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Biomedical subjects

P A Henricks

Publications and source records attributed to P A Henricks.

At least 19 recordsLinked to original sources
PubMed2001

Reactive oxygen species as mediators in asthma.

This review describes production and effects of reactive oxygen species (ROS) on airway function. ROS are important in many physiological processes but can also have detrimental effects on airway cells and tissues when produced in high quantities or during the absence of sufficient amounts of anti-oxidants. Therefore, these mediators play a prominent role in the pathogenesis of various inflammatory airway disorders, including asthma. Effects of ROS on airway function in asthma have been studied with isolated airway cells and tissues and with animal models and patients. With the use of inhibitors, transgenic animals and measurements of the release of ROS within the airways, it became clear that oxidative stress contributes to the initiation and worsening of inflammatory respiratory disorders.

Animals↗
PubMed2001

The role of sensory nerve endings in nerve growth factor-induced airway hyperresponsiveness to histamine in guinea-pigs.

1. Nerve growth factor induces an airway hyperresponsiveness in vivo in guinea-pigs, as we have shown previously. Since antagonizing the neurokinin-1 (NK(1)) receptor can prevent this NGF-induced airway hyperresponsiveness and since sensory nerves release tachykinins, we investigated the role of sensory nerves in the NGF-induced airway hyperresponsiveness. 2. We used isolated tracheal rings from guinea-pigs to measure tracheal contractility. In these rings sensory nerve endings are present, but these endings lack any contact with their cell bodies. 3. In this in vitro system, NGF dose-dependently induced a tracheal hyperresponsiveness to histamine. The NK(1) receptor antagonist SR140333 could block the induction of tracheal hyperresponsiveness. 4. To further investigate the involvement of sensory nerve endings we used the cannabinoid receptor 1 (CB(1)) agonist R-methanandamide to inhibit excitatory events at the nerve terminal. The CB(1) receptor agonist was capable of blocking the tracheal hyperresponsiveness to NGF in the isolated system, as well as the airway hyperresponsiveness to NGF in vivo. 5. This indicates that NGF can induce an increase in airway responsiveness in the absence of sensory nerve cell bodies. NGF may act by increasing substance P release from sensory nerve endings, without upregulation of substance P in the neurons. Substance P in its turn is responsible for the induction of the NGF-induced airway hyperresponsiveness.

Airway Resistance↗
PubMed1999

Effect of interleukin-16-blocking peptide on parameters of allergic asthma in a murine model.

In this study, we examined whether peptides based on the hydrophilic Cluster of Differentiation (CD) 4-binding part of the amino acid sequence of human interleukin-16 can block interleukin-16-induced chemotaxis of murine lymphocytes in vitro. Peptide 3 was capable of inhibiting interleukin-16-induced chemotaxis of murine splenocytes in vitro. Next, we compared the effects of intra-airway administration of peptide 3 with those of antibodies to interleukin-16 on antigen-induced features in a murine model of allergic asthma. Intra-airway administration of peptide 3 largely inhibited the development of antigen-induced airway hyperresponsiveness while airway eosinophilia was not affected. Similar effects were observed after intranasal application of antibodies to interleukin-16. These results indicate that treatment with peptide 3 causes the same effects as do antibodies to interleukin-16, possibly via the inhibition of interaction between interleukin-16 and its receptor CD4. Therefore, peptide 3 could be useful as a lead compound in attempting to limit airway hyperresponsiveness via binding to CD4.

Administration, Intranasal↗
PubMed1999

Cellular uptake of liposomes targeted to intercellular adhesion molecule-1 (ICAM-1) on bronchial epithelial cells.

Previously, it was demonstrated that immunoliposomes, bearing anti-intercellular adhesion molecule-1 (ICAM-1) antibodies (mAb F10.2), can specifically bind to different cell types expressing ICAM-1. In this study, we have quantified the amount of immunoliposomes binding to IFN-gamma activated human bronchial epithelial cells (BEAS-2B) in vitro and studied the subsequent fate of cell-bound anti-ICAM-1 immunoliposomes. We demonstrate that binding of the immunoliposomes to the epithelial cells depends on the liposome concentration used. After binding to the cell surface, the anti-ICAM-1 immunoliposomes are rapidly internalised by the epithelial cells. Sixty percent of cell-bound immunoliposomes were internalised by the epithelial cells within 1 h of incubation at 37 degrees C. The results indicate that ICAM-1 targeted immunoliposomes may be used as carriers for the intracellular delivery of anti-inflammatory drugs to sites of inflammation characterised by an increased expression of ICAM-1.

Antibodies, Monoclonal↗
PubMed1999

Nerve growth factor induces a neurokinin-1 receptor- mediated airway hyperresponsiveness in guinea pigs.

Because asthmatic patients show increased nerve growth factor (NGF) serum levels, we examined the effect of NGF on airway function. Intravenously administered NGF potentiates the histamine- induced bronchoconstriction with a maximum of over 200% in anesthetized spontaneously breathing guinea pigs. Doses of 8 ng and 80 ng NGF/kg body weight induce a significant hyperresponsiveness to histamine. NGF itself does not affect airway reactivity. Airway hyperresponsiveness is observed 30 min and 3 h after NGF administration, and has disappeared after 24 h. The neurokinin-1 receptor antagonist SR 140333 completely blocks the NGF-induced hyperresponsiveness, pointing to a role for tachykinins. This is the first report showing a direct relation between peripherally administered NGF and airway hyperresponsiveness. Taking into consideration that plasma NGF levels have been shown to be elevated in asthmatic patients, our result points to an important role for NGF in the pathogenesis of asthma.

Animals↗
PubMed1998

Pharmacological modulation of cell adhesion molecules.

Cell adhesion molecules mediate the contact between two cells or between cells and the extracellular matrix. They are essential for morphogenesis, organization of tissues and organs, regulation of immune cell responses and migration of inflammatory cells from the blood vessels into inflamed tissues. Many diseases have been shown to be associated with dysfunction or with overexpression of certain adhesion molecules. Increased cell adhesion molecule function and number are found in clinical disorders in which inflammation and immune cells are involved. Several possible therapeutic agents are described here which have been shown to reduce the expression and/or function of cell adhesion molecules. Anti-adhesion treatment can lead to diminished infiltration and activation of inflammatory immune cells resulting in decreased tissue injury and malfunction.

Animals↗
PubMed1998

Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma.

1. Since both histamine and 5-hydroxytryptamine (5-HT) can be released by murine mast cells, we investigated the possible role of these autacoids on airway hyperresponsiveness (AHR), eosinophil infiltration and serum-IgE levels in a murine model of allergic asthma. 2. Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml(-1)) or saline aerosols on 8 consecutive days. Starting one day before the challenge, animals were injected i.p. twice a day with a 5-HT-type 1 (5-HT1) or type 2 (5-HT2) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg(-1) and ketanserin, 12 mg kg(-1), respectively) or a histamine-type 1 (H1) or type 2 (H2) receptor antagonist (mepyramine, 12 or 20 mg kg(-1) and cimetidine, 10 or 25 mg kg(-1), respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an alpha-adrenoceptor antagonist (phentolamine, 5 mg kg(-1)). 3. In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was significantly (9 fold increase, P<0.01) increased when compared to vehicle-treated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a significant increase in both eosinophil numbers in bronchoalveolar lavage (BAL) fluid (0+/-0, vehicle/saline and 15.0+/-5.9 x 10(4) cells vehicle/ovalbumin, P<0.05) and ovalbumin-specific IgE levels in serum (157+/-69 and 617+/-171 units ml(-1), respectively, P<0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all different treatments. 4. Treatment with ketanserin or cimetidine resulted in a partial but significant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P<0.05) and reduced eosinophil infiltration after ovalbumin challenge by 60% and 58%, respectively. The combination of cimetidine and ketanserin almost completely abolished AHR whereas eosinophilia was decreased by 49%. No effects of these antagonists were observed on IL-16 levels in BAL fluid or on serum antigen-specific IgE levels. Treatment with either the H1-receptor, the 5-HT1-receptor or the alpha-adrenoceptor antagonist, did not decrease the observed ovalbumin-induced airway responsiveness or eosinophilia in vehicle-treated animals. Higher doses of either methiotepine (2.0 mg kg(-1)) or mepyramine (20 mg kg(-1)) did decrease ovalbumin-induced eosinophil infiltration (by 67%, P<0.05 and 73%, respectively), whereas no effects of these antagonists were observed on ovalbumin-specific IgE levels in serum. 5. From these data it can be concluded that both histamine and 5-HT play a role in antigen-induced AHR and eosinophilia in the mouse.

Airway Resistance↗
PubMed1998

Role of the epithelial layer in the generation of superoxide anion by the guinea-pig isolated trachea.

The lucigenin-dependent chemiluminescence generation by guinea-pig isolated tracheal two rings preparations was studied. Tracheal preparations stimulated with phorbol myristate acetate (PMA) or opsonized zymosan generated chemiluminescence. The total amount of chemiluminescence generated in 120 min was 754+/-63 mV x min for PMA and 4832+/-396 mV x min for zymosan. Generation of chemiluminescence was decreased by more than 50% when the tissues were co-incubated with superoxide dismutase (100 U/ml). Also, addition of direct donors of nitric oxide diminished chemiluminescence generation by zymosan-activated tracheal rings significantly by about 50%. However, the presence of the precursor or of inhibitors of nitric oxide synthase did not influence zymosan-induced chemiluminescence. Removal of the epithelial layer from tracheal rings caused an approximately 90% decrease in chemiluminescence response. However, isolated epithelial cell suspensions did not generate chemiluminescence. Histologic examination showed that the number of eosinophils in the tracheal tissue was reduced from 56+/-7 to 18+/-8 per mm basal membrane when the epithelial layer was removed. These results indicated that (1) superoxide anion formation can take place in the guinea-pig trachea, (2) eosinophils in the epithelial and submucosal layers of guinea-pig trachea are likely candidates for superoxide generation although other cell types can also be involved, and (3) besides relaxing airway smooth muscle, nitric oxide donors may also affect superoxide in the airways.

Animals↗
PubMed1997

Peroxynitrite: a two-faced metabolite of nitric oxide.

The discovery that nitric oxide (NO) reacts with superoxide (O2.-) forming peroxynitrite (ONOO-) (1) and the proof that this reaction occurs in vivo (2,3) holds enormous implications for the understanding of free radicals in biological systems. Not only in mammalian defense mechanisms against microorganisms, but also in pathophysiology during overexposure of tissues to radicals or other highly reactive species. Peroxynitrite is a highly reactive compound with harmful effects on cells and could therefore be an important microbicidal compound. Furthermore, the reaction of superoxide with NO interferes with NO signalling mechanisms. NO is not only released in response to inflammatory agents by inflammatory cells, but is also an important messenger molecule in paracrine mechanisms and neurotransmission. Whether peroxynitrite formation is a negative side effect of NO and superoxide release, or a functional characteristic is yet to be determined, and will be discussed in this review.

Animals↗
PubMed1997

Characterization of muscarinic receptors in equine tracheal smooth muscle in vitro.

This study was undertaken to assess the importance of muscarinic receptor subtypes in equine airway disease. Smooth muscle strips from the mid-cervical portion of the trachea of horses were placed in tissue baths and isometric contractile force was measured. Active force was measured in response to metacholine and the selective muscarinic receptor agonists McN-A-343 (M1-selective) and pilocarpine (M2-selective) in cumulative concentrations (10(-9)M through 10(-3)M), with and without preincubation with three or four concentrations of the selective muscarinic receptor antagonists pirenzepine (M1-selective), methoctramine (M2-selective), and 4-DAMP (M3-selective). The tissues contracted in response to all muscarinic agonists. The maximum responses (mean +/- sem) were 86.7 +/- 6.2 g for metacholine, 27.1 +/- 2.5 g for McN-A-343 and 37.6 +/- 3.5 g for pilocarpine. Preincubation with the selective muscarinic receptor antagonists resulted in dose-dependent rightward shifts of the concentration-effect curves for metacholine. pA2 values (means +/- sem) were 8.88 +/- 0.30 for 4-DAMP, 6.53 +/- 0.38 for methoctramine, and 6.72 +/- 0.31 for pirenzepine. Preincubation with 10(-7) M 4-DAMP resulted in a rightward shift of the concentration-effect curves for McN-A-343 and pilocarpine. These results indicate that the most important muscarinic receptor mediating contraction of equine tracheal smooth muscle is of the M3-type. Therefore relatively low concentrations of a M3-selective muscarinic receptor antagonist will inhibit acetylcholine-induced contraction of equine airway smooth muscle.

Animals↗
PubMed1997

Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human bronchial epithelial cells.

Bronchial epithelial cells express the intercellular adhesion molecule-1 that mediates binding of activated neutrophils via interaction with Mac-1 and/or leukocyte function-associated antigen-1. In this study, we examined whether increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) affected neutrophil adhesion to the human bronchial epithelial cells. It was found that the N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophil adhesion was concentration dependently inhibited when the cAMP analogs dibutyryl adenosine 3',5'-cyclic monophosphate or 8-bromoadenosine 3',5'-cyclic monophosphate were present. The beta-adrenergic receptor agonists isoprenaline and salmeterol, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), were also able to inhibit the fMLP-stimulated adhesion of neutrophils to bronchial epithelial cells. These agonists in combination with IBMX significantly increased the intracellular cAMP level in both neutrophils and epithelial cells. Preincubation of neutrophils with the long-acting beta2-adrenergic receptor agonist salmeterol (in the presence of IBMX) inhibited their fMLP-stimulated adhesion to epithelial cells, whereas pretreatment of epithelial cells did not influence the adhesion process. When ethanol-fixed epithelium was used, salmeterol pretreatment also diminished the adhesion of stimulated neutrophils. Moreover, combinations of salmeterol or isoprenaline with IBMX inhibited fMLP-upregulated Mac-1 expression. Therefore, we conclude from these data that elevation of intracellular cAMP in the neutrophil inhibits stimulated neutrophil adhesion to bronchial epithelial cells via Mac-1.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Induction of guinea pig airway hyperresponsiveness by inactivation of guanylate cyclase.

To examine the role of cyclic 3', 5'-guanosine monophosphate (cGMP) in airway responsiveness the effects of substances known to interfere with nitric oxide (NO) or cGMP were investigated on guinea pig airways. Using a perfused organ bath system, it was possible to apply the chemicals from either the serosal or the mucosal side independently. In addition, levels of intracellular cGMP were determined in tissues after various treatments. Sodium nitroprusside (a donor of NO), zaprinast (a specific inhibitor of cGMP phosphodiesterase) and 8-bromo-cGMP (8-Br-cGMP) caused a concentration-dependent relaxation of guinea pig trachea. These results indicate that cGMP is an important second messenger mediating tracheal relaxations. The above mentioned drugs caused a more profound relaxation when applied to the serosal side compared to the mucosal side, suggesting a barrier function of the epithelial layer. Incubation on the mucosal side of the tissues with 100 microM pyrogallol (a generator of superoxide that may inactivate NO) increased the contractile response to histamine at concentrations 0.3-3.2 microM (P < 0.05). Treatment of the preparations with 1 mM cystamine (an inactivator of guanylate cyclase) caused a 5-fold increase in the sensitivity to histamine (P < 0.05), indicating the involvement of the NO/cGMP pathway in the development of airway hyperresponsiveness. Incubation of the tissues with 100 microM histamine elevated the intracellular cGMP levels 10-fold; this effect was completely prevented by incubation of the tissues with methylene blue (a potent inactivator of guanylate cyclase). Mucosal incubation of the tracheal tubes with 10 microM methylene blue induced an 8-fold increase in sensitivity to histamine (P < 0.01) and the Emax was slightly increased. 25 min after instillation of 0.4 mumol methylene blue into the airways of anaesthetized guinea pigs, the lung resistance in response to histamine was elevated up to 395 +/- 82% (P < 0.001). The present study revealed that inactivation of NO or guanylate cyclase enhances the histamine-induced contractions of guinea pig tracheas. Therefore, it is suggested that the NO/cGMP pathway may be implicated in the pathogenesis of airway hyperresponsiveness and that drugs which enhance cGMP levels in airway smooth muscle may be of significance in the treatment of airway obstruction and enhanced reactivity.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Preferential formation of 13-hydroxylinoleic acid by human peripheral blood eosinophils.

Lipid mediators released by inflammatory and immune cells play an important role in inflammatory and immune processes. Most attention has been focussed on arachidonic-derived mediators, including prostaglandins, thromboxanes, leukotrienes, and lipoxins. Literature data, however, suggest that also metabolites of the unsaturated fatty acid linoleic acid may be important in this respect. We have studied the formation and release of 9-hydroxy- and 13-hydroxy-linoleic acid (9-HODE and 13-HODE) by enriched populations of human peripheral blood neutrophils, eosinophils, basophils, monocytes, and lymphocytes. We demonstrate that the eosinophil preferentially produces 13-HODE, whereas the other cell types produce equal amounts of 9-HODE and 13-HODE. The biological significance of these findings is discussed.

Arachidonic Acid↗
PubMed1996

Relaxation of guinea-pig trachea by sodium nitroprusside: cyclic GMP and nitric oxide not involved.

1. Sodium nitroprusside (SNP) completely relaxed the guinea-pig isolated, perfused trachea in a concentration-dependent manner. Although SNP was less potent by about 2 orders of magnitude, its maximal effect was 25% higher compared to isoprenaline. 2. SNP (3.2 microM) increased cyclic GMP levels by 300% and relaxed guinea-pig isolated, perfused trachea by 54%. The SNP-induced relaxations of the preparations were not affected by the guanylate cyclase inhibitor, methylene blue. Moreover, zaprinast, a cyclic GMP-specific phosphodiesterase inhibitor which was supposed to enhance SNP-induced relaxations, decreased the maximal relaxation by 22% (P < 0.001). 3. In contrast, 8Br-cyclic GMP (10 microM) increased the cyclic GMP levels by 1100% without inducing a marked relaxation. 4. SNP (10 microM) and S-nitroso-N-acetylpenicillamine (SNAP; a direct donor of nitric oxide; 10 microM), relaxed the tissues by 75% and 25%, respectively, without any nitric oxide (NO) release by SNP (< 1 pmol 100 microliters-1), but a substantial NO release by SNAP (560 pmol 100 microliters-1). 5. It is concluded that the SNP-induced tracheal relaxations are probably not mediated by cyclic GMP and NO.

Animals↗