Effects of Inhalation of Dust and Endotoxin on Respiratory Tracts of Pigs

in American Journal of Veterinary Research (1999), 60(9), 1055-1060

OBJECTIVE: To assess the effects of inhalation of feed flour dust and dustborne endotoxin on respiratory tracts of pigs. ANIMALS: 29 healthy Belgian Landrace pigs. PROCEDURE: Pigs housed in an ... [more ▼]

OBJECTIVE: To assess the effects of inhalation of feed flour dust and dustborne endotoxin on respiratory tracts of pigs. ANIMALS: 29 healthy Belgian Landrace pigs. PROCEDURE: Pigs housed in an environmental chamber were exposed for 6 days to feed flour dust (1 to 15 mg/m3) and dustborne endotoxins (50 to 2,500 ng/m3). Effects were evaluated by measuring albumin concentration, lactate dehydrogenase (LDH) activity, cell composition of nasal lavage (NL) and bronchoalveolar lavage (BAL) fluids and blood, and percentages of CD4+ and CD8+ T lymphocytes in blood and lavage fluids. Dustborne endotoxin was obtained by mixing endotoxins from Escherichia coli (serotype O127:B8) with feed flour before spraying the flour in the environmental chamber. RESULTS: Exposure did not affect cell composition of NL fluid or blood. Total cell counts of BAL fluids were increased in all groups exposed to dust. Macrophage counts were increased in pigs exposed to inhalable dust concentrations as low as 4.4 mg/m3, and lymphocyte counts were increased in groups exposed to high dust concentrations. Percentages of CD4+ and CD8+ T lymphocytes in blood and lavage fluids were unchanged. In all dust-exposed groups, albumin content of BAL fluid was increased, whereas LDH activity was unaffected. Macrophage and lymphocyte infiltration and edema in the bronchi were identified by light microscopy. Effects attributable to E. coli endotoxin exposure were not identified. CONCLUSIONS: Inhalation of feed flour dust did not affect nasal mucosa but did induce bronchial airway inflammation. Dustborne endotoxins did not have effects attributable to endotoxin alone. [less ▲]

A Morphometric and Functional Study of the Toxicity of Atmospheric Ammonia in the Extrathoracic Airways in Pigs

in Veterinary Research Communications (1996), 20(4), 381-399

The effects of atmospheric ammonia (NH3) on the nasal and tracheal mucosa of pigs were investigated by morphometric and functional methods. Pigs were exposed to four concentrations of NH3 [5 (control), 25 ... [more ▼]

The effects of atmospheric ammonia (NH3) on the nasal and tracheal mucosa of pigs were investigated by morphometric and functional methods. Pigs were exposed to four concentrations of NH3 [5 (control), 25, 50 and 100 ppm] for 6 days in a specially designed air-pollutant exposure chamber. Samples were taken from the turbinates and the trachea, and the respiratory mucosa was examined by light and scanning electron microscopy. Dose-response curves to carbachol and isoproterenol were constructed using isolated strips of tracheal smooth muscle, with or without epithelium. In pigs exposed to ammonia, considerable mucosal injuries were observed in the turbinates but not in the trachea. The number of neutrophils in the epithelial layer and in the lamina propria, and epithelial hyperplasia were closely and significantly correlated with the concentrations of ammonia (r = 0.894, p < 0.001; r = 0.727, P < 0.001; and r = 0.818, p < 0.001, respectively). Except for the lamina propria, all these changes were significant (p < 0.05) at ammonia concentrations as low as 25 ppm. The percentage of the surface of the turbinate mucosa that was ciliated tended to decrease with increasing ammonia concentration (r = 0.439, p < 0.082). Ammonia induced smooth-muscle hyperresponsiveness to carbachol with a close linear correlation between individual values of the carbachol-induced maximal effect and the NH3 concentrations (r = 0.526, p < 0.003). While mechanical destruction of the epithelium induced an increase in Emax in the control group, no difference was observed between the intact and denuded strips from animals exposed to ammonia. The response to isoproterenol was not influenced by ammonia. It was concluded that quantitative histological analysis of the inflammatory infiltration and epithelial hyperplasia in the turbinates is a useful tool for quantifying the effects of atmospheric pollutants in pigs; a 6-day exposure to ammonia induces nasal irritation and functional disturbances of the tracheal smooth-muscle contractions at concentrations as low as 25 ppm [less ▲]

Relationship between Parathion and Paraoxon Toxicokinetics, Lung Metabolic Activity, and Cholinesterase Inhibition in Guinea Pig and Rabbit Lungs

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 ▲]

Protective Effect of Various Antagonists of Inflammatory Mediators against Paraoxon-Induced Pulmonary Edema in the Rabbit

in Toxicology and Applied Pharmacology (1995), 132(2), 343-345

The protective effect of some antagonists of various inflammatory mediators against paraoxon-induced increases in endothelial permeability has been investigated in isolated perfused rabbit lungs. The ... [more ▼]

The protective effect of some antagonists of various inflammatory mediators against paraoxon-induced increases in endothelial permeability has been investigated in isolated perfused rabbit lungs. The edema induced by paraoxon has been previously related to a chain reaction mediated by acetylcholine. Lungs were ventilated and blood-free perfused with a constant flow. Arterial and venous pressures and lung weight were continuously recorded. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Paraoxon (4 x 10(-4) M) was injected in the perfusion circuit, in lungs with or without pretreatment with atropine, ketanserin, clonidine, morphine, indomethacin, and terfenadine plus cimetidine. Paraoxon induced a time-dependent increase in the Kf,c, a maximal effect being recorded 60 min after the injection. All the antagonists used as pretreatment significantly reduced the maximal effect recorded after paraoxon. These results show that muscarinic receptor antagonists, inhibitors of neuropeptides release, cyclooxygenase inhibitors, and 5-hydroxytryptamine and histamine receptor antagonists can protect the lung against the edema induced by paraoxon. This protective effect is due to inhibition of the chain reaction triggered by acetylcholine. [less ▲]

Endogenous Nitric Oxide Modulates Acetylcholine-Induced Edema and Vasoconstriction in Isolated Perfused Rabbit Lungs

in Journal of Pharmacology and Experimental Therapeutics (The) (1995), 274(2), 559-597

The modulatory role of endogenous nitric oxide (NO) on pulmonary edema induced by acetylcholine (ACh), capsaicin, substance P (SP) and 5-hydroxytryptamine (5-HT) was investigated by using an inhibitor of ... [more ▼]

The modulatory role of endogenous nitric oxide (NO) on pulmonary edema induced by acetylcholine (ACh), capsaicin, substance P (SP) and 5-hydroxytryptamine (5-HT) was investigated by using an inhibitor of NO synthase, N-omega-nitro-L-arginine (L-NNA). The effects of endogenous NO on the hemodynamic response to ACh, 5-HT and SP were also investigated. The capillary filtration coefficient (Kf,c), the total pressure gradient (delta Pt) and its four components [arterial (delta Pa), pre- (delta Pa') and post-capillary (delta Pv'), and venous gradient (delta Pv)] were evaluated on isolated, ventilated, perfused rabbit lungs. ACh (10(-8) to 10(-4) M) and SP (10(-10) to 10(-6) M) induced a concentration-dependent increase in the Kf,c. Capsaicin (10(-4) M) and 5-HT (10(-4) M) also increased this parameter. L-NNA (10(-4) M) completely inhibited the effects of ACh and capsaicin on the Kf,c, without preventing the effects of SP and 5-HT. ACh induced a concentration-dependent vasoconstriction in the precapillary segment. Pretreatment with L-NNA enhanced this increase in delta Pa' but also increased delta Pv' and delta Pv. 5-HT increased delta Pt and delta Pa proportionally to the concentration. This effect was enhanced by L-NNA, which also increased delta Pa'. SP had no significant hemodynamic effect. Pretreatment with L-NNA did not modify the response to SP. Sodium nitroprusside (10(-5) M) induced a left shift of the concentration-response curve to ACh on the Kf,c, although it did not change the response to SP. Sodium nitroprusside also inhibited the hemodynamic effect of ACh. It was concluded that endogenous NO is involved in ACh-and capsaicin-induced edema via a prejunctional stimulatory effect on the C-fibers. Endogenous NO can also modulate ACh- and 5-HT-induced vasoconstriction by exerting a vasodilator action on the whole pulmonary vascular bed [less ▲]

Modulation of the Acetylcholine- and Substance P-Induced Pulmonary Edema by Calcitonin Gene-Related Peptide in the Rabbit

in Journal of Pharmacology and Experimental Therapeutics (The) (1994), 270(1), 30-36

The effects of calcitonin gene-related peptide (CGRP) (6 x 10(-8) M) on hemodynamics and on pulmonary microvascular permeability were investigated in isolated, perfused rabbit lungs by measuring the ... [more ▼]

The effects of calcitonin gene-related peptide (CGRP) (6 x 10(-8) M) on hemodynamics and on pulmonary microvascular permeability were investigated in isolated, perfused rabbit lungs by measuring the arterial, capillary and venous pressures and the capillary filtration coefficient (Kf,c). CGRP was administered alone or in combination with capsaicin (10(-4) M), acetylcholine (ACh) (10(-11) M to 10(-7) M), substance P (SP) (10(-10) M to 10(-6) M) and serotonin (10(-4) M). The influence of a specific antagonist of CGRP receptors, CGRP8-37 (10(-8) M), on the pulmonary edema induced by these mediators was also considered. CGRP had no direct effect on the vascular pressures or on Kf,c. Capsaicin and serotonin induced an increase in Kf,c of 271 +/- 49% and 676 +/- 147% of base line, respectively. ACh and SP also increased the microvascular permeability, in proportion to the concentration. The effects of capsaicin, ACh and SP have been related to the activation of neurokinin NK1 receptors. Co-administration of CGRP with capsaicin and ACh enhanced the increase in Kf,c induced by these two drugs. By contrast, when co-injected with SP, CGRP inhibited the Kf,c increase induced by 10(-8) M and 10(-7) M of SP (P < .05) and significantly decreased the arterial and capillary pressures. CGRP also partly prevented the pulmonary edema induced by serotonin (P < .05). Pretreatment with CGRP8-37 partly prevented the effects of capsaicin and ACh on Kf,c but bestowed no protection against SP-induced pulmonary edema. These data suggest that CGRP is co-released with SP from the C-fibers upon the action of capsaicin and ACh in the rabbit lung. Because CGRP potentiated the pulmonary edema induced in capsaicin and ACh, but decreased the effects of SP, we hypothesize that CGRP exerts a positive retro-control on the release of neuropeptides by these fibers but can attenuate their effects on the target cells. [less ▲]

Multiple Muscarinic Receptor Subtypes Mediating Pulmonary Oedema in the Rabbit

in Pulmonary Pharmacology (1994), 7(3), 185-193

The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary ... [more ▼]

The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary filtration coefficient (Kf,c). This effect has been previously related to the activation of the capsaicin-sensitive nerve fibres and the release of substance P. Atropine, pirenzepine (M1-selective antagonist) and 4-DAMP (M3-selective antagonist) altered this response, producing a dose-dependent shift to the right of the ACh concentration-Kf,c response curve. By contrast, the M2-selective antagonist AFDX-116 shifted the ACh concentration-response curve to the left. Atropine, pirenzepine and 4-DAMP also significantly reduced the capsaicin-induced increase in the Kf,c, while AFDX-116 enhanced it. We conclude that multiple muscarinic receptor subtypes are present in the rabbit lung, located on the C-fibres, and are involved in the ACh-induced pulmonary oedema. M1 and M3 receptors seem to stimulate the release of neuropeptides from C-fibres, whereas M2 receptors have an inhibitory effect on these fibers. [less ▲]

Quantitative Assessment of Aerial Ammonia Toxicity to the Nasal Mucosa by Use of the Nasal Lavage Method in Pigs

in American Journal of Veterinary Research (1994), 55(9), 1335-1340

Effects of atmospheric ammonia (NH3) on the nasal mucosa and somatic growth were investigated in pigs exposed to 4 NH3 concentrations (0; 25; 50; and 100 ppm) for 6 days in a specifically designed air ... [more ▼]

Effects of atmospheric ammonia (NH3) on the nasal mucosa and somatic growth were investigated in pigs exposed to 4 NH3 concentrations (0; 25; 50; and 100 ppm) for 6 days in a specifically designed air-pollutant exposure chamber. Nasal lavage (NAL) was applied to quantify the ammonia-induced inflammatory response by measuring the number of neutrophils and the albumin (porcine serum albumin) concentration in the NAL liquid. In control pigs, these variables remained unchanged throughout the exposure period. In all other groups, an important ammonia concentration-related increase was recorded. The equation of the linear regression line established between the mean values of the number of neutrophils (x 10(3)) per milliliter of NAL liquid (y) recorded at the end of the exposure period and the ammonia concentrations (ppm) was: y = 69.7 + 3.3 [NH3] (r = 0.979; P < 0.020). The increase in the neutrophil count was significant (P < 0.05) at concentrations as low as 25 ppm. For albumin concentration nanograms per milliliter, the corresponding equation was: y = 574 + 14.3 [NH3] (r = 0.953; P < 0.045). However, the first significant change (P < 0.05) in this variable was only obtained for the higher concentration (100 ppm). In exposed pigs, a concentration-related depression of somatic growth was observed. The equation of the regression line plotted relating the individual values of the changes in body weight gain recorded over the exposure period expressed as percentage of the initial body weight (y) and the ammonia concentration was: y = 3.507-0.203 [NH3] + 0.001 [NH3]2 (r = 0.55; P < 0.010).(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

Permeability of the Endothelium and Partitioning of the Pulmonary Blood Flow Resistance in Isolated Perfused Pig Lungs: Effects of Breed and Age

in Veterinary Research Communications (1992), 16(1), 69-82

The right and left lungs of 5 healthy Minipigs and of 13 healthy Landrace piglets were isolated, perfused at constant pressure and maintained in an isogravimetric state under zone III conditions ... [more ▼]

The right and left lungs of 5 healthy Minipigs and of 13 healthy Landrace piglets were isolated, perfused at constant pressure and maintained in an isogravimetric state under zone III conditions (pulmonary venous pressure greater than alveolar pressure). By applying the double, arterial and venous, occlusion technique, the total blood flow resistance (R) was partitioned into four components: arterial (Ra), pre- (Ra') and post-capillary (Rv') and venous (Rv). The capillary filtration coefficient (Kf,c) was evaluated by measuring the weight gained by the lungs when the arterial and venous pressures were suddenly increased. In the youngest Landrace piglets (5 weeks old), there was an uncontrolled vasoconstriction which sometimes prevented perfusion of the lungs and induced a large increase in Rt. These high values of Rt were decreased by tolazoline administration. The values of Rt recorded in older pigs (12-13 weeks old) were lower in Minipigs (33.66 +/- 3.77 cmH2O min L-1 per 100 g of lungs; n = 5) than in Landrace piglets (55.20 +/- 6.18 cmH2O min L-1 per 100 g; n = 5). This breed difference was due to the differences in Ra' and Rv'. The mean values of Kf,c were 0.193 +/- 0.015 and 0.202 +/- 0.029 ml min (cmH2O)-1 per 100 g of the lungs in Minipigs and Landrace piglets respectively. All these parameters were stable for the 3 hours following the equilibrium period. It was concluded that: (1) There is an age-related maturation of the control of the vasomotor tone in porcine lungs. (2) Pulmonary microvascular haemodynamics are influenced by the breed of the pigs. (3) There was no difference in the Kf,c values between both the breeds. (4) A comparison of the values reported for dogs and rabbits with our data shows that the pre- and post-capillary resistances and, to a lesser extent, the arterial and venous resistances are relatively high in pigs [less ▲]