GM-CSF-deficient mice are susceptible to pulmonary group B streptococcal infection.
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-targeted mice (GM-/-) cleared group B streptococcus (GBS) from the lungs more slowly than wild-type mice. Expression of GM-CSF in the respiratory epithelium of GM-/- mice improved bacterial clearance to levels greater than that in wild-type GM+/+ mice. Acute aerosolization of GM-CSF to GM+/+ mice significantly enhanced clearance of GBS at 24 hours. GBS infection was associated with increased neutrophilic infiltration in lungs of GM-/- mice, while macrophage infiltrates predominated in wild-type mice, suggesting an abnormality in macrophage clearance of bacteria in the absence of GM-CSF. While phagocytosis of GBS was unaltered, production of superoxide radicals and hydrogen peroxide was markedly deficient in macrophages from GM-/- mice. Lipid peroxidation, assessed by measuring the isoprostane 8-iso-PGF2alpha, was decreased in the lungs of GM-/- mice. GM-CSF plays an important role in GBS clearance in vivo, mediated in part by its role in enhancing superoxide and hydrogen peroxide production and bacterial killing by alveolar macrophages. (+info)
Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness.
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ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an essential role for ICAM-2 in the development of the inflammatory and respiratory components of allergic lung disease. This phenotype is caused by the lack of ICAM-2 expression on non-hematopoietic cells. ICAM-2 deficiency on endothelial cells causes reduced eosinophil transmigration in vitro. ICAM-2 is not essential for lymphocyte homing or the development of leukocytes, with the exception of megakaryocyte progenitors, which are significantly reduced. (+info)
Hexavalent chromium responsible for lung lesions induced by intratracheal instillation of chromium fumes in rats.
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Lung toxicity of chromium fumes (Cr fumes) was examined by a single intratracheal instillation into rats of 10.6 mg and 21.3 mg Cr fumes/kg body weight and by repeated (3 times) instillations of 10.8 mg and 21.7 mg Cr fumes/kg. The pathological changes were compared with those induced by single administrations of 3.2 mg and 19.2 mg Na2CO3 solution-insoluble fraction of Cr fumes (Cr-Fr)/kg and 20.8 mg commercially available chromium (III) oxide powder (Cr (III) oxide)/kg. Single and repeated administrations of Cr fumes suppressed growth rate in a dose-dependent manner, but administrations of Cr-Fr and Cr (III) oxide did not. A single administration of Cr fumes produced granulomas in the entire airways and alveoli with progressive fibrotic changes, as well as severe mobilization and destruction of macrophages and foamy cells. Those histopathological changes were aggravated by the repeated administration of Cr fumes. On the other hand, single administrations of Cr-Fr and Cr (III) oxide produced no remarkable histopathological changes. Cr fumes were found to be composed of 73.5% chromium (III) oxide and 26.5% chromium (VI) oxide. The primary particles of Cr fumes and Cr-Fr were similar, 0.02 micron in size (sigma g: 1.25), and Cr (III) oxide particles were 0.30 micron in size (sigma g: 1.53), measured by analytical electron microscopy (ATEM). Diffuse clusters of the primary particles in Cr fumes were identified as Cr (VI) oxide. The present results suggested that the lung toxicity of Cr fumes was mainly caused by these Cr (VI) oxide (CrO3) particles in Cr fumes. (+info)
A new model rat with acute bronchiolitis and its application to research on the toxicology of inhaled particulate matter.
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The aim of the present study was to establish a useful animal model that simulates humans sensitive to inhaled particulate matter (PM). We have developed a new rat model of acute bronchiolitis (Br) by exposing animals to NiCl2 (Ni) aerosols for five days. Three days following the Ni exposure, the animals developed signs of tachypnea, mucous hypersecretion, and bronchiolar inflammation which seemed to progress quickly during the fourth to fifth day. They recovered from lesions after four weeks in clean air. To assess the sensitivity of the Br rats to inhaled particles, two kinds of PM of respirable size were tested with doses similar to or a little higher to the recommended threshold limit values (TLVs) for the working environment in Japan. Titanium dioxide (TiO2 = Ti) was chosen as an inert and insoluble particles and vanadium pentoxide (V2O5 = V), as a representative soluble and toxic airborne material. The Br rats exposed to either Ti or V were compared the pathological changes in the lungs and the clearance of particles to those in normal control or Br rats kept in clean air. The following significant differences were observed in Br rats: 1. delayed recovery from pre-existing lesions or exacerbated inflammation, 2. reductions in deposition and clearance rate of inhaled particles with the progress of lesions. The present results suggest that Br rats are more susceptible to inhaled particles than control rats. Therefore, concentrations of particulate matter lower than the TLVs for Japan, which have no harmful effects on normal lungs, may not always be safe in the case of pre-existing lung inflammation. (+info)
An animal exposure system using ultrasonic nebulizer that generates well controlled aerosols from liquids.
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Various aerosol generators have been developed for animal inhalation experiments and the performance tests of measuring instruments and respirators. It has been, however, difficult to generate aerosols from an aqueous solution or suspension keeping the concentration and particle size distribution constant for a long time. Resolving such difficulties, the present study developed an animal exposure system that generates well-controlled and stable aerosols from liquids. The exposure system consists of an aerosol generator using ultrasonic nebulizer, a mixing chamber and an exposure chamber. The validity of this system was confirmed in the generation of NiCl2 and TiO2 aerosol from solution and suspension, respectively. The concentration levels of NiCl2 aerosol were kept at 3.2 mg/m3 and 0.89 mg/m3 for 5 hours with good coefficients of variation (CVs) of 2.5% and 1.7%, respectively. For TiO2 aerosol, the concentration levels of 1.59 mg/m3 and 0.90 mg/m3 were kept for 5 hours with small CVs of 1.3% and 2.0%, respectively. This exposure system could be sufficiently used for inhalation experiments with even high toxic aerosols such as NiCl2 because a momentary high concentration possibly affects results and an extremely stable concentration is required. (+info)
A clearance model of inhaled man-made fibers in rat lungs.
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A clearance model of inhaled man-made fibers (MMFs) was developed, and the calculated fiber numbers and dimensions were compared with the experimental ones using a glass fiber (GF), ceramic fiber (RF1) and two potassium octatitanate whiskers (PT1, TW). If the translocation rate by macrophages is constant and the effect of dissolution and disintegration can be ignored, the fiber number is expected to decrease exponentially with time. In the experimental study, however, the fiber number did not always decrease exponentially. In the case of RF1, the fiber number decreased almost exponentially and the diameter decreased linearly with the time. The clearance rate constant of GF during 3 to 6 months after the end of one-month exposure was greater than that during 1 to 3 months. On the contrary, the clearance rate constants of PT1 and TW during 1 to 6 months were greater than next six months. The diameter and the length of GF did not change significantly. The fiber length of PT1 tends to become longer with time although the diameter did not change significantly. Our theoretical model gives a satisfactory fit to these experimental results. (+info)
Nitrogen dioxide formation during inhaled nitric oxide therapy.
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BACKGROUND: Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial. METHODS: The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy. RESULTS: Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature. CONCLUSIONS: Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time. (+info)
As-required versus regular nebulized salbutamol for the treatment of acute severe asthma.
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Current British guidelines for the administration of beta2-agonists in acute severe asthma recommend regular nebulized therapy in hospitalized patients, followed by as-required (p.r.n.) use via hand-held devices after discharge. Since beta2-agonists do not possess anti-inflammatory activity in vivo, and are thus unlikely to influence the rate of recovery from an asthma exacerbation, it was hypothesized that patients given the short-acting beta2-agonist salbutamol on an as-required basis after admission to hospital would recover as quickly as those on regular treatment, but with potential reductions in the total dose delivered. Forty-six patients with acute severe asthma were randomly assigned to either regular prescriptions of nebulized salbutamol or to usage on a p.r.n. basis, from 24 h after hospital admission. The primary outcome measures were length of hospital stay, time to recovery, and frequency of salbutamol nebulization from 24 h after admission to discharge. Secondary outcome measures were treatment side-effects (tremor, palpitations), and patient satisfaction. Length of hospital stay was reduced in those patients allocated to p.r.n. salbutamol (geometric mean (GM) 3.7 days) versus regular salbutamol (GM 4.7 days). Time taken for peak expiratory flow to reach 75% of recent best was the same in both groups. There was a highly significant reduction in the number of times nebulized therapy was delivered to the p.r.n. group (GM 7.0, range 1-30) compared with the regular treatment group (GM 14.0, range 4-57; p=0.003; 95% confidence interval for ratio of GMs 1.29-3.09). In addition, patients reported less tremor (p=0.062) and fewer palpitations (p=0.049) in the p.r.n. group. Of the patients in the p.r.n. group who had received regular nebulized therapy on previous admissions (n=12), all preferred the p.r.n. regimen. Prescribing beta2-agonists on a p.r.n. basis from 24 h after hospital admission is associated with reduced amount of drug delivered, incidence of side-effects, and possibly length of hospital stay. This has implications for the efficient use of healthcare resources. (+info)