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Notes: We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals with chronic airway inflammation (increased BAL eosinophils) and sustained airway hyperresponsiveness, a 7 day dosing scheme with a murine anti-human ICAM-1 monoclonal antibody (R6.5, 2 mg/kg/day; i.v.) did not reduce the existing airway inflammation or airway hyperresponsiveness. In contrast, a similar dosing scheme with dexamethasone (0.2 mg/kg/day, i.m.) was found to significantly reduce both the airway eosinophilia and hyperresponsiveness. However, one week after cessation of dexamethasone treatment, the airway inflammation and hyperresponsiveness returned to pre-treatment levels. In further experiments where animals were first treated with dexamethasone (7 days) followed by a 7 day treatment with R6.5, the reoccurrence of airway inflammation and subsequent increase in airway responsiveness was prevented. We conclude that the efficacy of ICAM-1 is primarily associated with inhibition of the influx of inflammatory cells into the airways and subsequent reduction in airway responsiveness. These data suggest that in lungs with pre-existing inflammation the modulation of ICAM-1 following treatment with glucocorticoids may be a novel and more selective long-term treatment for control of the chronic airway inflammation and hyperresponsiveness associated with bronchial asthma.

Notes: Platelet-activating factor (PAF) is a potent pro-inflammatory mediator that may play a role in the pathogenesis of airway hyper-responsiveness and asthma. In man, a single inhalation of PAF induces a small but prolonged increase in airway responsiveness in some individuals. The purpose of this study was to determine the effects of single and multiple inhalations of PAF on airway cell composition and responsiveness in monkeys. Anaesthetized and intubated adult male cynomolgus monkeys were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL). Airway responsiveness was measured by determining the concentration (PC100) of inhaled methacholine that caused a 100% increase in respiratory system resistance (Rrs). Airway cell composition (BAL) and responsiveness (PC100) were determined 1 day before and 20 hr after a single inhalation of PAF (∼200 μg) or 3 days before (Day 0) and 3 days after (Day 10) 3-alternate-day (Days 3, 5 and 7) inhalations of PAF (each ∼600 μg). The single inhalation of PAF (n= 8) caused an acute increase in Rrs (147±69%), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate (〉eight fold) in only one animal. The mean ±s.e. change in log PC100 was −0.29±0.18. The multiple inhalations of PAF (n=8) caused acute increases in Rrs (143±38%, 175±44% and 156±39%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate in two animals. The mean±s.e. change in log PC100 was −0.43±0.22. In summary, single and multiple inhalations of PAF in monkeys induce a granulocyte airway infiltration and, in some animals, an increase (usually small) in airway responsiveness.

Notes: Background Interleukin-4 (IL-4) is an immunoregulatory cytokine which has a wide variety of effects on immune cell function. In addition, recent studies suggest that IL-4 may have effects on other cells including endothelial cells in terms of the regulation of adhesion molecule expression and leucocyte extravasation from the vascular space to sites of tissue inflammation. Consequently, IL-4 may have an important role in the pathogenesis of allergic inflammation and disease.Objective The purpose of this study was to learn more about the potential role of IL-4 in inflammatory disease, specifically in regard to the potential of IL-4 to induce the expression of adhesion molecules on vascular endothelial cells and promote the adherence and transmigration of circulating leucocytes to sites of tissue inflammation.Methods Single subcutaneous injections of human IL-4 were administered to cynomolgus monkeys and tissue biopsy samples were obtained and analysed for adhesion molecule expression on vascular endothehum and inflammatory cell infiltrates. In another series of experiments, multiple subcutaneous injections of human IL-4 were administered (bid on four consecutive days) and the effects on peripheral blood leucocytes and plasma levels of various cytokines and chemokines were examined. Results Intradermal injection of IL-4 induced the expression of vascular cell adhesion molecule-1 (VCAM-l) on cutaneous vascular endothelium that was present at 8hr and persisted out to 24h post injection. The expression of VCAM-1 was associated with an inflammatory cell infiltrate comprised of granulocytes and mononuclear cells. Multiple injections of IL-4 resulted in a dose-related decrease in the relative percentage and total number of circulating lymphocytes and an increase in circulating neutrophils (4.6 ± 1–2.1 ± 0.2 ± 106/mL and 1.7 ± 0.3–7.0 ± 1 ± 106/mL, respectively). Analysis of cell surface markers by flow cytometry revealed a transient decrease in the number of CD4+ T lymphocytes and a sustained decrease in CD16+ cells. In addition. IL-4 administration resulted in a large increase in plasma MCP-1 concentration.Conclusion This is the first study to demonstrate an acute eflect of IL-4 consistent with lymphocyte trafficking out of the vascular space, the induction of VCAM-l expression on vascular endothelium and increases in plasma levels of MCP-1 in vivo. We suggest that IL-4 may be involved in the early recruitment of mononuclear cells to sites of tissue inflammation by the upregulation of VCAM-l expression on vascular endothelium and the generation and release of potent chemoattractants.

Notes: Previous studies from our laboratory have demonstrated a temporal relationship between eosinophil influx into the airways and the onset of airway hyperresponsiveness to inhaled methacholine. The purpose of the present study was to extend this observation by evaluating changes in airway cellular composition and measuring the levels of granulocyte-derived mediators recovered in BAL fluid during the onset and recovery from antigen-induced airway hyperresponsiveness. Airway cellular composition, airway responsiveness to inhaled methacholine and the levels of BAL fluid EPO and MPO were monitored over a 32 day study in eight adult male Ascaris suum sensitive cynomolgus monkeys. Repeated Ascaris suum inhalation (nine challenges during days 0–21) resulted in a selective, sustained airway eosinophilia that was temporally related with the onset and maintenance of airway hyperresponsiveness (r= 0.67, P 〈 0.001). The level of BAL eosinophil-derived EPO was increased and remained elevated concurrent with the increase in airway eosinophils and airway responsiveness. During the recovery phase (days 22–32) the actual number of eosinophils remained elevated, while BAL EPO levels were significantly decreased. The recovery phase was also associated with a transient increase in the number of BAL neutrophils and MPO concentration. We conclude that the number and state of activation of airway eosinophils directly correlate with the onset and maintenance of airway hyperresponsiveness. Recovery from airway hyperresponsiveness is associated with a decrease in eosinophil activation and a transient increase in the number of activated neutrophils.

Notes: Abstract The direct effect of intratracheal (IT) administration of human major basic protein (MBP) on pulmonary inspiratory pressure (PIP), and the effect on agonist-induced change in PIP, were determined in anesthetized, ventilated guinea pigs. 500 μg MBP increased PIP from 24.1±4.3 to 49.8±7.4 cm H2O (p〈0.002,n=10). Maximum PIP was achieved within 30 min after 500 μg MBP. The direct PIP response to 250 μg MBP was not different from vehicle. The PIP responses to intravenous (IV) acetylcholine (Ach) and 5-hydroxytryptamine (5-HT) were measured before and after administration of 250 μg MBP (n=12). MBP caused a modest, but significant potentiation of the increase in PIP induced by 1, 3 and 10 μg/kg Ach (24, 32 and 28%, respectively,p〈0.02) and to 1 μg/kg 5-HT (43%p〈0.02). We conclude that MBP at a dose that does not directly affect inspiratory pressure is capable of augmenting the PIP response to IV Ach and 5-HTin vivo.

Notes: Abstract Aerosol ovalbumin challenge (OA) of sensitized guinea pigs induced airway hyperreactivity (AH) to i.v. acetylcholine (Ach) and serotonin (5-HT) 24 hr post OA. Bronchoalveolar lavage fluid 24 hrs after OA showed increased leukocytes compared to unsensitized unchallenged animals. Treatment with monoclonal antibody R15.7 (3 mg/kg i.v.,) 1 hr prior and 4 hours after OA prevented the induction of AH to Ach but not to 5-HT and reduced influx of leukocytes. We conclude: 1) antigen inhalation induces an increase in AH with an increase in proinflammatory cell influx and 2) treatment with anti-CD18 antibody inhibits cell influx and airway hyperreactivity.