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Notizen: Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV, by 20% of baseline (PC20) from 0.7 to 〉 22.9 mg/ml for histamine (P 〈 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P 〈 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin. geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P 〈 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.

Notizen: Background:  Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5–15% of the exposed population suggesting an underlying genetic susceptibility.Methods:  To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)-α A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects.Results:  Neither the distribution of HLA class I antigens nor the distribution of TNF-α A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects.Conclusions:  These results suggest that HLA class I antigens and TNF-α A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma.

Notizen: Cyclosporin A is a potent immunosuppressive agent which inhibits activation of T cells and other inflammatory ceils. It has been shown to be of clinical benefit in patients with corticosteroid dependent asthma, but there are no data on its in vivo effects on airways inflammation. In this report, we describe the case of a 47-year-old man with chronic severe corticosteroid-dependent asthma who made a dramatic clinical response to therapy with cyclosporinA. Fibreoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsy were performed before and after a 12-month period of treatment with cyclosporin A and demonstrated a concomitant reduction in airway inflammatory indices.

Notizen: Background Interleukin-8 (IL-8) is a cytokine with potent neutrophil chemotactic and activating properties and is active in inflammatory conditions in man. It has been identified in human inflammatory skin conditions where it is likely to be responsible for both neutrophil recruitment from the circulation and possibly T-lymphocyte chemoattraction. Studies in animals also suggest that IL-8 may augment skin oedema.Objective To study the effects of intradermally administered IL-8 in humans on tissue oedema and cellular recruitment in atopic and non-atopic volunteers.Method Interleukin-8 (1.2 ± 10−7M) in the presence and absence of histamine was administered by intradermal injection. Wheal and erythema area were measured at regular intervals and 3 h following challenge punch biopsies were taken for immunocytochemistry. Cellular infiltrate was measured by immunocytochemical identification of neutrophils, eosinophils and T-lymphocytes in glycol-methacrylateembedded sections.Results In the presence of histamine, IL-8 provoked a significantly greater wheal area when compared to that produced by histamine alone (P 〈 0.001). In the presence of histamine, IL-8 produced a significantly greater neutrophil infiltrate (P 〈 0.05); however, neither lymphocyte or eosinophil infiltration was found to be increased with IL-8 challenge. There was no difference observed between atopic and non-atopic subjects, nor were any effects of IL-8 demonstrated in the absence of histamine.Conclusion This study demonstrates that in human skin, IL-8 induces increased microvascular permeability and neutrophil infiltration, but not eosinophil or T-lymphocyte chemoattraction.

Notizen: Allergic mucosal inflammation is characterized by tissue infiltration with eosinophils, and associated activation of mast cells and T lymphocytes. Tumour necrosis factor (TNF) alpha/cachectin is a candidate cytokine relevant to the pathogenesis of these events through its capacity to upregulate the expression of endothelial cell adhesion molecules, mediate granulocyte chemoattraction, and activate eosinophils, mast cells and T cells. To investigate the presence and localization of TNF α in the nasal mucosa in allergic rhinitis, nasal biopsies from perennial rhinitic (n=13) and non-rhinitic volunteers (n=11) were embedded in glycol methacrylate and immunostained with a monoclonal antibody directed against TNF α, and adjacent 2μm sections stained for tryptase, CD3 and eosinophil cationic protein. This identified positive immunostaining for TNF α in the submucosa of both the rhinitic and normal subjects (median cell counts 13 and 23 cells/mm2 respectively, P=0.24) with cellular localization to mast cells but not to T-lymphocytes or eosinophils. In a subsequent study of seven atopic subjects, nasal allergen challenge produced increases in lavage levels of histamine and albumin, which was associated with significant release of TNF α as early as 2 min post-allergen when compared with the saline control day (P=0.5). This difference was also apparent when studying the area under the curve both at 30 and 60 min post-challenge t-test (P=0.015 and 0.02 respectively). These findings which both locate immunoreactive TNF α to nasal mast cells and identify its release following in vivo exposure to allergen, provide evidence for mast cells as an important source of this cytokine in patients with allergic rhinitis.

Notizen: Abstract. Evidence suggests that atopic individuals may be predisposed to more severe rhinoviral colds coupled to a worsening of existing airway disease than those with asthma. The role of atopy and IgE levels, as well as their relationship to clinical disease expression have not been defined. We hypothesized that an allergic diathesis modulates rhinoviral colds and have initiated studies of normal, atopic and asthmatic subjects employing experimental rhinoviral infection, with measurements of symptom scores, viral shedding and cultures, albumin in nasal washes and serological responses. Twenty-two subjects (11 normal, 5 atopic, 6 atopic and asthmatic) participated and were inoculated with human rhinovirus serotype 16 (HRV 16). Measurements of neutralizing antibody and viral culture were performed at screening, pre-inoculation, during the cold and at 8–10 weeks convalescence. Daily symptoms were noted, nasal washes done, IgE measured and atopy was diagnosed by skin tests. Seventeen volunteers developed clinical colds as assessed by symptom scores, virus shedding was demonstrated (with positive culture) in all subjects and a fourfold or higher seroconversion occurred in 11/22. Neutralizing HRV antibody developed unexpectedly in 10 subjects between screening and inoculation and the presence or absence of this pre-inoculation antibody determined subsequent severity of colds in normal but not in atopic subjects. Atopic antibody positive individuals developed severe clinical colds that were independent of preinoculation antibody in contrast to normal subjects who developed mild colds in the presence of a neutralizing antibody (.P= 0.01). Both atopic and normal antibody negative subjects developed severe colds. This differential response was matched by nasal wash albumin levels which were significantly increased (P= 0–01) during the cold in atopic (but not in normal) volunteers with pre-inoculation antibody. Levels of IgE were not correlated with severity of clinical disease or viral shedding. Our studies of HRV disease in atopic subjects suggest heightened susceptibility to the detrimental effects of colds; additional studies are needed to clarify the relevant mechanisms.