Airway Hyper-Reactivity and Blood, Lung and Airway Eosinophilia in Rats Treated with Sephadex Particles

Laycock, S.M.; Smith, Haller J.; Spicer, Barbara A.

doi:10.1159/000234164

Cited by 44 publications

(30 citation statements)

References 10 publications

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“…Animals were sacrificed (sodium pentobarbitone, 200 mg/kg i.p.) at various times (2,4,6,12,24,48, and 72 h) after saline or Sephadex challenge. Cell populations and gene expression in lung tissue were determined as described below.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Reverse transcription. A 1-g portion of total RNA was subjected to first strand cDNA synthesis in a 25-l reaction mixture containing avian myeloblastosis virus reverse transcriptase (10 U), dNTP (2 mM concentrations of each dNTP), oligo(dT) [12][13][14][15][16][17][18] primers (10 M), and reaction buffer as supplied with the enzyme (50 mM Tris-HCl (pH 8.3), 50 mM KCl, 10 mM MgCl 2 , 0.5 mM spermidine, and 10 mM DTT). The samples were incubated in a PerkinElmer 480 thermal cycler (PerkinElmer, Wellesley, MA) at 42°C for 60 min followed by enzyme denaturation step at 94°C for 2 min.…”

Section: Lung Cytokine Gene Expression (Rt-pcr)mentioning

confidence: 99%

“…or i.v. Sephadex administration induced blood and lung eosinophilia (11)(12)(13)(14)(15). The increase in eosinophil numbers is accompanied by the development of pulmonary granulomas.…”

mentioning

confidence: 99%

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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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Section: Experimental Protocolsmentioning

confidence: 99%

Section: Lung Cytokine Gene Expression (Rt-pcr)mentioning

confidence: 99%

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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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“…We have produced a blood eosinophilia in rats by the intravenous injection of Sephadex particles (Laycock et al, 1986). We have used this model as a screen to detect compounds which reduce eosinophilia.…”

Section: Introductionmentioning

confidence: 99%

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

Spicer¹,

Baker²,

Hatt³

et al. 1990

British J Pharmacology

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Rats given an intravenous injection of Sephadex particles (0.5 mg of G200 in 1 ml of saline) on days 0, 2 and 5 had a blood eosinophilia which was maximal on day 7. On day 7, broncho‐alveolar lavage (BAL) fluids taken from the rats contained an increased number of eosinophils and fewer mononuclear cells but there was no change in the small number of neutrophils. In addition the rats were hyper‐sensitive to the increase in resistance to artificial respiration produced by 5‐hydroxytryptamine (5‐HT), given intravenously, with a shift to the left of the log dose‐response curve. Lung parenchymal strips, taken from the rats on days 6, 7 and 8, were hyper‐reactive to 5‐HT with an increase in slope of the log dose‐response curve. Compounds with a wide variety of activities were evaluated for their effects on the blood eosinophilia on day 7 when given before each injection of Sephadex. The eosinophilia was reduced by glucocorticosteroids, β‐adrenoceptor agonists, aminophylline, dapsone and phenidone. Dexamethasone, isoprenaline, dapsone and phenidone at doses that reduced the blood eosinophilia also reduced the changes in number of leucocytes in the BAL fluids and the hyper‐responsiveness to 5‐HT in vivo and in vitro, except that the effects of dapsone on the hyper‐sensitivity to 5‐HT in vivo did not reach significance. Aminophylline was the least effective of the drugs at reducing the blood eosinophilia and its effects on the other changes did not reach significance. Sodium cromoglycate reduced the BAL eosinophilia but had no effect on the other changes produced by Sephadex. The correlation coefficients between blood eosinophil numbers and reactivity to 5‐HT in vitro and sensitivity in vivo were r = 0.76, (n = 88; P > 0.001) and r = 0.53, (n = 61; P > 0.001) respectively. Doses of dexamethasone, isoprenaline, dapsone and phenidone that reduced the blood eosinophilia when given before each injection of Sephadex were inactive when given up to 8 h after the Sephadex. These data show an association between blood eosinophilia and hyper‐responsiveness of the lung. The blood eosinophilia in the rats was triggered within the first few hours of injecting the Sephadex and drugs have been identified which inhibit this trigger.

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“…Peripheral blood eosinophilia was not seen, nor were eosinophils observed by light microscopy in the affected tissues. The lack of eosinophilia may relate to experimental design or a species difference, although eosinophilia does develop in rats used in experimental studies of allergic, parasitic, and nutritional diseases (23)(24)(25)(26). The moderate degree of inflammation could be due to the duration of the study, species related differences in inflammatory responses, a dose-response effect dependent upon the amount of unknown contaminant(s) in the implicated L-TRP used, or the lack of peripheral eosinophilia, if eosinophil degranulation products play a role in amplifying the inflammatory and/or fibrotic response (3,4).…”

Section: Discussionmentioning

confidence: 99%

L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.

Crofford¹,

Rader²,

Dalakas³

et al. 1990

J. Clin. Invest.

102

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Tryptophan-associated eosinophilia-myalgia syndrome (L-TRP-EMS) is a newly described syndrome which occurred in epidemic fashion in the United States in the summer and fall of 1989. Epidemiologic data has linked the syndrome to intake of L-tryptophan (L-TRP) from one specific manufacturer, but the precise etiologic compound(s) must be established by replication of the syndrome in an appropriate animal model.In this study, implicated L-TRP, United States Pharmacopeia (USP) grade L-TRP, or vehicle was administered by gavage in a blinded fashion for 38 d to female Lewis rats at doses comparable with those ingested by patients who developed the eosinophilia-myalgia syndrome. Animals receiving implicated L-TRP, but not those receiving USP grade L-TRP or vehicle, developed histologic signs consistent with fasciitis and perimyositis, specific pathologic features of human L-TRP-EMS. Peripheral blood eosinophilia was not observed. Hypothalamic corticotropin releasing hormone mRNA levels were lower and plasma corticosterone levels tended to be lower in the animals that received implicated L-TRP. Plasma L-kynurenine was higher in both L-TRP-treated groups compared to the vehicletreated animals.The female Lewis rat is known to be susceptible to a wide variety of inflammatory diseases. Identification of specific inflammatory changes in this rat following exposure to implicated L-TRP indicates that this animal model will be important in subsequent investigations into the etiology, pathogenesis, and treatment of human L-TRP-EMS. (J.

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Airway Hyper-Reactivity and Blood, Lung and Airway Eosinophilia in Rats Treated with Sephadex Particles

Cited by 44 publications

References 10 publications

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

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

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

L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.

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