nitrogen-dioxide and Drug-Hypersensitivity

We investigated whether acute exposure to nitrogen dioxide (NO2) causes major inflammatory responses (inflammatory cell recruitment, oedema and smooth muscle hyperresponsiveness) in guinea pig airways. Anaesthetised guinea pigs were exposed to 18 ppm NO2 or air for 4 h through a tracheal cannula. Bronchoalveolar lavage was performed and airway microvascular permeability and in vitro bronchial smooth muscle responsiveness were measured. Exposure to NO2 induced a significant increase in eosinophils and neutrophils in bronchoalveolar lavage fluid, microvascular leakage in the trachea and main bronchi (but not in peripheral airways), and a significant in vitro hyperresponsiveness to acetylcholine, electrical field stimulation, and neurokinin A, but not to histamine. Thus, this study shows that in vivo exposure to high concentrations of NO2 induces major inflammatory responses in guinea pig airways that mimic acute bronchitis induced by exposure to irritant gases in man.

Topics: Acetylcholine; Anesthesia; Animals; Bronchitis; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Dose-Response Relationship, Drug; Drug Hypersensitivity; Electric Stimulation; Guinea Pigs; Histamine; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Neurokinin A; Nitrogen Dioxide; Tracheitis

The aim of this study was to investigate whether in vitro exposure to NO2 affects responsiveness in ovalbumin-sensitized guinea-pig bronchi. Twenty-three animals were sensitized by three weekly intraperitoneal injections of 1 mg ovalbumin in saline with Freund's adjuvant; twenty-one control guinea-pigs received the diluent alone. From each animal, the two main bronchi were obtained and cannulated, then exposed in vitro to a constant intraluminal flow of: (i) either air or 2.5 ppm NO2 with four spikes of 10 ppm NO2 for 2 h; (ii) either air or 10 ppm NO2 for 4 h. A bronchial ring obtained from each animal before exposure was kept in aerated Krebs-Henseleit solution. Rings from bronchi exposed to air, NO2, or kept in Krebs solution were studied isometrically. We performed overall and non-adrenergic non-cholinergic voltage-response curves to electrical field stimulation, concentration-response curves to acetylcholine and to neurokinin A, followed by administration of 10 mg/ml ovalbumin. We did not find any significant difference in bronchial smooth muscle responsiveness between nonexposed, air-exposed and NO2-exposed bronchi, as well as between bronchi from control and sensitized animals. We conclude that in vitro exposure to NO2 does not alter bronchial smooth muscle responsiveness to either specific or non-specific stimuli.

Topics: Acetylcholine; Air Pollutants; Animals; Bronchi; Dose-Response Relationship, Drug; Drug Hypersensitivity; Electric Stimulation; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth; Neurokinin A; Nitrogen Dioxide; Ovalbumin

In the present study, we investigated (1) whether airway responsiveness to inhaled histamine-aerosol could be induced during 7-d exposure of guinea pigs to 4 ppm NO2 and, if so, (2) whether thromboxane A2 may be involved in such increase. Female Hartley guinea pigs were divided into 6 groups (n = 15/group). Three groups were exposed to filtered air and the other 3 groups were exposed to NO2 for 1, 3, or 7 d (24 h/d). Baseline specific airway resistance (SRaw0) did not change significantly after exposure to 4 ppm NO2 or air. Airway responsiveness was determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Prior to exposure to NO2, the EC200His, the concentrations of inhaled histamine necessary to double SRawNaCl (SRaw after inhalation of 0.9% NaCl), were 1.07 +/- 0.20, 1.30 +/- 0.20, and 1.01 +/- 0.18 mM for the 3 groups later given NO2 for 1, 3, and 7 d, respectively. Following exposure to NO2 for 1, 3, or 7 d, EC200His values were 1.42 +/- 0.25, 0.66 +/- 0.10 (p < .05), and 1.05 +/- 0.22 mM, respectively. These results show that 7-d exposure to 4 ppm NO2 induced a significant increase in airway responsiveness on d 3. Exposure to air had no significant effect on the airway responsiveness. This transient hyperresponsiveness was inhibited by a specific inhibitor of thromboxane synthetase, OKY 046. These results indicated that (1) a lower concentration (4 ppm) of NO2 than that previously reported can induce transient hyperresponsiveness in guinea pigs during appropriate long-term exposure, and (2) thromboxane A2 may play an important role in this transient airway hyperresponsiveness.

Topics: Administration, Inhalation; Air Pollutants; Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Female; Guinea Pigs; Histamine; Lung; Methacrylates; Nitrogen Dioxide; Thromboxane A2; Thromboxane-A Synthase; Time Factors

Pulmonary histamine and the weight of lungs were studied in mice, exposed to a single one-hour effect of high concentrations of edemagenic gas nitrogen dioxide in a metabolic chamber. Nitrogen dioxide concentrations were chosen according to the results of nitrogen dioxide analysis of the mining atmosphere immediately after the mining blasts. The results were estimated by the method of paired comparison with the findings registered in mice, exposed to the effect of air atmosphere under identical experimental conditions. The intervals following immediately the exposure and 5 hours after were chosen for the evaluation, with regard to the dynamics of the early and late stages of hypersensitivity of the first type. i) Immediately after the exposure to the concentrations of 43, 250, 387 and 540 mg.m-3, no significant differences were observed in the amount of pulmonary histamine. In concentrations higher than 43 mg.m-3, the weight of lungs increased (the proportion of pulmonary water and the dry tissue). ii) Five hours after the exposure (nitrogen dioxide concentrations 66, 130, 137 and 270 mg.m-3), pulmonary histamine decreased, at the concentration of 137 mg.m-3 in a significant way, on the other hand, it increased significantly at the concentration of 270 mg.m-3. Both concentrations higher than 130 mg.m-3 manifested an increased weight of lungs (increased proportion of dry tissue and pulmonary water). The obtained data do not allow to establish unambiguously the part of histamine on the pulmonary changes following the effect of nitrogen dioxide. The edemagenic effect of nitrogen dioxide estimated after one-hour influence can be considered as reversible up to five hours after the exposure in concentrations lower than 130 mg.m-3. The metodical part of the study gives detailed description of exposure technique and it brings a survey of methods of histamine determination in blood and tissues.

Topics: Animals; Drug Hypersensitivity; Histamine Release; Lung; Mice; Mice, Inbred Strains; Nitrogen Dioxide; Organ Size; Reference Values

Topics: Acetylcholine; Aerosols; Animals; Drug Hypersensitivity; Guinea Pigs; Male; Nitrogen Dioxide; Ozone; Sulfur Dioxide; Time Factors