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Biomedical subjects

G Folkerts

Publications and source records attributed to G Folkerts.

72 records · Page 4Linked to original sources
PubMed1989

Endotoxin-induced hyperreactivity of the guinea-pig isolated trachea coincides with decreased prostaglandin E2 production by the epithelial layer.

1. Pretreatment of guinea-pigs with endotoxin (1 mg kg-1 b.w., i.p., 4 days before the experiments) results in respiratory airway hyperreactivity in vitro. Dose-response curves with either arecoline or histamine on isolated tracheae from these animals display increased maximal contractions, and decreased EC50 values. 2. Tracheae denuded of epithelium respond with a similar hyperreactivity to histamine as observed in preparations from endotoxin pretreated animals. Removal of the epithelial layer of tracheae from endotoxin pretreated guinea-pigs did not additionally affect the histamine dose-response curve. 3. The cyclo-oxygenase inhibitor indomethacin (10 microM) induces histamine hyperreactivity which is equal in intact and epithelium-denuded tracheae from saline or endotoxin pretreated guinea-pigs. Similar results are obtained with the combined lipoxygenase/cyclo-oxygenase inhibitor nordihydroguaiaretic acid (10 microM). 4. Histamine (0.1 mM) induces an increase in prostaglandin E2 (PGE2) formation by the tracheal spiral in vitro, which is reduced by 34% by endotoxin pretreatment, and by about 60% following epithelium removal irrespective of endotoxin pretreatment. 5. Arachidonic acid (AA, 22 microM) stimulation of the guinea-pig trachea in vitro induces a relaxation, and an increase in PGE2 production. In preparations lacking the epithelium, AA induces a contraction which coincides with a 60% reduced increase in PGE2 formation. These effects are not altered by endotoxin pretreatment. 6. It is concluded that the endotoxin-induced respiratory airway hyperreactivity may be caused by a disturbed ability of epithelial cells to synthesize PGE2. The decreased formation of this prostaglandin is rather the consequence of a diminished liberation of AA from the phospholipid stores than a dysfunction of the cyclo-oxygenase enzyme.

Airway Resistance↗
PubMed1988

Involvement of the spleen in the endotoxin-induced deterioration of the respiratory airway and lymphocyte beta-adrenergic systems of the guinea pig.

The beta-adrenergic binding sites on splenic lymphocyte membranes of the guinea pig were characterized with the radio-ligand [125I]cyanopindolol and showed a maximal number of binding sites (Bmax) of 125 fmol/mg protein and an affinity (Kd) of 170 pM. The potency of various beta-adrenoceptor antagonists to compete for [125I]cyanopindolol binding suggested that the receptor is of the beta 2 subtype. Endotoxin (1 mg/kg) induced a 35% decrease in the number of beta-adrenergic binding sites on lymphocytes, 4 days after i.p. administration. The reduction in the number of beta-adrenoceptors on the lymphocytes was accompanied by a 30% decrease in the relaxation of isolated guinea pig tracheal spirals to isoprenaline and a 20% reduction in the number of beta-adrenergic binding sites in peripheral lung tissue. The endotoxin-induced deterioration of the beta-adrenergic system in the respiratory airways was completely prevented by splenectomy. It is concluded that the spleen, and or cells or products derived from the spleen, are involved in the changes of the beta-adrenergic system in the respiratory airways and lymphocytes.

Animals↗
PubMed1988

Effects of dietary linoleic acid on beta-adrenergic responsiveness of the guinea pig respiratory system.

Respiratory autonomic beta-adrenergic receptor function was investigated in isolated tracheal spirals of guinea pigs receiving different diets. Comparison was made between control and Haemophilus influenzae treated animals; this latter group serving as animal model for atopy. The different semi-synthetic diets (35 energy%) varying in their linoleic acid contents (5.85, 11.25 and 22.05 en%), exerted profound effects on membrane fatty acid composition. No influence of these diets on either food intake or growth could be detected. Isoprenaline induced relaxation of guinea pig tracheal spirals was maximal in the dietary group receiving moderate linoleic acid (11.25 en%). Both the addition and the withdrawal of linoleic acid to this diet resulted in a significant impairment of beta-adrenergic receptor function, to the same extent as can be induced by Haemophilus influenzae. The results are discussed in view of current concepts for atopy.

Animals↗
PubMed1988

Effects of anterior hypothalamic lesions and sham-operations on bacterial endotoxin-induced non-specific airway hyperreactivity in vivo and in vitro.

1. In the present study the effects of anterior hypothalamic (AHA) lesions and sham-operations were investigated on the endotoxin-induced airway hyperreactivity in guinea-pigs. Unoperated, sham-operated and AHA-lesioned guinea-pigs were injected intraperitoneally with Escherichia coli endotoxin and the airway reactivity tested four days later in isolated tracheal spirals and in spontaneously breathing anaesthetized animals. Control animals were given sterile saline. 2. Sham-operated control animals demonstrated a diminished responsiveness of the tracheal spirals in vitro and of the lung resistance (delta R1) in vivo to histamine receptor and cholinoceptor-muscarinic agonists as compared to unoperated control animals. 3. AHA-lesioned control animals showed a responsiveness of the respiratory airways in vitro and in vivo between the values of unoperated and sham-operated control animals, suggesting that lesions partially restored the diminished responsiveness. 4. In unoperated and sham-operated guinea-pigs, endotoxin administration induced hyperreactivity of the tracheal spirals and delta R1 to histamine receptor and cholinoceptor-muscarinic agonists with respect to the control groups. 5. In AHA-lesioned animals, the endotoxin-induced airway hyperreactivity in vitro and in vivo to histamine receptor and cholinoceptor-muscarinic agonists was absent.

Airway Resistance↗
PubMed1988

Endotoxin-induced inflammation and injury of the guinea pig respiratory airways cause bronchial hyporeactivity.

It was investigated whether an endotoxin-induced airway inflammation and injury correlated with the induction of bronchial hyperreactivity. Guinea pigs were treated with an endotoxin aerosol, and 4 and 24 h later lung lavages were performed and a differential cell count was made. The number of neutrophils and monocytes was significantly increased (p less than 0.005) at these times. After 24 h, the number of eosinophils and lymphocytes was also increased (p less than 0.005). The number of alveolar macrophages remained unchanged. Histologic examination revealed increased intraluminal mucus and an influx of erythrocytes and neutrophils in the tracheal and bronchial lumen at both time points after the endotoxin aerosol. The epithelium was morphologically changed and contained many neutrophils. Focal matting and/or loss of cilia also occurred. Airway smooth muscle responsiveness was measured in vitro on isolated guinea pig tracheal smooth muscle preparations 4 and 24 h after endotoxin aerosol. No differences in the maximal responses or slope factors of the dose-response curves for carbachol, histamine, or isoprenaline were detected between the control and endotoxin-exposed groups. The EC50 value of the histamine dose-response curve 4 h after endotoxin nebulization was slightly but significantly (p less than 0.05) increased, indicating decreased sensitivity. Responsiveness in vivo was measured in anesthetized spontaneously breathing guinea pigs 24 h after the endotoxin aerosol. The histamine-induced increase in pulmonary resistance was reduced by about 35% in the endotoxin-nebulized group (p less than 0.01). It can be concluded that an influx of inflammatory cells accompanied by injury of the airways induces hyporeactivity of the guinea pig respiratory tract.

Aerosols↗
PubMed1987

Haemophilus influenzae-induced decreases in lung beta-adrenoceptor function and number coincide with decreases in spleen noradrenaline.

In the guinea-pig intraperitoneal administration of the Gram-negative bacterium Haemophilus influenzae induces a decrease of beta-adrenoceptor number and results in impairment of beta-adrenoceptor function in the peripheral and central airways, respectively. In the present study, the time-course of these events was studied and compared with changes in catecholamines in plasma, in organs involved in immunoregulation (spleen, thymus), and in the heart and the lung. The number of beta-adrenoceptor binding sites in peripheral lung tissue and beta-adrenoceptor function in isolated tracheal spirals were significantly decreased 3 and 4 days after administration of H. influenzae (24-33%). No significant changes were observed at day 1 and day 8. The effects on tracheal beta-adrenergic receptor function were characterized by a decrease of maximal relaxation only, whereas EC50-values were not affected. These data are indicative of an effect on the functional coupling of the receptors to the biochemical events leading to smooth muscle relaxation. No changes were observed in catecholamine concentrations in the lung, heart, and the thymus after H. influenzae-treatment. Plasma noradrenaline, though, was significantly increased at day 1 after H. influenzae. At day 8 plasma noradrenaline had returned to control levels. Interestingly, the effect on spleen noradrenaline was opposite to the effect seen in plasma. A significant decrease in spleen noradrenaline was observed after H. influenzae at days 1, 3, and 8, with a maximum of 42% at day 1. It is suggested that the decrease in spleen noradrenaline may have a causal relationship with the changes in lung beta-adrenoceptors.

Airway Resistance↗
PubMed1986

The influence of Bordetella pertussis and its constituents on the beta-adrenergic receptor in the guinea pig respiratory system.

In the present study, the effect of vaccination of guinea pigs with Bordetella pertussis was investigated, 4 days after treatment, on the cholinergic and beta-adrenergic receptor function in isolated tracheal spirals and the number of beta-adrenoceptor binding sites in guinea pig lung. It was found that B. pertussis caused an impairment in the beta-adrenoceptor function and a decrease in its number. Similar results were obtained with endotoxin. Leucocytosis promoting factor, however, was ineffective. These results indicate that endotoxin is the constituent responsible for the beta-adrenoceptor blocking effects of the bacterium. Also the combined whole cell diphtheria, B. pertussis and tetanus toxoid vaccine induced a beta-adrenoceptor blockade; the acellular vaccine was less effective. The results obtained with the B. pertussis vaccines are discussed in relation to the possible side-effects that sometimes occur after immunization of infants.

Animals↗
PubMed1985

Haemophilus influenzae induces a potentiated increase in guinea-pig pulmonary resistance to histamine.

The human respiratory pathogen Haemophilus influenzae (H.i.) induced bronchial hyperreactivity to histamine (1.0-8.0 micrograms/100 g b.w. i.v.) in vivo in anaesthetized spontaneously breathing guinea-pigs. This hyperreactivity was caused by a potentiated increase in pulmonary resistance. Decreases in dynamic compliance did not differ. Atropine prevented the potentiation at 1.0 and 2.0 micrograms histamine/100 g b.w. These results show that H.i. induces bronchial hyperreactivity in vivo which is mediated by direct and reflex effects of histamine in the central airways.

Airway Resistance↗
PubMed1983

Induction in guinea-pigs of airway hyperreactivity and decreased lung beta-adrenoceptor number by 15-hydroperoxy-arachidonic acid.

Administration to guinea-pigs of 15-hydroperoxy-arachidonic acid (0.2 mg kg-1 i.p.) caused a 20% reduction of lung beta-adrenoceptor number. Furthermore, in vivo, a hyperreactivity of the airways to nebulized histamine was observed. In contrast, administration of 15-hydroxy-arachidonic acid (0.2 mg kg-1 i.p.) did not cause a significant change in either of these parameters.

Airway Resistance↗
PubMedDate not supplied

Airway hyperresponsiveness: first eosinophils and then neuropeptides.

Airway hyperreactivity to bronchoconstrictor mediators is a main characteristic in the majority of asthmatic patients and correlates well with the severity of the disease. The airways of asthmatic patients are characterized by an inflammatory state resulting in activation of lung tissue cells and attraction and infiltration of leukocytes from the blood. The accumulation of eosinophilic leukocytes is a prominent feature of inflammatory reactions that occurs in allergic asthma. The increase in number of eosinophils is important since it correlates in time with an increase in bronchial hyperresponsiveness. Viral respiratory infections can also induce eosinophilia and airway hyperresponsiveness in humans and animals and can worsen asthmatic reactions. This report reviews current opinions on the relationship between inflammation-induced eosinophil accumulation/activation and the development of airway hyperresponsiveness and the possible role for sensory neuropeptides in this process. Firstly, CC chemokines play an important role in allergic airway inflammation and respiratory viral infections leading to eosinophil recruitment. Secondly, it can be concluded that IL5 is involved in the development in airway hyperresponsiveness. IL5 has profound effects on eosinophils as promoter of growth, differentiation and proliferation, chemoattractant, activator and primer. However, it is conceivable that in animal models for allergic asthma besides IL5 other regulatory mediators may be involved in eosinophil migration and activation in the lung, which in turn will lead to airway hyperresponsiveness. Recent data support the possible role of eotaxin and its eosinophil-specific receptor CCR-3 in eosinophil chemotaxis and activation in allergic asthma. Moreover, it is suggested that the development of airway eosinophilia in vivo involves a two-step mechanism, elicited by eotaxin and IL5. The precise mechanism by which eosinophils induce bronchial hyperresponsiveness is at present unknown. Sensory neuropeptides could be important mediators in this process, since it has been demonstrated that airway nerves are surrounded by and infiltrated with eosinophils after antigen challenge. Sensory neuropeptides could be the final, more downstream, common pathway after eosinophil infiltration and activation in inducing airway hyperresponsiveness due to allergen inhalation or respiratory viral infections. In conclusion, in the process of the development of airway hyperresponsiveness observed during viral infections or in allergic asthma, the IL5/eotaxin-induced infiltration and activation of eosinophils in the airways is evident. Following this step, eosinophil-derived inflammatory mediators will induce the release of sensory neuropeptides (possibly NK2-receptor activating tachykinins) which in turn will lead to airway hyperresponsiveness.

Animals↗
PubMedDate not supplied

Nitric oxide and bronchial hyperresponsiveness.

Increasing evidence points to an important role for nitric oxide in the regulation of pulmonary functions and in pulmonary disease. In the respiratory tract, sensory nerves, endothelial cells, vascular and airway smooth muscle cells, inflammatory cells and the airway epithelium are sources of nitric oxide. Different nitric oxide synthases have been isolated, cloned and sequenced. Functionally, there are constitutive and inducible forms of nitric oxide synthase. A number of cytokines have been shown to inhibit or induce the expression of the inducible nitric oxide synthase. In human airways, endogenous nitric oxide appears to account for the bronchodilator nonadrenergic and noncholinergic response. Nitric oxide-containing vasodilators, such as glyceryl trinitrate and sodium nitroprusside, induce relaxation of the isolated airway smooth muscle, activate guanylate cyclase and raise c-GMP levels. Nitric oxide (constitutive), produced by the epithelial layer, appears to be important in blunting the histamine contractile response of the airway tissue. Furthermore, tracheal relaxation by, e.g., bradykinin or potassium chloride, is mediated by the release of nitric oxide. The virus (Parainfluenza type 3)-induced airway hyperreactivity in guinea-pigs is correlated with a deficiency in endogenous constitutive nitric oxide production by the airways and can be blocked by low doses of L-arginine. In inflamed tissue, nitric oxide quickly reacts with superoxide anion, resulting in the formation of the toxic peroxynitrite which promotes lipid and sulfhydryl oxidation. Asthmatic patients have higher amounts of nitric oxide in the expired air, possibly due to the inflammation. This increased nitric oxide production can be inhibited by inhaled corticosteroids. The effect of inhaled nitric oxide on the lung function of asthmatic patients is variable. In contrast, low doses of inhaled nitric oxide are effective in reversing the pulmonary vasoconstriction. These results point to an important role for nitric oxide in modulating airway reactivity.

Animals↗