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Biomedical subjects

J C Kips

Publications and source records attributed to J C Kips.

At least 55 records · Page 3Linked to original sources

Pitfalls in the diagnosis of hypereosinophilic syndrome: a report of two cases.

The idiopathic hypereosinophilic syndrome is empirically defined as the presence of prolonged eosinophilia without identifiable underlying cause, and with evidence of end-organ dysfunction. Virtually any organ system may be involved, most frequently the heart, the central and peripheral nervous system, the lungs and the skin. We report two cases where the diagnosis of hypereosinophilic syndrome was proposed although the classic criteria were not met. In the first case total peripheral eosinophil counts were relatively low, but pathological evidence clearly showed infiltration of eosinophils in the damaged tissues. An hypothesis to explain this discrepancy is formulated. The second case did not fulfil the first feature either, although the clinical presentation and disease course corresponded well with other cases reported in the literature. The delay in diagnosis was caused by early institution of corticosteroids, clearing all evidence of eosinophil involvement in the observed tissue damage.

Adolescent↗

Preoperative pulmonary evaluation.

The incidence of peri-operative pulmonary complications varies, depending on surgery and patient related determinants. Risk factors include upper abdominal or thoracic surgery, duration of anaesthesia, age, obesity, smoking history and underlying respiratory diseases such as COPD. The preoperative evaluation of patients undergoing general surgery is predominantly based on medical history and physical examination. A preoperative chest radiograph and pulmonary function tests are indicated in some high risk patient groups, and in all patients about to undergo lung resection surgery. If in this latter group, the preoperative lung function is severely compromised, a quantitative perfusion scan and exercise testing may be useful for the assessment of the operative risk. Prevention of postoperative pulmonary complications should begin with discontinuation of smoking at least 8 weeks prior to surgery. In high risk patients preoperative chest physiotherapy, including incentive spirometry, is clearly beneficial.

Age Factors↗

The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects.

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.

Adenosine↗

Cytokine manipulation in animal models of asthma.

We have developed in C57 Black 6 mice an in vivo model of allergic airway inflammation characterized by the presence of IgE antibodies to an inhaled antigen, peribronchial infiltrates with an increased number of eosinophils, and an increased airway responsiveness to nonantigenic bronchoconstrictor stimuli. In this animal model we have investigated the role of different cytokines in the development of IgE antibodies to inhaled antigen, eosinophilic airway inflammation, and airway hyperresponsiveness. The studies were performed by using knockout mice or by exogenous administration of cytokines or cytokine antagonists. Interleukin-4 (IL-4) knockout mice were unable to develop an allergic eosinophilic airway infiltration and did not produce specific IgE antibodies. Chronic aerosol exposure to antigen also did not induce an increase in airway responsiveness. In studies of wild-type mice, pretreatment with the combination of anti-IL5 and anti-IL-5 receptor antibodies, given in an attempt to fully inhibit the effect of endogenously released IL-5, caused a pronounced inhibition of the antigen-induced airway eosinophilia but did not prevent the increase in airway responsiveness. Treatment with IL-12 during the active immunization prevented airway eosinophilia, production of specific IgE antibodies, and the antigen-induced increase in airway responsiveness. In contrast, administration of IL-12 to actively immunized mice during the aerosol exposure abolished airway eosinophilia and airway hyperresponsiveness without affecting the production of specific IgE.

Animals↗

Role of IFN-gamma in the inhibition of the allergic airway inflammation caused by IL-12.

T-helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of the eosinophilic airway inflammation observed in asthma. In a murine model of allergen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), we have shown that interleukin (IL)-12 can suppress antigen-induced airway changes despite the presence of circulating specific IgE. In the present study, we investigated the role of interferon-gamma (IFN-gamma) in the inhibitory effects of IL-12 on allergic airway inflammation. Repeated daily exposure of actively immunized mice to aerosolized ovalbumin (OVA), as compared with aerosolized saline (SAL), induced a significant increase in bronchoalveolar lavage fluid (BALF) eosinophilia and OVA-specific serum IgE in both IFN-gamma-receptor-deficient (IFN-gammaR KO) and wild-type mice. As compared with placebo (PLAC), administration of recombinant murine IL-12 (rmIL-12) during the daily aerosol exposure (but not at the time of immunization) significantly inhibited BALF eosinophilia in both IFN-gammaR KO mice and wild-type controls, without influencing the production of specific IgE. In contrast, administration of rmIL-12 during the active immunization inhibited both BALF eosinophilia and specific IgE in wild-type mice as compared with littermates given PLAC; however, treatment with rmIL-12 during immunization, in comparison with PLAC, caused a significant increase in BALF eosinophilia and specific IgE in IFN-gammaR KO mice. These results demonstrate that inhibition of the allergen-induced eosinophil influx in murine airways by IL-12 is IFN-gamma-dependent during the initial sensitization, but becomes IFN-gamma-independent during the secondary response.

Animals↗

Interleukin-12 inhibits antigen-induced airway hyperresponsiveness in mice.

The airway inflammation observed in allergic asthma is thought to be orchestrated by an antigen-driven T-helper-2 (Th2) lymphocyte response. In vitro data indicate that the presence of interleukin-12 (IL-12) during the primary stimulation of T-lymphocytes with antigen favors the development of Th1 cells. The aim of the present study was to examine the effect of IL-12 in vivo on antigen-induced airway changes in a murine model. C57BL/6 mice were actively sensitized to ovalbumin; 14 d later, they were exposed daily for 7 d to aerosolized ovalbumin. This resulted in airway eosinophilia, production of ovalbumin-specific IgE, and airway hyperresponsiveness to carbachol. Administration of recombinant murine IL-12 (rmIL-12) during the active immunization prevented these antigen-induced changes. In contrast, administration of rmIL-12 to actively immunized mice during the daily aerosol exposure (but not at the time of immunization) abolished airway eosinophilia and hyperresponsiveness without influencing the production of specific IgE. These results suggest that IL-12 can suppress antigen-induced airway changes despite the presence of circulating specific IgE.

Animals↗

The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics.

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.

Administration, Inhalation↗

Are cytokines responsible for the asthmatic state of the airways?

Chronic mucosal airway inflammation is currently considered to be the central element in the pathophysiology of asthma. This inflammatory process is regulated by a complex network of mutually interacting cytokines. The overall pattern of cytokine expression in asthma is one of increased expression of T-helper 2-like cytokines, including interleukin (IL)-4 and IL-5, in addition to proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta. The precise functional importance of each of these cytokines within the global network remains to be fully established. This question has been addressed in a number of in vivo animal studies. Combining these data with descriptive findings in man makes it possible to address somewhat further the question of the in vivo significance of a specific cytokine in the asthmatic state of the airways. This paper reviews some of the data currently available on this subject.

Animals↗

Genetic control of indirect airway responsiveness in the rat.

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoconstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains, F344 and BDE. BDE-rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3-adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE- and F344-rats is probably related to a higher number of A3-receptors on the airway mast cells of BDE-rats. In contrast, F344-rats have a higher airway responsiveness to tachykinins than BDE-rats. Tachykinins cause bronchoconstriction in F344-rats mainly by an indirect mechanism, involving stimulation of NK1-receptors and mast cell activation. In BDE-rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2-receptors. Finally we also observed a difference between F344- and BDE-rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsaicin. In F344-rats but not in BDE-rats mast cell activation and the release of 5-hydroxytryptamine is partly responsible for this plasma protein extravasation.

Adenosine↗

The effect of a nitric oxide synthase inhibitor on the modulation of airway responsiveness in rats.

The possible role of nitric oxide (NO) in the regulation of airway tone remains to be fully explored. In the present study we examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on airway responsiveness in rats. The effect of L-NAME on endotoxin (lipopolysaccharide; LPS)-induced changes in airway responsiveness was also evaluated. L-NAME (1 mg/kg given intravenously) caused a 33.3 +/- 6.9% increase in blood pressure, but did not influence baseline airway tone or the provocative dose of carbachol causing a 50% increase in pulmonary resistance (RL)(PD50RL). Exposure of F344 rats to LPS induced a transient increase in airway responsiveness at 90 min after exposure, followed by a significant hyporesponsiveness between 9 and 12 h after exposure. L-NAME (1 mg/kg intravenously) did not influence the increase in responsiveness but inhibited the LPS-induced hyporesponsiveness; in LPS-exposed, L-NAME-treated animals, the PD50RL for carbachol was 3.0 +/- 0.1, versus 4.8 +/- 0.3 micrograms/kg in the LPS-exposed, placebo-pretreated group (p < 0.05). The effect of L-NAME was abolished by pretreatment with L-arginine but not with D-arginine. L-NAME did not influence the LPS-induced increase of neutrophils in bronchoalveolar lavage fluid (BALF). These results suggest that in rats, consitutive NO synthesis does not contribute either to basal airway tone or to the basal degree of airway responsiveness, but that inducible NO synthesis mediates endotoxin-induced hyporesponsiveness.

Airway Resistance↗

Characterization of neurogenic inflammation in the airways of two highly inbred rat strains.

Tachykinins released from sensory airway nerves have been shown to increase vascular permeability and plasma-protein extravasation (PPE) in rodent airways. We previously demonstrated that in Fisher (F344) rats, tachykinins cause bronchoconstriction mainly by indirect mechanisms involving the activation of NK1 receptor and mast cells, whereas in the less responsive BDE rats tachykinins have a direct NK2 receptor-mediated effect on bronchial smooth muscle. Using Evans blue dye as an intravascular marker, we demonstrated that F344 rats are hyperresponsive for the PPE induced by substance P (SP) and capsaicin. The NK1 receptor antagonist RP 67,580 reduced the neurogenic PPE in both strains, whereas the NK2 receptor antagonist SR 48,968 had no effect, indicating that only NK1 receptors are involved in the PPE. Pretreatment with the 5-HT antagonist methysergide decreased the neurogenic PPE in F344 rats but not in BDE rats. In F344 rats depleted of mast-cell mediators with compound 48/80, the SP-induced PPE was significantly reduced. Pretreatment with the H1 antagonist mepyramine and the H2 antagonist cimetidine caused a similar reduction in SP-induced PPE in main bronchi of both strains. Pretreatment with atropine, indomethacin, or the leukotriene antagonist ICI 198,615 did not affect the SP-induced PPE. In conclusion, neurogenic PPE in rat airways involves the activation of NK1 receptors. In F344 but not in BDE rats, an additional indirect mechanism involving 5-HT release and mast-cell activation participates in the neurogenic PPE.

Animals↗

Tachykinins contract trachea from Fischer 344 rats by interaction with a tachykinin NK1 receptor.

The contractile effect of substance P, neurokinin A, carbachol and serotonin (5-HT) on isolated Fischer 344 rat trachea was studied. Contractions of two distal tracheal rings were measured isometrically in a 2-ml organ bath. Cumulative concentration-response curves were obtained for carbachol (EC50 ring 1: 1.6 x 10(-7) M and ring 2: 2.2 x 10(-7) M) and for 5-HT (EC50 ring 1: 10.2 x 10(-7) M and ring 2: 10.5 x 10(-7) M). Non-cumulative administration of substance P and neurokinin A (10(-8) to 10(-5) M) caused a concentration-dependent contraction with an EC50 (x 10(-7) M) of 1.10 +/- 0.27 and 1.97 +/- 0.45 respectively. The maximal contraction was 32.6 +/- 2.5% (substance P) and 32.6 +/- 1.5% (neurokinin A) of the maximal contraction with carbachol. In contrast, neither substance P nor neurokinin A caused contraction of trachea from BDE rats. The tachykinin NK1 receptor agonist, Ac[Arg6, Sar9, Met(O2)11] substance P-(6-11), caused a concentration-dependent contraction with an EC50 (x 10-(-9) M) of 1.38 +/- 0.09 and a maximal effect of 25.5 +/- 2.1% of the maximal contraction with carbachol. The tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10), had a small contractile effect at 10(-6) M (8.4 +/- 0.8% of the maximal contraction with carbachol) while the tachykinin NK3 receptor agonist, senktide, had no effect up to 3.3 x 10(-6) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Attenuation of allergic airway inflammation in IL-4 deficient mice.

To investigate the role of IL-4 in vivo in allergic asthma, we developed a murine model of allergen-induced airway inflammation. Repeated daily exposures of actively immunized C57BL/6 mice to aerosolized ovalbumin (OVA) induced a peribronchial inflammation and an increase in eosinophils and lymphocytes in bronchoalveolar-lavage (BAL) fluid. In IL-4 deficient (IL4-/-) mice, treated in the same way, there were substantially fewer eosinophils in BAL and much less peribronchial inflammation compared with wild type mice. In this model, mast cell deficient (W/Wv) mice developed a similar degree of BAL eosinophilia and peribronchial inflammation as wild type mice, demonstrating that the mast cell is not required for the induction of chronic airway inflammation. In contrast, BAL eosinophilia and airway inflammation were absent in OVA-treated MHC ClassII deficient (B6.Aa-/-) mice which lack mature CD4+ T lymphocytes. In conclusion, these results indicate that IL-4 is a central mediator of allergic airway inflammation, regulating antigen-induced eosinophil recruitment into the airways by a T cell dependent mechanism.

Animals↗

In vivo characterization of the tachykinin receptors involved in the direct and indirect bronchoconstrictor effect of tachykinins in two inbred rat strains.

Three receptors for the tachykinins, NK1, NK2, and NK3, have been defined pharmacologically and have been cloned. We previously demonstrated that in Fisher 344 (F344) rats neurokinin A (NKA) and substance P (SP) cause bronchoconstriction mainly by indirect mechanisms that involve both cholinergic nerves and mast cells. Preliminary results suggested that in a less responsive strain, the BDE strain, tachykinins did not activate airway mast cells. We have now compared in F344 and BDE rats the airway effects of the tachykinins SP and NKA with those of specific NK1 and NK2 receptor agonists and have studied the effect of potent and specific nonpeptide NK1 and NK2 receptor antagonists on NKA-induced airway effects. Lung resistance (RL) and serotonin in bronchoalveolar lavage fluid (BAL 5HT) were measured in anaesthetized, mechanically ventilated, rats. In contrast to F344 rats, BDE rats were less sensitive to SP and NKA challenge, and no subsequent increase in BAL 5HT was observed. In F344 rats, the specific NK1 receptor agonists, [Sar9, Met(O2)11]SP and Ac[Arg6,Sar9,Met(O2)11]SP(6-11), caused a dose-dependent bronchoconstriction and increase in BAL 5HT comparable to those of NKA and SP. The NK1 receptor agonists had no effect in BDE rats. The NK2 receptor agonist [beta Ala8]NKA(4-10) caused a small, dose-dependent increase in RL in the F344 as well as in the BDE rat, but it had no effect on BAL 5HT. The NK1 receptor antagonists RP 67580 and CP 96,345 significantly reduced the increase in RL and BAL 5HT caused by NKA in the F344 rat, but they had no effect on the NKA-induced bronchoconstriction in the BDE rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

Sensory neuropeptides and the human lower airways: present state and future directions.

The sensory neuropeptides, substance P and neurokinin A, are present in human airway nerves, beneath and within the epithelium, around blood vessels and submucosal glands, and within the bronchial smooth muscle layer. Studies on autopsy tissue, bronchoalveolar lavage and sputum suggest that in asthma the substance P content of the airways may be increased. Neurokinin A is a more potent bronchoconstrictor than substance P. Asthmatics are hyperresponsive to neurokinin A and substance P. The neuropeptide degrading enzyme, neutral endopeptidase is present in the airways and is involved in the degradation of endogenously released and exogenously administered substance P and neurokinin A, both in normal and asthmatic subjects. As for other indirect bronchoconstrictor stimuli, the effect of neurokinin A on airway calibre in asthmatics can be inhibited by pretreatment with nedocromil sodium. Evidence is accumulating, not only from studies in animals but also from experiments on human airways, that tachykinins may also cause mucus secretion and plasma extravasation. They also have important proinflammatory effects, such as the chemoattraction of eosinophils and neutrophils, the adhesion of neutrophils, and the stimulation of lymphocytes, macrophages and mast cells. The tachykinins interact with the targets on the airways by specific tachykinin receptors. The NK1 and the NK2 receptor have been characterized in human airways, both pharmacologically and by cloning. The NK2 receptor is responsible for the in vitro contraction of normal airways, whilst the NK1 receptor is responsible for most of the other airway effects. Because of their presence in the airways and because of their ability to mimic the various pathophysiological features of asthma, substance P and neurokinin A are presently considered as possible mediators of asthma. The present development of potent and selective tachykinin antagonists will allow us to further define the role of tachykinins in the pathogenesis of asthma.

Amino Acid Sequence↗