Karalasingam Rajakulasingam - Academia.edu (original) (raw)
Papers by Karalasingam Rajakulasingam
Clinical and Experimental Allergy, 1994
Clinical and Experimental Allergy, 2002
Biomedicine & Pharmacotherapy, 2007
Allergic rhinitis is a common condition, but many people still experience suboptimal control of s... more Allergic rhinitis is a common condition, but many people still experience suboptimal control of symptoms despite measures such as allergen avoidance, intra-nasal steroids and antihistamines. Specific immunotherapy (SIT) has been used for many years, but though many studies show clinical efficacy, its mechanism of action is still not clearly understood. Earlier studies showed changes in antibodies and it may be that SIT works through mechanisms that alter the ratio of 'protective' IgG4 to 'pro-allergenic' IgE. Other studies have shown a reduction in eosinophil migration to nasal mucosa as well as a reduction in inflammatory mediator release including basophil histamine release. More recent studies have proposed that SIT works through inhibition of T-helper 2 lymphocytes (Th2) which preferentially produce cytokines that promote allergic responses. SIT may cause a deviation from Th2 to Th1 (T-helper 1 lymphocytes) or may induce T-regulatory cells (T-regs) which inhibit Th2 responses directly or through inhibitory cytokines.
Clinical and Experimental Allergy, 1991
Thorax, 1993
Background-Bradykinin may contribute to the pathogenesis of allergic rhinitis. Like histamine, na... more Background-Bradykinin may contribute to the pathogenesis of allergic rhinitis. Like histamine, nasal challenge with bradykinin induces rhinorrhoea, nasal blockage, and plasma protein leakage. Their comparative nasal potencies have not, however, been fully elucidated. Methods-Three double blind, randomised, placebo controlled and crossover studies were undertaken to compare objectively the nasal effects of bradykinin, histamine, and vehicle. Results-Both bradykinin and histamine produced dose dependent increases in nasal airways resistance (NAR). There was no significant difference in the effects of bradykinin and histamine on NAR at any dose level. On a molar basis, however, bradykinin was 6-98 times more potent than histamine in inducing a 50% increase in NAR. Nasal challenge with bradykinin and histamine also induced significant rhinorrhoea compared with vehicle. The amount of rhinorrhoea induced by histamine was significantly greater than that induced by bradykinin at any dose level. Bradykinin and histamine induced dose dependent nasal pain and nasal itch respectively. When administered as single doses both bradykinin (1 9 ,umol) and histamine (1 9 4umol)
European Respiratory Journal, 1994
in nd di ic ce es s o of f a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s i in n a... more in nd di ic ce es s o of f a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s i in n a as st th hm ma at ti ic c s su ub bj je ec ct ts s ABSTRACT: Asthma is characterized by airway hyperresponsiveness, a physiopathological abnormality which may result from the complex interplay between inflammatory cells and proinflammatory mediators. Although kinins are thought to play a role in the pathogenesis of bronchial asthma, it is not known whether bradykinin is able to induce airway hyperresponsiveness.
Clinical and Experimental Allergy, 1991
Journal of Allergy and Clinical Immunology, 1991
Mast cells were enumerated in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from norm... more Mast cells were enumerated in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from normal subjects (n= 12) and from patients with atopic asthma (36), intrinsic asthma (9) or chronic cough ; and the concentrations of mast cell tryptase and histamine were determined in BAL fluid. Eighteen patients with atopic asthma, and all but one with intrinsic asthma were taking inhaled steroids.
Journal of Allergy and Clinical Immunology, 1995
Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of th... more Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of the bronchoconstrictor response in asthma. It is not known whether cross-refractoriness exists between these stimuli. Objective: We postulated that repeated bradykinin and hypertonic saline bronchial challenges might reduce the airway response to subsequent hypertonic saline and bradykinin challenges, respectively. Methods: Eleven atopic asthmatic subjects underwent two concentration-response studies, separated by 1 hour, with either inhaled histamine or bradykinin. After recovery, a hypertonic saline challenge was performed. During the next phase, nine subjects underwent two concentration-response studies, separated by I hour, with hypertonic saline. After recovery, a bradykinin challenge was performed. Results: On the histamine study day, the mean provocative volume of agonist required to produce 20% drop in forced expiratory volume in 1 second (PD:o) hypertonic saline was 220. 7 L (+_42. 7 L) and this was not significantly different from that measured at baseline. On the bradykinin study day, the geometric mean provocative concentration of agonist required to produce a 20% drop in forced expiratory volume in 1 second (PCeo) was 0.39 mg/ml (0.01 to 11. 73 mg/ml) fo r the first test and significantly higher at 1.38 mg/m ! (0.01 to >16.0 mg/ml) for the second test (p = 0.006). The hypertonic saline PD2o increased significantly from a baseline of 159.2 L (+_27.3 L) to 377.6 (+_64.7L) (p = 0.003). On the hypertonic saline study day, the mean PD2o was 152.8 L for the first test, and 337. 7 L for the second test (p = 0.01). PC2o bradykinin increased significantly from a baseline of 0.57 to 2.56 mg/ml (p = 0.02). A significant correlation was found between loss of response to bradykinin and to hyperton& saline (rs, O. 63 and O. 76). Conclusion: Refractoriness produced by repeated exposure of the airways to bradykinin and hypertonic saline results in loss of responsiveness to hypertonic saline and bradykinin respectively, suggesting a shared mechanism for refractoriness produced by these stimuli. (J ALLERGY CLIN 1MMUNOL 1995,'96:502-9.) Bradykinin is a potent vasoactive nonapeptide formed as cleavage product from the action of plasma kallikrein on high molecular weight kininogen. When inhaled by asthmatic subjects, bradykinin causes bronchoconstriction. 1-3 Bradykinin pro-From the 502 Abbreviations used FEVI: Forced expiratory volume in 1 second HS: Hypertonic saline PC2o: Provocative concentration of agonist required tO produce 20% drop in FEV~ PD2o: Provocative volume of agonist required to produce 20% drop in FEV 1 duces many of its effects by interacting with specific receptors, designated [32. Although in vivo structure-activity studies have suggeste d that bradykinin produces bronchoconstriction by stimulating [32 receptors, 2 the physiologic mechanism(s) involved are not clearly understood. Although both the J ALLERGY CLIN IMMUNOL Rajakulasingam et ai. 503 VOLUME 96, NUMBER 4
Clinical and Experimental Allergy, 1992
Clinical and Experimental Allergy, 1992
Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To asse... more Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 μg) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days. This study, therefore, demonstrates that cholinergic pathways and mast cell release of histamine do not contribute to increase in NAR, rhinorrhoea and plasma protein extravasation induced by bradykinin.
Journal of Allergy and Clinical Immunology, 2002
Mediators of Inflammation, 1993
THE time course of effect of the B2-receptor agonist kallidin (K) on induced changes of nasal air... more THE time course of effect of the B2-receptor agonist kallidin (K) on induced changes of nasal airflow, rhinorrhoea, nasal pain, sneezing and nasal microvascular leakage has been examined and compared with its B2 metabolite agonist bradykinin (B) and the Bl-agonist [des-argg]-bradyki nin (D). When administered as a single dose K and B induced an immediate sensation of pain, rhinorrhoea, elevations in lavage albumin and protein levels and a sustained increase in nasal airways resistance (NAR) for 5-40 min post-challenge. [des-argg]-Bradykinin and vehicle placebo (V) were without effect on any of these indices. These studies identify the action of K and B within the nose and differentiate the neural and vascular effects of these kinins in addition to suggesting the potential that nasal blockage and nasal microvascular leakage represent alterations in differing vascular compartments. These findings have implications for the understanding and therapeutic manipulation of rhinitis.
Journal of Allergy and Clinical Immunology, 1993
Journal of Allergy and Clinical Immunology, 1993
A randomized, double-blind placebo-controlled study was conducted to compare the effects of two c... more A randomized, double-blind placebo-controlled study was conducted to compare the effects of two chemically unrelated 'loop" diuretics, furosemide (40 mg) and bumetanide (2 mg) on the bronchoconsttictor response to inhaled adenosine S-monophosphate (AMP) in 12 subjects with asthma. In eight additional volunteers with asthma, we also carried out a separate randomized double-blind study to examine in more detail the time course of change in bronchial reactivity to inhaled AMP after administration of nebulized fumsemide and bumetanide. Inhaled loop diuretics significantly increased the provocative concentration of AMP causing a 20% fall in forced expiratory volume in I second (FEV,) from the value of 21.2 mglml (range, 2.5 to 96.9 mglml) after placebo administration to 83.4 mglml (range, 11.3 to 345.0 mglml) (p c 0.01) and 33.8 mglml (range, 4.7 to 120.9 mglml) @ c 0.05) after administration of furosemide and bumetanide, respective& After placebo administration, the provocative concentration of AMP causing a 20% fall in FEV1 (PC,, AMP) at 10, 30, and 120 minutes did not differ significant&; their geometric mean (range) values were 57.8 mglml (10.9 to 341.0 mglml), 55.0 mglml (13.2 to 304.1 mglml), and 52.8 mglml (14.4 to 252.2 mglml), respective& When compared with placebo, inhaled furosemide significantly reduced the airway responsiveness to AMP at all time points; the PC,, AMP values at 10, 30, and 120 minutes were 154.6 mglml (29.4 to 658.7 mglml) @ < O.Ol), 142.6 mglml (25.5 to 439.9 mglml) (p < O.Ol), and 103.9 mglml (12.5 to 605.5 mglml) 0, c 0.05), respectively. The PC,,, values for AMP after pretreatment with bumetanide were significantly increased up to 110.2 mglml (25.9 to 639.0 mglml) (p < 0.01) and to 92.0 mglml (21.6 to 531.7 mglml) (p c 0.05) at 10 and 30 minutes, respectively. At 120 minutes, inhaled bumetanide failed to affect AMP airway responsiveness; the PC,, AMP was not significantly different from that of placebo, with a value of 71.5 mglml (22.6 to 318.0 mglml). We conclude that comparable equidiuretic doses of furosemide and bumetanide are effective in attenuating the airway response to AMP with furosemide being approximately 2.5 times more potent than bumetanide (p < 0.01). The time course of change in bronchial reactivity to AMP is similar for both drugs with a peak effect at 10 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled loop diuretics in asthma may be distinct from those responsible for their diuretic properties. (J ALLERGY CLIN IMMUNOL 1993;92:288-97.)
![Research paper thumbnail of Skin responses to bradykinin, kallidin, and [desArg]-bradykinin in nonatopic and atopic volunteers](https://attachments.academia-assets.com/49260701/thumbnails/1.jpg)
](Journal of Allergy and Clinical Immunology, 1993
Background: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of ... more Background: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of inf7ammator-y diseases of the skin by interacting with specific receptors designated B, and B, In this study we have investigated the structure-activity relationship of intradermally injected bradykinin, kalhifin (lysine-bradykinin), and [de&$]-bradykinin in atopic (n = 8) and
Journal of Allergy and Clinical Immunology, 1991
The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg oral... more The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine-and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV,. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV, from the postsaline baseline value (PCJ for histamine and AMP was 0.63 and 5 mglml, respectively. Terfenadine displaced the FEV, concentration-response curves obtained with both histamine (GM PC,,, values increasing to 26.92 mglml) and AMP (GM PC,, values increasing to 26.7 mglml) to the right. IB had a small, but signijcant, protective effect against the fall in FEV, produced by histamine and AMP, the GM PC,, values increasing to I .69 and to 12.6 mglml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC,, values increasing to 54.76 and 47.7 mglml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man. (JALLERGY CLINIMMUNOL 1991;87:939-47.) The mechanism by which adenosine and its related nucleotide, AMP, cause bronchoconstriction when it is inhaled by atopic', 2 and nonatopic'. 3 subjects with asthma remains to be clarified. Adenosine has been demonstrated to potentiate the release of the preformed mediators P-hexosaminidase and histamine from immunologically activated rodent4 and humans mast cells in vitro, probably through an interaction with specific cell-surface receptors of the A, subtype.+ 5 Additional support for mast cell involvement in AMP-induced
Thorax, 1994
Background -Inhaled frusemide exerts a protective effect against bronchoconstriction induced by s... more Background -Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma. This effect could be caused by interference with neural pathways. The effect of inhaled frusemide on bronchoconstriction induced by inhaled bradykinin, which is thought to cause bronchoconstriction via neural mechanisms, was studied and compared with the effects of adenosine 5'-monophosphate (AMP) which probably produces its airway effects by augmenting mast cell mediator release and interfering with neural pathways. Methods -Patients first underwent AMP and bradykinin challenges. They were then studied in a randomised, placebo controlled, double blind fashion. Ten atopic asthmatic subjects, studied on four days, were pretreated with inhaled frusemide (40 mg) or placebo for 10 minutes, five minutes before challenge with increasing concentrations of nebulised AMP or bradykinin. Results -On the open visit days the provocative concentrations required to reduce forced expiratory volume in one second (FEVI) by 20% from baseline (PC20) for AMP and bradykinin were 16-23 (1P42-67 16) and 2 75 (0-81-66) mg/ ml. There was a significant correlation between baseline AMP and bradykinin PC20 values. For AMP the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 80-97 (9-97-> 400-0) and 14-86 Immunopharmacology (2-6-104-6) mg/ml respectively (95% CI Group, University of 0 49 to 0-98). For bradykinin the geomet-Southampton, University ric mean PC20 values following pretreat-Medicine, Southampton ment with inhaled frusemide and Southampton S09 4XY matched placebo were 13-22 (2 53-> 16-0) K Rajakulasingam and 2 52 (0-45-5-61) mg/ml respectively M K Church (95% CI 0 43 to I 01). Frusemide afforded P H Howarth 5*45 and 5 24 fold protection against S T Holgate AMP and bradykinin-induced broncho-
Journal of Allergy and Clinical Immunology, 1998
It has previously been shown that cells mRNA+ for T(H2)-type cytokines (IL-4 and IL-5) infiltrate... more It has previously been shown that cells mRNA+ for T(H2)-type cytokines (IL-4 and IL-5) infiltrate the site of allergen-induced cutaneous late-phase reactions (LPR) in atopic subjects. In this study we have used the same experimental model to identify the cell source of both IL-4 and IL-5 mRNA and protein product. Allergen-induced LPRs were provoked in the skin of atopic individuals and the sites microscopically examined at 6, 24, and 48 hours. Using single in situ hybridization and immunohistochemistry, we first showed that the numbers of IL-4 and IL-5 mRNA and protein product positive cells peaked at 24 hours. This coincided with the magnitude of the LPR. By double in situ hybridization/immunohistochemistry, we then established (in 24-hour biopsy specimens) that the percentage of CD3+ T lymphocytes, EG2+ eosinophils, and tryptase-positive mast cells that were either IL-4 or IL-5 mRNA+ was 19%, 24%, and 5% and 19%, 20%, and 5%, respectively. Conversely, the percentage of EG2+ and tryptase-positive cells that were IL-4 or IL-5 protein product positive were 62% and 53% and 72% and 29%, respectively. IL-4 and IL-5 protein did not colocalize to CD3+ cells. CD68+ macrophages were negative in both in situ hybridization and immunohistochemistry. With eosinophils we obtained direct evidence of time-dependent stimulus-induced IL-4 and IL-5 mRNA transcription by semiquantitative reverse transcription-polymerase chain reaction of cells incubated with either IgG- or sIgA-coated particles in vitro. Taken together, these experiments suggest that eosinophils, mast cells, and T cells all contribute in variable degrees to the expression of IL-4 and IL-5 in human cutaneous LPR. The failure to colocalize IL-4/IL-5 protein (as opposed to mRNA) to CD3+ cells is attributed to the inability of T lymphocytes to store and concentrate sufficient intracellular amounts of these cytokines to produce positive immunostaining.
Journal of Allergy and Clinical Immunology, 1997
Nitric oxide (NO) is produced in large amounts in the noses of normal individuals. We have measur... more Nitric oxide (NO) is produced in large amounts in the noses of normal individuals. We have measured NO by chemiluminescence in the noses and exhaled air of subjects with symptomatic allergic rhinitis, some of whom had concomitant asthma, during the pollen season and compared this with values measured in normal subjects and in patients treated with nasal and~or inhaled glucocorticoids. We found that nasal levels of NO were significantly (p < 0.001) elevated in patients with untreated rhinitis (1527 +-87 ppb, n = 12) compared with normal individuals (996 +_ 39 ppb, n = 46) or subjects treated with nasal steroids (681 +-34 ppb, n = 10), whereas exhaled NO in patients with untreated rhinitis was similar to that in normal subjects (10 +_ 2 ppb vs 7 + 0.6 ppb, respectively). In five subjects who were nasally challenged with allergen, there was a significant decrease in nasal NO 1 hour after challenge, and this was significantly correlated with increased rhinitis symptoms. In patients with rhinitis and concomitant asthma, nasal NO was also significantly elevated (1441 +_ 76 ppb, n = 16) but not when they were treated with nasal or inhaled steroids; whereas exhaled NO was elevated in untreated patients and in patients treated with nasal, but not inhaled, steroids. Our data suggest that the increase in exhaled NO in patients with allergic rhinitis is likely to be due to increased local production, caused by long-term exposure to allergen, which is suppressed by locally administered steroids. Measurement of nasal NO may be useful to study the inflammatory response in rhinitis and its response to antiinflammatory treatments. (J AUergy Clin Immunol 1997;99:58-64.)
Clinical and Experimental Allergy, 1994
Clinical and Experimental Allergy, 2002
Biomedicine & Pharmacotherapy, 2007
Allergic rhinitis is a common condition, but many people still experience suboptimal control of s... more Allergic rhinitis is a common condition, but many people still experience suboptimal control of symptoms despite measures such as allergen avoidance, intra-nasal steroids and antihistamines. Specific immunotherapy (SIT) has been used for many years, but though many studies show clinical efficacy, its mechanism of action is still not clearly understood. Earlier studies showed changes in antibodies and it may be that SIT works through mechanisms that alter the ratio of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;protective&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; IgG4 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;pro-allergenic&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; IgE. Other studies have shown a reduction in eosinophil migration to nasal mucosa as well as a reduction in inflammatory mediator release including basophil histamine release. More recent studies have proposed that SIT works through inhibition of T-helper 2 lymphocytes (Th2) which preferentially produce cytokines that promote allergic responses. SIT may cause a deviation from Th2 to Th1 (T-helper 1 lymphocytes) or may induce T-regulatory cells (T-regs) which inhibit Th2 responses directly or through inhibitory cytokines.
Clinical and Experimental Allergy, 1991
Thorax, 1993
Background-Bradykinin may contribute to the pathogenesis of allergic rhinitis. Like histamine, na... more Background-Bradykinin may contribute to the pathogenesis of allergic rhinitis. Like histamine, nasal challenge with bradykinin induces rhinorrhoea, nasal blockage, and plasma protein leakage. Their comparative nasal potencies have not, however, been fully elucidated. Methods-Three double blind, randomised, placebo controlled and crossover studies were undertaken to compare objectively the nasal effects of bradykinin, histamine, and vehicle. Results-Both bradykinin and histamine produced dose dependent increases in nasal airways resistance (NAR). There was no significant difference in the effects of bradykinin and histamine on NAR at any dose level. On a molar basis, however, bradykinin was 6-98 times more potent than histamine in inducing a 50% increase in NAR. Nasal challenge with bradykinin and histamine also induced significant rhinorrhoea compared with vehicle. The amount of rhinorrhoea induced by histamine was significantly greater than that induced by bradykinin at any dose level. Bradykinin and histamine induced dose dependent nasal pain and nasal itch respectively. When administered as single doses both bradykinin (1 9 ,umol) and histamine (1 9 4umol)
European Respiratory Journal, 1994
in nd di ic ce es s o of f a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s i in n a... more in nd di ic ce es s o of f a ai ir rw wa ay y r re es sp po on ns si iv ve en ne es ss s i in n a as st th hm ma at ti ic c s su ub bj je ec ct ts s ABSTRACT: Asthma is characterized by airway hyperresponsiveness, a physiopathological abnormality which may result from the complex interplay between inflammatory cells and proinflammatory mediators. Although kinins are thought to play a role in the pathogenesis of bronchial asthma, it is not known whether bradykinin is able to induce airway hyperresponsiveness.
Clinical and Experimental Allergy, 1991
Journal of Allergy and Clinical Immunology, 1991
Mast cells were enumerated in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from norm... more Mast cells were enumerated in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from normal subjects (n= 12) and from patients with atopic asthma (36), intrinsic asthma (9) or chronic cough ; and the concentrations of mast cell tryptase and histamine were determined in BAL fluid. Eighteen patients with atopic asthma, and all but one with intrinsic asthma were taking inhaled steroids.
Journal of Allergy and Clinical Immunology, 1995
Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of th... more Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of the bronchoconstrictor response in asthma. It is not known whether cross-refractoriness exists between these stimuli. Objective: We postulated that repeated bradykinin and hypertonic saline bronchial challenges might reduce the airway response to subsequent hypertonic saline and bradykinin challenges, respectively. Methods: Eleven atopic asthmatic subjects underwent two concentration-response studies, separated by 1 hour, with either inhaled histamine or bradykinin. After recovery, a hypertonic saline challenge was performed. During the next phase, nine subjects underwent two concentration-response studies, separated by I hour, with hypertonic saline. After recovery, a bradykinin challenge was performed. Results: On the histamine study day, the mean provocative volume of agonist required to produce 20% drop in forced expiratory volume in 1 second (PD:o) hypertonic saline was 220. 7 L (+_42. 7 L) and this was not significantly different from that measured at baseline. On the bradykinin study day, the geometric mean provocative concentration of agonist required to produce a 20% drop in forced expiratory volume in 1 second (PCeo) was 0.39 mg/ml (0.01 to 11. 73 mg/ml) fo r the first test and significantly higher at 1.38 mg/m ! (0.01 to >16.0 mg/ml) for the second test (p = 0.006). The hypertonic saline PD2o increased significantly from a baseline of 159.2 L (+_27.3 L) to 377.6 (+_64.7L) (p = 0.003). On the hypertonic saline study day, the mean PD2o was 152.8 L for the first test, and 337. 7 L for the second test (p = 0.01). PC2o bradykinin increased significantly from a baseline of 0.57 to 2.56 mg/ml (p = 0.02). A significant correlation was found between loss of response to bradykinin and to hyperton& saline (rs, O. 63 and O. 76). Conclusion: Refractoriness produced by repeated exposure of the airways to bradykinin and hypertonic saline results in loss of responsiveness to hypertonic saline and bradykinin respectively, suggesting a shared mechanism for refractoriness produced by these stimuli. (J ALLERGY CLIN 1MMUNOL 1995,'96:502-9.) Bradykinin is a potent vasoactive nonapeptide formed as cleavage product from the action of plasma kallikrein on high molecular weight kininogen. When inhaled by asthmatic subjects, bradykinin causes bronchoconstriction. 1-3 Bradykinin pro-From the 502 Abbreviations used FEVI: Forced expiratory volume in 1 second HS: Hypertonic saline PC2o: Provocative concentration of agonist required tO produce 20% drop in FEV~ PD2o: Provocative volume of agonist required to produce 20% drop in FEV 1 duces many of its effects by interacting with specific receptors, designated [32. Although in vivo structure-activity studies have suggeste d that bradykinin produces bronchoconstriction by stimulating [32 receptors, 2 the physiologic mechanism(s) involved are not clearly understood. Although both the J ALLERGY CLIN IMMUNOL Rajakulasingam et ai. 503 VOLUME 96, NUMBER 4
Clinical and Experimental Allergy, 1992
Clinical and Experimental Allergy, 1992
Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To asse... more Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 μg) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days. This study, therefore, demonstrates that cholinergic pathways and mast cell release of histamine do not contribute to increase in NAR, rhinorrhoea and plasma protein extravasation induced by bradykinin.
Journal of Allergy and Clinical Immunology, 2002
Mediators of Inflammation, 1993
THE time course of effect of the B2-receptor agonist kallidin (K) on induced changes of nasal air... more THE time course of effect of the B2-receptor agonist kallidin (K) on induced changes of nasal airflow, rhinorrhoea, nasal pain, sneezing and nasal microvascular leakage has been examined and compared with its B2 metabolite agonist bradykinin (B) and the Bl-agonist [des-argg]-bradyki nin (D). When administered as a single dose K and B induced an immediate sensation of pain, rhinorrhoea, elevations in lavage albumin and protein levels and a sustained increase in nasal airways resistance (NAR) for 5-40 min post-challenge. [des-argg]-Bradykinin and vehicle placebo (V) were without effect on any of these indices. These studies identify the action of K and B within the nose and differentiate the neural and vascular effects of these kinins in addition to suggesting the potential that nasal blockage and nasal microvascular leakage represent alterations in differing vascular compartments. These findings have implications for the understanding and therapeutic manipulation of rhinitis.
Journal of Allergy and Clinical Immunology, 1993
Journal of Allergy and Clinical Immunology, 1993
A randomized, double-blind placebo-controlled study was conducted to compare the effects of two c... more A randomized, double-blind placebo-controlled study was conducted to compare the effects of two chemically unrelated 'loop" diuretics, furosemide (40 mg) and bumetanide (2 mg) on the bronchoconsttictor response to inhaled adenosine S-monophosphate (AMP) in 12 subjects with asthma. In eight additional volunteers with asthma, we also carried out a separate randomized double-blind study to examine in more detail the time course of change in bronchial reactivity to inhaled AMP after administration of nebulized fumsemide and bumetanide. Inhaled loop diuretics significantly increased the provocative concentration of AMP causing a 20% fall in forced expiratory volume in I second (FEV,) from the value of 21.2 mglml (range, 2.5 to 96.9 mglml) after placebo administration to 83.4 mglml (range, 11.3 to 345.0 mglml) (p c 0.01) and 33.8 mglml (range, 4.7 to 120.9 mglml) @ c 0.05) after administration of furosemide and bumetanide, respective& After placebo administration, the provocative concentration of AMP causing a 20% fall in FEV1 (PC,, AMP) at 10, 30, and 120 minutes did not differ significant&; their geometric mean (range) values were 57.8 mglml (10.9 to 341.0 mglml), 55.0 mglml (13.2 to 304.1 mglml), and 52.8 mglml (14.4 to 252.2 mglml), respective& When compared with placebo, inhaled furosemide significantly reduced the airway responsiveness to AMP at all time points; the PC,, AMP values at 10, 30, and 120 minutes were 154.6 mglml (29.4 to 658.7 mglml) @ < O.Ol), 142.6 mglml (25.5 to 439.9 mglml) (p < O.Ol), and 103.9 mglml (12.5 to 605.5 mglml) 0, c 0.05), respectively. The PC,,, values for AMP after pretreatment with bumetanide were significantly increased up to 110.2 mglml (25.9 to 639.0 mglml) (p < 0.01) and to 92.0 mglml (21.6 to 531.7 mglml) (p c 0.05) at 10 and 30 minutes, respectively. At 120 minutes, inhaled bumetanide failed to affect AMP airway responsiveness; the PC,, AMP was not significantly different from that of placebo, with a value of 71.5 mglml (22.6 to 318.0 mglml). We conclude that comparable equidiuretic doses of furosemide and bumetanide are effective in attenuating the airway response to AMP with furosemide being approximately 2.5 times more potent than bumetanide (p < 0.01). The time course of change in bronchial reactivity to AMP is similar for both drugs with a peak effect at 10 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled loop diuretics in asthma may be distinct from those responsible for their diuretic properties. (J ALLERGY CLIN IMMUNOL 1993;92:288-97.)
Journal of Allergy and Clinical Immunology, 1993
Background: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of ... more Background: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of inf7ammator-y diseases of the skin by interacting with specific receptors designated B, and B, In this study we have investigated the structure-activity relationship of intradermally injected bradykinin, kalhifin (lysine-bradykinin), and [de&$]-bradykinin in atopic (n = 8) and
Journal of Allergy and Clinical Immunology, 1991
The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg oral... more The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine-and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV,. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV, from the postsaline baseline value (PCJ for histamine and AMP was 0.63 and 5 mglml, respectively. Terfenadine displaced the FEV, concentration-response curves obtained with both histamine (GM PC,,, values increasing to 26.92 mglml) and AMP (GM PC,, values increasing to 26.7 mglml) to the right. IB had a small, but signijcant, protective effect against the fall in FEV, produced by histamine and AMP, the GM PC,, values increasing to I .69 and to 12.6 mglml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC,, values increasing to 54.76 and 47.7 mglml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man. (JALLERGY CLINIMMUNOL 1991;87:939-47.) The mechanism by which adenosine and its related nucleotide, AMP, cause bronchoconstriction when it is inhaled by atopic', 2 and nonatopic'. 3 subjects with asthma remains to be clarified. Adenosine has been demonstrated to potentiate the release of the preformed mediators P-hexosaminidase and histamine from immunologically activated rodent4 and humans mast cells in vitro, probably through an interaction with specific cell-surface receptors of the A, subtype.+ 5 Additional support for mast cell involvement in AMP-induced
Thorax, 1994
Background -Inhaled frusemide exerts a protective effect against bronchoconstriction induced by s... more Background -Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma. This effect could be caused by interference with neural pathways. The effect of inhaled frusemide on bronchoconstriction induced by inhaled bradykinin, which is thought to cause bronchoconstriction via neural mechanisms, was studied and compared with the effects of adenosine 5'-monophosphate (AMP) which probably produces its airway effects by augmenting mast cell mediator release and interfering with neural pathways. Methods -Patients first underwent AMP and bradykinin challenges. They were then studied in a randomised, placebo controlled, double blind fashion. Ten atopic asthmatic subjects, studied on four days, were pretreated with inhaled frusemide (40 mg) or placebo for 10 minutes, five minutes before challenge with increasing concentrations of nebulised AMP or bradykinin. Results -On the open visit days the provocative concentrations required to reduce forced expiratory volume in one second (FEVI) by 20% from baseline (PC20) for AMP and bradykinin were 16-23 (1P42-67 16) and 2 75 (0-81-66) mg/ ml. There was a significant correlation between baseline AMP and bradykinin PC20 values. For AMP the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 80-97 (9-97-> 400-0) and 14-86 Immunopharmacology (2-6-104-6) mg/ml respectively (95% CI Group, University of 0 49 to 0-98). For bradykinin the geomet-Southampton, University ric mean PC20 values following pretreat-Medicine, Southampton ment with inhaled frusemide and Southampton S09 4XY matched placebo were 13-22 (2 53-> 16-0) K Rajakulasingam and 2 52 (0-45-5-61) mg/ml respectively M K Church (95% CI 0 43 to I 01). Frusemide afforded P H Howarth 5*45 and 5 24 fold protection against S T Holgate AMP and bradykinin-induced broncho-
Journal of Allergy and Clinical Immunology, 1998
It has previously been shown that cells mRNA+ for T(H2)-type cytokines (IL-4 and IL-5) infiltrate... more It has previously been shown that cells mRNA+ for T(H2)-type cytokines (IL-4 and IL-5) infiltrate the site of allergen-induced cutaneous late-phase reactions (LPR) in atopic subjects. In this study we have used the same experimental model to identify the cell source of both IL-4 and IL-5 mRNA and protein product. Allergen-induced LPRs were provoked in the skin of atopic individuals and the sites microscopically examined at 6, 24, and 48 hours. Using single in situ hybridization and immunohistochemistry, we first showed that the numbers of IL-4 and IL-5 mRNA and protein product positive cells peaked at 24 hours. This coincided with the magnitude of the LPR. By double in situ hybridization/immunohistochemistry, we then established (in 24-hour biopsy specimens) that the percentage of CD3+ T lymphocytes, EG2+ eosinophils, and tryptase-positive mast cells that were either IL-4 or IL-5 mRNA+ was 19%, 24%, and 5% and 19%, 20%, and 5%, respectively. Conversely, the percentage of EG2+ and tryptase-positive cells that were IL-4 or IL-5 protein product positive were 62% and 53% and 72% and 29%, respectively. IL-4 and IL-5 protein did not colocalize to CD3+ cells. CD68+ macrophages were negative in both in situ hybridization and immunohistochemistry. With eosinophils we obtained direct evidence of time-dependent stimulus-induced IL-4 and IL-5 mRNA transcription by semiquantitative reverse transcription-polymerase chain reaction of cells incubated with either IgG- or sIgA-coated particles in vitro. Taken together, these experiments suggest that eosinophils, mast cells, and T cells all contribute in variable degrees to the expression of IL-4 and IL-5 in human cutaneous LPR. The failure to colocalize IL-4/IL-5 protein (as opposed to mRNA) to CD3+ cells is attributed to the inability of T lymphocytes to store and concentrate sufficient intracellular amounts of these cytokines to produce positive immunostaining.
Journal of Allergy and Clinical Immunology, 1997
Nitric oxide (NO) is produced in large amounts in the noses of normal individuals. We have measur... more Nitric oxide (NO) is produced in large amounts in the noses of normal individuals. We have measured NO by chemiluminescence in the noses and exhaled air of subjects with symptomatic allergic rhinitis, some of whom had concomitant asthma, during the pollen season and compared this with values measured in normal subjects and in patients treated with nasal and~or inhaled glucocorticoids. We found that nasal levels of NO were significantly (p < 0.001) elevated in patients with untreated rhinitis (1527 +-87 ppb, n = 12) compared with normal individuals (996 +_ 39 ppb, n = 46) or subjects treated with nasal steroids (681 +-34 ppb, n = 10), whereas exhaled NO in patients with untreated rhinitis was similar to that in normal subjects (10 +_ 2 ppb vs 7 + 0.6 ppb, respectively). In five subjects who were nasally challenged with allergen, there was a significant decrease in nasal NO 1 hour after challenge, and this was significantly correlated with increased rhinitis symptoms. In patients with rhinitis and concomitant asthma, nasal NO was also significantly elevated (1441 +_ 76 ppb, n = 16) but not when they were treated with nasal or inhaled steroids; whereas exhaled NO was elevated in untreated patients and in patients treated with nasal, but not inhaled, steroids. Our data suggest that the increase in exhaled NO in patients with allergic rhinitis is likely to be due to increased local production, caused by long-term exposure to allergen, which is suppressed by locally administered steroids. Measurement of nasal NO may be useful to study the inflammatory response in rhinitis and its response to antiinflammatory treatments. (J AUergy Clin Immunol 1997;99:58-64.)