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At least 1,315 records · Page 73Linked to original sources
PubMed1994

Formation of biologically active autacoids is regulated by calcium influx in endothelial cells.

The blocker of receptor-mediated calcium entry SK&F 96365 was used to evaluate the contribution of calcium influx to the formation of biologically active endothelial prostanoids and endothelium-derived relaxing factor (EDRF). SK&F 96365 inhibited histamine-stimulated calcium entry into human umbilical vein endothelial cells but not its discharge from intracellular stores as determined spectrofluorometrically by changes of intracellular calcium concentration in fura-2-loaded cells. Concordantly, SK&F 96365 inhibited histamine-induced endothelial synthesis of 6-keto-prostaglandin F1 alpha and thromboxane B2 in a dose-dependent manner. To assess the functional significance of endothelial formation of prostacyclin and EDRF to platelets, the cAMP- and cGMP-dependent phosphorylation of two platelet proteins, rap1B and a 50-kD vasodilator-stimulated phosphoprotein (VASP), was analyzed in coincubation experiments of endothelial cells with platelets. Autacoids released by histamine-stimulated endothelial cells caused the phosphorylation of rap1B and VASP in platelets, which was only partly inhibited by either indomethacin or NG-monomethyl-L-arginine but was almost completely suppressed by SK&F 96365. The concomitant endothelial release of thromboxane A2 had no effect on protein kinase C- and calcium-dependent phosphorylation of platelet proteins. The results demonstrate that blockade of receptor-mediated calcium entry by SK&F 96365 markedly reduced the release of biologically active prostacyclin and EDRF from endothelial cells. Thus, calcium influx but not calcium release from intracellular stores plays a critical role in the receptor-stimulated formation and liberation of prostacyclin and EDRF in endothelial cells.

Animals↗
PubMed1987

Presynaptic and postsynaptic effects of histamine and histamine agonists in the superior cervical ganglion of the rat.

Extracellular and intracellular recording techniques were used to study the effects of histamine and the histamine agonists [impromidine (IMP) and 2-thiazolylethylamine (2-TH)] on synaptic transmission in the superior cervical ganglion of the rat in vitro. At the concentrations employed (up to 10(-5) M) these compounds did not produce detectable effects on the electrical properties of the postsynaptic neurons. Histamine produced a dose-dependent reduction in the amplitude of the extracellularly-recorded presynaptic and postsynaptic compound action potential. The H2 receptor agonist impromidine reduced only the postganglionic compound action potential. Cimetidine, a specific H2 receptor antagonist, produced parallel shifts in the log dose-response curves for impromidine. Impromidine also reduced the average size of the evoked excitatory postsynaptic potential. The reduction of the mean amplitude of the excitatory postsynaptic potential was due to a decrease in the amount of acetylcholine (ACh) liberated by each preganglionic volley (mean quantal content, m) and a diminution in quantal size. The H1 receptor agonist, 2-TH produced a dose-dependent increase in the presynaptic and postsynaptic compound action potential and in m. The increase in m was not associated with changes in quantal size. The H1 antagonists, pyrilamine and promethazine, did not prevent facilitation of ganglionic transmission induced by 2-TH. It is concluded that histamine H1 and H2 receptors exist on preganglionic axons, or terminals in sympathetic ganglia of the rat. Activation of H1 receptors facilitates release of ACh whereas H2 receptor activation results in depressed release.

Action Potentials↗
PubMed1993

Small reduction of capsaicin-induced neurogenic inflammation in human forearm skin by the glucocorticoid prednicarbate.

Capsaicin applied to human skin provokes a response known as neurogenic inflammation. Neuropeptides (substance P, CGRP), released from afferent C-fiber terminals and histamine, secondarily released from mast cells, are supposed to participate in this reaction. We investigated the contribution of arachidonic acid and metabolic products to neurogenic inflammation, using a potent topically applied glucocorticoid and the corresponding vehicle. Arachidonic acid is liberated from membrane phospholipids by phospholipase A2, an enzyme that can be blocked by glucocorticoids. In 12 healthy volunteers, neurogenic inflammation was induced by capsaicin 1% on both upper forearms after 16 h of topical pretreatment with either prednicarbate or vehicle. Neurogenic inflammation was assessed by laser Doppler flowmetry and by planimetry of flare sizes. Prednicarbate significantly reduced the laser Doppler flow values inside the flare responses, as well as the flare sizes themselves. These results show that to some extent glucocorticoids reduce capsaicin-induced neurogenic inflammation.

Administration, Topical↗
PubMed1981

Molecular mechanisms of inflammation.

Among a vast number of chemical mediators of inflammation such as histamine, 5-hydroxytryptamine, bradykinin, SRS-A the metabolites of arachidonic acid (AA) attracted vivid attention in the last ten years. Aspirin-like drugs are inhibitors of AA cyclo-oxygenation, while anti-inflammatory steroids inhibit the liberation of AA from phospholipids. These biochemical effects of steroidal and non-steroidal anti-inflammatory drugs lead to a suppression of generation of primary prostaglandins (e.g. PGE2) and therefore the curative action of these drugs has been explained in terms of depletion of pro-inflammatory prostaglandins. Recently, Samuelsson et al. described a new class of AA metabolites--leukotriens. Leukotrien C, which derives from 5-hydroperoxyeicosatetranoic acid and cysteine, is supposed to be SRS-A. The discovery of Samuelsson revived a known idea, that any biochemical transformation of AA (including the cyclo-oxygenase pathway) is initiated by its lipoxydation. Thus formed highly active hydroperoxy fatty acids and deriving oxygen-centred free radicals are important not only for a further biochemical transformation of AA, but also because of their biological action per se. In this respect Kuehl et al. proposed the most interesting idea that a true mediator of inflammation is PGG2 owing to the presence of 15-hydroperoxy group in its molecule, and its capability to generate either TXA2 or free hydroxy radical. It may well be that primary prostaglandins play a secondary role in inflammation, whereas unstable metabolites of AA are the real mediators of inflammation, owing to generation of either destructive free radicals or non-prostaglandin pro-inflammatory mediators (e.g. thromboxane A2, leukotrien C, prostacyclin).

Arachidonic Acids↗
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↗
PubMed2001

Innate diversity of adult human arterial smooth muscle cells: cloning of distinct subtypes from the internal thoracic artery.

Vascular smooth muscle cells (SMCs) perform diverse functions and this functional heterogeneity could be based on differential recruitment of distinct SMC subsets. In humans, however, there is little support for such a paradigm, partly because isolation of pure human SMC subsets has proven difficult. We report the cloning of 12 SMC lines from a single fragment of human internal thoracic artery and the elucidation of 2 distinct cellular profiles. Epithelioid clones (n=9) were polygonal at confluence, 105+/-9 micrometer in length, and had a doubling time of 39+/-2 hours. Spindle-shaped clones (n=3) were larger (267+/-18 micrometer long, P<0.01) and grew slower (doubling time 65+/-4 hours, P<0.01). Both types of clones expressed smooth muscle (SM) alpha-actin, SM-myosin heavy chains, h-caldesmon, and calponin, but only spindle-shaped clones expressed metavinculin. Epithelioid clones displayed greater proliferation in response to platelet-derived growth factor-BB and fibroblast growth factor-2 and were more responsive to the migratory effect of platelet-derived growth factor-BB. Spindle-shaped clones showed more robust Ca(2+) transients in response to angiotensin II, histamine, and norepinephrine, crawled more quickly, and expressed more type I collagen. On serum withdrawal, spindle-shaped clones differentiated into a contraction-competent cell. A regional basis for diversity among SMCs was suggested by stepwise arterial digestion, which liberated small, SM alpha-actin-positive cells from the abluminal medial layers and larger SMCs from all layers. These results identify inherent SMC diversity in the media of the adult internal thoracic artery and suggest differential participation of SMC subsets in the regulation of human arterial behavior.

Actins↗
PubMed1991

Mast cell proteases liberate stable encephalitogenic fragments from intact myelin.

Protease-containing supernatants from activated rat mast cells were found to degrade purified rat myelin with a subsequent release of a stable encephalitogenic peptide. The two most abundant peptides were identified as residues 69-87 (GSLPQKSQRTQDENPVV) and residues 69-88 (GSLPQKSQRTQDENPVVH). While additional exposure to the mast cell supernatants removes the COOH terminal histamine from peptide 69-88 to yield peptide 69-87, additional proteolytic degradation of the 69-87 peptide was not detected. Immunization with this peptide emulsified in CFA caused the development of clinical experimental autoimmune encephalomyelitis (EAE) in Lewis rats. In addition this 69-87 sequence was found to activate resting encephalitogenic myelin basic protein-reactive T cell lines to adoptively transfer clinical EAE. The release of stable encephalitogenic peptides from the myelin sheath by mast cell proteases may play a role in activation of encephalitogen-specific T cells during the progression of EAE.

Amino Acid Sequence↗
PubMed1992

Elevation of tissue kallikrein and kinin in the airways of asthmatic subjects after endobronchial allergen challenge.

Bronchial tissue kallikrein is the major kininogenase activity in the airways of asthmatic subjects. The relationship of IgE-mediated events to its release and/or activation is unknown, however, and is the subject of this report. Seven subjects with mild atopic asthma underwent endobronchial challenge with relevant aeroallergen. Baseline pre-allergen lavage and sequential post-challenge lavages were collected over an approximate 10-minute time course. Individual aliquots were analyzed separately and compared with saline control lavages performed in a separate lobe. In five of the seven subjects, an increase in tissue kallikrein activity, measured by cleavage of the synthetic substrate Val-Leu-Arg-pNA, was identified in the post-challenge lavages. The antigenic identity of the enzymatic activity was confirmed as a tissue kallikrein in each case by immunoblotting. Tissue kallikrein activity was highly correlated with the appearance of immunoreactive histamine and kinin (p = 0.0001). High molecular weight kininogen influx and cleavage was detected in the post-challenge samples by immunoblotting and paralleled the detection of kinin in BAL fluid. Two of the subjects, despite clinical profiles similar to those of the five positive responders, failed to react to endobronchial challenge. Saline control lavages contained detectable kallikrein, kinin, and histamine in two subjects; in each case, however, this was significantly less than in the post-allergen samples. The results demonstrate a close association between immediate type hypersensitivity events in the lower airway and the appearance of active kallikrein, kininogen substrate, and the liberation of kinin.

Adult↗
PubMed2000

Prostaglandin E2 induces expression of P-selectin (CD62P) on cultured human umbilical vein endothelial cells and enhances endothelial binding of CD4-T-cells.

Interaction of endothelial P-selectin with sialyl Lewis(x)-glycoprotein or P-selectin glycoprotein ligand (PSGL)-1 on leukocytes represents an early step in leukocyte recruitment. Redistribution of P-selectin to the endothelial cell surface occurs rapidly after challenge with several proinflammatory agents, for example, histamine, leucopterins, or lipopolysaccharide. We present evidence that prostaglandin E2 (PGE2) is an efficient inductor of surface P-selectin on cultured human umbilical vein endothelial cells (HUVEC). The increase in P-selectin-immunoreactivity coincided with redistribution of cytoplasmic P-selectin-reactive granulae to the endothelial cell surface, as visualized by confocal laser microscopic examination. CD4-T-cell adhesion to PGE2-stimulated HUVEC was also enhanced by a factor of 4, and blocking mAb directed against the binding site of P-selectin almost completely abrogated this increase in CD4-T-cell adhesion. In summary, our findings show that liberation of PGE2 is an important inductor of P-selectin surface expression on endothelial cells, resulting in enhanced recruitment of inflammatory cells.

CD4-Positive T-Lymphocytes↗
PubMed1986

The release of a neutrophil chemotactic factor from peritoneal macrophages by endotoxin: inhibition by glucocorticoids.

Glucocorticoids inhibit the migration of neutrophils induced by endotoxin (E. coli lipopolysaccharide, LPS) in vivo. Macrophage monolayers stimulated by LPS showed a dose-dependent release into the supernatant of a chemotactic factor for neutrophils, MNCF, which was active in vivo and in vitro. Dexamethasone reduced the neutrophil migration into the abdominal cavities of rats that was induced by LPS, but did not affect the migration induced by MNCF. The release of MNCF by LPS-pretreated macrophage monolayers was inhibited by dexamethasone and hydrocortisone but not by indomethacin and BW755C. MNCF was stable at 56 degrees C and did not release histamine from mast cells. Thus, MNCF activity seems not to be due to arachidonic acid metabolites or C5/C5a. MNCF shares some properties with interleukin-I, such as the blockade of its release by glucocorticoids, the association of its activity with a material of a molecular weight greater than 10 000 Daltons and the abolition of its activity by incubation with phenylglyoxal. However MNCF liberation was not blocked by cycloheximide and the time course of its release by macrophage monolayers stimulated by LPS differed from that described for interleukin-1. In addition human interleukin-1 when tested in dexamethasone-treated test rats failed to induce neutrophil migration. It is suggested that inhibition by glucocorticoids of LPS-induced neutrophil migration in vivo is not due to a direct effect upon the migrating cells but rather to an indirect one, i.e. through blockade of MNCF release by macrophages.

Animals↗
PubMed1998

Secretory IgA induces degranulation of IL-3-primed basophils.

We examined whether secretory IgA (sIgA), known to mediate eosinophil stimulation, has an effect on basophil functions. An immobilized preparation of sIgA, but not of monomeric IgA, induced histamine release (approximately 15% of total histamine contents) from human basophils in vitro. sIgA-induced basophil histamine release was totally dependent on pretreatment with IL-3. IL-5 and granulocyte-macrophage CSF also primed basophils for sIgA-mediated release. Exogenous divalent ions, i.e., Ca2+ and Mg2+, were essential for sIgA-mediated basophil degranulation, and the degranulation was completed within 45 min. A newly synthesized lipid mediator, leukotriene C4, was also liberated from IL-3-primed, sIgA-stimulated basophils. Enzyme digestion experiments revealed that the (Fc)2 x secretory component portion of sIgA is important for sIgA-mediated basophil activation, but the functional binding sites of sIgA on basophils were surmised to be different from FcalphaR. These observations reveal the novel finding that sIgA is able to stimulate basophils as well as eosinophils. Since sIgA is the most abundant Ig isotype in the secretions from mucosal tissues, and basophils are active participants in allergic late-phase reactions, sIgA-mediated basophil mediator release is potentially involved in exacerbation of the inflammation associated with allergic disorders.

Basophils↗
PubMed1994

On the natural history of peptic ulcer.

BACKGROUND: Three out of 1000 individuals have peptic ulcer every year, and 20% of the ulcer episodes are associated with bleeding. Whether major innovations such as endoscopy and strong acid-suppressing drugs have had any impact on the natural course of peptic ulcer disease is largely unknown. METHODS: Three hundred and fifty-one patients (median age, 63 years) with endoscopically proven peptic ulcer during 1979-1984 were included in the study and retrospectively followed up via medical records. The total population is based on two different groups of patients, the first comprising 229 consecutively diagnosed ulcer patients during 1979-81 and, to increase the number of bleeders, a second group including 122 bleeding ulcer patients consecutively diagnosed during 1981-84. At the end of the follow-up period all non-ulcer-operated patients were asked to answer a questionnaire on symptoms, investigations, and medication. RESULTS: The male to female ratio was 2.4:1 in duodenal ulcer patients, but a 1:1 ratio was shown both in gastric and prepyloric/pyloric ulcer patients (p < 0.001). Patients with bleeding ulcers were significantly older than non-bleeders (68 years versus 58 years; p < 0001), as were patients with gastric ulcers compared with prepyloric/pyloric or duodenal ulcer patients (68 years versus 63 and 61 years, respectively; p < 0.01). The 10-year cumulative mortality in the unselected group (median age, 62 years) was 43%, and the annual risk of dying of peptic ulcer disease was 0.6%. No difference in 10-year recurrence rate was seen between patients with bleeding ulcer at inclusion and non-bleeders (46.2% versus 44.3%; p = NS), but the annual risk of bleeding was 5.3% and 0.8%, respectively (p < 0.0001). In the group of patients answering the questionnaire 51% reported upper abdominal pain during the last year of follow-up. CONCLUSIONS: In spite of today's treatment regimens almost half of the patients with peptic ulcer disease experienced recurrence during a 10-year period, and more than half had ulcer symptoms after 10 years. Most probably, maintenance treatment with H2-receptor antagonists should have been offered more liberally during the 1980s.

Age Factors↗
PubMed1990

Reflex effects on gamma fusimotor neurones of chemically induced discharges in small-diameter muscle afferents in decerebrate cats.

The effects on fusimotor discharge rate of algesic agents (bradykinin, potassium chloride, histamine, 5-hydroxytryptamine) and lactic acid, applied by close arterial injection into triceps surae muscles, were investigated in decerebrate cats. Fusimotor discharge was recorded from filaments dissected free from otherwise intact nerves to the triceps muscles. The substances applied induced an increase in discharge rate of spontaneously active gamma fusimotor neurones as well as a recruitment of previously silent ones. Skeletomotor discharges and/or muscle tension changes occurred only occasionally. The increase in fusimotor discharge rate was not always completely abolished by severing the nerves to triceps. What remained was a short-lasting burst at the very onset of blood-pressure fall. It was concluded that the increase in fusimotor discharge rate was mainly, but not solely, elicited reflexly by discharges from Group III and/or IV muscle afferents sensitive to algesic agents. An elevated fusimotor activity might be expected to accompany muscle inflammation and/or trauma when these agents are liberated in muscle tissue. The increase in fusimotor discharge rate elicited by lactic acid injections indicates that the fusimotor system might also be involved in neural processes of muscular fatigue.

Action Potentials↗
PubMed1986

Prostaglandin interaction with histamine release and parietal cell activity in isolated gastric glands.

The effects of different prostanoids on parietal cell activity and glandular histamine (Hi) release were examined in isolated rabbit gastric glands. [14C]aminopyrine accumulation and glandular oxygen consumption were used as indices of parietal cell activity, and Hi was determined fluorophotometrically in the supernatant of the glandular suspensions. Both prostaglandins (PG) E2 and E1 dose dependently (10(-8) and 10(-6) M) increased the release of endogenous Hi. Carbacyclin was less effective and PGF2 alpha was almost without effect. Hi release induced by acetylcholine (Ach) and pentagastrin (Pg) was markedly potentiated in the presence of PGE2 (10(-8) to 10(-5) M). The Ach-induced sti ulation of Hi release was also potentiated by arachidonic acid (10(-5) M), an effect that was inhibitable by the cyclooxygenase inhibitor meclofenamate (3 X 10(-5) M). Somatostatin partially inhibited the response to Pg (3 X 10(-9) M) in combination with PGE2 (10(-5) M). Atropine (10(-5) M) strongly reduced the response elicited by Ach (3 X 10(-6) M) combined with PGE2 (10(-6) M). All prostanoids inhibited Hi (10(-4) M)-induced parietal cell activity in a dose-dependent manner (60-70%) but displayed different potency. The stimulatory response to Ach (3 X 10(-6) M) or Pg (3 X 10(-9) M) in combination with isobutylmethylxanthine (IBMX, 10(-5) M) was inhibited by PGE2 in a dose-dependent fashion. PGE2 (10(-6) M) was considerably more effective than cimetidine (10(-5) M) in inhibiting IBMX (10(-4) M)-stimulated oxygen consumption, and the remaining IBMX-PGE2 response (approximately 40%) was dose dependently (10(-8) to 10(-5) M) inhibited by cimetidine. Addition of Hi (10(-7) to 4 X 10(-7) M) or Pg (3 X 10(-10) to 3 X 10(-9) M) counteracted the PGE2 inhibition of the IBMX response. In addition, IBMX (10(-4) M) combined with PGE2 (10(-6) M) gave rise to a threefold increase in Hi release. These results suggest that prostaglandins have two opposing effects, i.e., liberation of endogenous Hi and inhibition of the action of Hi on the parietal cell.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Immunological aspects and inflammatory mechanisms of allergic reactions.

The tissue changes and symptoms that occur during an allergic reaction in the upper respiratory tract are due to inflammatory reactions. The authors give a survey of the different allergic reactions and discuss the different components of the IgE mediated hypersensitivity which is the most important type of hypersensitivity in the upper airways. The production of IgE, the immunoglobulin of the immediate hypersensitivity reaction, is modulated by T-cells through the activity of cytokines. Antigen presenting cells, including Langerhans cells, play an important role in the sensitisation phase. Mast cells and basophils degranulate as a result of a complex enzymatic pathway, in which phosphatidylinositol plays an important role. The mediators released by these cells include vasoactive substances, chemotactic agents and inflammatory proteases; these mediators and those liberated by secondary recruited cells, such as eosinophils and basophils will be responsible for the early and late symptoms.

Basophils↗
PubMed1991

Processing of proenkephalin in adrenal chromaffin cells.

The processing of proenkephalin was studied using [35S]methionine pulse-chase techniques in primary cultures of bovine adrenal medullary chromaffin cells. Following radiolabeling, proenkephalin-derived peptides were extracted from the cells and separated by reverse-phase HPLC. Fractions containing proenkephalin fragments were digested with trypsin and carboxypeptidase B to liberate Met-enkephalin sequences and subjected to a second HPLC step to demonstrate association of radiolabel with Met-enkephalin. Processing of proenkephalin is complete within 2 h of synthesis, suggesting completion at or soon after incorporation into storage vesicles. Pretreatment of the cells with nicotine, histamine, or vasoactive intestinal peptide to enhance the rate of proenkephalin synthesis failed to alter the time course of processing and had minimal effects on the distribution of products formed. Addition of tetrabenazine, an inhibitor of catecholamine uptake into chromaffin vesicles, during radiolabeling and a 6-h chase period caused enhanced proenkephalin processing. These results suggest that the full range of proenkephalin fragments normally found in the adrenal medulla (up to 23.3 kDa) represents final processing products of the tissue and that termination of processing may depend on the co-storage of catecholamines.

Animals↗