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K F Rabe

Publications and source records attributed to K F Rabe.

At least 91 records · Page 5Linked to original sources
PubMed1998

Mechanisms of immune sensitization of human bronchus.

Bronchial hyperresponsiveness (BHR), the increased sensitivity to a wide variety of stimuli that narrow the airways, is a central abnormality in patients with asthma, and is frequently observed in patients with chronic obstructive pulmonary disease. In the study of the underlying mechanisms of BHR, various animal models have been employed, using methods of active and passive immunization. These studies have led to a changed understanding of smooth muscle hyperreactivity, questioning both the past paradigm of altered neural activity and the modern concepts of inflammation as the single most factor determining BHR, and emphasizing the particular importance of the end organ- the smooth muscle cell. More recently, passive sensitization of human airways has been used by several investigators to describe the mechanisms of allergic sensitization and to study the role of functional abnormalities of human airway smooth muscle, which may represent the key to understanding human BHR, and thus lead to novel treatment approaches for the future.

Animals↗
PubMed1998

Protein kinase C inhibition enhances platelet-activating factor-induced eicosanoid production in human eosinophils.

Previous investigations have suggested that protein kinase C (PKC) may regulate guinea pig eosinophil responses through a suppressive "negative feedback" mechanism. Using the selective PKC inhibitors bisindolylmaleimide I (Bis I, GF 109203X) and calphostin C, we examined the role of PKC in platelet-activating factor (PAF)-induced respiratory burst and generation of arachidonic acid metabolites in human peripheral blood eosinophils. Bis I inhibited PAF-induced generation of superoxide anion with substantially lower potency (geometric mean IC50 = 1.41 microM, 95% CI 0.94-2.11 microM) than it exhibited against responses to the phorbol esters 4-beta-phorbol 12-myristate 13-acetate (PMA; IC50 = 0.25 microM, 0.09-0.72 microM; P < 0.01) and 4-beta-phorbol 12,13-dibutyrate (IC50 = 0.48 microM, 0.20-1.14 microM; P < 0.05). The production of thromboxane (measured as TxB2) induced by 1 microM PAF was increased significantly by Bis I at concentrations of 1 microM (162 +/- 7.5% of control PAF response; P < 0.01) and 10 microM (194 +/- 17%; P < 0.001); TxB2 release induced by PMA was unaffected by concentrations of Bis I up to 1 microM and inhibited by 10 microM Bis I (48 +/- 11%; P < 0.05). Bis I (1 microM) significantly increased both thromboxane and leukotriene C4 (LTC4) production induced by 2 microM (P < 0.01 and P < 0.05, respectively) or 20 microM PAF (both P < 0.001). The actions of Bis I on PAF-stimulated thromboxane and leukotriene production were mimicked by a second PKC inhibitor, calphostin C, whereas the non-PKC-inhibitory analog, bisindolylmaleimide V, caused no enhancement of TxB2 or LTC4 production. The increase in intracellular free calcium induced by 1 microM PAF was heightened and prolonged in cells pre-treated with 1 microM Bis I or 1 microM calphostin C (peak increase, P < 0.05 for both drugs; level 60 s after addition of PAF, P < 0.001 and P < 0.05 for Bis I and calphostin C, respectively; time to return to 50% of peak, P < 0.05 for Bis I). We conclude that PKC inhibition causes augmentation of thromboxane and LTC4 production in PAF-stimulated human eosinophils despite suppressing respiratory burst activity, indicating that different signaling pathways predominate in these two responses and that PKC mediates a suppression of an early stage in an alternative pathway of activation.

Arachidonic Acid↗
PubMed1998

Expression of Fas (CD95) and FasL (CD95L) in human airway epithelium.

The cell surface molecule Fas (CD95) is a member of the tumor necrosis factor receptor family. Ligation of the Fas receptor can lead to induction of apoptosis in inflammatory cells. It has been suggested that expression of the Fas receptor and its ligand (FasL) in airway epithelium may modulate the inflammatory response commonly found in asthmatic lungs. We examined Fas and FasL expression on primary human tissues, on bronchial epithelial cells in primary culture, and on the immortalized human airway epithelial cell line, 1HAEo-. Receptor and ligand expression were demonstrated using multiple antibodies and multiple techniques, including immunohistochemistry, flow cytometry, Western blots, and reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining demonstrated that both columnar and basal cells of intact human lung tissues expressed cell surface Fas and FasL. In addition, both primary cultured and immortalized 1HAEo- cells expressed cell surface Fas and FasL, as demonstrated by flow cytometry; expression of Fas and FasL was confirmed at the transcription level using RT-PCR and, for additional confirmation of FasL, using Western blots. We demonstrate that both Fas and FasL are expressed by human airway epithelial cell subtypes. Expression of these molecules may play an important role in regulation of the inflammatory response.

Apoptosis↗
PubMed1998

Effects of a 5-lipoxygenase inhibitor, ABT-761, on exercise-induced bronchoconstriction and urinary LTE4 in asthmatic patients.

The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated for its effect on exercise-induced bronchoconstriction in asthmatic subjects. The relationship between 5-LO inhibition and effects on the response of the airways to exercise was examined. In a double-blind, randomized, crossover clinical trial, 10 patients with mild to moderate persistent asthma (who exhibited a fall in forced expiratory volume in one second (FEV1) > or = 20% following standardized exercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung function, urinary leukotriene E4 (LTE4) and ex vivo calcium ionophore-stimulated LTB4 release in whole blood were measured prior to dosing, prior to exercise and at various time points up to 4 h post-exercise. The mean (SD) maximal percentage fall in FEV1 after exercise was 27.1 (12)% on placebo and 19.9 (10)% on ABT-761 days, respectively (p<0.05). Post-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 and 30 min after exercise and the mean area under curve, representing the overall effect of exercise from 0-45 min post-challenge, was also significantly attenuated by ABT-761 (p<0.001). Ex vivo LTB4 release was inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Urinary LTE4 in the post-exercise period was significantly lower after ABT-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg x mg creatinine(-1); p<0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise FEV1 decline (r=0.711; p<0.05). We conclude that ABT-761 is effective in suppressing exercise-induced bronchoconstriction and that this protection is related quantitatively to the degree of 5-lipoxygenase inhibition.

Adult↗
PubMed1998

Theophylline and airway inflammation.

The view of theophylline as a second-line bronchodilator in asthma therapy has begun to be reconsidered in recent years as the details of its additional actions on airway inflammation have emerged. Increasing understanding of the mechanisms of action of theophylline has led to an appreciation of the ways in which this, and other related drugs, may influence the development and maintenance of the airway inflammation that underlies asthma through alteration of inflammatory cell function. In addition, recent demonstrations that theophylline can suppress late-phase asthmatic reactions at serum concentrations below those traditionally regarded as therapeutically useful have provided evidence that theophylline's beneficial actions in asthma extend beyond mild bronchodilation. The apparent suppression of airway inflammation by theophylline in asthmatic patients reinforces data from ill vitro experiments, showing inhibitory actions of theophylline on the pro-inflammatory functions of many immune cells. Here, we review some recent advances in the understanding of theophylline's actions that suggest its role as an anti-inflammatory drug in asthmatic airways.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Inherent tone of human bronchus: role of eicosanoids and the epithelium.

1. Airway preparations of different species possess varying degrees of inherent tone which is the result of different metabolites of arachidonic acid in different species. In human bronchial smooth muscle in vitro we have investigated the effects of 5-lipoxygenase inhibition (zileuton, 10 microM), cyclo-oxygenase inhibition (indomethacin, 1 microM) and mechanical epithelium removal on inherent tone. The shunting of arachidonic acid by inhibition of one or other of these enzymes, as a possible explanation for the effects observed, has also been investigated. 2. Zileuton caused a significant fall in tone either alone (-107 +/- 33 mg) or after cyclo-oxygenase inhibition (-203 +/- 48 mg) and this effect was not significantly altered by epithelial removal (-191 +/- 43 mg alone; -333 +/- 88 mg after indomethacin). Indomethacin increased tone when applied alone (160 +/- 94 mg), but this effect only reached statistical significance after 5-lipoxygenase inhibition, (210+/-81 mg; P<0.05). Epithelial removal did not alter the effect of indomethacin when applied alone (213+/-97 mg), but significantly reduced the effect of indomethacin after 5-lipoxygenase inhibition (34 +/- 23 mg; P<0.05). 3. These data suggest that inherent tone in human bronchus is largely the result of contractile 5-lipoxygenase products. However, the involvement of cyclo-oxygenase products cannot entirely be discounted, since in the presence of 5-lipoxygenase inhibition contractile and relaxant eicosanoids originating from the bronchial epithelium appear to influence significantly inherent tone.

Adult↗
PubMed1997

Augmentation of human neutrophil and alveolar macrophage LTB4 production by N-acetylcysteine: role of hydrogen peroxide.

1. The actions of N-acetylcysteine (NAC) on hydrogen peroxide (H2O2) and leukotriene B4 (LTB4) production by human resting and stimulated peripheral blood neutrophils and alveolar macrophages were investigated. 2. At a concentration of 100 microM, NAC significantly (P < 0.01) suppressed the accumulation of H2O2 in the incubation medium of resting and opsonized zymosan (OZ; 0.5 mg ml[-1])- or N-formylmethionyl-leucyl-phenylalanine (fMLP; 1 microM)-stimulated neutrophils and of resting and OZ-stimulated macrophages. At concentrations of 10 microM and above, NAC augmented significantly the level of LTB4 in the supernatants of OZ- and fMLP-stimulated neutrophils (P < 0.01 and P < 0.05, respectively) and OZ-stimulated macrophages (P < 0.05 at 10 microM, P < 0.01 at 100 microM NAC). 3. NAC (100 microM) caused a significant (P < 0.01) reduction in the quantity of measurable H2O2 when incubated with exogenous H2O2 concentrations equivalent to those released from OZ-stimulated neutrophils and macrophages. At no concentration did NAC affect quantitites of measurable LTB4 when incubated with exogenous LTB4. 4. Superoxide dismutase (SOD), which catalyzes the conversion of superoxide anion to H2O2 had no significant effect on LTB4 production by human neutrophils. In contrast, catalase, which catalyzes the conversion of H2O2 to H2O and O2, caused a pronounced, statistically significant (P < 0.01) increase in the levels of LTB4 measured in the supernatants of OZ- and fMLP-stimulated neutrophils. 5. H2O2 (12.5 microM and 25 microM, concentrations equivalent to those measured in the supernatants of activated neutrophils and alveolar macrophages, respectively) caused a small (13%) decrease in the quantity of measurable LTB4 (P = 0.051 and P < 0.05 at 12.5 microM and 25 microM, respectively) that was inhibited by NAC (100 microM) but not by catalase (400 u ml[-1]). 6. In conclusion, the anti-oxidant drug, NAC, increases LTB4 production by human neutrophils and alveolar macrophages, probably through the elimination of cell-derived H2O2. LTB4 undergoes a H2O2-dependent oxidation that is inhibited by NAC but this is unlikely to account fully for the increased levels of LTB4, suggesting that NAC may increase LTB4 production by blocking the H2O2-dependent inhibition of a synthetic enzyme, such as 5-lipoxygenase.

Acetylcysteine↗
PubMed1997

Conservation of bronchiolar wall area during constriction and dilation of human airways.

We assessed the effect of smooth muscle contraction and relaxation on airway lumen subtended by the internal perimeter (Ai) and total cross-sectional area (Ao) of human bronchial explants in the absence of the potential lung tethering forces of alveolar tissue to test the hypothesis that bronchoconstriction results in a comparable change of Ai and Ao. Luminal area (i.e., Ai) and Ao were measured by using computerized videomicrometry, and bronchial wall area was calculated accordingly. Images on videotape were captured; areas were outlined, and data were expressed as internal pixel number by using imaging software. Bronchial rings were dissected in 1.0- to 1.5-mm sections from macroscopically unaffected areas of lungs from patients undergoing resection for carcinoma, placed in microplate wells containing buffered saline, and allowed to equilibrate for 1 h. Baseline, Ao [5.21 +/- 0.354 (SE) mm2], and Ai (0.604 +/- 0.057 mm2) were measured before contraction of the airway smooth muscle (ASM) with carbachol. Mean Ai narrowed by 0.257 +/- 0.052 mm2 in response to 10 microM carbachol (P = 0.001 vs. baseline). Similarly, Ao narrowed by 0.272 +/- 0.110 mm2 in response to carbachol (P = 0.038 vs. baseline; P = 0.849 vs. change in Ai). Similar parallel changes in cross-sectional area for Ai and Ao were observed for relaxation of ASM from inherent tone of other bronchial rings in response to 10 microM isoproterenol. We demonstrate a unique characteristic of human ASM; i.e., both luminal and total cross-sectional area of human airways change similarly on contraction and relaxation in vitro, resulting in a conservation of bronchiolar wall area with bronchoconstriction and dilation.

Bronchi↗
PubMed1997

Passive sensitization of human airways induces myogenic contractile responses in vitro.

We assessed effects of passive sensitization on human bronchial smooth muscle (BSM) response to mechanical stretching in vitro. Bronchial rings were sham (control) or passively sensitized overnight by using sera from donors demonstrating sensitivity to Dermatophagoides farinae and having immunoglobulin E (IgE) concentrations of 2,600 +/- 200 U/ml. Tissues were fixed isometrically to force transducers to measure responses to electrical field stimulation (EFS) and quick stretch (QS). The myogenic response to QS was normalized to the maximal response to EFS (%EFS). The myogenic response of sensitized BSM was 47.9 +/- 10.9 %EFS to a QS of approximately 6.5% optimal length (Lo); sham-sensitized tissues had a myogenic response of 13.5 +/- 6.4 %EFS (P = 0.012 vs. passively sensitized). A QS of approximately 13% Lo in sensitized BSM caused a response of 82.8 +/- 20.9 %EFS; sham-sensitized tissues developed a response of 38.2 +/- 17.3 %EFS (P = 0.004). BSM incubated with serum from nonallergic donors did not demonstrate increased QS response (4.6 +/- 1.4 %EFS, P = not significant vs. tissue exposed to atopic sera). However, tissues incubated in sera from nonatopic donors supplemented with hapten-specific chimeric IgE (JW8) demonstrated augmented myogenic response to QS of approximately 6.5% Lo (21.9 +/- 6.2 %EFS, P = 0. 027 vs. nonatopic sera alone). We demonstrate that passive sensitization of human BSM preparations causes induction and augmentation of myogenic contractions to QS; this hyperresponsiveness corresponds to the IgE concentration in sensitizing sera.

Allergens↗
PubMed1997

Role of IgE in hyperresponsiveness induced by passive sensitization of human airways.

Incubation of airways from nonatopic patients with serum from patients with high IgE levels confers responsiveness to "specific" (allergen) and hyperresponsiveness to "nonspecific" (histamine) stimuli. We have tested the hypothesis that the level of IgE determines the degree of specific and nonspecific responsiveness. Bronchial rings from nonatopic patients were sensitized overnight with serum containing high levels of allergen-specific IgE, or with an allergen-specific chimeric IgE (JW8) in physiologic buffer. In vitro responsiveness to allergen and histamine was evaluated and compared with non-sensitized tissues from the same patients. Responses to specific allergen were demonstrated in all tissues sensitized with atopic serum or chimeric IgE, but not in nonsensitized tissues. Allergen responses were specific, since tissues sensitized using serum containing high Dermatohagoides farinae-specific IgE only, did not respond to either horse or dog allergens. The potency and magnitude of the maximal contraction to histamine was significantly (p < 0.05) increased in tissues sensitized using atopic serum with high total IgE concentrations compared with nonsensitized preparations, but was unchanged in tissues sensitized using chimeric IgE or serum with low total IgE levels. Therefore, specific IgE determines allergen responsiveness in passively sensitized human airways, but histamine hyperresponsiveness is independent of specific IgE and appears to be related to some other factor associated with serum containing high concentrations of total IgE.

Aged↗
PubMed1997

Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo.

High retention of inhaled glucocorticoids in the airways means prolonged anti-inflammatory action and low delivery into the serum. The objective of this study was to investigate the retention in and distribution of inhaled fluticasone propionate (FP) between central and peripheral human lung tissue and serum in vivo. In 17 patients undergoing lung resection surgery, a single 1.0 mg dose of FP was inhaled at varying time-points (range 2.8-21.7 h) preoperatively. Peripheral and central lung tissue was obtained, and blood was drawn simultaneously. FP concentrations in central lung tissue were approximately three to four times higher than peripheral lung tissue concentrations, which in turn, exceeded those found in serum by 10 times. FP was detectable up to 21 and 16 h, respectively, after inhalation, with drug levels falling almost in parallel in peripheral lung tissue and in serum. The results of this study demonstrate that fluticasone propionate is retained in lung tissue for a long time. Serum concentrations after a single inhaled dose are low. Retention of high concentrations of fluticasone propionate in the airways may promote high topical anti-inflammatory activity.

Administration, Inhalation↗
PubMed1996

Isolated, electrically-stimulated airway preparations--their use in determining beta-adrenoceptor agonist activity.

We have assessed the suitability of electrically-stimulated superfused preparations of guinea-pig trachea, cat trachea and human bronchus for investigating the relaxant activity of the beta-adrenoceptor agonist, isoprenaline. Superfused strips of guinea-pig trachea, cat trachea and human bronchus all contracted in response to electrical stimulation. Guinea-pig trachea possesses inherent tone, and in its presence, electrical stimulation caused biphasic responses, comprising a modest, transient contraction, usually followed by a longer lasting relaxation. Human bronchus also possesses inherent tone, but responses were variable, generally monophasic, comprising a transient contraction of variable magnitude, but a longer lasting relaxation was occasionally observed after the transient contraction. Cat trachea possesses no inherent tone, and electrical stimulation of this preparation caused simple monophasic contractile responses. On guinea-pig trachea, addition of indomethacin (2.8 microM) abolished the inherent tone, and under these conditions, electrical stimulation caused monophasic contractile responses similar to those observed in cat trachea. On human bronchus, however, indomethacin enhanced inherent tone, which tended to uncover or exaggerate any relaxant component in the responses to electrical stimulation. The 5-lipoxygenase inhibitor, zileuton (10 microM), reduced, but did not abolish, the tone and converted the electrically-induced response to a monophasic contraction. In all preparations in which inherent tone was low or absent, whether naturally (cat trachea) or through pharmacological intervention (guinea-pig trachea with indomethacin, or human bronchus with zileuton), isoprenaline (1-100 nM) inhibited electrically-stimulated contractions in a concentration-related fashion (EC50s: 9-100 nM). In preparations exhibiting inherent tone (guinea-pig trachea with indomethacin or human bronchus with or without indomethacin), this tone was inhibited by isoprenaline. This relaxant activity, on guinea-pig trachea at least, was concentration-related (EC50: 5.4 nM). Such isoprenaline-induced relaxations complicated the analysis of inhibitory effects against electrically-induced contractions. Thus, in such experiments, only at higher concentrations did isoprenaline reliably inhibit these contractions (EC50: 23-119 nM), lower concentrations of isoprenaline often resulting in an apparent enhancement. The enhancement was probably artefactual, resulting from the fact that the electrically-induced contractions originated from a lower baseline. These data suggest that electrically-stimulated airway preparations are suitable for evaluating the relaxant activity of beta-adrenoceptor agonists, but the relaxant potency should be assessed in preparations lacking inherent tone, such as cat trachea, guinea-pig trachea in the presence of cyclo-oxygenase inhibition, or human bronchus in the presence of 5-lipoxygenase inhibition.

Adrenergic beta-2 Receptor Agonists↗
PubMed1996

Pharmacological basis for duration of effect: formoterol and salmeterol versus short-acting beta 2-adrenoceptor agonists.

The mechanisms behind the long duration of bronchodilating action of the beta 2-adrenoceptor agonists formoterol and salmeterol are only partially understood. This review compares pharmacological characteristics of long-acting versus short-acting beta 2-adrenoceptor agonists in human and animal airways. Based upon the reviewed evidence, it is concluded that for beta 2-adrenoceptor agonists, long duration of action may depend upon several factors. Both formoterol and salmeterol display a higher lipophilicity and have a higher affinity, selectivity, and potency than most short-acting agonists at the beta 2-adrenoceptor. Of these factors, lipophilicity may prove to be one of the most important ones by determining the amount of drug entering into the cell membrane in the vicinity of the beta 2-adrenoceptor. However, the receptor affinity, maximal relaxant effect (efficacy or intrinsic activity), potency, and receptor selectivity may also be of importance in determining how much beta 2-adrenoceptor agonist must remain at the receptor for sustained action.

Adrenergic beta-Agonists↗
PubMed1996

Reproducibility of airway response to inhaled bradykinin and effect of the neurokinin receptor antagonist FK-224 in asthmatic subjects.

OBJECTIVE: Inhaled neurokinins have been shown to induce bronchoconstriction in asthmatic subjects. We have investigated the effect of a neurokinin receptor antagonist, FK-224, on bradykinin (BK)-induced bronchoconstriction, and have compared its effect with the spontaneous variability of BK responsiveness. METHODS: Thirteen subjects with mild extrinsic bronchial asthma participated in the study. Four BK inhalation challenge tests (Study Days 2 to 5) were performed over a period of several weeks. On Study Days 4 and 5 subjects inhaled either 2 mg FK-224 or placebo 30 min before the BK challenge. RESULTS: The geometric mean PC20FEV1 of BK was 0.04, 0.06, and 0.10 mg.ml-1 on the first and second BK challenge and after placebo. Mean PC20FEV1 after FK-224 was 0.20 mg.ml-1 and was not different from placebo, whereas there was a significant effect in PC15FEV1. The mean shift in PC20FEV1 after FK-224 vs placebo was 1.0 doubling concentrations. The mean changes in BK responsiveness on the second BK challenge and placebo days compared to the first BK challenge were 0.6 and 1.3 doubling concentrations. We observed a significant fall in FEV1 after inhalation of saline plus ethanol, which was the diluent for BK (mean decrease 4.2%). CONCLUSION: The data demonstrate that inhalation of 2 mg FK-224 is only marginally effective against BK-induced bronchoconstriction in mild asthmatic subjects and that its effect is similar to the variability in BK responsiveness assessed over several weeks.

Administration, Inhalation↗
PubMed1996

Eosinophil VLA-4 binding to fibronectin augments bronchial narrowing through 5-lipoxygenase activation.

We examined the effect of ligation of human eosinophils activated by platelet-activating factor (PAF) to soluble human fibronectin (FN) on the augmented contractile response of human bronchial explants. Styrene microplate wells were FN-coated and eosinophils were allowed to adhere in the presence of 1) buffer control, 2) 20 micrograms/ml monoclonal antibody (HP2/1) to the alpha 4 beta 1 ligand (VLA-4) on the eosinophils, 3) 20 micrograms/ml anti-CD18 R15.7, 4) 20 micrograms/ml anti-CD16 3G8, or 5) 10(-6) M A63162, a 5-lipoxygenase inhibitor. Sixty minutes later, treated cells were activated with either buffer or 10(-6) M PAF. Airway luminal diameter was assessed by computerized videomicrometry as a function of pixel number, and activation of eosinophils was confirmed by measurement of leukotriene C4 (LTC4) secretion. Ligation with FN caused an increase in PAF-stimulated LTC4 secretion from 276 +/- 75.6 pg/10(6) cell at baseline to 606 +/- 90.2 pg/10(6) cell (P < 0.01). This corresponded to augmented luminal narrowing of human bronchial explants from 25.3 +/- 9.39% (PAF activation alone) to 42.9 +/- 8.0% (PAF-activated eosinophils + FN) (P < 0.01). Both augmented airway luminal narrowing and increased LTC4 secretion caused by PAF-activated cells after FN ligation were blocked completely by anti-VLA-4 MAb (P < 0.05 vs. control). Pretreatment with 10(-6) MA63162 inhibited completely the PAF-stimulated LTC4 secretion to baseline level ( P < 0.001). Inhibition of 5-lipoxygenase similarly blocked luminal narrowing caused by eosinophils stimulated by PAF by > 95% (P < 0.001). We demonstrate that the binding of human eosinophils to the matrix protein FN causes augmented secretion of LTC4 which, in turn, causes augmented luminal narrowing of explanted human bronchi in vitro. We also demonstrate that the augmented activity is blocked selectively by pretreatment with specific monoclonal antibody against VLA-4 and blockade of eosinophil 5-lipoxygenase inhibits both LTC4 secretion and airway narrowing after PAF-stimulation.

Acetamides↗
PubMed1996

[Tachyphylaxis of airway response to inhaled bradykinin over several days].

Tachyphylaxis of airway responses has been described for a variety of pharmacological stimuli. A decrease in airway responsiveness to inhaled bradykinin has been reported when challenges were repeated within intervals of 60 minutes. Especially within the framework of drug studies, it is important to know whether tachyphylaxis persist over days. The aim of our study was to assess the occurrence of tachyphylaxis to inhaled bradykinin within several days. Thirteen patients with mild extrinsic bronchial asthma were included into the study. We performed two bradykinin inhalation challenges separated by an interval of three days and determined the provocative concentrations of bradykinin (PC20FEV1) which produced a 20% fall in FEV1. Geometric mean of PC20FEV1 was 0.033 mg/mL in the first and 0.105 mg/mL in the second challenge. These values were significantly different (p < 0.05). Our data demonstrate that tachyphylaxis of the airway response to bradykinin persists over a time period of three days.

Aerosols↗