The potential role of tumour necrosis factor alpha in asthma.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
J C Kips
Publications and source records attributed to J C Kips.
The effect of zardaverine, an inhibitor of phosphodiesterase isoenzymes III and IV, on endotoxin-induced airway changes in rats.
Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed as a potential therapeutic agent for asthma. In this study we evaluated the effect of zardaverine in an in vivo animal model of airway inflammation and hyperresponsiveness. Endotoxin exposure in rats causes a transient increase in airway responsiveness and a neutrophilic inflammation of the bronchi, which are both at least partly mediated through the secondary release of tumour necrosis factor alpha (TNF alpha). Groups of 10 animals each were pretreated with placebo or zardaverine (1, 10, 30 mumol/kg) i.p., 30 min prior to exposure to aerosolized endotoxin (LPS) or saline. Ninety minutes later, airway responsiveness to 5-HT was assessed and bronchoalveolar lavage (BAL) performed. Zardaverine did not influence baseline lung resistance (RL), but inhibited dose dependently the 5-HT induced increase in RL in control animals. In placebo pretreated animals LPS exposure caused a significant decrease in PC50RL5-HT (provocative concentration of 5-HT causing a 50% increase in RL), compared to the saline exposed control group (1.1 +/- 0.1 vs 2.7 +/- 0.4 micrograms/kg) (P < 0.01). This decrease in PC50RL5-HT was significantly inhibited by zardaverine 30 mumol/kg (5.4 +/- 1.8 vs 1.1 +/- 0.1 micrograms/kg) (P < 0.05). Compared to placebo pre-treated, LPS exposed animals, zardaverine 30 mumol/kg also significantly inhibited to LPS induced neutrophil increase (193.0 +/- 50.0 vs 915.6 +/- 181.3 x 10(3)) (P < 0.01), increase in elastase activity (23 +/- 11 vs 54 +/- 9 nmol substrate/h/ml) (P < 0.05) and TNF alpha release in BAL fluid (93.1 +/- 19.5 vs 229.5 +/- 24.8 U/ml BAL fluid) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tumor necrosis factor causes bronchial hyperresponsiveness in rats.
We have previously reported that exposure of rats to aerosolized endotoxin (LPS) causes a transient, dose-dependent increase in bronchial responsiveness (BR) to 5 hydroxytryptamine (5HT), 90 min after exposure. In the present study we examined whether LPS induces the release of tumor necrosis factor (TNF) in the airways and whether TNF contributes to the increase in BR. After 90 min following exposure to aerosolized LPS, at a concentration of 1 or 10 micrograms/ml, TNF concentrations in bronchoalveolar lavage (BAL) fluid were 17.9 +/- 6.9 and 80.5 +/- 7.8 U/ml, respectively. No TNF was detected in BAL fluid of saline-exposed animals. At 90 min after exposure to aerosolized recombinant human TNF (rhTNF) (1 microgram/ml) an increase in BR was observed: the provocative concentration of 5HT causing a 50% increase in lung resistance (PC50RL 5HT) was 2.7 +/- 0.4 versus 4.4 +/- 0.3 microgram/kg in saline-exposed animals (p less than 0.01). Pretreatment with anti-TNF antibodies 30 min before LPS exposure significantly diminished the increase in BR: PC50RL 5HT was 2.3 +/- 0.4 versus 1.2 +/- 0.5 microgram/kg in control pretreated LPS-exposed rats (p less than 0.01). Exposure to aerosolized TNF also induced a significant influx of neutrophils in BAL fluid (12.1 +/- 3.7 versus 1.7 +/- 0.4% in saline-exposed animals) (p less than 0.01). The LPS-induced neutrophil influx in BAL fluid was partly inhibited by pretreatment with anti-TNF antibodies (55.2 +/- 5.1 versus 76.0 +/- 3.9%) (p less than 0.01). We conclude that TNF causes bronchial hyperresponsiveness and airway inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Aerosols↗
Effect of acute and chronic antigen inhalation on airway morphology and responsiveness in actively sensitized rats.
Bronchial hyperresponsiveness (BHR) is a major characteristic of bronchial asthma. The pathogenesis of BHR remains to be fully elucidated, but is considered to be closely linked to airway inflammation. Animal models might provide us with useful data for a better understanding of the interrelationship between these phenomena. In the present study we investigated the effect of a single and chronic exposure to inhaled antigen on bronchial responsiveness and airway morphology in actively sensitized Brown Norway rats. Immunization to ovalbumin (OA) did not cause airway inflammation, but induced a small, transient decrease in bronchial responsiveness to 5-hydroxytryptamine (5HT) on Day 10, which returned to baseline on Day 16. By 24 h after a single exposure to aerosolized OA, a significant decrease in the provocative concentration of 5HT causing a 50% increase in lung resistance (PC50RL 5HT) was observed, compared with immunized, saline-exposed animals (7.7 +/- 0.8 versus 10.8 +/- 1.0 micrograms/kg). This was accompanied by the influx of neutrophils and few eosinophils in bronchoalveolar lavage fluid. Repeated daily or intermittent exposure to aerosolized OA enhanced airway inflammation, characterized by the presence of neutrophils, eosinophils, and lymphocytes in bronchoalveolar lavage fluid. Histologic analysis revealed patchy inflammatory infiltrates, located predominantly around bronchi and bronchioli. Despite these inflammatory changes, bronchial responsiveness was not significantly different from that of control animals. We therefore conclude that the induction of airway inflammation is not always associated with BHR.
Aerosols↗
Bronchodilatory action of cysteinyl-leukotriene receptors.
Explore the source record for details and available documents.
Azides↗
The effect of aerosolized SK&F 104353-Z2 on the bronchoconstrictor effect of leukotriene D4 in asthmatics.
Leukotriene D4 (LTD4) is a potent bronchoconstrictor and vasoactive mediator that has been implicated in the pathogenesis of bronchial asthma. We have studied the effect of SK&F 104353-Z2, a specific LTD4 antagonist, on LTD4-induced bronchoconstriction in asthmatics. A total of 12 mild asthmatics (mean baseline FEV1 +/- SEM: 85.9% +/- 2.6) received on 2 separate days, double-blind and cross-over, 800 micrograms SK&F 104353-Z2 or placebo via aerosol. After 30 min, doubling concentrations of LTD4 (0.078 to 20.1 microM in the first 4 patients and up 80.4 microM in the other patients) were inhaled with intervals of 30 min. Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1) were measured. On the placebo-day LTD4 inhalation caused a concentration dependent bronchoconstriction. The effect of SK&F 104353-Z2 on baseline sGaw and FEV1 could be evaluated in 10 patients. After inhalation of SK&F 104353-Z2 a small, but significant increase, in sGaw (0.107 +/- 0.013 to 0.132 +/- 0.011 cm H2O-1s-1) and FEV1 (3.39 +/- 0.23 to 3.56 +/- 0.25 liter) was observed. The effect of SK&F 104353-Z2 on the dose-response curve for LTD4 was evaluated in the six patients who inhaled concentrations of LTD4 up to 80 microM. On the active treatment day, the dose-response curve for LTD4 was significantly shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human.
MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.
Adolescent↗
The effect of endotoxin inhalation on airway responsiveness and cellular influx in rats.
Studies in humans suggests that airway inflammation may modulate nonspecific airway responsiveness. We studied in a rat model the effect of the inhalation of endotoxin on the cellular composition of the bronchoalveolar lavage (BAL) fluid and airway responsiveness. The exposure to an aerosol of endotoxin caused a rapid influx of neutrophils in the airways. The neutrophils persisted up to 24 h after exposure. Elastase activity in lavage fluid became detectable 30 min after the endotoxin exposure and peaked 9 h later. The exposure to the endotoxin aerosol was followed 1 to 2 h later by a significant increase in the airway responsiveness to 5-hydroxytryptamine (5HT). However, the increase in responsiveness disappeared, and 9 to 12 h following the end of the exposure a significant decrease in airway 5HT responsiveness was observed at the moment that more than 80% of the cells contained in the BAL fluid were neutrophils. The effect of endotoxin on airway responsiveness and inflammation was dose dependent. We also compared in three different inbred rat strains the effect of endotoxin inhalation. The aerosol exposure induced in all three strains a comparable neutrophil influx in the airways, but only two of the three strains became hyperresponsive to 5HT. We conclude that the inhalation of endotoxin causes a neutrophilic airway inflammation in rats. The relationship between this airway inflammation and airway responsiveness is dependent on the time following the exposure and the animal strain used.
Administration, Inhalation↗
Importance of interleukin-4 and interleukin-12 in allergen-induced airway changes in mice.
T helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of atopic asthma. In this study, we attempted to evaluate the in vivo effect of suppressing Th2 cell development on allergen-induced airway changes. Repeated exposure of actively sensitized C57Bl/6 mice to aerosolized ovalbumin (OA) causes, in comparison to saline-exposed control animals, synthesis of specific IgE, increase of eosinophils in bronchoalveolar lavage fluid and airway hyperresponsiveness. These effects are not observed in OA-exposed, sensitized IL-4-knockout mice. Likewise, these effects are inhibited in OA-exposed C57Bl/6 mice treated with IL-12 during initial antigen exposure. These results suggest that suppressing Th2 cell development in vivo might have profound inhibitory effects on allergen-induced airway changes.
Aerosols↗
Tachykinin antagonists and the airways.
There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tissue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P and NKA are potent bronchoconstrictors of human airways, asthmatics being more sensitive than normal persons. The major enzyme responsible for the degradation of the tachykinins, the neutral endopeptidase, is present in the airways and is involved in the breakdown of exogenously administered SP and NKA, both in normal and asthmatic persons. Other, less well documented airway effects of SP and NKA include mucus secretion, vasodilation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, whereas NK1 receptors were found to be involved in mucus secretion, microvascular leakage and vasodilatation, and in most of the effects on inflammatory cells. The first clinical trial with FK224, a peptide NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 receptor antagonist, are negative. However, FK224 failed to block the bronchoconstrictor effect of NKA in asthmatics and the dose of CP99994, needed to antagonize tachykinin effects in man, remains to be determined.
Animals↗