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At least 883 records · Page 49Linked to original sources
PubMed1980

Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources.

Slow reacting substance(s) of anaphylaxis (SRS-A) was isolated from both human (lung) and rat sources and compared with three synthetic SRS-As of known structure-leukotrienes (LTs) C-1, C-2, and D. Reversed-phase liquid chromatography was used both as a final purification step and a means of comparison of biologically derived and synthetic substances. Two major peaks of SRS-A activity of both rat and human origin corresponded chromatographically with LTC-1 and LTD, respectively, and had equivalent specific activities on the guinea pig ileum. With guinea pig ileum, the specific activities (units/pmol) for synthetic leukotrienes and anaphylactic peaks were (mean +/- SEM): synthetic LTC-1, 1.93 +/- 0.13; SRS-A(rat) peak I, 1.69 +/- 0.43; synthetic LTD, 6.10 +/- 1.15; SRS-A(rat) peak II, 7.14 +/- 0.51; and SRS-A(hu) peak II, 1.90. Both synthetic LTC-1 and LTD and their SRS-A natural counterparts had a preferential contractile activity on guinea pig peripheral airway compared to central airways and were at least 200 times more active than histamine on peripheral airways on a molar basis. Leukotriene D is the major SRS-A of human lung and accounts for almost all of the biological activity. It likely is formed from leukotriene C-1 in vivo by an enzymic process of the well-known gamma-glutamyltransferase type.

Animals↗
PubMed1981

Formation of 11-trans slow reacting substances.

Under strongly basic conditions [excess LiOH, dimethoxyethane/water (4:1, vol/vol)], purified slow reacting substances (SRSs) SRS-GSH and SRS-Cys were not isomerized to their corresponding 11-trans isomers. However, addition of thiols such as glutathione (GSH) or L-cysteine to this basic medium produced various amounts of 11-trans-SRS, depending on the thiol concentration. This chemical isomerization was inhibited by the radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidinooxy free radical (HTMP); the inhibition suggests that the thiyl radical (RS) is added reversibly to the triene system at C-12, resulting in the overall cis leads to trans isomerization of the 11,12 double bond. Because the amount of 11-trans-SRS-Cys produced by intact rat basophilic leukemia (RBL-1) cells was consistently higher than the amount produced in boiled cells, we believe that intact RBL-1 cells contain enzyme systems that form peroxides, which are known to enhance the formation of thiyl radicals, required for cis leads to trans isomerization. Likewise, HTMP inhibited the formation of 11-trans-SRS-Cys in this cell system.

Animals↗
PubMed1982

Generation of leukotriene C4 from a subclass of mast cells differentiated in vitro from mouse bone marrow.

Bone marrow-derived mast cells, differentiated in vitro, demonstrate surface IgE, receptors and contain histamine in metachromatic granules, which are composed of chondroitin sulfate E proteoglycan rather than heparin proteoglycan. Activation of this subclass of mast cells with calcium ionophore A23187 resulted in generation of immunoreactive C-6-sulfidopeptide leukotriene in a dose- and time-dependent fashion. Isolation of immunoreactive C-6-sulfldopeptide leukotriene by reverse-phase high-performance liquid chromatography (RP-HPLC) revealed a retention time and a specific biologic activity identical to those of synthetic leukotriene C4 (LTC4). Neither radiolabeled nor immunoreactive conversion products of [3H]LTC4/LTC4 were recognized during RP-HPLC resolution of the supernatants. The failure of fresh bone marrow cultures to generate C-6-sulfidopeptide leukotriene in response to ionophore indicates that leukotriene generation is dependent upon cellular differentiation into a mast cell population. The amount of LTC4 generated during optimal ionophore stimulation, 90.9 +/- 7.5 ng per 10(6) cells, contrasts with the relatively low amounts of C-6-sulfidopeptide leukotriene generated by the conventional heparin-containing rat mast cells or mouse mastocytoma cells.

Animals↗
PubMed1968

Antigen-induced release of slow reacting substance of anaphylaxis (SRS-A rat) in rats prepared with homologous antibody.

The polymorphonuclear leukocyte appears to be an essential cellular prerequisite for the antigen-induced release of SRS-A(rat) in the peritoneal cavity of rats prepared with homologous, hyperimmune antisera. Depletion of PMN leukocytes is associated with a marked suppression of SRS-A(rat) release, whereas depletion of circulating lymphocytes or peritoneal mast cells does not influence the antigen-induced release of SRS-A(rat). A local increase in the number of PMN leukocytes produced by the induction of a peritoneal exudate was associated with an enhanced release of SRS-A(rat). A distinct difference in the cellular requirements for the antigen-induced release of histamine and SRS-A(rat) in the rat was observed. Homocytotropic antibody-mediated histamine release could be achieved in leukopenic rats but not in mast cell-depleted animals. Conversely, SRS-A(rat) release was suppressed in leukopenic rats but was unaffected by mast cell depletion. Diethylcarbamazine inhibited the antigen-induced release of SRS-A(rat) following preparation with homologous, hyperimmune antisera but did not interfere with homocytotropic antibody-mediated histamine release. In preventing SRS-A(rat) release, diethylcarbamazine did not interfere with antigen-antibody interaction since desensitization of tissues was possible in the presence of this inhibitor. This observation is consistent with the view that diethylcarbamazine inhibits the reaction sequence leading to the formation and release of SRS-A(rat) at some step subsequent to antigen-antibody interaction. These studies support the view that the immunologic pathways leading to the release of SRS-A(rat) and histamine in the rat are distinctly different in terms of the immunoglobulins involved, the cellular prerequisites, and the effective pharmacologic inhibitors.

Animals↗
PubMed1972

Immunological release of histamine and slow reacting substance of anaphylaxis from human lung.

The immunologic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from human lung tissue can be enhanced by stimulation with either alpha adrenergic agents (phenylephrine or norepinephrine in the presence of propranolol) or cholinergic agents (acetylcholine or Carbachol). The finding that atropine prevents cholinergic but not comparable alpha adrenergic enhancement is consistent with the view that cholinergic and alpha adrenergic agonists interact with separate receptor sites on the target cells involved in the immunologic release of chemical mediators. The consistent qualitative relationship between the antigen-induced release of mediators and the level of cyclic adenosine monophosphate (cyclic AMP) as measured by the isolation of (14)C-labeled cyclic AMP after incorporation of adenine-(14)C into the tissues or by the cyclic AMP binding protein assay suggests that changes in the level of this cyclic nucleotide mediate adrenergic modulation of the release of histamine and SRS-A. The addition of 8-bromo-cyclic guanosine monophosphate (cyclic GMP) produces an enhancement of the immunologic release of mediators while dibutyryl cyclic AMP is inhibitory. As cholinergic-induced enhancement was not associated with a measurable change in the levels of cyclic AMP, the possibility is suggested that cyclic GMP may be the intracellular mediator of cholinergic-induced enhancement of the immunologic release of histamine and SRS-A.

Acetylcholine↗
PubMed1980

Dynamics of leukotriene C production by macrophages.

A method for the radiochemical assay of LTC production by mouse peritoneal macrophages in vitro is presented. The method involves labeling macrophages in culture with [5,6,8,9,11,12,14,15-3H]20:4 followed by stimulation of arachidonic acid (20:4) release under the experimental conditions desired. Radiolabeled leukotriene C (LTC) is recovered from the culture medium by extraction and silicic acid chromatography in 40% yield with full retention of biological activity. Because this LTC is radiochemically pure, the quantity of LTC release may be estimated from the amount of radioactivity in the sample. Use of the radioassay to study parameters affecting LTC synthesis by macrophages indicated that the time course of LTC synthesis and its relationship to the dose of a phagocytic stimulus (zymosan) were very similar to those of prostaglandin (PG) release. LTC release was also similar to that of PG in that lower levels of both metabolites were produced by Corynebacterium parvum-elicited macrophages than by resident cells. Finally, LTC release was stimulated in response to a challenge with antigen-antibody complexes, but lower maximal levels were attained than those with zymosan. The data presented here are consistent with the hypothesis that challenge of macrophages with a phagocytic stimulus leads to the release of 20:4 by an inducible phospholipase. Cyclooxygenase and lipoxygenase then compete for the released 20:4, leading to the production of PG, hydroxyeicosatetraenoic acids, and LTC.

Animals↗
PubMed1982

Leukotriene generation by eosinophils.

Horse eosinophils purified to greater than 98% generated slow reacting substance (SRS) when incubated with the calcium ionophore A23187. On a per cell basis, eosinophils generated four to five times the SRS produced by similarly treated horse neutrophils. Eosinophil SRS production was inhibited by 5,8,11,14-eicosatetraynoic acid and augmented by indomethacin and arachidonic acid, suggesting that it was a product(s) of the lipoxygenase pathway of arachidonic acid metabolism. Compounds with SRS activity were purified by high-pressure liquid chromatography (HPLC) and identified by ultraviolet spectra, spectral shift on treatment with lipoxygenase, incorporation of [14C]arachidonic acid, gas chromatography-mass spectrometry, and comparison of retention times on HPLC to authentic standards. The eosinophil products characterized were 5-(S), 12-(R)-dihydroxy-6-cis-8, 10-trans-14-cis-eicosatetraenoic acid (leukotriene B4) and its 5-(S), 12-(R)-6-trans and 5-(S), 12-(S)-6-trans isomers, 5-(S)-hydroxy-6-(R)-S-glutathionyl-7,9-trans-11, 14-cis-eicosatetraenoic acid (leukotriene C4) and its 11-trans isomer, and 5-(S)-hydroxy-6-(R)-S-cysteinylglycine-7,9-trans-11,14-cis-eicosatetraenoic acid (leukotriene D4).

Animals↗
PubMed1979

Capillary filtration coefficient: the technique and its application to the small intestine.

In this review, we discuss the physiological basis of the capillary filtration coefficient (Kf,c), and its measurement in the small intestine. First the various techniques by which Kf,c can be measured are discussed and assessed; the second part of the review considers the volumetric method of determining Kf,c in more detail, in an attempt to identify the causes of variability in published values for intestinal Kf,c. Finally, we discuss changes in intestinal Kf,c due to sympathetic nerve stimulation and the administration of drugs and hormones. The majority of estimates of intestinal Kf,c are about 0.38 to 0.60 (innervated) to 0.60 to 0.75 (denervated) cm3 . min-1 . kPa-1 . 100g-1. These values are increased by most vasodilator drugs and hormones, and decreased by sympathetic nerve stimulation and by vasoconstrictor drugs.

Adenosine↗
PubMed1983

A comparison of platelet count and acute phase proteins in the measurement of disease activity in rheumatoid arthritis.

Platelet count (PC) was compared with standard acute phase reactants (ESR, plasma viscosity and C-reactive protein) and clinical measurements to assess its usefulness as a measure of disease activity in 165 patients with active rheumatoid arthritis. Although PC was elevated (greater than 400 X 10(9) 1(-1) in 45% of patients and was seen to fall under the influence of second-line drugs, it was considered to be unsuitable as an indication of disease activity since levels fall for reasons other than disease improvement.

Anti-Inflammatory Agents↗
PubMed1990

Effect of leukotriene inhibitor LY-171883 on the pulmonary response to Escherichia coli endotoxemia.

The effect of the leukotriene D4 (LTD4) receptor antagonist, LY-171883, on the respiratory and cardiovascular changes in endotoxemia was studied in 20 unanesthetized sheep. In group 1 (n = 2), 4 mg/kg LY-171883 was injected iv. In group 2 (n = 12), Escherichia coli endotoxin (1 micrograms/kg) was infused iv, and in group 3 (n = 6), 4 mg/kg LY-171883 was administered 15 min before and 30 min after the same dose of endotoxin. Infusion of LY-171883 in group 1 did not alter baseline ventilatory and cardiovascular measurements. A two-phase pulmonary response was observed in group 2: an early pulmonary hypertension phase in which pulmonary artery pressure (PAP) increased from 18.7 to 51.2 mm Hg (p less than .001), with a fall in cardiac index (CI) from 171 to 114 ml/min.kg (p less than .01). The ratio of peak inspiratory/expiratory flow rate (PIF/PEF) increased from 1.08 to 1.35 (p less than .01) and the respiratory rate from 50 to 70 breath/min (p less than .005) 30 min postendotoxin. The flow rate measured at midexpiration time (V50) decreased from 81% to 25% of its peak expiration (p less than .001) and the airway resistance increased from 3.8 to 32.7 cm H2O/L.sec (p less than .001). The second permeability phase was characterized by an increase in pulmonary lymph flow (QL) from 8.5 to 35.2 ml/h (p less than .01), a decrease in PaO2 from 76 to 61 torr (p less than .01), and an increase in pulmonary shunt ratio (Qsp/Qt) from 16% to 31% (p less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Endothelial adrenoceptors.

alpha2 -Adrenergic agonists cause endothelium-dependent relaxation in a number of isolated blood vessels. This effect is explained by the activation of endothelial alpha 2 -adrenoceptors linked to nitric oxide synthase by G i -coupling proteins. The endothelial response to alpha 2 -adrenergic agonists is blunted considerably after regeneration of the endothelium and in atherosclerotic arteries. The relaxation of isolated arteries caused by beta-adrenergic agonists is reduced by removal of the endothelium and, in most cases, by inhibitors of the l -arginine nitric oxide pathway. Likewise, in the intact animal and in the human forearm the vasodilatation to beta 2 -adrenergic agonists is blunted by inhibitors of nitric oxide synthase. Whether these findings reflect the presence of functional beta-adrenoceptors on the endothelium remains controversial. Several beta-adrenergic blockers cause endothelium-dependent relaxation in vitro or augment the production of nitric oxide in vivo. However, these responses cannot be attributed to interactions with endothelial beta-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1983

Biochemical modulation of angiogenesis in the chorioallantoic membrane of the chick embryo.

A variety of substances potentially having effects on angiogenesis in the skin were assayed on the chorioallantoic membrane of the chicken embryo (CAM). Millipore filter discs alone and saturated with saline 0.9% (controls), keratinocyte-conditioned medium, lactic acid 10(-1) M, adenosine 10(-4) M, sodium fluoride 10(-4) M, dinitrophenol 10(-4) M, histamine 10(-4) M, 5-hydroxytryptamine 10(-4) M, acetylcholine 10(-4) M, prostaglandin E2 3 X 10(-4) M, prostaglandin F2 alpha 3 X 10(-4) M, arachidonic acid 10(-4) M, epidermal growth factor 5 X 10(-5) g/ml, human plasma fibronectin 10(-4) g/ml, acetylsalicylic acid 10(-3) M, and arachis oil were applied to the CAM and the vascular responses quantitated 4 days later. None of the agents with the exception of keratinocyte-conditioned medium stimulated new vessel growth as compared to the controls. However, arachis oil (p less than 0.001) and ADP (p less than 0.01) were associated with significantly decreased vascular responses relative to controls. The specimens incubated with saline, fibronectin, ADP, and arachis oil were examined histologically; with the exception of arachis oil all displayed ectodermal epithelial and mesenchymal hyperplasia of the membrane in association with increased vascularity. Almost no perceptible change was noted histologically with arachis oil.

Acetylcholine↗
PubMed1980

Basophil mediators and their release, with emphasis on BK-A.

During IgE-mediated events, basophils secrete small molecular weight mediators (histamine, slow reacting substance, Eosinophil chemotactic factor) which are thought to participate in inflammatory processes. We here describe the IgE-mediated secretion of large molecular weight mediators which have the potential for the activation of the Hageman factor dependent pathways, and the generation of biologically active peptides. These large molecular weight basophil derived mediators may, through the activation of the Hageman factor dependent pathways, influence mechanisms which participate in both acute and chronic cell-mediated inflammatory processes. We suggest that these proteases may participate not only as mediators of the immediate hypersensitivity reaction, but may also function in important aspects of the entire inflammatory response.

Autacoids↗
PubMed1992

Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms.

The upper and lower airways have complimentary roles in the ultimate object of supplying the body with oxygen whilst removing waste products of metabolism. Pathology in one area may trigger a response in another, the physiology of which, in the case of virus-induced asthma exacerbations remains poorly characterized. Viral infection of the upper airways by common cold viruses frequently triggers a response in the lower airways leading to prolonged morbidity, especially in subjects with significant pre-existing airway disease. The induction or amplification of BHR may be an important mechanism whereby asthmatic symptoms are produced although the cellular and tissue events or reflex mechanisms activated by viral illnesses and underlying BHR changes are poorly defined and may be dependent on the type and the severity of infection. Children and asthmatics tend to develop frequent colds setting in motion a sequence of events culminating in airway obstruction and symptoms of wheezing, coughing and chest tightness. This may reflect independent inflammatory changes caused by a simply additive effect of viral damage to the mucosa superimposed upon pre-existing allergic inflammation (Fig. 1). Few if any symptoms will develop in normal subjects with a mild cold whereas significant symptoms may ensue if the cold is severe and induces marked lower airway swelling, secretions and smooth muscle contraction; pathology to which children who have small calibre airways may be particularly susceptible. In asthmatics even a mild cold frequently induces exacerbation of symptoms, while serious life-threatening asthma attacks may occur associated with a severe cold. Some studies have suggested that this effect is not only additive but also synergistic and brought about by release of the mediators already present in increased quantities, the induction of IgE synthesis, or by the potentiation of neural and epithelial damage. The combined effect of both asthma and viruses may thus be amplified and result in a sustained and refractory period of airway obstruction, severe symptoms and unstable asthma. As most hospital admissions for asthma occur over the winter months and soon after the start of the school terms [115], spread of viruses through the community to susceptible individuals may be the single most important cause of sustained exacerbations of asthma. Definition of the pathological and physiological mechanisms involved will lead to better understanding and may thus provide a basis for prevention and the development of effective forms of treatment for virus-induced asthma.

Airway Obstruction↗