in Toxicology (2005), 208(1), 105-113

Particulate air pollution is associated with respiratory and cardiovascular morbidity and mortality. It has been suggested that ultrafine particles are able to translocate from the airways into the ... [more ▼]

Particulate air pollution is associated with respiratory and cardiovascular morbidity and mortality. It has been suggested that ultrafine particles are able to translocate from the airways into the bloodstream in vivo. We have investigated this in an isolated perfused and ventilated rabbit lung preparation lacking pulmonary lymphatic flow. Fluorescent polystyrene particles of different diameters (24, 110 or 190 nm) and surface chemistry (carboxylate or amine modified) were injected either intratracheally (i.t.) or intravascularly (i.v.) and, after a period of 2 h, their presence in the perfusion liquid or in the bronchoalveolar lavage (BAL) fluid, was assessed by spectrofluorimetry. Vascular pressures and lung weights were monitored. Following the i.t. administration, no particle translocation was observed from the alveoli into the vascular compartment. Similarly, no particle translocation was found after i.v. administration of particles. However, when microvascular permeability was pharmacologically increased by administering histamine (10(-4) M) in the vascular compartment, inducing a positive driving force provided by fluid filtration, a fluorescent signal in BAL was recorded (2.5 +/- 1% of the dose of particles administered), suggesting a translocation of particles through the alveolo-capillary barrier. We conclude that ultrafine polystyrene particles cannot significantly diffuse from lung into the vascular compartment in our model, but they are able to translocate in the opposite direction when the microvascular permeability is increased by histamine. The relevance of these ex vivo findings for the in vivo translocation of inhaled ultrafine particles remains to be established [less ▲]

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See detailEffect of polystyrene particles on lung mirovascular permeability in isolated perfused rabbit lungs : role of size and surface proporties
Hamoir, J.; Nemmar, A.; Halloy, D. et al

in Toxicology and Applied Pharmacology (2003), 190

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See detailRole of Substance P and Tachykinin Receptor Antagonists in Citric Acid-Induced Cough in Pigs
Moreaux, B.; Nemmar, A.; Vincke, G. et al

in European Journal of Pharmacology (2000), 408(3), 305-312

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in ... [more ▼]

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK(1), NK(2) or NK(3) receptor antagonists, SR 140333 (nolpitantium), SR 48968 (saredutant) and SR 142801 (osanetant), respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK(1), NK(2), NK(3) receptors are also demonstrated in this reflex. [less ▲]

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See detailInhibiting Effect of Ammonia on Citric Acid-Induced Cough in Pigs: A Possible Involvement of Substance P
Moreaux, B.; Nemmar, A.; Beerens, Dominique ULg et al

in Pharmacology & Toxicology (2000), 87(6), 279-285

The effect of ammonia on the cough response to citric acid and on substance P release from C-fibers involved in this reflex was assessed. For a period from one to four days, piglets were exposed, in an ... [more ▼]

The effect of ammonia on the cough response to citric acid and on substance P release from C-fibers involved in this reflex was assessed. For a period from one to four days, piglets were exposed, in an inhalation chamber, to ammonia at a concentration of 15 or 30 ppm. During exposure, cough induction tests were done every two days. Recovery of the cough reflex after ammonia exposure was also determined. In a separate group of piglets exposed for 2 days to 30 ppm ammonia, substance P content was determined in bronchial and tracheal lavage fluids and in the tracheal and bronchial mucosa. Ammonia (30 ppm) was found to inhibit coughing significantly (the cough frequency was reduced by 64%) after a two-day exposure. In animals exposed for 4 days to this ammonia concentration, the recovery ranged from 3 to 7 days (mean: 5 days). The same ammonia concentration also caused the substance P content to increase significantly in bronchoalveolar lavage fluid (to 432% of its initial value) and tracheal lavage fluid (to 149%) and to decrease significantly in the tracheal mucosa (-58%), however the content in bronchial mucosa was not significantly affected (-43%). Exposure to 15 ppm ammonia had no effect on the frequency of citric acid-induced coughing. In conclusion, ammonia inhibits citric acid-induced coughing in pigs at concentrations that can be detected in piggeries. This inhibitory effect may be related to substance-P depletion in C-fiber endings [less ▲]

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See detailInflammatory Effect of Intratracheal Instillation of Ultrafine Particles in the Rabbit: Role of C-Fiber and Mast Cells
Nemmar, A.; Delaunois, Annie ULg; Nemery, B. et al

in Toxicology and Applied Pharmacology (1999), 160(3), 250-61

The effects of ultrafine polystyrene carboxylate-modified (fluorospheres) on inflammatory processes are being investigated in rabbit lungs. One milliliter of sterile NaCl (0.9%) containing 4 mg of ... [more ▼]

The effects of ultrafine polystyrene carboxylate-modified (fluorospheres) on inflammatory processes are being investigated in rabbit lungs. One milliliter of sterile NaCl (0.9%) containing 4 mg of ultrafine particles (UFP) was intratracheally instilled into anesthetized rabbits. The control animals were only instilled with sterile NaCl (0.9%). Twenty hours after being instilled, the rabbits were killed and their lungs were excised and then tracheally perfused with phosphate-buffered physiological solution (PBS). The lung effluents, collected from small holes made in the pleura, were analyzed for substance P (SP) and histamine content by radioimmunoassay (RIA) methods, after administration of drugs. In addition, in other groups of rabbits, the lung wet/dry (W/D) weight ratio was monitored, as were the cellular and protein contents in bronchoalveolar lavage (BAL). Electron microscopy examination was also performed. In tracheally superfused experiments, UFP induced a significant enhancement of both SP and histamine releases after administration of capsaicin (10(-4) M), to stimulate C-fiber, and carbachol (10(-4) M), a cholinergic agonist. A significant increase in histamine release was also recorded in the UFP-instilled group following the administration of both SP (10(-6) M) plus thiorphan (10(-5) M) and compound 48/80 (C48/80) (10(-3) M) to stimulate mast cells. In addition, the BAL fluid analysis of UFP groups showed an influx of neutrophils and an increase in total protein concentration. An increase in the lung WW/DW ratio was also recorded. Both epithelial and endothelial injuries were observed in the lungs of UFP-instilled rabbits. The pretreatment of rabbits in vivo with a mixture of either SR 140333 and SR 48368, a tachykinin NK(1) and NK(2) receptor antagonist, or a mixture of terfenadine and cimetidine, a histamine H(1) and H(2) receptor antagonist, prevented UFP- induced neutrophil influx and increased total proteins and lung WW/DW ratio. Therefore, it can be concluded that chemicaly inert, electrically charged UFP induce a pulmonary inflammatory process during which the release of SP and histamine from C-fibers and mast cells was enhanced after various stimuli. These latter mediators can also modulate the inflammatory process. [less ▲]

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See detailModulatory Effect of Imetit, a Histamine H3 Receptor Agonist, on C-Fibers, Cholinergic Fibers and Mast Cells in Rabbit Lungs in Vitro
Nemmar, A.; Delaunois, Annie ULg; Beckers, Jean-François ULg et al

in European Journal of Pharmacology (1999), 371(1), 23-30

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release ... [more ▼]

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10(-4) M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine release (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H3 receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H3 receptors on C-fibers was confirmed. [less ▲]

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See detailRadioimmunoassay of Substance P in Lung Perfusate
Nemmar, A.; Gustin, Pascal ULg; Delaunois, Annie ULg et al

in Journal of Pharmacological & Toxicological Methods (1998), 39(2), 109-115

A radioimmunoassay of the undecapeptide substance P (SP) and its application in rabbit lung superfusate has been developed. The assay was based on the use of a radioactive tracer, 125I-SP-Tyr8, which ... [more ▼]

A radioimmunoassay of the undecapeptide substance P (SP) and its application in rabbit lung superfusate has been developed. The assay was based on the use of a radioactive tracer, 125I-SP-Tyr8, which showed, with an excess of antibodies, a specific binding greater than 90% and a nonspecific binding lower than 2%. This tracer was stable for 4 weeks at -20 degrees C. Its specific radioactivity was 384 Ci/mmol. The assay's lower limit of detection was 10 pg/ml (0.7 fmol). The determination of SP in rabbit lung perfusate required extraction and concentration using octadecylsilane cartridges. Under these conditions, the recovery of SP from experiments on lung perfusates (n=4) was 75.0+/-4.5%, and the intraassay and interassay coefficients of variation were 7.3+/-1.9% and 10.7+/-1.3%, respectively. Amounts of SP released in rabbit lung perfusates were determined following stimulation of pulmonary C fibers with capsaicin (10(-4) M). During the stimulation period, the values of SP from lung perfusates (n=6) increased significantly when compared with baseline values. [less ▲]

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See detailRelationship between Parathion and Paraoxon Toxicokinetics, Lung Metabolic Activity, and Cholinesterase Inhibition in Guinea Pig and Rabbit Lungs
Lessire, Françoise ULg; Gustin, Pascal ULg; Delaunois, Annie et al

in Toxicology and Applied Pharmacology (1996), 138(2), 201-210

Kinetic parameters of parathion and paraoxon uptake were determined in isolated and perfused rabbit and guinea pig lungs. They were related to organophosphate-induced lung cholinesterase inhibition. A ... [more ▼]

Kinetic parameters of parathion and paraoxon uptake were determined in isolated and perfused rabbit and guinea pig lungs. They were related to organophosphate-induced lung cholinesterase inhibition. A single pass procedure was used to perfuse the lungs with an artificial medium perfusate containing paraoxon or parathion. The paraoxon and parathion concentrations were determined in the effluents collected at chosen intervals over an 18-min period beginning at the start of perfusion. Three inflowing concentrations (1 nmol/ml, 10 nmol/ml, and 20 nmol/ml) were tested in guinea pig lungs and one (10 nmol/ml) in rabbit lungs. Cholinesterase activity was determined at time 0 and at the end of the experiment. The lungs abundantly extracted paraoxon and parathion over the perfusion period. The extraction ratio was consistently greater in guinea pig than in rabbit lungs. The uptake velocity varied biexponentially in time, suggesting the existence of two compartments. Initial uptake velocities (A, B) and slopes (alpha and beta) were calculated for both compartments. In guinea pigs, A, B and A + B increased proportionally to the supply rate of paraoxon and parathion while a and b remained constant. No significant difference was observed between parathion and paraoxon uptake kinetics. Parameter B was the only one to differ significantly between the two species (rabbits: 8.19 +/- 1.53 for parathion and 6.85 +/- 1.26 for paraoxon; guinea pigs: 12.75 +/- 0.88 for parathion and 15.02 +/- 3.84 for paraoxon). In the lungs of both species, there was a linear relation between y, the percentage of cholinesterase inhibition induced by either organophosphate, and X, the total amount of drug taken up by the lung tissue (in nmol/g/18 min). The following equations were obtained: y = 0.128 x + 0.979 (R2 = 0.89, p < 0.001 for paraoxon); y = 0.120 x - 6.57 (R2 = 0.82, p < 0.005 for parathion). No difference was observed between the two organophosphates. After treatment with the cytochrome P450 inhibitor piperonyl butoxide, the above relations ceased to apply, but this treatment did not influence the kinetics of paraoxon and parathion uptake. The IC50 value calculated for paraoxon, i.e., the paraoxon concentration required to produce 50% inhibition of lung cholinesterase activity, was similar for guinea pigs (2.22 10(-7) +/- 0.22 M) and rabbits (2.36 10(-7) +/- 0.24 M). In conclusion, the biexponential evolution of the velocity of paraoxon and parathion uptake by the lungs thus demonstrates the presence of two pools. The lower extraction ratios calculated for rabbit lungs reflect the lower initial uptake velocity of the second compartment. In the range of concentrations investigated in guinea pigs, no saturable mechanism could be demonstrated for paraoxon and parathion. Cytochrome P450-related lung metabolic activity, through which parathion is converted to paraoxon, appears as a major step in parathion-induced lung cholinesterase inhibition, although it does not appear to affect parathion toxicokinetics [less ▲]

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