kallidin and Asthma

The past decade has seen renewed interest in the potential role of kinins in airway diseases. The correlation between kinin generation and symptoms of inflammation, together with the demonstration that administration of kinins to the airway mucosa can induce relevant symptoms, provides strong circumstantial support for a role of kinins in the pathogenesis of airway diseases, such as allergic and viral rhinitis and asthma. Definitive studies of the effects of blockade of kinin actions on symptomatic responses, however, are still needed. The effects of kinins in the airways, and the mechanisms by which they exert their actions clearly vary depending on the presence of inflammation in the airways. Although a growing body of evidence implicates activation of sensory nerves as an important component of kinin effects in inflamed airways, the components of inflammation that modify the response of these sensory nerves, the mechanisms by which neuronal responsiveness alters, and the degree of selectivity of neuronal activation to bradykinin are all topics that require further delineation.

Topics: Animals; Asthma; Bradykinin; Bradykinin Receptor Antagonists; Bronchi; Humans; Kallidin; Kinins; Lung; Muscle, Smooth; Receptor, Bradykinin B2; Rhinitis

To further define the role of neural responses in the hyperreactivity of inflamed human upper airways to bradykinin (BK), we determined if repeated challenges with BK led to tachyphylaxis of neurally mediated responses in subjects with perennial allergic rhinitis. We also tested the hypothesis that enhanced reactivity to kinins in inflamed airways was caused by induction of B1-kinin receptors by comparing the effects of the selective B1-receptor agonist, des-Arg10-lysylbradykinin, and the B2 receptor agonist, BK, in the lower airways of asthmatics and in the upper airways of subjects with perennial allergic rhinitis. Repeated BK challenges led to tachyphylaxis of sneezing and of neurally mediated serous glandular secretion in subjects with perennial allergic rhinitis. Surprisingly, tachyphylaxis of increased local vascular permeability was also observed. By contrast, repeated challenges with BK in normal subjects led to reproducible increases in vascular permeability. Provocation with des-Arg10-lysylbradykinin did not cause bronchoconstriction in asthmatic subjects or increase glandular secretion or vascular permeability in the upper airways of subjects with rhinitis. We conclude that increased reactivity to kinins in inflamed human airways is mediated, at least in part, by neural reflexes, and is not caused by induction of B1-receptors.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchoconstriction; Capillary Permeability; Cross-Over Studies; Double-Blind Method; Female; Follow-Up Studies; Humans; Inflammation; Kallidin; Kinins; Male; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Reflex; Rhinitis, Allergic, Perennial; Tachyphylaxis

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adult; Asthma; Bradykinin; Bronchial Provocation Tests; Bronchoconstriction; Double-Blind Method; Female; Forced Expiratory Volume; Histamine; Humans; Kallidin; Male; Tachyphylaxis

Bradykinin, kallidin (lys-bradykinin), and [des-Arg9]bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of asthma by interacting with specific receptors designated B1 and B2. In this study, we have investigated the airway response to inhaled bradykinin, kallidin, and [des-Arg9]bradykinin in normal and asthmatic subjects. Changes in airway caliber were followed as maximum expiratory flow at 30% of the vital capacity (Vp30) and as forced expiratory volume in 1 s (FEV1). Only one of the six normal subjects responded to bradykinin at the maximum cumulative concentration (5.33 mg/ml). Neither kallidin nor [des-Arg9]bradykinin had any measurable bronchoconstrictor effect in the normal subjects whether airway caliber was measured as Vp30 or FEV1. In the 10 subjects with asthma, bradykinin and kallidin, but not [des-Arg9]bradykinin, produced a concentration-related fall in FEV1. The geometric mean provocation concentrations of inhaled agonist reducing FEV1 by 20% of baseline were 0.03, 0.08, and 0.44 mg/ml for bradykinin, kallidin, and histamine, respectively. Bronchoconstriction produced by bradykinin and kallidin was maximal within 3 to 5 min with recovery occurring over 30 to 45 min. Because bradykinin and kallidin are agonists of B2 receptors and [des-Arg9]bradykinin is an agonist for B1 receptors, these in vivo structure activity studies suggest that asthmatic, but not normal, airways are hyperresponsive to kinins when compared to histamine and that this potent bronchoconstrictor action is a specific pharmacologic effect compatible with the stimulation of B2 receptors or a variant of these.

Topics: Adult; Asthma; Bradykinin; Bronchial Provocation Tests; Bronchoconstriction; Forced Expiratory Volume; Humans; Kallidin; Middle Aged; Receptors, Bradykinin; Receptors, Neurotransmitter

This study tested the hypothesis that proinflammatory kinin peptides are involved in modulating human dendritic cell (DC) function. Inflammation is accompanied by an increased maturation of DCs and the generation of kinins, particularly Lys-des[Arg(9)]-bradykinin (Lda-BK). We assessed the role of Lda-BK in the activation and migration of human monocyte-derived DCs (hMo-DCs) matured through the use of LPS, TNF-α + IL-1β, or CD40 ligand. Kinin B(1) and B(2) receptor mRNA and protein expression were assessed by confocal microscopy, flow cytometry, and RT-PCR. The effects of Lda-BK on the migration of mature hMo-DCs were assessed in Transwell chambers, whereas the expression of costimulatory molecules and the secretion of IL-12 were assessed by flow cytometry and ELISA, respectively. The expression of the kinin B(1) receptor (B(1)R) was down-regulated during the maturation of hMo-DCs, whereas the expression of B(2)R was unchanged. The B(1)R agonist Lda-BK was not chemotactic for hMo-DCs matured using LPS, TNF-α + IL-1β, or CD40 ligand, but Lda-BK enhanced the secretion of IL-12p70 and inhibited the secretion of IL-12p40 by mature hMo-DCs. However, the exposure of hMo-DCs matured with TNF-α + IL-1β to Lda-BK for 6 hours decreased subsequent migration in response to Lda-BK, the chemokine CCL19, or Lda-BK combined with CCL19. The expression of B(1)R was increased in hMo-DCs from subjects with asthma compared with subjects without asthma, in keeping with a tendency toward increased in vitro migration of asthmatic hMo-DCs in response to Lda-BK. The increased formation of Lda-BK and the enhanced expression of B(1)R as a consequence of inflammation may alter the migration of mature, antigen-laden DCs to regional lymph nodes in response to CCL19, may modulate the secretion of cytokines by these DCs, and may contribute to the accumulation of mature DCs in the lungs of patients with asthma.

Topics: Adult; Asthma; Bradykinin; Case-Control Studies; CD40 Ligand; Cell Movement; Chemotactic Factors; Cytokines; Dendritic Cells; Humans; Interleukin-12; Kallidin; Ligands; Monocytes; Receptor, Bradykinin B1; Receptors, CCR7; RNA, Messenger

Bradykinin, kallidin and [desArg9]-bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors. The structure-activity relationship of kinins within the lower airways has been investigated in 16 asthmatic subjects. The findings of the present study suggest a complex action of kinins on asthmatic airways probably involving more than one receptor subtype.

Topics: Asthma; Bradykinin; Forced Expiratory Volume; Humans; Kallidin; Receptors, Bradykinin; Receptors, Neurotransmitter; Tachyphylaxis