The effects of drugs on Sephadex‐induced eosinophilia and lung hyper‐responsiveness in the rat

Spicer, Barbara A.; Baker, Richard C.; Hatt, P.A.; Laycock, S.M.; Smith, Haller J.

doi:10.1111/j.1476-5381.1990.tb14164.x

Cited by 36 publications

(31 citation statements)

References 35 publications

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“…We could find no report in the literature describing peripheral eosinophilia due to Cyc-A in the rats. There were reports of other drugs such as Sephadex given by injection causing peripheral eosinophilia in rats [38]. Possibly there is a migration of eosinophils from the lung to the peripheral blood in Cyc-A-pretreated rats.…”

Section: Discussionmentioning

confidence: 99%

Effect of Inhaled Cyclosporin on the Rat Airway: Histologic and Bronchoalveolar Lavage Assessment

Ceyhan

Sungur²,

Çelikel³

et al. 1998

Respiration

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Airway inflammation plays a pivotal role in asthma. Over the last 10 years, evidence has accumulated for the potential role of lymphocytes in airway inflammation. Since cyclosporin A (Cyc-A) can profoundly influence lymphocyte activation, it is appropriate to consider this drug as a novel antiasthmatic. The effect of inhalation of low doses of Cyc-A on airway inflammation remains unclear. The purpose of this study was to investigate the bronchoalveolar lavage (BAL), peripheral blood cell profiles, and lung biopsy specimens in Cyc-A-pretreated rats. Twenty-nine rats (8 controls, 10 ovalbumin sensitized, and 11 Cyc-A inhaling and ovalbumin sensitized) were included in the study. A commercial intravenous Cyc-A solution was given as a single dose of 20 mg/kg 1 h prior to inhalation of ovalbumin via nebulizer. The total number of BAL cells significantly increased in rats inhaling Cyc-A when compared with ovalbumin-sensitized rats (2.37 ± 2.34 × 10⁶/ml and 1.01 ± 0.49 × 10⁶/ml respectively, p < 0.05). There was a significant increase in the percentage of lymphocytes (14.5 ± 8.5 versus 27.4 ± 7.4%, p < 0.03), a nonsignificant increase in the percentage of eosinophils (0.8 ± 1.0 versus 3.0 ± 4.6%), and a significant decrease in the percentage of polymorphonuclear leukocytes (9.4 ± 6.9 versus 3.4 ± 3.8%, p < 0.01) and macrophages (75.4 ± 5.1 versus 50.2 ± 11.8%, p < 0.02) in BAL in the ovalbumin-sensitized group as compared with controls. Differential cell counts revealed a higher percentage of neutrophils and macrophages in the BAL of Cyc-A-pretreated rats than in that of the ovalbumin-sensitized group (26.3 ± 26.8 versus 3.4 ± 3.8%, p < 0.01 and 66.1 ± 7.7 versus 50.2 ± 11.8%, p < 0.02). There was a nonsignificant decrease of lymphocytes and eosinophils in the Cyc-A-pretreated group when compared with the ovalbumin-sensitized group (27.4 ± 7.4 versus 21.1 ± 12.4 and 3.0 ± 4.6% versus 2.4 ± 2.6%). The peripheral blood total white blood cell count decreased in the ovalbumin-sensitized and Cyc-A-pretreated groups as compared with the control group (2,520 ± 1,098/mm³, 3,591 ± 2,251/mm³, and 5,975 ± 2,787/mm³, respectively, p < 0.01). In addition, peripheral eosinophilia was detected in the Cyc-A-pretreated group when compared with controls and the ovalbumin-sensitized group (6.9 ± 4.7, 2.4 ± 1.1, and 2.6 ± 2.4%, respectively, p < 0.01). Light-microscopic examination of the airways revealed prominent eosinophilia in tracheal, bronchial, and bronchiolar sections in the ovalbumin-sensitized group: counts were 1.8 ± 2.3/HPF, 10.3 ± 11.4/HPF, 63.3 ± 45.0/HPF, respectively. Cyc-A resulted in a decrease of the eosinophil counts/HPF to 0/HPF in trachea (p < 0.05), to 4.3 ± 9.4/HPF in bronchi (p < 0.02), to 19.4 ± 38.4 in bronchioles (p < 0.004).In conclusion, the present study supports the theory that locally administered inhaled low-dose Cyc-A is effective on inflammatory cells of sensitized airways and peripheral cells. It may therefore be useful in elucidating the inflammato...

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Section: Discussionmentioning

confidence: 99%

Effect of Inhaled Cyclosporin on the Rat Airway: Histologic and Bronchoalveolar Lavage Assessment

Ceyhan

Sungur²,

Çelikel³

et al. 1998

Respiration

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“…To our knowledge, few studies have examined the effect of P-adrenoceptor agonists on other aspects of acute-inflammation, although Spicer et al (1990) demonstrated that a number of P-adrenoceptor agonists prevent sephadex-induced blood eosinophilia in rats while subcutaneous isoprenaline also inhibited sephadex-induced eosinophil accumulation in rat lung. Furthermore, in spite of the experimental evidence, currently available P2-adrenoceptor agonists with a short duration of action, such as salbutamol, do not appear to have any significant anti-inflammatory activity in therapeutic situations such as atopic dermatitis or the late phase response in asthmatics following antigen challenge (Cockroft & Murdock, 1987;Archer & Macdonald, 1987;Green et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea‐pig lung and skin

Whelan

Johnson

1992

British J Pharmacology

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1. The long-acting P2-adrenoceptor agonist, salmeterol has been evaluated for its anti-inflammatory effects in the guinea-pig lung and skin. 2. Salmeterol, administered in bronchodilator doses to conscious guinea-pigs by both oral (0.01-1.0 mg kg-') and inhaled (nebulizer concentration, 0.001-1.0 mg ml-') routes, inhibited histamineinduced plasma protein extravasation (PPE) into the airway lumen. 3. Inhibition of PPE by salmeterol was long-lasting (>6 h) and was inhibited by prior administration of propranolol (1 mg kg-1, s.c.), indicating an effect mediated by P-adrenoceptors. 4. Inhaled salbutamol (nebulizer concentration, 0.00 1-1.0 mg ml-') also inhibited PPE in guinea-pig lung but, in contrast to salmeterol, this effect was short-lived with substantial loss of activity 2 h after administration. 5. Inhaled salmeterol (0.1 mg ml-') and salbutamol (1.0mg ml-') inhibited the accumulation of neutrophils in guinea-pig lung in response to lipopolysaccharide (100pgml-'). Salmeterol, but not salbutamol, inhibited the infiltration of eosinophils into the airway lumen in response to platelet activating factor (100 Lgml-'). These effects of salmeterol were blocked by prior administration of propranolol (5 mg kg-', s.c.), indicating that they were also P-adrenoceptor-mediated.6. Oral salmeterol (10mg kg-', p.o.), but not salbutamol (10 and 100mg kg-', p.o.), inhibited zymosan-induced granulocyte accumulation and PPE in guinea-pig skin. Lower doses of salmeterol (0.1 and 1 mg kg-') inhibited PPE, but not granulocyte accumulation. The effects of salmeterol were blocked by prior administration of propranolol (1mgkg-', s.c.). Both salmeterol and salbutamol inhibited histamine-induced PPE in guinea-pig skin.7. Intradermal salmeterol (10-'mol per site), but not salbutamol, was also effective in inhibiting zymosan-induced granulocyte accumulation and PPE in guinea-pig skin. 8. It is concluded that salmeterol, at bronchodilator doses in the guinea-pig, inhibits granulocyte accumulation and PPE, possibly by an action on the vasculature. As this profile of activity is not shared by the shorter-acting compound, salbutamol, it would seem that anti-inflammatory activity is associated with P-adrenoceptor agonism of long duration. The implications of these findings for the use of salmeterol in the treatment of bronchial asthma are discussed.

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“…or intratracheally (i.t.) 2 administered Sephadex (particles of crosslinked dextran) (8,9). Rats have an endogenous hypersensitivity to dextrans such as Sephadex, which results in an eosinophilic inflammatory response (10).…”

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confidence: 99%

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

Haddad¹,

Underwood²,

Dabrowski

et al. 2002

The Journal of Immunology

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Intratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4+ T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the αβ-TCR caused 54% depletion of total (CD2+) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.

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The effects of drugs on Sephadex‐induced eosinophilia and lung hyper‐responsiveness in the rat

Cited by 36 publications

References 35 publications

Effect of Inhaled Cyclosporin on the Rat Airway: Histologic and Bronchoalveolar Lavage Assessment

Effect of Inhaled Cyclosporin on the Rat Airway: Histologic and Bronchoalveolar Lavage Assessment

Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea‐pig lung and skin

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

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