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1.
Leukotriene B 4 (LTB 4) is a proinflammatory product of arachidonic acid metabolism that has teen implicated as a mediator in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB 4 elicits a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1 -benzopyran-2-carboxylic acid, a first-generation LTB 4 receptor antagonist inhibitedthe chemotactic actions of LTB 4 when coadministered into the dermal site and when given orally with ED 50 values of 340 ng and 1.7 mg/kg, respectively. The secondgeneration LTB 4 receptor antagonists SC-50605 7-[3-[2(cyclopropylmethyl)-3-methoxy-4-(4-thiazolyl)phenoxy] propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and SC-51146 7-[3-[2(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran2-propanoic acid inhibited LTB 4-induced chemotaxis when coadministered with ED 50 values of 70 ng and 32 ng, respectively, and when given intragastrically with ED 50 values of 0.10 and 0.09 mg/kg, respectively. SC-41930, SC-50605, and SC-51146 had oral durations of action of 5.5, 15, and 21 h, respectively. These potent, LTB 4 receptor antagonists may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, where LTB 4 is implicated as an inflammatory mediator. 相似文献
2.
Leukotriene B 4 (LTB 4) and 12( R)-hydroxyeicosatetraenoic acid [12( R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB 4 and 12( R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB 4 receptor antagonist, inhibited the chemotactic actions of LTB 4 when given orally with an ED 50 value of 1.7 mg/kg. The second-generation LTB 4 receptor antagonist, SC-53228 [(+)-( S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy} propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], inhibited LTB 4-induced chemotaxis when given intragastrically with an ED 50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12( R)-HETE-induced granulocyte chemotaxis with an oral ED 50 value of 5.8 mg/kg. When dosed orally over a range of 0.03–100 mg/kg, SC-53228 gave C
max plasma concentrations of 0.015–41.1 g/ml. SC-53228 inhibited LTB 4-primed membrane depolarization of human neutrophils with an IC 50 value of 34 nM. As a potent LTB 4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB 4 and/or 12( R)-HETE are implicated as inflammatory mediators. 相似文献
3.
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes ulcerative colitis and Crohn's disease. Leukotriene B 4 is thought to be a prominent proinflammatory mediator in these diseases, in that leukotriene B 4 levels are increased in the colonic mucosa of inflammatory bowel disease patients and there is increased polymorphonuclear leukocyte infiltration of these tissues. SC-53228 (+)-(S)-7-[3-[2(-cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid, a second generation LTB 4 receptor antagonist, was evaluated for therapeutic efficacy in a rodent model of acute colonic inflammation induced by short chain organic acids, as well as for effects on rodent liver. When given intracolonically to mice, SC-53228 inhibited neutrophil infiltration, assessed by myeloperoxidase (MPO) levels, with an ED 50 value of 9±1.2 mg/kg. When given by gavage, SC-53228 inhibited neutrophil influx in colitic mice with an ED 50 value of 30 mg/kg. These results were also confirmed histologically. Furthermore, high dose oral SC-53228 treatment had no effect on liver cytochrome P-450 content, fatty acyl CoA oxidase or liver weight in rats and mice. Together, these data suggest that SC-53228 may be efficacious orally and locally, as well as safe for use in trials for the medical management of IBD. 相似文献
4.
Leukotriene B 4 (LTB 4) is a lipid mediator derived from arachidonic acid (AA) by the sequential action of 5-lipoxygenase (5-LOX), 5-lipoxygenase-activating protein (FLAP) and LTA 4 hydrolase (LTA 4H). It was initially recognized for its involvement in the recruitment of neutrophils and is one of the most potent chemotactic agents known to date. A large body of data has indicated that LTB 4 plays a significant role in many chronic inflammatory diseases, such as arthritis, chronic obstructive pulmonary disease (COPD), cardiovascular disease, cancer and more recently, metabolic disorder. In this review, we focus on the biosynthesis of LTB 4 and its biological effects. In particular, we will describe a basic biochemical understanding integrated with recent developments in the field of structural biology of the three key enzymes (5-LOX, FLAP and LTA 4H) in LTB 4 biosynthesis, and also summarize the most outstanding work on in vivo biological and pathogenic roles of these enzymes and the development of enzyme inhibitors. 相似文献
5.
Cotton-top tamarins (CTTs) with histologically confirmed persistent and active colitis were given the leukotriene B4 (LTB4) receptor antagonist, SC-41930, (10 mg/kg BW, by gavage b.i.d.) for eight weeks. Anti-inflammatory activity was evaluated by colonic biopsy, stool consistency and the level of the lipid mediators LTB4 and prostaglandin E2 (PGE2) in rectal dialysates. Stool consistency did not improve with treatment but did not worsen. Blood chemistry (ALT, AST, LDH) and hematological parameters neither showed any untoward effects of SC-41930 treatment nor was there any effect on body weight. In rectal dialysate LTB4 levels were significantly reduced from pretreatment level of 4.87±1.46 ng/ml to 1.07±0.67 and 2.45±0.13 ng/ml at 4 and 8 weeks, respectively, and higher prostaglandin E2 (PGE2) over time. Histologically, 5/7 improved, 1/7 remained the same and 1/7 worsened. Oral SC-41930 treatment was safe and associated with an anti-colitic effect. The reduced LTB4 levels (affecting granulocyte degranulation and recruitment into tissues) and increased PGE2 (perhaps exerting a mucosal protective effect) may, in part explain the observed efficacy of this compound in active tamarin colitis. Use of the CTT model could provide insight into the inflammatory mediator contribution to idiopathic colitis and serve as a useful bridge between preclinical pharmacology and the assessment of these compounds in the medical management of human inflammatory bowel disease. 相似文献
6.
5(S),12(R)-dihydroxy-6-cis-8,10 tran-14-cis-eicosatetraenoic acid (LTB 4) is a potent inflammatory mediator generated by human cells. A receptor assay using membranes from cultured HL-60 cells has been developed to quantitate LTB 4 with a range of sensitivity from 10 pg to 5 ng. The initial metabolite of LTB 4, 20-OH LTB 4, has a cross reactivity of 28% while other, lipoxygenase products do not significantly compete. This assay has been used to study ionomyocin-induced formation of LTB 4 by human neutrophils. The use of membranes from HL-60 cells for the measurement of LTB 4 provides a sensitive and highly selective alternative to radioimmunoassay for the determination of the levels of this important eicosanoid in biological fluids and should be useful in the development of antagonists of the LTB 4 receptor. 相似文献
7.
Summary Leukotriene B 4 (LTB 4) plays an important role in acute and chronic inflammatory and hypersensitive reactions. We studied the time course of LTB 4 biosynthesis in whole blood in 18 patients with end-stage renal failure maintained on regular hemodialysis with two different membranes, cuprophane and polyacrylonitrile (AN 69). The basal levels of LTB 4 from dialysis patients did not differ significantly from a normal control group. Compared to predialytic values, the cuprophane membrane caused a maximal release of LTB 4 by a factor of about 4.5 ( p<0.01) within the first 10 to 20 minutes. Thereafter the level fell and returned to baseline range at the end of the hemodialysis session. With the use of the AN 69 membrane no significant increase of LTB 4 could be demonstrated. The changes in LTB 4 concentration showed a close temporal correlation to the alterations in white blood cell count. We conclude that (1) LTB4 is a biologically important mediator of neutrophil activation during hemodialysis, and (2) LTB 4 may be a sensitive marker of biocompatibility in vivo.Abbreviations LTB 4
Leukotriene B 4
- 5-HETE
5-Hydroxyeicosatetraenoic acid 相似文献
8.
The aim of the present work was to study interactions between the synthesis of platelet-activating factor (PAF) and leukotriene B 4 (LTB 4) in human polymorphonuclear leukocytes (PMNs) in vitro. PAF, at nanomolar concentrations, stimulated calcium ionophore A23187-activated PMNs to release LTB 4 and 5-hydroxyeicosatetraenoic acid (5-HETE). This seems to be a receptor-mediated process as it was blocked by a PAF receptor antagonist WEB 2086 (IC 50 6.6±3.9 M). Moreover, LTB 4 stimulated the formation of PAF in activated PMNs. WEB 2086 did not, however, alter PMN migration towards either LTB 4 or the chemotactic peptide FMLP. This suggests that the enhancement of PAF synthesis in response to LTB 4 is a concomitant event rather than a mediating process in LTB 4-induced chemotactic movement of PMNs. These effects are implicated in the complex network of interactions between inflammatory mediators that results accumulation and activation of PMNs in the exacerbation of inflammatory processes. 相似文献
9.
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB 4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7–16 times more potent than SC-41930 in LTB 4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB 4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically. 相似文献
10.
The canine has become an accepted research model for the examination of a number of human clinical conditions. Despite it's status as a research model, little is known regarding the peripheral effects of inflammatory mediator substances. Products of arachidonic acid metabolism (leukotrienes) are reported capable of altering leukocyte functions. Because of the emerging importance of the canine research model and leukotrienes we examined the effects of leukotriene B 4 (LTB 4) on several in vitro functions of isolated canine peripheral polymorphonuclear leukocytes (PMN). Changes in forward angle light scatter properties of the cells were used as one measure of PMN activation. Other functional changes examined following LTB 4 pretreatment included chemotactic capability, the electrophysiological state of the cell plasma membrane, and the metabolic oxidative response (i. e. H 2O 2 production). Random cellular movement of PMNs increased by 120% and 72% following preincubation with 10 ?7 and 10 ?9 M LTB 4, respectively. LTB 4 between 10 ?7 and 10 ?13 M did not significantly alter cellular resting membrane potential. Between 10 ?7 and 10 ?9 M LTB 4 elicited significant levels of cellular H 2O 2 production. Although significant, H 2O 2 production was <40% that induced by phorbol myristate acetate (PMA). In numerous respects, canine in vitro PMN responses parallel previous reports of human cell function(s) in the presence of inflammatory mediators and may represent an attractive alternative for investigation of PMN dysfunctions. 相似文献
11.
Lipoxins are derived from the oxygenation products of arachidonic acid in human leukocytes. They have exhibited selective biological effects different from those of other eicosanoids. We have examined the effect of lipoxin A 4 and B 4 (LXA 4, LXB 4) on the production of leukotriene B 4 (LTB 4) in human neutrophils. Cultured human polymorphonuclear leukocytes were preincubated with LXA and B and their ability to inhibit LTB 4 generation was assessed after incubation with calcium ionophore A23187. We found that the pretreatment of neutrophils with lipoxins inhibit the release of LTB 4 by A23187 stimulated PMNs. Our data suggests that LXA 4 and B 4 can contribute to immunosuppression in an inflammatory state via the inhibition of LTB 4 synthesis. 相似文献
12.
Among arachidonic acid metabolites, leukotriene B 4 (LTB 4) plays an important role in inflammation, such as in the activation, adhesion, chemotaxis, and invasion of leukocytes. In this paper, we examined the effect of LTB 4 on endothelial cell injury induced by polymorphonuclear leukocytes (PMNLs). 51Crrelease, a marker of cellular injury, was elicited from prelabeled endothelial cells when the cells were cocultured with PMNLs activated by phorbol ester (TPA, 12- 0-tetradecanoyl-phorbol-13-acetate). Under this condition, pretreatment of PMNLs with LTB 4 enhanced their injury in a dose-dependent manner (0.2–2 M). However, LTB 4 alone at any dose could not induce any cellular injury. We also determined the amount of active oxygen species produced by PMNLs in response to TPA. The intensity of luminoldependent chemiluminescence, a marker of active oxygen production, in PMNLs was also increased by pretreatment with 1 M LTB 4. These data suggest that LTB 4 enhances endothelial cell injury by the priming effect on active oxygen production in activated PMNLs. 相似文献
13.
Leukotriene B 4 (LTB 4) was measured in synovial fluid from 20 patients with rheumatoid arthritis and 15 patients with osteoarthritis. The level of LTB 4 was significantly higher in synovial fluid from rheumatoid arthritis patients as compared with synovial fluid from osteoarthritis patients. LTB 4 levels also significantly correlated with cell numbers, rheumatoid factor, and immune complexes in synovial fluid from rheumatoid arthritis patients. There was an inverse correlation between LTB 4 levels and complement components. The high-pressure liquid chromatography peak of immunoreactivity extracted from the synovial fluid occurred at a retention volume identical to that of authentic LTB 4. These results suggest that the increased level of this mediator in synovial fluid may contribute to perpetuation of inflammation and tissue destruction in rheumatoid arthritis. 相似文献
14.
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a potent in vitro leukotriene-B 4 (LTB 4) receptor antagonist. LTB 4 levels are elevated in colonic tissue of inflammatory bowel disease (IBD) patients which may account for the high degree of neutrophil (PMN) infiltration. The guinea pig acetic acid-induced colonic inflammation model has characteristics of IBD including PMN infiltration, edema, ulceration and necrosis. The model was used to evaluate the effect of SC-41930. SC-41930 was given orally, 30 min before and after intrarectal administration of 3% acetic acid. The PMN marker enzyme, myeloperoxidase, was measured along with histological evaluation to assess inflammation. Both parameters showed significantly less inflammation in SC-41930 treated animals with an oral ED 50 of 20 mg/kg. These study results with an LTB 4 receptor antagonist indicate a role for LTB 4 in colonic inflammation and that an LTB 4 receptor antagonist may be beneficial for treatment of IBD. 相似文献
15.
We studied release of leukotriene B 4 (LTB 4) by human polymorphonuclear leukocytes (PMNs) during phagocytosis of staphylococci in the presence or absence of arachidonic acid. The 12×10 7 PMNs incubated with 3×10 9 opsonized S. aureus and 50 M arachidonic acid released 1.45±0.42 nmol LTB 4. No LTB 4 was detected after stimulation of PMNs with S. aureus or arachidonic acid by themselves. However, by increasing the concentration of arachidonic acid to 200 or 400 M, 1.22±0.45 and 1.98±0.49 nmol LTB 4, respectively, was released by PMNs. The effect of different bacteria-PMN ratios on LTB 4 production was also studied. LTB 4 varied from 0.3 to 2.0 nmol when bacteria/PMN ratios increased from 5 to 50 (respectively) in the presence of 50 M arachidonic acid. Thus, phagocytizing PMNs produce LTB 4 in the presence of arachidonic acid, and its production is dependent on the number of bacteria phagocytized. 相似文献
16.
Leukotriene B 4 (LTB 4), one of 5-lipoxygenase (5-LO) products of arachidonic acid, was reported to be more potent than leukotriene B 5 (LTB 5), one of 5-LO products of eicosapentaenoic acid, in the activation of neutrophil functions through the differential potency between these leukotrienes in calcium mobilization. So we compared the effect of LTB 4 and LTB 5 on the induction of interleukin 1 (IL-1)-like activity and calcium mobilization in human blood monocytes. LTB 4 significantly augmented IL-1-like activity in monocytes, however, LTB 5 had no significant effect. Also LTB 4 was apparently more potent than LTB 5 in inducing calcium mobilization in fura-2-loaded monocytes. IL-1 production in monocytes was reported to be partly dependent on cytosolic free calcium. These results, therefore, may indicate that the different activity between LTB 4 and LTB 5 in the enhancement of IL-1-like activity could be partly ascribed to the different potency in inducing calcium mobilization between LTB 4 and LTB 5 in human blood monocytes. 相似文献
17.
SM-15178, a new hydroxyacetophenone derivative, was evaluated to determine its antiinflammatory activity and antagonistic activity against leukotriene B 4 (LTB 4). SM-15178 inhibited [ 3H]LTB 4 binding to its receptors on human neutrophils (IC 50=0.30 M). It inhibited LTB 4-induced chemotaxis of human neutrophils (IC 50 =0.72 M) with little inhibitory effect against C5a or FMLP-induced chemotaxis at concentrations up to 30 M. The compound alone did not cause human neutrophil chemotaxis at concentrations up to 10 M. LTB 4-induced chemotaxis of mouse and rat neutrophils and guinea pig eosinophils was also inhibited by the compound, with IC 50 values of 0.55, 0.52, and 0.58 M, respectively. In an in vivo study, SM-15178, given orally, significantly prevented LTB 4-induced transient leukopenia. It also suppressed LTB 4-induced bronchoconstriction in the guinea pig almost completely when given orally at a dose of 40 mg/kg. Furthermore, orally given SM-15178 suppressed arachidonic acid-induced neutrophil infiltration in mouse ears and Arthus reaction-induced paw edema in the mouse in a dose-dependent manner. These results suggest that SM-15178 is a selective and orally active LTB 4 antagonist and that it might be effective for the treatment of some types of inflammatory diseases. 相似文献
18.
The present study was designed to compare peripheral blood neutrophil migration and leukotriene (LT) release between patients with rheumatoid arthritis (RA) and healthy controls and to correlate the neutrophil functions with clinical disease activity. Nineteen patients with moderately active RA and 19 age and sex matched healthy volunteers participated in this study. Isolated peripheral blood neutrophils from RA patients released equal amounts of LTB 4 but their random migration was enhanced as compared with neutrophils from healthy controls. LTB 4 release in whole blood was significantly lower in samples from RA patients than in those from the healthy volunteers (13.5±1.4 and 19.1±1.4 ng/10 6 neutrophils respectively; P<0.001). LTB 4 release from isolated RA neutrophils correlated with the levels of C-reactive protein, duration of morning stiffness and Ritchie articular swelling index. Concentrations of hyaluronate, cyclic AMP and 13,14-dihydro-15-keto-prostaglandin were not different between patients with RA and healthy volunteers. Neither was there any difference in TXB 2 production by platelets during blood clotting. In conclusion, peripheral blood neutrophils of RA patients seem to be primed and/or activated as their random migration is enhanced as compared with those of healthy volunteers. In RA, LTB 4 release from peripheral blood neutrophils seems to reflect the clinical activity of the disease. However, RA neutrophils released smaller (in whole blood) or equal (isolated cells) amounts of LTB 4 as compared with the respective controls. These contradictory findings suggest that LTB 4 release from peripheral blood neutrophils has no major role in the regulation of disease activity in rheumatoid arthritis. 相似文献
19.
Leukotriene induction of the fluid and cellular phases of the inflammatory response in the mouse was evaluated. Intraperitoneal injection of leukotriene C 4 (LTC 4 250 ng) led to dye extravasation but not polymorphonuclear leukocyte (PMN) infiltration, whereas injection of leukotriene B 4 (LTB 4 250 ng), led to PMN infiltration but not dye extravasation. The injection of both leukotrienes did not result in synergy. LTC 4 did not appear to induce significant release or formation of chemotactic mediators, but the dye extravasation induced by LTC 4 was inhibited by the vasoactive amine antagonist cyproheptadine and not by the eicosanoid inhibitors phenidone or naproxen. The response was markedly inhibited by the cytokine and eicosanoid inhibitors SK&F 86002 and SK&F 104493. PMN infiltration induced by LTB 4 was not inhibited by SK&F 86002 or phenidone but was abrogated by colchicine treatment. LTB 4 in this model did not appear to cause release or formation of vasoactive mediators. These leukotrienes appeared to be independent, complementary, and sufficient to mount a complete inflammatory response in the mouse. 相似文献
20.
The accepted model for the human demyelinating disease, multiple sclerosis (MS), is experimental allergic encephalomyelitis (EAE). We assessed the ability of SC-41930(7-[3(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxyl acid), to modulate the symptoms of acute EAE generated in guinea pigs. Animals were pretreated with SC-41930 (20 mg/kg, i.p.) for two days followed by thrice-weekly maintenance. At day 52, a significant number of the SC-41930-treated animals were alive as compared to EAE alone. Control animals had an increase in body weight while EAE animals lost over 20% ( p<0.5) of their body weight by day 18. SC-41930-treatment significantly reduced, but did not completely inhibit the cachectic response. The results indirectly implicate LTB 4 in the pathogenesis of EAE. Agents that modify this model be useful in the treatment of human MS. 相似文献
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