bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of monocyte and neutrophil function by recombinant IL‐2
Authors: Smith Susan E. , Warren Gayle D. , Thong Yee-Hing , McCormack Joe G.
Published: March 2007

Little IS known about the influence of IL‐2 on phagocytes. We now describe the effects of human recombinant IL‐2 on human neutrophil and monocyte functions related to mobility, phagocytosis, glucose uptake, respiration and degranulation. Neutrophil adherence and hexose monophosphate shunt activities were both suppressed after incubation with IL‐2. IL‐2 had no effect on neutrophil migration, phagocytosis, deoxyglucose uptake or degranulation, ionocytes demonstrated a greater sensitivity to IL‐2 with suppression of monocyte adherence, random and stimulated migration, glucose uptake and hexose monophosphate shunt activity, even after addition of phorbol myristate acetate. Monocyte phagocytosis and degranulation were not affected. All of the effects observed were dose‐dependent within a biologically active range for IL‐2. These studies suggest that IL‐2 may have an important down‐regulatory role across a broad range of monocyte functions including movement, deoxyglucose uptake and respiration. However, its role in regulation of neutrophil function is limited to adherence and respiration. IL‐2 may be a more versatile cytokine than has previously been appreciated.
Hepatic changes during a carrageenan induced granuloma in rats
Authors: Muntané J. , Fernandez Y. , Mitjavila S. , Mitjavila M. T.
Published: March 2007

Hepatic changes during inflammation were studied in rats bearing a carrageenan induced granuloma. In spite of a decrease in the metabolic capacity of microsomes to induce lipid peroxidation during inflammation, the endogenous lipid peroxidation remained unchanged and unrelated with the hepatic activities measured. The continuous increase in hepatic cAMP observed during acute and chronic phases could be related to adenylate cyclase stimulation by mediators, and could be an initial step in the hepatocyte adaptation leading to the increased level of hepatic caeruloplasmin, to the reduction of cytochrome P‐450 level and to the modifications of Ca2+ sequestration by microsomes.
The role of the neutrophil and formed elements of the blood in an in vitro model of reperfusion injury
Authors: Barrett John A. , Derian Claudia K. , Swillo Robert S. , Woltmann Richard F. , Perrone Mark H.
Published: March 2007

Using The globally ischaemic isolated guinea‐pig heart we conducted studies to assess the role of activated neutrophils (PMNs) and the role of the endothelium in reperfusion injury. Reperfusion injury was induced by a 20 min period of global ischaemia followed by a 30 min reperfusion with Krebs′ buffer supplemented with f‐Met–Leu–Phe (fMLP) and heparinized blood. Ischaemia alone or blood alone resulted in a complete recovery in contractile function measured by developed pressure, fMLP (500 μM) and blood, administered to normoxic hearts did not affect contractile function. The combination of 100 μM fMLP and blood beginning at reperfusion and continuing for 30 min decreased the recovery in contractile function (max. 33 ± 6% reovery) while buffer and 100 pM fMLP resulted in a complete recovery in function. In hearts infused with buffer and neutropenic blood incubated with 100 μM fMLP a complete recovery in function was observed. Isolated peritoneal neutrophils, 7–70 × 105 PMN/ min, incubated with 100 μM fMLP and Krebs′ solution decreased contractile function in a concentration‐related manner (max. 44 ± 11% recovery). Platelets, plasma or red blood cells alone incubated with fMLP did not decrease recovery in developed pressure. Platelets and PMN incubated with 100 μM fMLP did not, while red blood cells and PMN did, elicit a reduction in recovery in contractile function (34 ± 4% recovery). A 20 min period of global ischaemia destroys the functional integrity of the endothelium (response to Ach). Pre‐treatment of the heart with sufficient H2O2 to functionally damage the endothelium, followed by infusion of Krebs′ solution supplemented with blood and 100 μM fMLP also elicited a reduction in recovery of contractile function (42 ± 15% recovery). In summary, partially activated neutrophils play a major role in reperfusion injury and there exists a cooperativity between the RBC and PMN in this model.
Soluble interleukin‐2 receptors in ulcerative colitis
Authors: Nielsen O. H. , Brynskov J.
Published: March 2007

T‐Cell activation results in the release or shedding of a soluble form (45 kDa) of the cellular (55 kDa) low‐affinity interleukin‐2 receptor (α‐chain) (slL‐2R). The present study was performed to investigate if the serum concentration of sIL‐2R is a marker of disease activity in patients with ulcerative colitis (UC), a chronic inflammatory bowel disease. Twenty‐seven UC patients (about half of them in remission) and 13 healthy volunteers were studied, sIL‐2R concentrations were measured by an enzyme‐linked immunosorbent assay, and significantly elevated median sIL‐2R values were found in clinically active UC (150 pg/ml; range 100–420), compared to inactive UC (145 pg/ml; range 110–255), and healthy controls (110 pg/ml; range 80–165) (p < 0.01). There was no correlation between sIL‐2R concentrations and extent of the disease. Due to the overlap of serum sIL‐2R concentrations between different disease stages and controls, the general diagnostic value seems to be limited. However, since slL‐2R release is an IL‐2 dependent phenomenon, we conclude that the demonstration of increased serum sIL‐2R concentrations in UC suggests the existence of an enhanced T‐cell activation in vivo in this disease. Further longitudinal studies are required to elucidate if repeated measurements of sIL‐2R levels provide an additional way of monitoring UC disease activity in individual patients.
Hepatocyte growth factor stimulates neutrophil degranulation but not respiratory burst
Authors: Kowanko I. C. , Ferrante A. , Nakamura T.
Published: March 2007

Neutrophil function is regulated in part by cytokines with growth factor activities for different cell types. Hepatocyte growth factor (HGF) is a cytokine produced during injury to the liver and other organs. Neutrophils are numerous in such tissue injury sites and may be influenced by HGF. In the present study the effect of HGF on neutrophils was investigated. The data show that HGF at 1–10 ng/ml increased lysosomal enzyme release from both specific and azurophilic granules of cytochalasin‐B treated neutrophils. The release of specific granule contents in response to N‐formyl‐methionyl‐leucylphenylalanine was also increased by HGF. In contrast there were no significant effects of HGF on neutrophil respiratory burst, adherence or locomotion. It is concluded that HGF modulates neutrophil granule exocytosis.
Effect of PAF on polyrnorphonuclear leucocyte plasma membrane polarity: a fluorescence study
Authors: Kantar A. , Giorgi P. L. , Fiorini R.
Published: March 2007

The effect of PAF on the plasma membrane polarity of polymorphonuclear leukocytes (PMNs) was investigated by measuring the steady‐state fluorescence emission spectra of 2‐dimethylamino(6‐1auroyl) naphthalene (Laurdan), which is known to be incorporated at the hydrophobic‐hydrophilic interface of the bilayer, displaying spectral sensitivity to the polarity of its surrounding. Laurdan shows a marked steady‐state emission blue‐shift in non‐polar solvents, with respect to polar solvents. Our results demonstrate that PAF (10−7 M) induces a blue shift of the fluorescence emission spectra of Laurdan. These changes are blocked in the presence of the PAF antagonist, L‐659,989. Our data indicate that the interaction between PAF and PMNs is accompanied by a decrease in polarity in the hydrophobic‐hydrophilic interface of the plasma membrane.
Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin‐1 and tumour necrosis factor‐alpha
Authors: Seow W. Kim , Nakamura Kazuhiro , Sugimura Yukio , Sugimoto Yukihiro , Yamada Yasuyuki , Fairlie David P. , Thong Y.H.
Published: March 2007

Synthesis of IL‐1β and TNFα by human monocytesmacrophages was significantly inhibited by eleven bisbenzylisoquinolines and one half‐molecule (benzylisoquinoline), with IC50 values in the μM range. The results indicate that these compounds may have value in the therapy of human diseases where these inflammatory cytokines have a central role in pathogenesis.
Enhanced levels of leukotriene B4 in synovial fluid in Lyme disease
Authors: Mayatepek E. , Hassler D. , Maiwald M.
Published: March 2007

The purpose of this study was to evaluate the potential role of LTB4 and cysteinyl leukotrienes in Lyme disease (LD). Therefore, a total number of 34 patients divided into four groups was studied. The patients were classified as having Lyme arthritis (n = 7) or Lyme meningitis (n = 10), and as control groups patients with a noninflammatory arthropathy (NIA) (n = 7) and healthy subjects (n = 10). LTB4 as well as LTC4 secretion from stimulated polymorphonuclear leukocytes (PMNL) from all groups of patients showed no statistical differences. LTB4 levels in synovial fluid were significantly increased in patients with Lyme arthritis (median 142 ng/ml, range 88–296) when compared to the control subjects with NIA (median 46 ng/ml, range 28–72) (p < 0.05). No statistical difference of urinary LTE4 levels between all the different groups of patients was observed. These results show that cysteinyl leukotrienes do not play an important role in the pathogenesis of LD. In contrast to previous findings in rheumatoid arthritis, LTB4 production from stimulated PMNL was not found to be increased in LD. However, the significantly elevated levels of LTB4 in synovial fluid of patients with Lyme arthritis underline the involvement of LTB4 in the pathogenesis of this disease.
Antibodies directed to antigens secreted by murine epithelioid macrophages modulate BCG‐induced granulomata
Authors: Mariano Mario , Aguiar Tania , Carneiro Celia R. W. , Postol Edilberto , Alves Venânclo A. F. , Ribeiro-dos-Santos Ricardo
Published: March 2007

The authors have previously shown that epithelioid cells isolated from mice secrete a factor, called macrophage deactivating factor (MDF), that promptly deactivates superoxide release by activated macrophages and neutrophils. In this paper some biological properties of a polyclonal rat antiserum directed to MDF and other substances secreted by these cells are described. The immunoglobulin fraction of this antiserum reacted, by immunocytochemical methods, with epitopes in the cell membrane of macrophages adherent to coverslips subcutaneously implanted for 14 days; but not for 5 days. It also reacted with antigens within and outside cells in BCG‐induced granulomas. This antiserum blocked completely the macrophage deactivating activity of epithelioid cell culture supernatants. Anti‐IL‐10 monoclonal antibody, did not block MDF activity. The administration of the immunoglobulin fraction from immunized rats to C5 deficient mice bearing BCG‐induced granulomatas in the footpad, significantly reduced the size of the lesions. A marked necrosis of inflammatory cells and mononuclear cells phagocyting debris of necrotic cells were observed in these lesions.
Inhibitory effect of interferon‐beta on mouse spleen‐derived mast cells
Authors: Konno S. , Adachi M. , Asano K. , Okamoto K. , Takahashi T.
Published: March 2007

Preparations of murine recombinant interferon (Mu‐rIFN)‐alpha, ‐beta and ‐gamma were assessed for their influence on in vitro growth of mast cells from normal mouse spleen cells (Sp C). Mast cell growth was inhibited by Mu‐rIFNs when Sp C were exposed throughout the entire culture period to Mu‐rIFNs. The most potent inhibitor of mast cell growth was Mu‐rIFN‐γ, followed by Mu‐rIFN‐β; Mu‐rlFN‐α had little effect. When added to IC‐2 cells, clonal mast cell progenitor, both Mu‐rlFN‐β and −γ), significantly inhibited proliferative response of the target cells. The suppressive effect of Mu‐rIFNs on IC‐2 cells was selectively abolished by monoclonal antibodies against Mu‐rIFN‐β and −γ.
Pulmonary granulocyte influx and impaired alveolar macrophage adenylyl cyclase responsiveness in developing respiratory distress
Authors: Amsterdam J. G. C. van , Heijde R. M. J. L. van der , Grotjohan H. P. , Beusenberg F. D.
Published: March 2007

Alveolar macrophages have recently been postulated as being involved in the aetiology of adult respiratory distress syndrome (ARDS). To evaluate their role, basal cyclic AMP levels and responsiveness of adenylyl cyclase alveolar macrophages were determined at four intermediate stages of developing respiratory distress in piglets using a protocol with repeated lung lavage. Examination of alveolar cells recovered from the subsequent lavages reveals an influx of granulocytes (neutrophils and eosinophils) within 1 h of two intensive lung lavages. During the developing respiratory distress the basal cyclic AMPlevel of alveolar macrophages increases and adenylyl cyclase responsiveness to prostaglandin E2 (PGE2) and isoprelanaline diminishes. The previously observed impairment of macrophage activity can then be explained at a subcellular level.
Attenuation of amiodarone induced lung fibrosis and phospholipidosis in hamsters, by treatment with the platelet activating factor receptor antagonist, WEB 2086
Authors: Giri S. N. , Hyde D. M. , Haynam D. R. , Casias M.
Published: March 2007

Therapeutic use of amiodarone (AMD), a Class III antiarrhythmic drug is complicated by the development of lung fibrosis (LF) and phospholipidosis (PL). In the present study, the effectiveness of a PAF antagonist, WEB 2086, against AMD induced LF and PL has been tested in hamsters. The animals were randomly divided into four groups: (1) saline + H2O; (2) WEB + H2O; (3) saline + AMD; and (4) WEB + AMD. Saline or WEB (10 mg/kg i.p.) was given 2 days prior to intratracheal instillation of water or AMD (1.5 μmol/0.25 ml/100 g BW) and thereafter daily throughout the study. Twenty‐eight days after intratracheal instillation, the animals were killed and the lungs processed for various assays. The amount of lung hydroxyproline, an index of LF, in saline + H2O, WEB + H2O, saline + AMD, and WEB + AMD groups were 959 ± 46, 1035 ± 51, 1605 ± 85 and 1374 ± 69 μg/lung, respectively. Total lung PL, an index of phospholipidosis, in the corresponding groups were 8.4 ± 0.4, 8.3 ± 0.3, 11.7 ± 0.3 and 9.9 μg/lung. Lung malondialdehyde, an index of lipid peroxidation and superoxide dismutase activity in saline + H2O WEB + H2O, saline + AMD, and WEB + AMD were 93.0 ± 4.3, 93.0 ± 2.7, 138.9 ± 6.0 and 109.0 ± 3.8 nmol/lung and 359.7 ± 13.9, 394.0 ± 22.8, 497.5 ± 19.7 and 425.5 ± 4.9 units/lung, respectively. Administration of AMD alone caused significant increases in all the above indexes of lung toxicity, and treatment with WEB 2086 minimized the AMD induced toxicity as reflected by significant decreases in these indexes. Histopathological studies revealed a marked reduction in the extent and severity of lung lesions in the WEB + AMD group compared with the saline + AMD group. Treatment with WEB 2086 also reduced the acute mortality from 35% in saline + AMD group to 22% in WEB + AMD group. It was concluded that PAF is involved in the AMD induced lung fibrosis and phospholipidosis and that the PAF receptor antagonist may, therefore, be potentially useful in reducing AMD induced lung toxicity.
Heparan sulphate inhibition of cell proliferation induced by TGFβ and PDGF
Authors: Silber lan E. , Walenga Jeanine M. , Fareed Jawed , Kovacs Elizabeth J.
Published: March 2007

The effect of glycosaminoglycans (GAGs) on the proliferation of smooth muscle cells (SMC) and fibroblasts was assessed by culturing cells with or without GAGs. Porcine heparan sulphate (HS) inhibited proliferation in a dose dependent manner. At 167 μg/ml of HS this reached 88% and 72% inhibition of SMC and fibroblast growth, respectively. Pig and beef mucosal heparins also blocked proliferation, but to a lesser extent. In contrast, beef lung heparin, chondroitin sulphate, and dermatan sulphate failed to block growth factor induced proliferation. Continuous presence of HS was not required, suggesting that the inhibitory effects resulted from a direct effect on the cell rather than an interaction of the GAG with growth factors. The mechanism by which GAGs inhibit proliferation will be addressed in future studies.
Mechanisms of tumor necrosis factor‐α and interleukin‐6 induction during human liver transplantation
Authors: Hamilton Gerhard , Vogel Sonja , Fuegger Reinhold , Gnant Franz X. M.
Published: March 2007

In human orthotopic liver transplantation (LTX) intraoperative elevations of TNF‐α (> 100 pg/ml) and IL‐6 (>800 pg/ml) have been found to correlate with early post‐operative rejections and infections respectively. In this study the possible mechanism responsible for the induction of these cytokines has been investigated during liver allografting in 38 recipients. Intraoperative elevations of TNF‐α (> 100 pg/ml) were detected in the majority of pre‐transplant endotoxin positive recipients (8/12, > 10 endotoxin units/ml), the patients turning endotoxin positive until the end of grafting (3/5), and in a subgroup (6/21 patients), apparently endotoxin negative for the whole operation. Therefore endotoxin (ET) seems to stimulate release of TNF‐α in approximately 50% of the patients, whereas sensitized Kupffer graft cells or immediate allograft reactivity of the host are likely to account for the remaining TNF‐α positive cases. Elevations of IL‐6 > 800 pg/ml) were found in approximately 50% of the TNF‐α positive cases, indicating partially independent regulatory pathways for IL‐6 induction in the TNF‐α negative patients. In agreement with a previous study, 11/13 (85%) of the intraoperative TNF‐α positive recipients rejected their grafts within the first 10 days post‐operatively. These data demonstrate that ET/infection associated as well as ET independent/reperfusion associated intraoperative TNF‐α elevations, promote the initiation of allograft rejection in human liver transplantation. The transient and low endotoxaemia caused by the liver grafting procedure performed without veno‐venous bypass seems to be of minor importance in the intraoperative induction of TNF‐α.
Bradykinin receptors in intestinal smooth muscles and their post‐receptor events related to calcium
Authors: Öztürk Yusuf , Altan V. Melih , Yıdızoğlu-Arı Nuray , Altınkurt Orhan
Published: March 2007

The effects of trifluoperazine and verapamil on bradykinin‐ and des‐Arg9‐bradykinin induced responses of isolated rat duodenum and guinea‐pig ileum were investigated to elucidate post‐bradykinin receptor events. Verapamil and trifluoperazine inhibited bradykinin induced relaxations and contractions and des‐Arg9‐ bradykinin induced contractions in rat duodenum. Bradykinin induced contractions of ileum were also inhibited by trifluoperazine and. verapamil. Since non‐competitive affinity constants of trifluoperazine and verapamil for the relaxant responses to bradykinin in duodenum and for the contractile responses to bradykinin in ileum are different, post‐bradykinin receptor events related to calcium may be different in ileum and duodenum. In addition, affinity constants of bradykinin in guinea‐pig ileum and rat duodenum are also disparate suggesting the presence of different types of bradykinin B2 receptors in these two organs.
Effects of methylprednisolone on exercise‐induced increases of plasma levels of polymorphonuclear elastase and myeloperoxidase in man. Preliminary results
Authors: Camus G. , Pincemail J. , Deby-Dupont G. , Deby C. , Juchmès-Ferir A. , Lamy M.
Published: March 2007

The aim of the present study was to verify whether a single oral dose of methylprednisolone could modulate the exercise‐induced release of polymorphonuclear neutrophil (PMN) elastase and myeloperoxidase. Four healthy, male subjects were submitted to a 20 min downhill run (−20%) at 60% VO2 max, 3 h after oral absorption of a placebo or a single dose of 32 mg methylprednisolone. A marked neutrophilia (+103% of basal PMN count; p < 0.02) was observed 3 h after methylprednisolone ingestion. During both exercise trials, placebo and methylprednisolone, PMN counts were increased by 46% and 19% (p < 0.05), respectively. The running test caused marked and significant (p < 0.05) increases in plasma myeloperoxidase concentration (MPO). The magnitude of MPO changes was the same in the two trials (+110%). Exercise also resulted in significant changes in plasma elastase concentration (EL) in both experimental conditions (placebo: +104%, p < 0.05; methylprednisolone: +338%, p < 0.005). Plasma elastase levels reached at the end of exercise on methylprednisolone were significantly higher than after placebo (p < 0.05). A significant relationship was found between EL and PMN in methylprednisolone trial only (r = 0.72; l0 < 0.005). These results showed that the transient exercise‐induced release of elastase and myeloperoxidase were not decreased by methylprednisolone.
Inflammatory response to strenuous muscular exercise in man
Authors: Camus G. , Deby-Dupont G. , Deby C. , Juchmès-Ferir A. , Pincemail J. , Lamy M.
Published: March 2007

Based on the humoral and cellular changes occurring during strenuous muscular work in humans, the concept of inflammatory response to exercise (IRE) is developed. The main indices of IRE consist of signs of an acute phase response, leucocytosis and leucocyte activation, release of inflammatory mediators, tissue damage and cellular infiltrates, production of free radicals, activation of complement, and coagulation and fibrinolytic pathways. Depending on exercise intensity and duration, it seems likely that muscle and/or associated connective tissue damage, contact system activation due to shear stress on endothelium and endotoxaemia could be the triggering mechanisms of IRE. Although this phenomenon can be considered in most cases as a physiological process associated with tissue repair, exaggerated IRE could have physiopathological consequences. On the other hand, the influence of several factors such as age, sex, training, hormonal status, nutrition, anti‐inflammatory drugs, and the extent to which IRE could be a potential risk for subjects undergoing intense physical training require further study.
Nitrite is produced by elicited but not by circulating neutrophils
Authors: Stewart A. G. , Dusting G. J. , Giarracca R. G. , Harris T. , Lim Y. , Sobey C. G.
Published: March 2007

The generation of nitrite () was used as an index of the production of nitric oxide by human and rat polymorphonuclear leukocytes (PMN) and rat peritoneal macrophages. Human peripheral blood PMN did not produce significant levels of . Attempts to induce generation in human PMN by incubation with GM–CSF (1 nM), TNFα (0.3 nM), endotoxin (1 μg/ml) or formyl‐Met‐Leu‐Phe (100 nM) for up to 16 h were not successful. Addition of human PMN primed by GM–CSF (1 nM) to rabbit aortic ring preparations precontracted with phenylephrine had no effect on tone. In contrast to these observations, PMN, isolated from the peritoneum of oyster glycogen treated rats, generated via a pathway sensitive to inhibition by the nitric oxide synthase inhibitor, NG‐monomethyl L‐arginine. However, peripheral blood rat PMN obtained from the same animals did not produce , even during prolonged incubation for periods of up to 16 h. It is suggested that detectable NO production by PMN requires NO synthase activity to be induced either by the process of PMN migration or by exposure to certain cytokines produced locally at the site of inflammation.
The effect of cocaine on gastric mucosal PGE2, LTC4 and ulcerations
Authors: Angus L. D. G. , Stein T. A. , Auguste L. J. , Gintautas J. , Westervelt J. , Wise L. , Shaftan G. W.
Published: March 2007

The association between cocaine use and acute gastroduodenal perforation is known. The effect of cocaine and stress on gastric mucosal ulceration and the levels of prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) was studied in 40 Sprague–Dawley rats. Controls received intraperitoneal (i.p.) saline, ten received i.p. cocaine (35 mg/kg), ten were stressed by the cold restraint method, and ten had i.p. cocaine and stress. Cocaine alone did not induce ulceration, but decreased PGE2 levels. Stress alone caused ulceration, but was not associated with a change in either PGE2 or LTC4 levels. When combined with stress, however, cocaine caused a three‐fold increase in ulceration and a significant increase in PGE2 and LTC4 levels. Stress may predispose the cocaine addict to loss of gastroduodenal mucosal integrity, which is related to an imbalance of PGE2 and LTC4 synthesis.
TNF and PGE2 in human monocyte‐derived macrophages infected with Chlamydia trachomatis
Authors: Manor E. , Schmitz E. , Sarov I.
Published: March 2007

In this study levels of prostaglandin E2 (PGE2), tumour necrosis factor (TNF) and interleukin‐1 (IL‐1) alpha in medium from monocyte derived macrophages (MdM) infected with Chlamydia trachomatis (L2/434/Bu or K biovars). TNF and PGE2 were found in both cases while IL‐1 alpha was not detected. Both TNF and PGE2 levels were higher in the medium of the MdM infected with K biovars. TNF reached maximum levels 24 h postinfection, and then declined, while PGE2 levels increased continuously during the infection time up to 96 h post‐infection. Addition of dexamethasone inhibited production of TNF and PGE2. Inhibition of PGE2 production by indomethacin resulted in increased production of TNF, while addition of PGE2 caused partial inhibition of TNF production from infected MdM.
Prostaglandin cyclooxygenase products but not thromboxane A2 are involved in the pathogenesis of ewthromelalgia in thrombocythaemia
Authors: Michiels J. J. , Zijlstra F. J.
Published: March 2007

Fluid of artificial blisters from erythromelalgic skin areas in primary thrombocythaemia contained a high amount of prostaglandin‐E‐like activity. Dazoxiben did not alleviate the erythromelalgia in patients with primary thrombocythaemia despite complete inhibition of platelet malondialdehyde and thromboxane B2 synthesis and no inhibition of prostaglandin‐E‐like material. During a 10‐day dazoxiben treatment period, persistent erythromelalgia was associated with a significant shortened mean platelet life span of 3.2 days. During subsequent treatment with low dose acetylsalicylic acid daily complete relief of erythromelalgia was associated with inhibition of platelet prostaglandin endoperoxide production and correction of platelet mean life span to normal, 7.9 days. These observations indicate that prostaglandin E2, or another prostaglandin endoperoxide metabolite, is involved in the pathogenesisof erythromelalgia. The presented study does not give one single clue as to the origin (platelet, vessel wall or other) of the prostanoid, but very likely originates from platelets because a very low dose of acetylsalicylic acid (250 to 500 mg every other day), which irreversibly inhibits platelet cyclooxygenase, is highly effective in the prevention of erythromelalgia in thrombocythaemia.
Arachidonic acid metabolism in TNS‐induced chronic and immunologic enteritis in rats, and the effect of 5‐ASA
Authors: Zijlstra F. J. , Dijk A. P. M. van , Selve N. , Wilson J. H. P.
Published: March 2007

Inflammation of the rat distal intestine was induced by intradermal sensitization and subsequent multiple intrajejunal challenge with the hapten 2,4,6‐trinitrobenzenesulphonic acid (TNBS) via an implanted catheter. The time course of the inflammatory reaction was followed by determination of the enteritis score and measurement of in vitro eicosanoid formation of homogenates of the gut after 0, 1, 2, 4, 7, 14 and 21 days of local daily challenge with 0.08% TNBS. There was a small initial increase of eicosanoid formation, reached at days 1 and 2, followed by a significant increase in metabolism of arachidonic acid on day 21. Although at day 1 a four‐fold increase in inflammation score was reached, no further significant changes were observed during the following 3 weeks. The greatest increase in metabolite formation was observed in prostanoids TxB2, PGE2. and PGD2 and the 5‐lipoxygenase product LTC4, whereas minor changes were found for LTB4 and other lipoxygenase products such as 12‐ and 15‐HETE. The formation of these metabolites was already inhibited by low‐dose 5‐aminosalicylic acid (5‐ASA), given orally twice daily during the 3 weeks challenge period, while the enteritis score was affected dosedependently.
Pathological changes in platelet histamine oxidases in atopic eczema
Authors: Kiehl Reinhold , Ionescu Gruia
Published: March 2007

Increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet‐rich plasma of atopic eczema (AE) patients. The diamine oxidase has almost normal cofactor levels (pyridoxal phosphate and Cu2+) but the cofactor levels for type B monoamine oxidase (flavin adenine dinucleotide and Fe2+) are lowered. The biogenic amines putrescine, cadaverine, spermidine, spermine, tyramine and serotonin in the sera, as well as dopamine and epinephrine in EDTA‐plasma were found to be normal. It is unlikely, therefore, that these amines are responsible for the decreased activities of monoamine and diamine oxidase in these patients. The most likely causative factors for the inhibition of the diamine oxidase are nicotine, alcohol, food additives and other environmental chemicals, or perhaps a genetic defect of the diamine oxidase.
Inhibitory effect of LY 255283 on the synthesis of leukotriene B4 and thromboxane A2 in human peripheral blood polymorphonuclear leukocytes and monocytes
Authors: Uğur M. , Melli M.
Published: March 2007

LY 255283 [(1‐(5‐ethyl‐2‐hydroxy‐4‐(6‐methyl‐6‐)1H‐tetrazol‐5‐yl)‐heptyloxy) phenyl)ethanone], a specific leukotriene B4 (LTB4) receptor antagonist, inhibited the production of LTB4 in human peripheral blood polymorphonuclear leukocytes (PMNL) and in monocytes activated by calcium ionophore A23187. In human monocytes activated by ionophore it inhibited also the production of thromboxane B2 (TXB2). The effect of LY 255283 on 5‐lipoxygenase (5‐LO) and LTA4 hydrolase activities which catalyse the production of LTB4 and LTA4 has not been studied yet. It is thought that LY 255283 may inhibit the production of LTB4 and TXA2 by antagonising the effect of ionophore‐induced LTB4 on 5‐lipoxygenase and cyclooxygenase in human peripheral blood PMNL and monocytes.
In vitro interleukin 4 and interferon‐gamma production by mononuclear cells from atopic dermatitis patients
Authors: Well Serge , Diel Friedhelm
Published: March 2007

In order to elucidate further the possible role of specific cytokines in the pathogenesis of atopic dermatitis (AD) the in vitro production of interleukin 4 (IL‐4) and interferon‐gamma (IFN‐γ) in patients with severe atopic dermatitis (n = 4) was compared with that in a group of non‐atopic healthy controls. Overall IL‐4 production by PHA‐ and PWM‐driven PBMNCs was increased in controls during the first 48 h in culture. Addition of interleukin 2 (IL‐2) into parallel cultures generated an insignificant (p > 0.05) increase in IL‐4 production in AD patients compared with that from controls. IFN‐γ production by PWM‐stimulated PBMNCs was markedly decreased in AD patients compared with controls (p < 0.01). Addition of IL‐2 (250 U/ml) to parallel cultures failed to restore IFN‐γ production in AD patients. Finally, no IL‐4 or IFN‐γ activity could be detected in any of the sera. In conclusion, the data suggest a possible dysregulation of cytokine production in at least a subgroup of AD patients, with an impaired capacity to secrete IFN‐γ, but a partially intact IL‐4 generating capacity.
Endothelin‐1 stimulates human monocytes in vitro to release TNF‐α , IL‐1β and IL‐6
Authors: Helset E. , Sildnes T. , Seljelid R. , Konopski Z.S.
Published: March 2007

Increased plasma‐ and tissue levels of endothelin‐1 (ET‐1) during inflammatory diseases, have suggested a role of ET‐1 in the pathophysiology of inflammatory reactions. The authors have studied the effect of ET‐1 on cytokine release from monocytes and monocyte‐derived macrophages. ET‐1 increased secretion of TNF‐α, IL‐1β and IL‐6 in a dose‐ and time‐dependent manner. Optimal ET‐1 concentration ranged from 0.01 to 1 nM. The maximal response was a 200 to 400% increase in cytokine release. A time‐course study revealed that the pattern of cytokines induced by ET‐1 was different in monocytes and macrophages, although an early increase in TNF‐α was observed in both monocyte and macrophage supernatants. In conclusion, ET‐1 stimulates monocytes and macrophages to release cytokines thereby demonstrating a potential role for ET‐1 in regulation of inflammatory responses.
Chronic cigarette smoking enhances spontaneous release of tumour necrosis factor‐α from alveolar macrophages of rats
Authors: Pessina G. P. , Paulesu L. , Corradeschi F. , Luzzi E. , Tanzini M. , Aldinucci C. , Di Stefano A. , Bocci V.
Published: March 2007

Some biological effects of chronic cigarette smoking (two cigarettes for 2 h, daily for 4 months) in rats were evaluated. During the smoking period, body weight of smoker rats was always significantly lower than that of control rats. Immediately after the last smoking session the carboxyhaemoglobin concentration in the blood was about 8.5% and the polymorphonuclear cells in the bronchoalveolar fluid increased significantly. At the same time, enzymatic analyses on the supernatants of bronchoalveolar fluid revealed a significant increase of β‐glucuronidase in the smoker group. Alveolar macrophages, collected 0, 8 and 24 h after the last smoking session, significantly increased the generation of superoxide anion and, after incubation for 24 h at 37° C in a humidified atmosphere, released significantly high amounts of TNF‐α. When challenged with lipopolysaccharide, alveolar macrophages of smoker rats released much more TNF‐α but, in such a case, TNF‐α release was about one half of that observed in the control group. Peritoneal macrophages of both control and smoker rats were unable either to generate high levels of superoxide anion or to release significant amounts of TNF‐α. The results clearly demonstrated the activated state of alveolar macrophages and the resting state of peritoneal macrophages.
RNA from LPS‐stirnulated macrophages induces the release of tumour necrosis factor‐α and interleukin‐1 by resident macrophages
Authors: Ribeiro R. A. , Lucca F. L. De , Flores C. A. , Cunha F. Q. , Ferreira S. H.
Published: March 2007

The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L‐RNA, induced the release of TNF‐α and IL‐1 from monolayers of peritoneal resident macrophages. The activity of L‐RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(−) and poly A(+) fractions obtained from L‐RNA applied to oligo(dT)–cellulose chromatography induced TNF‐α and IL‐1 release. The L‐RNA‐induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin‐D. The LPS‐stimulated macrophages, when pre‐incubated with [5‐3H]‐uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL‐1β but not with TNF‐α, IL‐6 or IL‐8. The substance secreted (3H‐RNA) sediments in the 4–5S region of a 5–20% sucrose gradient. These results show that L‐RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population.
Isolation and function of a human endothelial cell C1q receptor
Authors: Daha M. R. , Dunn L. , Berg R. van den , Lange Y. Muizert-de , Gerritsen A. , Es L. A. van
Published: March 2007

It has been shown previously that cultured human venous and arterial endothelial cells (EC) bind C1q in a time‐ and dose‐dependent manner. Cultured human endothelial cells express an average number of 5.2 × 105 binding sites/cell. In the present study the putative receptor for C1q (C1qR) was isolated from the membranes of 1–5 × 109 human umbilical cord EC by affinity chromatography on C1q–Sepharose. During isolation, C1qR was detected by its capacity to inhibit the lysis of EAC1q in C1q‐deficient serum. The eluate from C1q–Sepharose was concentrated, dialysed and subjected to QAE‐A50 chromatography and subsequently to gel filtration on HPLC–TSK 3000. C1qR filtered at an apparent molecular weight of 60 kDa. Purified C1qR exhibited an apparent molecular weight of 55–62 kDa in the unreduced state and a molecular weight of 64–68 kDa in reduced form. Two IgM monoclonal antibodies (mAb) D3 and D5 were raised following immunization of mice with purified receptor preparations. Both monoclonal antibodies increased the binding of 125I‐C1q to endothelial cells but F(ab′)2 anti‐C1qR mAb inhibited the binding of a125I‐C1q to EC in a dosedependent manner. The D3 mAb recognized a band of 54–60 kDa in Western blots of membranes of human EC and polymorphonuclear leukocytes. Previously, the authors showed that C1q induces the binding of IgM‐containing immune complexes to EC. Therefore, it was hypothesized that during a primary immune response generation of IgM‐IC may occur, resulting in binding and activation of C1, dissociation of activated C1 by C1 inhibitor and subsequent interaction of IgM‐IC bearing C1q with EC–C1qR.
Bacterial endotoxins: biological properties and mechanisms of action
Authors: Galanos C. , Freudenberg M. A.
Published: March 2007

Endotoxins (lipopolysaccharides, LPS) are agents of pathogenicity of Gram‐negative bacteria, implicated in the development of Gram‐negative shock. Endotoxin reacts with lipopolysaccharide‐sensitive cells producing endogenous mediators such as tumour necrosis factor alpha (TNFα). Macrophages are cells mediating the toxic activities of LPS and TNFα is the primary mediator of the lethal action of endotoxin. This review article discusses the various mechanisms by which endotoxin hypersensitivity in bacteria‐sensitized animals develops. The paper concludes with a discussion on the possible protective effect of carnitine congeners against the lethal action of LPS.
Modulation of cytokine production by carnitine
Authors: Kouttab Nicola M. , De Simone Claudio
Published: March 2007

The ability of carnitine congeners to modulate cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. Modulation of cytokine production by PBMC of young (30 years of age or younger) and old (70 years of age or older) normal donors was first compared. The PBMC were collected over Ficoll–Hypaque and incubated in the presence of various concentrations of acetyl L‐carnitine for 24 h. Subsequently the supernatants were collected and examined for cytokine production. The presence of cytokines in tissue culture supernatants was examined by ELISA. The cytokines measured included IL‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, TNFα, GM–CSF, and IFNγ. The results showed that at 50 μg/ml of acetyl L‐carnitine the most significant response was obtained for TNFα. In this regard four of five young donors responded, but only one of five old donors responded. More recently these studies were expanded to examine the ability of L‐carnitine to modulate cytokine production at higher doses, 200 and 400 μg/ml, in young donors. The results of these studies showed that in addition to TNFα, significant production of IL‐1β and IL‐6 was observed. These preliminary studies provide evidence that carnitine may modulate immune functions through the production of selected cytokines.
Regulation of normal human polyrnorphonuclear leucocytes by carnitine
Authors: Fattorossi Andrea , Biselli Roberto , Casciaro Anna , Tzantzoglou Sonia , de Simone Claudio
Published: March 2007

The effect of carnitine, a drug that plays an essential role in mitochondria metabolism, on some of the most important human polymorphonuclear leucocytes (PMN) activation steps including modulation of adhesion molecule density, reactive oxygen species production, and tumour necrosis factor‐α (TNFα) production was investigated. The capability of carnitine in protecting PMN from deter ioration on storage was also studied. Data shows that carnitine exerts considerable effects on all PMN functions investigated. Although the ultimate effect was often donor dependent, TNFα production was exceptional in that carnitine was able to consistently reduce TNFα production in Staphylococcus aureus stimulated PMN in a clear dose‐dependent fashion. It is concluded that carnitine may represent a useful active agent in situations characterized by PMN mobilization/activation.
LPS‐induced serum TNF production and lethality in mice: effect of L‐carnitine and some acyl‐derivatives
Authors: Ruggiero Vito , D′Urso Claudio M. , Albertoni Claudio , Campo Silvia , Foresta Piero , Martelli Edoardo Arrigoni
Published: March 2007

The effect of L‐carnitine and some of its acyl derivatives on serum TNF production and lethality in a murine experimental endotoxin shock model was investigated. In some instances, serum IL‐6 production was also evaluated. In this experimental model, C57BL/6 mice received 30 mg/kg LPS (E. cell 055:B5) injected intraperitoneally, while L‐carnitine and its derivatives were administered according to different schedules. Serum levels of TNF and IL‐6 were evaluated 1 h following LPS injection. The treated animals were also monitored daily for differences in body temperature, feeding, and survival for 10 days after LPS injection. Although some derivatives were able to significantly affect TNF production, the marked decrease in serum TNF levels of LPS‐treated mice was not paralleled by a substantial increase in survival.
Amelioration of popolysaccharide‐induced sepsis in rats by free and esterified carnitine
Authors: Gallo Linda L. , Tian Yan , Orfalian Zaven , Fiskum Gary
Published: March 2007

The purpose of this study was to determine if free or esterified carnitine could alter fatty acid metabolism and ameliorate sepsis in lipopolysaccharide (LPS)‐treated rats. Throughout a 96 h observation post‐LPS, i.p. administration of both markedly reduced illness and accelerated recovery. Carnitine prevented the acute LPS‐induced rise in serum triglycerides (45 ± 6, 59 ± 5 vs. 83 ± 8 mg/ml, p < 0.001), respectively. This difference was accompanied by a significant increase in liver lipogenesis in LPS controls compared to both carnitines and normal rats (6.1 ± 0.3 vs. 3.9 ± 0.5, 4.3 ± 0.5, and 1.8 ± 0.4 μmol/h, respectively, p < 0.04). Compared to normal rats, total liver carnitine was significantly elevated in LPS controls and even higher in the carnitine groups (357 ± 40 vs. 736 ± 38, 796 ± 79, and 1081 ± 21 nmol/g). The data suggest that carnitines may be of therapeutic value in sepsis treatment and one action may be to partition fatty acids from esterification to oxidation.
Phospholipase A2 Activity in Gingival Crevicular Fluid from Patientswith Periodontal Disease: A possible Marker of Disease Activity
Authors: Ishida H. , Shinohara H. , Nagata T. , Nishikawa S. , Wakano Y.
Published: March 2007

The activity of phospholipase A2 in human gingival crevicular fluid
(GCF) associated with periodontal disease was demonstrated. Based
upon the presence or absence of bleeding on probing (BOP), which is
a marker for the disease activity, there were higher levels of the
enzyme activity in BOP positive, than in negative sites. When the
BOP positive sites became negative after periodontal therapy, the
enzyme activity decreased dramatically to almost undetectable
levels. There were no significant differences between the activity
before and after treatment when the BOP positive sites remained
unchanged. These results suggest that the activity in GCF reflects
periodontal disease conditions and that it can be used as a marker
for disease activity.
PAF and Haematopoiesis. I. 5‐Fluoro‐Uracil Induces PAF Production in Haematopoietic Organs of Rats
Authors: Denizot Y. , Praloran V.
Published: March 2007

Haematopoietic organs of rats were examined for the presence of
platelet‐activating factor (PAF) and acetylhydrolase before and
after treatment with 5‐fluoro‐uracil (5‐FU) (200 mg/kg) a
chemotherapeutic compound with apoptotic effects. PAF was reported
in thymus, spleen and femoral bone marrow of rats with or without
5‐FU. Although acetylhydrolase activity in organs was not affected
by 5‐FU treatment, elevated levels of PAF were observed in thymus
and spleen. For the first time PAF is reported in haematopoietic
organs of rats, strengthening in vitro data suggesting its role in
the apoptotic processes in thymus, in the modulation of the immune
response, and in the regulation of haematopoiesis.
The Effect of Lyso‐PAF on Ciliary Activity of Human Paranasal Sinus Mucosa in vitro
Authors: Ganbo T. , Hisamatsu K. , Inoue H. , Nakajima T. , Murakami Y.
Published: March 2007

The effect of lyso‐PAF on ciliated cells was investigated in vitro.
Normal mucosa was surgically obtained from human paranasal sinuses
and incubated in the form of tissue culture. Ciliated epithelium was
magnified under an inverted microscope, and ciliary movement was
photo‐electrically measured. Ciliary activity was significantly
inhibited by 10−8 M lyso‐PAF and could be restored. The effect of
lyso‐PAF was completely blocked by CV‐6209, a specific PAF
antagonist. The PAF concentration in the incubation medium of
lyso‐PAF was determined by radioimmunoassay, because PAF is a well
known inhibitor of ciliary activity. PAF gradually increased and
after 20 min reached its maximal level. These findings indicated the
existence of an enzyme in the paranasal sinus mucosa, by which
lyso‐PAF is converted to PAF, and that lyso‐PAF can inhibit ciliary
activity by means of PAF.
Involvement of A pertussis Toxin Sensitive G‐Protein in theInhibition of Inwardly Rectifying K+ Currents byPlatelet‐Activating Factor in Guinea‐Pig Atrial Cardiomyocytes
Authors: Gollasch M. , Kleppisch T. , Krautwurst D. , Lewinsohn D. , Hescheler J.
Published: March 2007

Platelet‐activating factor (PAF) inhibits single inwardly rectifying
K+ channels in guinea‐pig ventricular cells. There
is currently little information as to the mechanism by which these
channels are modulated. The effect of PAF on quasi steady‐state
inwardly rectifying K+ currents (presumably of the
IK1 type) of auricular, atrial and ventricular cardiomyocytes from
guinea‐pig were studied. Applying the patch‐clamp technique in the
whole‐cell configuration, PAF (10 nM) reduced the K+
currents in all three cell types. The inhibitory effect of PAF
occurred within seconds and was reversible upon wash‐out. It was
almost completely abolished by the PAF receptor antagonist BN 50730.
Intracellular infusion of atrial cells with guanine
5′‐(β‐thio)diphosphate (GDPS) or pretreatment of cells
with pertussis toxin abolished the PAF dependent reduction of the
currents. Neither extracellularly applied isoproterenol nor
intracellularly applied adenosine 3′,5′‐cyclic
monophosphate (cyclic AMP) attenuated the PAF effect. In
multicellular preparations of auricles, PAF (10 nM) induced
arrhythmias. The arrhythmogenic activity was also reduced by BN
50730. The data indicate that activated PAF receptors inhibit
inwardly rectifying K+ currents via a pertussis
toxin sensitive G‐protein without involvement of a cyclic
AMP‐dependent step. Since IK1 is a major component in
stabilizing the resting membrane potential, the observed inhibition
of this type of channel could play an important role in PAF
dependent arrhythmogenesis in guinea‐pig heart.