Biomedical subjects

J C Foreman

Publications and source records attributed to J C Foreman.

At least 19 recordsLinked to original sources

PubMed2001

Role of kinins in seasonal allergic rhinitis: icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia induced by antigen.

BACKGROUND: Icatibant, a bradykinin B(2) receptor antagonist, inhibits the reduction in nasal patency after challenge with house dust mite antigen in sensitive subjects and abolishes the nasal hyperresponsiveness induced by platelet-activating factor in nonatopic subjects. OBJECTIVE: We sought to investigate the effect of icatibant on the response to nasal antigen challenge in subjects with seasonal allergic rhinitis. METHODS: Patients allergic to grass pollen antigen (n = 9-13) were included in a double-blind, randomized-block, placebo-controlled, crossover study outside the pollen season. Subjects first received an intranasal spray of icatibant (200 microg per nostril) or a saline control. Subjects were then challenged with antigen or diluent (control), and their responses were monitored by using acoustic rhinometry. Six hours later, nasal lavage fluid was collected and quantified for inflammatory cells and various inflammatory mediators (kinin, eosinophil cationic protein, IL-5, and IL-8). At 24 hours, the response of the nasal airways to 200 microg of histamine was assessed, and a further nasal lavage was carried out. RESULTS: Antigen challenge caused a significant increase in nasal obstruction and albumin extravasation, which was not affected by icatibant. Nasal hyperresponsiveness to histamine was present 24 hours after antigen and was abolished by pretreatment with icatibant. Icatibant also reduced the antigen-induced increase in eosinophils, eosinophil cationic protein, kinin, and IL-8 in nasal lavage fluid. CONCLUSION: Pretreatment with icatibant does not affect the acute inflammatory response in seasonal allergic rhinitis. However, our results imply the involvement of kinins and the bradykinin B(2) receptor in the development of antigen-induced hyperresponsiveness and the associated eosinophilia in the human nasal airway.

Adult↗

PubMed2000

Involvement of kinins in hyperresponsiveness induced by platelet activating factor in the human nasal airway.

1. The aim of this study was to investigate the role of kinins in the development of nasal hyperresponsiveness induced by platelet activating factor (PAF) in normal human subjects. 2. Intranasal administration of PAF, 60 micrograms, induced an increased responsiveness to histamine, 200 micrograms per nostril, 6 h later. This effect was abolished by pretreatment with the bradykinin B2 receptor antagonists icatibant and [1-adamantaneacetyl-D-Arg0,Hyp3,beta-(2-thienyl)-Al a5,8,D-Phe7]-bradykinin ([Ad]-BK), both at 200 micrograms, every 2 h following PAF administration. 3. In a separate experiment, utilizing the same protocol, nasal lavage was used to measure the release of mediators into the nasal cavity following treatment with PAF. PAF increased the levels of eosinophil cationic protein (ECP) and kinin detected in the lavage samples, compared with a saline control. The levels of these mediators were reduced by pretreatment with either icatibant or [Ad]-BK. 4. Administration of lyso-PAF, 60 micrograms intranasally, did not cause a rise in kinin or ECP levels in nasal lavage fluid. 5. Exogenous bradykinin, 500 micrograms, or a saline control, applied topically to the nasal mucosa every 30 min for 2 h, failed to cause hyperresponsiveness to histamine. 6. We conclude that bradykinin itself does not cause hyperresponsiveness, but is involved in the hyperresponsiveness induced by PAF in the human nasal airway.

Adamantane↗

PubMed2000

Induction by inhibitors of nitric oxide synthase of hyperresponsiveness in the human nasal airway.

1. The effects of inhibitors of nitric oxide synthase (NOS) on the responsiveness of the human nasal airway were investigated, by measuring the nasal response to histamine and bradykinin. 2. Repeated intranasal administration of N(G)-nitro-L-arginine methyl ester (L-NAME) or N(G)-monomethyl-L-arginine (L-NMMA), 1 micromol per nostril every 30 min for 6 h, increased the nasal obstruction induced by histamine, 50 - 500 microg, and bradykinin, 200 microg per nostril. A single administration of L-NAME, 1 micromol per nostril did not induce hyperresponsiveness to histamine. 3. Pretreatment with L-arginine, 30 micromol, abolished the hyperresponsiveness to histamine caused by L-NAME, 1 micromol. Pretreatment with N(G)-nitro-D-arginine methyl ester (D-NAME), 1 micromol, did not induce hyperresponsiveness to histamine. 4. Repeated administration of L-NAME, 1 micromol, caused a significant reduction in the amount of nitric oxide measured in the nasal cavity. 5. Neither L-NMMA, 1 micromol, nor L-arginine, 30 micromol, altered the nasal hyperresponsiveness induced by platelet activating factor (PAF), 60 microg. PAF did not alter the levels of nitric oxide in the nasal cavity. 6. The results suggest that inhibition of nitric oxide synthase induces a hyperresponsiveness in the human nasal airway, and that this occurs by a mechanism different from that involved in PAF-induced hyperresponsiveness.

Adult↗

PubMed1999

The role of reactive oxygen species in triggering proliferation and IL-2 secretion in T cells.

This paper examines the hypothesis that reactive oxygen species (ROS) play an important role as second messengers in T cell activation. Activation of T cells with phorbol ester in combination with either calcium ionophore, or anti-CD3 antibody results in a large rapid flux of ROS activity. In contrast, co-stimulation with CD28 does not enhance ROS activity. The ROS signal was sensitive to ascorbic acid, desferrioxamine and dimethyl sulfoxide, suggesting that the major active species being generated was the hydroxyl radical, probably by iron-catalyzed decomposition of hydrogen peroxide. The generation of ROS in T cells was regulated by an accessory population within the peripheral blood. An anti-CD2 antibody induced a strong ROS flux, suggesting that the CD2/LFA-3 interaction may be important in this regulation. T cell activation was inhibited by the same panel of anti-oxidants as ROS generation, but much higher concentrations were required for inhibition of proliferation and IL-2 release than those required to block ROS generation. These data imply that ROS are not obligate second messengers for initiation of T cell activation. The results are compatible, however, with a role for activation-dependent T cell ROS generation in modulating the overall T cell response via autocrine and paracrine signalling pathways.

Antibodies, Monoclonal↗

PubMed1999

Hyperresponsiveness in the human nasal airway: new targets for the treatment of allergic airway disease.

Allergic rhinitis is a condition which affects over 15% of the population in the United Kingdom. The pathological process involves two stages: nasal inflammation, and the development of nasal airway hyperresponsiveness (AHR) to allergen and a number of other stimuli. This results in the amplification of any subsequent allergic reaction, contributing to the chronic allergic state. A number of different hypotheses have been proposed to explain the underlying mechanism of AHR, including a role for eosinophil-derived proteins, free radicals and neuropeptides. While there may be a number of independent pathways which can result in AHR, evidence obtained from both animal models and in vivo experiments in humans indicate that some mediators may interact with one another, resulting in AHR. Further research into these interactions may open new avenues for the pharmacological treatment of chronic allergic rhinitis, and possibly other allergic airway diseases.

Animals↗

PubMed1998

Cutaneous responses to endothelin-1 and histamine in patients with vibration white finger.

Vibration white finger (VWF) is the episodic blanching of the fingers that occurs in response to cold in those who work with hand-held vibrating tools. Clinically the condition differs from primary Raynaud's phenomenon as persistent pain and paresthesia are common in the hands and arms and occur independently of the "white attacks." We have previously reported a decrease in protein gene product 9.5 and calcitonin gene-related peptide-immunoreactive nerve fibers in the digital skin of individuals with VWF. In this study, we have sought to determine whether this deficit of immunoreactive sensory-motor nerves has a functional counterpart in vivo. Histamine produces a rapid wheal and flare response following intradermal injection, whereas endothelin-1 (ET-1) produces a central area of pallor with a surrounding neurogenic flare. In contrast, calcitonin gene-related peptide produces a non-neurogenic erythema. In this study, histamine and ET-1 were injected into the dorsum of the middle phalanx and the local neurovascular response was assessed by measuring the area of the visible flare or pallor. Basal finger blood flow was also measured by laser Doppler flowmetry in each of the digits prior to intradermal injection. The experiments were performed at 21 degrees C and 4 degrees C. Patients with VWF and asymptomatic vibration-exposed workers had significantly lower resting skin blood flow at both 21 degrees C and 4 degrees C than heavy manual workers with no vibration exposure. The size of the histamine- and ET-1-induced flares at both 21 degrees C and 4 degrees C was significantly smaller in patients with VWF when compared with the asymptomatic vibration-exposed workers and heavy manual workers. The size of the ET-1-induced pallor was smaller in patients with VWF when compared with the heavy manual workers at both 21 degrees C and 4 degrees C. In contrast, the area of erythema induced by intradermal injection of calcitonin gene-related peptide at both 21 degrees C and 4 degrees C was of a similar size in patients with VWF and in heavy manual workers. These results indicate that the neuroneal deficit identified by immunohistochemistry in the digital skin of patients with VWF has a functional counterpart in vivo and is evident as a reduced ability to propagate an axon-reflex vasodilator response when challenged with histamine and ET-1. Furthermore, these results enable patients with VWF to be differentiated from both asymptomatic vibration-exposed workers, in whom the histamine- and ET-1-induced flares are normal, and those with primary Raynaud's disease, in whom the ET-1 flare is reduced and the histamine-induced flare is normal.

Adult↗

PubMed1997

Fc epsilon RI-mediated chloride uptake by rat mast cells: modulation by chloride transport inhibitors in relation to histamine secretion.

1. We have examined the role of extracellular chloride in the mast cell secretion process. The immunologically-directed ligand, antibody to IgE (anti-IgE) required extracellular chloride ions for optimum secretion from rat peritoneal mast cells. In contrast, replacement of extracellular chloride did not alter the mast cell secretory response to compound 48/80, calcium ionophore A23187 or substance P. 2. Anti-IgE-stimulation of mast cells evoked a significant uptake of chloride ions compared to non-stimulated cells. The magnitude of chloride uptake correlated with the magnitude of stimulated histamine secretion. 3. Compound 48/80, substance P and A23187 did not alter the rate of chloride ion uptake, although these agents caused significant histamine secretion. 4. The Na+/K+/2Cl- cotransport inhibitor, furosemide, reduced the rate of anti-IgE-stimulated chloride uptake at a relatively high concentration (700 microM). However, the more potent Na+/K+/2Cl- cotransport inhibitors, bumetanide (100 microM) and piretanide (100 microM) had no effect on the stimulated chloride uptake. 5. Furosemide inhibited anti-IgE-induced histamine secretion, bumetanide potentiated the response and piretanide had no effect. This suggests that their respective action on histamine secretion are unrelated to inhibition of the Na+/K+/2Cl- carrier. 6. The chloride channel blocker, 5-nitro-2-((3-phenylpropyl)-amino)-benzoic acid (NPPB), reduced both anti-IgE-stimulated chloride uptake and the corresponding histamine secretion in a dose-dependent manner. The magnitude of the inhibitory action of the drug on these two cellular processes was comparable, implying that chloride channel activity is related to the mechanism of histamine secretion. 7. It is concluded that chloride uptake has a role in the control of Fc epsilon RI-mediated histamine secretion from rodent mast cells.

Animals↗

PubMed1996

The contribution of histamine to the action of bradykinin in the human nasal airway.

Bradykinin, 10 to 1000 micrograms given by aerosol into the nasal cavity of normal, healthy volunteers, produced a dose-related increase of nasal airway resistance. Bradykinin also reduced the minimal nasal cross-sectional area (Amin), increased albumin release into nasal lavage fluid and increased the symptoms of nasal inflammation. Pretreatment with cetirizine (10 mg orally) reduced the fall in Amin induced by bradykinin, 300 micrograms, but not by bradykinin, 100 micrograms. Pre-treatment of the subjects with the H1 histamine receptor antgonist cetirizine (10 mg, orally) or terfenadine (60 mg, orally) 3 h before bradykinin administration caused significant reduction of the bradykinin-induced increase in nasal airway resistance in the upper range of bradykinin doses (300-1000 micrograms) but not in the lower range (10-100 micrograms). Cetirizine reduced the albumin release into the nasal airway and the symptoms induced by bradykinin, 1000 micrograms. Following nasal challenge with bradykinin 300 micrograms or 1000 micrograms, no increase could be detected in the histamine content of nasal lavage fluid. Isolated human nasal cells released histamine in response to bradykinin, 33 and 100 microM, anti-IgE and calcium ionophore, A23187. We conclude that the actions of bradykinin in the human nasal airway are, in part, accounted for by the release of histamine.

Adult↗

PubMed1996

Inhibitors of nitric oxide synthase in human skin.

The aim of this study was to investigate in human skin in vivo the role of nitric oxide in maintaining resting vascular tone, in the vasodilatation caused by local warming and by ultraviolet B light exposure, and in the response to exogenous calcitonin gene-related peptide (CGRP). Cutaneous blood flow was assessed by planimetry of the visible erythema or pallor and by laser Doppler flowmetry. Intradermal injection of the inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (L-NAME; 25 nmol), into forearm skin produced a visible pallor and a reduction of blood flow at a controlled ambient temperature of 21 degrees C. The control, NG-nitro-D-arginine methyl ester (D-NAME; 25 nmol) or NG-monomethyl-L-arginine (L-NMMA; 25 nmol) did not cause pallor or reduce blood flow. L-NAME and L-NMMA caused dose- and time-dependent increases in pallor, and reductions in cutaneous blood flow in skin that had been locally warmed by immersion in water at 45 degrees C and in skin that had been exposed to ultraviolet B light. D-NAME and D-NMMA at comparable concentrations did not have the effects on skin blood flow observed with the L forms. L-NAME and L-NMMA both inhibited the increased blood flow in human skin caused by the intradermal injection of CGRP (12.5 or 25 pmol). The reduction of CGRP-induced increase of blood flow by L-NAME was reversed by L-arginine. Neither D-NAME nor D-NMMA inhibited the increase in blood flow caused by CGRP. Neither L-NAME nor L-NMMA inhibited the increase in blood flow in human skin caused by the intradermal injection of prostaglandin E2 (63 pmol). The data show that nitric oxide is involved in the maintenance of resting blood flow in human skin and also in the cutaneous vasodilator responses to local warming, ultraviolet B irradiation, or injection of CGRP.

Adolescent↗

PubMed1996

Attenuation of human nasal airway responses to bradykinin and histamine by inhibitors of nitric oxide synthase.

1. The effects of inhibitors of nitric oxide synthase and local anaesthetics were studied on changes in human nasal airway patency and albumin extravasation in response to bradykinin and histamine, in vivo. 2. Compared with the action of the vasoconstrictor, ephedrine, 2.5 mumol, NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol alone, did not change the resting value of the minimal cross-sectional area (A min) of the human nasal airway. L-NAME, 0.1 to 10 mumol, produced a dose-related inhibition of the reduction in A min caused by bradykinin, 300 micrograms. NG-monomethyl-L-arginine (L-NMMA), 1 mumol, similarly reduced the effect of bradykinin, 300 micrograms, on A min, but NG-nitro-D-arginine methyl ester (D-NAME), had no effect. L-NAME, 0.1 to 10 mumol, or L-NMMA, 10 mumol, failed to inhibit the effect of histamine, 300 micrograms on A min. 3. The inhibition by L-NAME, 1 mumol of the action of bradykinin, 300 micrograms on A min was maximal between 15 and 30 min after pretreatment with L-NAME. 4. L-NAME, 1 and 10 mumol, inhibited the extravasation of albumin into the nasal cavity induced by bradykinin, 300 micrograms, and also by histamine, 300 micrograms. D-NAME, 1 and 10 mumol had no effect on the extravasation of albumin in response to bradykinin or histamine. 5. L-Arginine, 30 mumol, reversed the effect of L-NAME, 1 mumol, on the bradykinin- and histamine-induced albumin extravasation into the nasal airway. 6. Local anaesthesia of the nasal airway with lignocaine, 10 mg, or benzocaine, 10 mg, failed to inhibit the reduction in A min or the albumin extravasation induced by either bradykinin, 300 micrograms, and histamine, 300 micrograms. 7. We conclude that the extravasation of plasma albumin caused by bradykinin and by histamine involves the generation of nitric oxide. The nasal blockage induced by bradykinin involves nitric oxide generation but the nasal blockage induced by histamine does not.

Adult↗

PubMed1996

Characterization of the bradykinin receptor in the human nasal airway using the binding of [125I]-Hoe 140.

1. The aim of this study was to characterize the kinin receptor in the human nasal airway using [125I]-Hoe 140 binding to a membrane preparation from human nasal turbinates and to compare Ki values from binding displacement by antagonists with the functional effects of these drugs in vivo. We also investigated the effect of Hoe 140 ([D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), on bradykinin release into the nasal airway. 2. In a membrane preparation from human nasal turbinates removed during surgery, [125I]-Hoe 140 labelled a single, saturable binding site. The equilibrium dissociation constant (at 20 degrees C) for [125I]-Hoe 140 binding to the receptor was 0.46 +/- 0.08 nM. The Bmax was 0.136 +/- 0.003 pmol mg-1 protein and the Hill coefficient was 1.01 +/- 0.07. 3. The association rate constant for [125I]-Hoe 140 binding to the receptor was 0.20 +/- 0.06 nM-1 min-1 and the dissociation rate constant was 0.14 +/- 0.01 min-1. These values were determined at 4 degrees C. The equilibrium dissociation constant calculated from these rate constants was 0.70 nM. 4. Bradykinin and the B2 receptor antagonists, NPC 567, NPC 17731, NPC 17761, [1-adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, WIN 64338 and Hoe 140 displaced [125I]-Hoe 140 binding: the Ki values from binding displacement are consistent with values expected from a B2 receptor. The B1 agonist, [des-Arg9]-bradykinin and the B1 antagonist, [des-Arg9]-Hoe 140 failed to displace [125I]-Hoe 140 binding at concentrations up to 1 microM. 5. The bradykinin antagonist, Hoe 140, 10 to 200 micrograms, given by intranasal aerosol, produced a dose-related inhibition of the reduction in minimal nasal cross-sectional area (Amin) induced by bradykinin in normal subjects and by house dust mite antigen in subjects with allergic rhinitis to house dust mite. Hoe 140, 10 to 200 micrograms, also caused a dose-related inhibition of the release of albumin into the nasal cavity following challenge with bradykinin. 6. [1-Adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, 30 to 200 micrograms, caused a dose-related inhibition of the reduction in Amin and the release of albumin into the nasal cavity induced by bradykinin. NPC 567 ([D-Arg0, Hyp3, D-Phe7]-bradykinin) failed to inhibit the reduction in Amin or the release of albumin into the nasal cavity at a dose of 10 mg. 7. Challenge of allergic subjects with house dust mite antigen caused a significant elevation of the bradykinin concentration in nasal lavage fluid and a reduction in Amin. Hoe 140, 100 micrograms, prevented the antigen-induced reduction in Amin and also abolished the antigen-induced increase of bradykinin in nasal lavage fluid. 8. We conclude that there is a B2 bradykinin receptor in the human nasal airway which mediates nasal blockage and plasma extravasation induced by either bradykinin or antigen challenge. It is possible that Hoe 140 inhibits kallikrein in the human nasal airway as well as blocking the B2 receptor.

Adult↗

PubMed1996

Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon.

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. We undertook a pharmacological study to investigate the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin.

Adult↗

PubMed1995

Reduction by NG-nitro-L-arginine methyl ester (L-NAME) of antigen-induced nasal airway plasma extravasation in human subjects in vivo.

In non-allergic subjects, histamine induced a reduction of minimal nasal cross-sectional area (Amin) and an increase in albumin release into nasal lavage. The effect of histamine on albumin release was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol but not by D-NAME, 1 mumol. L-NAME, 1 and 10 mumol, did not inhibit the histamine-induced reduction of Amin. In subjects allergic to grass pollen, antigen challenge induced a reduction in Amin that was not changed by pretreatment with L-NAME, and an increase in albumin release that was inhibited by L-NAME, 1 mumol. The data support a role for nitric oxide in mediating plasma extravasation in the nose induced by antigen challenge or histamine.

Adult↗

PubMed1994

A study of the action of bradykinin and bradykinin analogues in the human nasal airway.

1. The aim of this study was to investigate the action of bradykinin on resistance to airflow and on vascular permeability in the human nasal airway, and to explore the receptor mediating these effects. 2. Aerosol administration of bradykinin (10-1000 micrograms) caused a dose-related increase in nasal airway resistance (NAR) and an increase in albumin content of nasal lavage. 3. The bradykinin antagonists, [1-adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, 100 micrograms, and [D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin, 100 micrograms, given 2 min before bradykinin, inhibited the increase in NAR and the increase of albumin content of nasal lavage caused by bradykinin. 4. The bradykinin antagonist, [D-Arg0, Hyp3, D-Phe7]-bradykinin (100 micrograms) did not affect the increase in NAR produced by bradykinin, or the albumin content of nasal lavage. Increasing the dose of the antagonist to 1000 micrograms did not change the increase in NAR induced by bradykinin. 5. The selective B1 kinin receptor agonist, [Des-Arg10]-kallidin (100 micrograms) did not affect NAR or the albumin content of nasal lavage. 6. The receptor mediating increased NAR and the release of albumin induced by bradykinin in the human nasal airway appears not to be a B1 kinin receptor. The data are not entirely consistent with the effects of bradykinin in the human nasal airway being mediated by a B2 kinin receptor.

Adult↗

PubMed1994

The gold anti-rheumatic drug auranofin governs T cell activation by enhancing oxygen free radical production.

Gold-containing drugs continue to be used in the treatment of rheumatoid arthritis, but their mode of action remains unknown. One model to explain gold action is that gold-containing compounds can alter free radical production in cells of the immune system, but direct evidence for this hypothesis has been lacking. In this study we show that auranofin can enhance the rapid flux of reactive oxygen species (ROS), which accompanies phytohemagglutinin activation of peripheral blood T cells. Blocking this enhancement by the addition of antioxidants can reverse the functional effects of the drug on T cell responses, which we have previously demonstrated. These results provide strong experimental support for a model in which gold anti-rheumatics act by modulating ROS production. Furthermore, our experiments suggest that auranofin may be a useful tool to investigate the postulated role of ROS in the intra cellular T cell signaling pathway.

Auranofin↗

PubMed1994

Stimulation and release of interleukin-1 from peritoneal macrophages of the mouse.

Lipopolysaccharide (LPS) caused a concentration-dependent increase of released and cell-associated interleukin-1 (IL-1) in resident peritoneal macrophages from the mouse. LPS was about 30 times more potent at stimulating the level of cell-associated IL-1 than it was at stimulating the release of IL-1. Human recombinant tumour necrosis factor-alpha (TNF-alpha) and the calcium ionophores A23187 and ionomycin induced a concentration-dependent increase of cell-associated IL-1 but failed to cause release of IL-1 at concentrations producing maximal stimulation of cell-associated IL-1. The phorbol ester, 4 beta-phorbol dibutyrate, stimulated the release of IL-1 from mouse macrophages but failed to induce an increase in cell-associated IL-1. Substance P, neurokinin A, neurokinin B, calcitonin gene-related peptide and platelet-activating factor did not increase the released or cell-associated IL-1 in mouse macrophages. These agents also failed to alter released or cell-associated IL-1 stimulated by LPS, 1 microgram ml-1. It appears that a calcium signal is sufficient for the transcription and translation of IL-1 mRNA but does not result in the secretion of biologically active forms of IL-1. Our data also indicate that different intracellular signals may control the release and the cell accumulation of IL-1. We conclude that inflammatory mediators may independently increase either the release of, or the cell accumulation of IL-1.

Animals↗

PubMed1994

Acoustic rhinometry compared with posterior rhinomanometry in the measurement of histamine- and bradykinin-induced changes in nasal airway patency.

1. Acoustic rhinometry is a relatively new method for objectively assessing nasal airway patency. In this paper we compare acoustic rhinometry with active posterior rhinomanometry. 2. Twenty normal healthy volunteers underwent nasal challenge with either histamine or bradykinin, 100 micrograms to 1000 micrograms, and responses were assessed by acoustic rhinometry. A further 20 subjects received identical nasal challenges and responses were assessed by active posterior rhinomanometry. 3. On a subsequent occasion, the subjects challenged previously with histamine, were given the selective H1-receptor antagonist, cetirizine, 10 mg orally, 3 h before repeat nasal challenge with histamine, 100-1000 micrograms. Again, responses were assessed by active posterior rhinomanometry and acoustic rhinometry. 4. The acoustic reflection measurements and the nasal airway resistance measurements showed comparable, significant dose-related changes in nasal patency to both histamine and bradykinin. Pretreatment with cetirizine blocked the histamine-induced change in nasal patency as measured by both methods. 5. We conclude that acoustic rhinometry has a number of advantages over posterior rhinomanometry. It is quick to perform, requires minimal subject co-operation and gives a reliable objective, measurement of dose-related changes in nasal airway patency before and after pharmacological treatment.

Acoustics↗

PubMed1994

Reduction by Hoe 140, the B2 kinin receptor antagonist, of antigen-induced nasal blockage.

In subjects with allergic rhinitis to house-dust mite (HDM), antigen challenge produced a significant increase in nasal blockage but had no effect on nasal vascular permeability. The B2 kinin receptor antagonist, [D-Arg0,Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140), 200 micrograms administered by intranasal aerosol 2 min prior to challenge with HDM, 500 u significantly reduced nasal blockage induced by the antigen challenge. The data are compatible with a role for B2 kinin receptors in the nasal response to challenge with antigen which is responsible for nasal blockage.

Adult↗