Riccardo Polosa

Involvement of the epidermal growth factor receptor in epithelial repair in asthma

Epithelial damage and airway remodeling are consistent features of bronchial asthma and are correlated with disease chronicity, severity, and bronchial hyperreactivity. To examine the mechanisms that control bronchial epithelial repair, we investigated expression of the epidermal growth factor receptor (c‐erbB1, EGFR) in asthmatic bronchial mucosa and studied repair responses in vitro. In biopsies from asthmatic subjects, areas of epithelial damage were frequently observed and exhibited strong EGFR immunostaining. EGFR expression was also high in morphologically intact asthmatic epithelium. Using image analysis, EGFR immunoreactivity (% of total epithelial area, median (range) was found to increase from 9.4 (4.1‐20.4) in normal subjects (n=10) to 18.4 (9.3‐28.9) in mild asthmatics (P<0.01, n=13) and 25.4 (15.4‐31.8) in severe asthmatics (P<0.00, n=5). Epithelial EGFR immunoreactivity remained elevated in patients treated with corticosteroids and was positively correlated with subepithelial reticular membrane thickening. Using 16HBE 14o‐ bronchial epithelial cells, we found that EGF accelerated repair of scrape‐wounded monolayers and that the EGFR‐selective inhibitor, tyrphostin AG1478, inhibited both EGF‐stimulated and basal wound closure whereas dexamethasone was without effect. Intrinsic activation of the EGFR was confirmed by analysis of tyrosine phosphorylated proteins, which revealed a rapid, damage‐induced phosphorylation of the EGFR, irrespective of the presence of exogenous EGF. To assess the relationship between EGFR‐mediated repair and tissue remodeling, release of the profibrogenic mediator TGF‐β2 was also measured. Scrape wounding increased release of TGF‐β2 from epithelial monolayers and EGF had no additional stimulatory effect. However, when repair was retarded with AG1478, the amount of TGF‐β2 increased significantly. These data indicate that the EGFR may play an important role in bronchial epithelial repair in asthma and that impairment of this function may augment airway remodeling.—Puddicombe, S. M., Polosa, R., Richter, A., Krishna, M. T., Howarth, P. H., Holgate, S. T., Davies, D. E. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 14, 1362–1374 (2000)

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.

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.

The effect of histamine‐H1 receptor antagonism with terfenadine on concentration‐related AMP‐induced bronchoconstriction in asthma

Selective histamine‐H1 receptor antagonists inhibit adenosine 5′‐monophosphate (AMP)‐induced bronchoconstriction by > 80% when expressed as a percentage inhibition of the FEV1 time–response curve following inhalation of the provocation concentration of AMP required to produce a 20% decrease in FEV1 from baseline (PC20). To investigate this further we have determined that, in eight mild atopic asthmatic subjects, terfenadine (180 mg), administered 3 hr pre‐challenge, increases the geometric mean PC20 for histamine from 0.4 (range 0.03–3) mg/ml after placebo, to 20.2 (range 0.6–64) mg/ml following active treatment (P<0.0001). For AMP, the PC20 increased from 9.3 (range 1.0–113.3) mg/ml after placebo, to 150.2 (range 32.1–1177.7) mg/ml with terfenadine (P<0.0001). This 16.2‐fold (range, 5.5–47.9) displacement to the right of the AMP concentration–response curve by a selective histamine‐H1 receptor antagonist emphasizes the central role of histamine in the airways response to this nucleotide.

Anaphylaxis after prednisone

A reactions to corticosteroids are relatively uncommon (1, 2). These reactions may be immunologic or nonimmunologic in nature, and the clinical signs of anaphylaxis may be seen with both types of reaction. It is somewhat paradoxical that on rare occasions steroids themselves can induce systemic adverse reactions. We describe here the case of a girl with asthma and aspirin intolerance who developed severe systemic symptoms and loss of consciousness after a single dose of 25 mg prednisone.

Skin responses to bradykinin, kallidin, and [desArg9]-bradykinin in nonatopic and atopic volunteers

BACKGROUND Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of inflammatory diseases of the skin by interacting with specific receptors designated B1 and B2. In this study we have investigated the structure-activity relationship of intradermally injected bradykinin, kallidin (lysine-bradykinin), and [desArg9]-bradykinin in atopic (n = 8) and nonatopic (n = 8) subjects. METHODS On two separate occasions, each separated by a week, subjects randomly underwent intradermal challenge with incremental doses (0.5, 5, and 50 nmol) of either the B1-agonist [desArg9]-bradykinin, the B2-agonists bradykinin or kallidin, or vehicle placebo. In a separate randomized double-blind study we have also examined the effect of an orally administered antihistamine, terfenadine, on kinin-induced wheal and flare responses and their repeatability in a group of nine volunteers. The skin responses were monitored objectively by measurement of wheal and flare areas. RESULTS Both bradykinin and kallidin induced a dose-dependent increase in wheal and flare areas in all subjects studied. Although the effects of the two lowest doses (0.5 and 5 nmol) of [desArg9]-bradykinin on skin responses were indistinguishable from those of placebo, this kinin at the highest dose administered (50 nmol) caused a significant increase in wheal and flare areas in all subjects studied. No difference could be identified in the skin responses to kinins between atopic and nonatopic subjects. In addition kinin-induced cutaneous responses were not altered by pretreatment with terfenadine. CONCLUSIONS These in vivo structure activity studies suggest that in human beings the skin responses to kinins may be compatible with the stimulation of B2 receptors, which is unrelated to histamine release from cutaneous mast cells.

Adenosine as a pro-inflammatory mediator in asthma.

Adenosine, which may be formed by all cells during relative energy or oxygen deficit, may act as an autocoid by modifying the function of other cells in the local environment. In asthmatic, but not normal, subjects, inhalation of adenosine causes a marked bronchoconstriction which may be reduced by the purinoceptor antagonist theophylline, sodium cromoglycate, nedocromil sodium, histamine, H1-antagonists and cyclo-oxygenase inhibitors. Repeated exposure to adenosine induces a state of tachyphylaxis and cross-tachyphylaxis with exercise-induced bronchoconstriction but not with that provoked by allergen. Although the mechanisms by which adenosine induces changes in airways function are not clear, it is suggested that it has an indirect effect, possibly by up-regulating bronchoconstrictor factors already present in asthma such as mast cell mediator release or neuronal reflexes.

Advances in Asthma Management

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Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects☆☆☆

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The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5′-monophosphate and histamine in asthma

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