Bengt-Eric Skoogh

Airway allergy to trimellitic anhydride in guinea pigs: Different time courses of IgG1 titer and airway responses to allergen challenge

BACKGROUNDnTrimellitic anhydride (TMA) is a low molecular weight chemical that may cause occupational asthma in human beings. The objectives of this study were to determine the time course of immune and airway responses to TMA in guinea pigs and to relate the immunologic response to the immediate responses in lung resistance (RL) and plasma exudation induced by allergen challenge.nnnMETHODSnWe studied the effects of time course after sensitization on airway response to TMA in guinea pigs actively sensitized to free TMA, given by intradermal injection (0.1 ml of 0.3% TMA in corn oil). During weeks 1, 2, 3, 5, and 8 after sensitization, anesthetized animals were challenged with TMA conjugated to guinea pig serum albumin (TMA-GPSA), instilled via the airway route. Nonsensitized animals were challenged with the same amount of conjugate 4 weeks after intradermal injection of corn oil only. In the same animal, we measured both RL to monitor airflow obstruction and extravasation of Evans blue dye (20 mg/kg) to quantify airway plasma exudation.nnnRESULTSnInstillation of TMA-GPSA (0.5%; 50 microliters) into the tracheal lumen caused a significant increase in RL, reaching a maximum at 2.5 minutes after the instillation in the 1-week group (9.0 +/- 5.9 cm H2O/ml/sec) and between 5 and 6 minutes in the 2-, 3-, 5-, and 8-week groups (9.4 +/- 4.8, 12.7 +/- 5.5, 3.7 +/- 1.1, and 1.7 +/- 0.2 cm H2O/ml/sec, respectively). The maximal increase in RL after the challenge in nonsensitized animals was 0.39 +/- 0.05 cm H2O/ml/sec. TMA-GPSA also produced significant extravasation of Evans blue dye at all airway levels in the sensitized groups, and the amount of dye in the peripheral airways was significantly greater than that in the trachea. Furthermore, the level of Evans blue dye in airway tissue increased with the time after sensitization, up to the latest time point tested (8 weeks). Specific IgG1 antibodies to TMA-GPSA demonstrated by ELISA were detected in all animals in the 3-, 5-, and 8-week groups, with maximal levels 5 weeks after sensitization. Specific IgG1 titers to TMA-GPSA significantly correlated with the level of Evans blue dye induced by challenge with TMA-GPSA but not with the increase in RL.nnnCONCLUSIONSnIntradermal sensitization to free TMA induces specific airway allergy for a long period after sensitization. Specific IgG1 antibodies to allergen may influence allergen-induced plasma exudation rather than the airflow obstruction in this animal model of TMA-induced asthma.

An intranasal glucocorticoid inhibits the increase of specific IgE initiated during birch pollen season.

BACKGROUNDnRecent in vitro findings show that glucocorticoids in combination with IL-4 can induce the synthesis of IgE, indicating that glucocorticoids may promote allergy.nnnOBJECTIVEnA double-blind, placebo-controlled study was performed to evaluate the effect of an intranasal glucocorticoid on the levels of birch pollen-specific IgE antibodies in serum from patients with allergic rhinitis.nnnMETHODSnEighteen patients with allergic rhinitis received treatment with an intranasal glucocorticoid (beclomethasone dipropionate, 400 microg/day) or placebo for 5 weeks, starting from the beginning of the birch pollen season. Blood samples for anti-birch IgE evaluation were taken before treatment was initiated and at 2 and 5 weeks after the beginning of the study.nnnRESULTSnThe beclomethasone group (n = 9) had significantly lower symptom scores when compared with the placebo group (n = 9) (0.86 +/- 0.26 vs 2.79 +/- 0.76, p value = 0.01). Both the treatment group and the placebo group showed a trend of an increase in anti-birch IgE levels 2 weeks after the beginning of the treatment (from 33.1 +/- 13.1 kU/L to 44.9 +/- 20.9 kU/L in the beclomethasone group and from 53.2 +/- 18.9 kU/L to 64.1 +/- 22.1 kU/L in the placebo group). Treatment with beclomethasone returned anti-birch IgE levels to baseline by the end of the study, whereas in the placebo group the anti-birch IgE levels continued to increase (final values, 33.1 +/- 11.9 kU/L vs 72.6 +/- 23.2 kU/L, respectively). The change in IgE antibody levels in the placebo group was significantly higher than that in the beclomethasone group. No statistically significant changes in total IgE or soluble CD23 levels were detected.nnnCONCLUSIONnWe conclude that treatment with an intranasal glucocorticoid initiated at the beginning of the pollen season inhibits the induced increase in specific IgE.

The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients*

Background:u2002 Fluid retention with oedema is an important clinical problem in advanced chronic obstructive pulmonary disease (COPD).

Bradykinin‐induced airflow obstruction and airway plasma exudation: effects of drugs that inhibit acetylcholine, thromboxane A2 or leukotrienes

1 The mechanisms behind bradykinin‐induced effects in the airways are considered to be largely indirect. The role of cholinergic nerves and eicosanoids, and their relationship in these mechanisms were investigated in guinea‐pigs. 2 The role of cholinergic nerves was studied in animals given atropine (1 mg kg−1, i.v.), hexamethonium (2 mg kg−1, i.v.), or vagotomized. To study the role of eicosanoids, animals were pretreated with a thromboxane A2 (TxA2) receptor antagonist (ICI 192,605; 10−6 mol kg−1, i.v.) or with a leukotriene (LT) receptor C4/D4/E4 antagonist (ICI 198,615; 10−6 mol kg−1, i.v.). 3 After pretreatment with a drug, bradykinin (150 nmol) was instilled into the tracheal lumen. We measured both airway insufflation pressure (Pi), to assess airway narrowing, and the content of Evans blue dye in airway tissue, to assess plasma exudation. 4 Bradykinin instillation into the trachea caused an increase in Pi and extravasation of Evans blue dye. The increase in Pi was significantly attenuated by atropine or the TxA2 receptor antagonist, but not by hexamethonium, vagotomy or the LT receptor antagonist. 5 The bradykinin‐induced exudation of Evans blue dye was significantly attenuated in the intrapulmonary airways by the TxA2 receptor antagonist, but not by atropine, hexamethonium, cervical vagotomy or the LT receptor antagonist. 6 A thromboxane‐mimetic, U‐46619 (20 nmol kg−1, i.v. or 10 nmol intratracheally), caused both an increase in Pi and extravasation of Evans blue dye at all airway levels. Atropine pretreatment slightly attenuated the peak Pi after the intratracheal administration of U‐46619, but not after i.v. administration. 7 We conclude that peripheral cholinergic nerves are involved in bradykinin‐induced airflow obstruction but not plasma exudation, and that TxA2 is involved in both airflow obstruction and airway plasma exudation induced by bradykinin given via the airway route. TxA2‐induced airflow obstruction is mediated only to a minor degree, via the release of acetylcholine in the airways.

Development of Antigen-Specific IgE after Sensitisation with Trimellitic Anhydride in Rats Is Attenuated by Glucocorticoids and Cyclosporin A

BACKGROUNDnTrimellitic anhydride (TMA) is a low-molecular-weight compound capable of inducing occupational asthma in man. We have characterized the TMA-induced antibody responses in Brown-Norway rats (BNR) and evaluated the effects of treatment with the glucocorticoid betamethasone or with cyclosporin A (CsA) on this response.nnnMETHODSnAnimals were sensitised by two intradermal injections of 0.1 ml TMA suspended in corn oil, and development of specific antibodies was assessed using ELISA.nnnRESULTSnBoth IgE and IgG anti-TMA antibodies started to rise between weeks 1 and 3 after immunisation, reached their highest levels 7 weeks after sensitisation with 3% of TMA and then started to decline. Betamethasone and CsA given orally over the time of sensitisation (8 days in total) inhibited the development of specific IgE and IgG anti-TMA antibodies. Betamethasone given 10-17 days after sensitisation attenuated the IgE and IgG antibody responses as well while treatment with CsA after sensitisation had no effect on the production of specific antibodies. Levels of total IgE and IgG were not affected except for a small decrease in total IgE using medium-dose betamethasone after sensitisation.nnnCONCLUSIONnWe conclude that TMA-sensitised BNR develop specific IgE and IgG anti-TMA antibodies, and that glucocorticoids and CsA attenuate this response.

Treatment with cyclosporin A during sensitization with trimellitic anhydride attenuates the airway responses to allergen challenge three weeks later

The present studies examined the effects of oral treatment with cyclosporin A, betamethasone or azelastine administered over the time of sensitization with trimellitic anhydride on allergen-induced airway responses, compared to those of control animals given corn oil alone. Drugs were given for 8 days. The animals were sensitized with trimellitic anhydride (0.1 ml of 0.3% w/v) in corn oil given intradermally on days 4 and 5 of drug treatment. Three to four weeks after sensitization with free trimellitic anhydride, the animals were anesthetized, tracheostomized and challenged with trimellitic anhydride conjugated to guinea pig serum albumin (trimellitic anhydride-guinea pig serum albumin; 0.5%; 50 microliters) instilled via the airway route. In the same animal, we measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye (20 mg/kg) to quantify airway plasma exudation. In control animals, instillation of trimellitic anhydride-guinea pig serum albumin into the tracheal lumen caused a slowly progressing increase in RL over the observation period (6 min), in addition to extravasation of Evans Blue dye at all airway levels. In animals treated with 50 mg/kg of cyclosporin A, both the allergen-induced increase in RL and extravasation of Evans Blue dye in intrapulmonary airways were significantly attenuated. However, neither betamethasone nor azelastine significantly affected these responses. We conclude that cyclosporin A may influence the immune system in the guinea pig during the induction of allergy, thus leading to attenuation of allergen-induced airway obstruction at later time points.