bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumour necrosis factor‐α in nasal allergy
Authors: Hisamatsu K. , Ganbo T. , Nakazawa T. , Nakajima T. , Ko J. , Goto R. , Murakami Y. , Misui K.
Published: March 2007

Tumour necrosis factor‐α (TNF‐α) was measured by enzyme‐linked immunosorbent assay and eosinophil cationic protein (ECP) by radio‐immunoassay to evaluate TNF‐α in nasal allergy. There was no significant difference either between the mean concentrations of TNF‐α in nasal secretions from the patients with perennial nasal allergy and those of normal subjects, or between the TNF‐α and ECP concentrations. However, reverse transcription polymerase chain reaction showed a specific increase of TNF‐α mRNA and IFN‐γ mRNA in allergic nasal mucosa after allergen challenge in vitro. These findings suggest a possibility that T cell‐derived IFN‐γ up‐regulates macrophages to elaborate TNF‐α, which may play a role in amplifying allergic inflammation in the nose through the cytokine network.
Regulation of TXB2 and PGE2 production by TGF‐β1 in in vitro silica dust‐exposed rat alveolar macrophage
Authors: Orlinska Urszula , Kuhn Douglas C.
Published: March 2007

We investigated the effect of transforming factor factor‐β1 (TGF‐β1) on thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) production in in vitro silica dust‐exposed rat alveolar macrophages (AM). In the presence of 5 μg of anti‐TGF‐β1 antibodies, TXB2 production decreased, but PGE2 production increased. Addition of 2 ng of TGF‐β1 to the culture medium potentiated TXB2 production, but PGE2 production apparently did not change. At 50 ng of TGF‐β1, TXB2 production decreased, and PGE2 production varied. Our data suggest that in rat AM: (1) both endogenous and exogenous TGF‐β1 regulate TXB2 production; and (2) in the absence of endogenous TGF‐β1 the liberation of PGE2 increases; however, exogenous TGF‐β1 does not have a regulatory effect on PGE2.
Role of lipoxygenase products in the effects of angiotensin II in the isolated aorta and perfused heart of the rat
Authors: Dam J. P. M. , Worm E. van den , Vleeming W. , Post M. J. , Porsius A. J. , Wemer J.
Published: March 2007

The objective of this study was to determine whether arachidonate metabolites are involved in the vasoconstrictive effects of angiotensin II in rats. In the isolated perfused heart, dexamethasone (4 mg/kg) significantly suppressed the maximal decreases in coronary flow induced by angiotensin II and vasopressin (reference drug). In the heart, the nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1 μM) markedly suppressed the angiotensin II‐induced decreases in coronary flow. NDGA (10 μM) inhibited both angiotensin II‐ and methoxamine‐ (reference drug) induced contractions in aortic rings with (in the presence of L‐NAME) and without endothelium. In the heart, the leukotriene synthesis inhibitor MK‐886 (0.3 μM) significantly reduced the maximal effects to angiotensin II, but the leukotriene antagonist FPL 55712 (0.1 and 0.3 μM) had no effect. We conclude that in the isolated perfused rat heart angiotensin II‐induced decreases in coronary flow are in part mediated by Hpoxygenase products, which might be derived from the 5‐Hpoxygenase pathway, but are probably not leukotrienes. Furthermore, endothelium independent Hpoxygenase products mediate part of the contractile responses to angiotensin II in the isolated rat aorta.
Lower leukotriene C4 levels in bronchoalveolar lavage fluid of asthmatic subjects after 2.5 years of inhaled corticosteroid therapy
Authors: Oosterhoff Y. , Overbeek S. E. , Douma R. , Noordhoek J. A. , Postma D. S. , Hoogsteden H. C. , Zijlstra F. J.
Published: March 2007

Long‐term treatment with inhaled corticosteroids has been shown to result in improvement of symptoms and lung function in subjects with asthma. Arachidonic acid (AA) metabolites are thought to play a role in the pathophysiology of asthma. It was assessed whether differences could be found in bronchoalveolar lavage (BAL) AA metabolite levels between subjects with asthma who were treated for 2.5 years with inhaled bronchodilators alone or in combination with inhaled corticosteroids. Prostaglandin (PG)D2, PGF2α, 6‐keto‐PGF1α, thromboxane B2, leukotriene (LT)C4 and LTB4 levels and cell numbers were assessed in BAL fluid from 22 non‐smoking asthmatic subjects. They were participating in a randomized, double‐blind multicentre drug trial over a period of 2.5 years. Results of the group treated with inhaled corticosteroids (CS+: beclomethasone 200 μg four times daily) were compared with the other group (CS−) which was treated with either ipratropium bromide (40 μg four times daily) or placebo. BAL LTC4 levels of asthmatic subjects were significantly lower after 2.5 years inhaled corticosteroid therapy (CS+, 9(1–17) pg/ml vs. CS−, 16(6‐53) pg/ml; p = 0.01). The same trend was observed for the PGD2 levels. The results suggest that inhaled corticosteroids may exert their beneficial effect on lung function via a mechanism in which inhibition of LTC4 synthesis in the airways is involved.
Cytotoxicity towards human endothelial cells, induced by neutrophil myeloperoxidase: protection by ceftazidime
Authors: Mathy-Hartert M. , Deby-Dupont G. , Deby C. , Jadoul L. , Vandenberghe A. , Lamy M.
Published: March 2007

We investigated the effects of the antibiotic ceftazidime (CAZ) on the cytolytic action of the neutrophil myeloperoxidase–hydrogen peroxide–chloride anion system (MPO/H2O2/Cl−). In this system, myeloperoxidase catalyses the conversion of H2O2 and CI− to the cytotoxic agent HOCl. Stimulated neutrophils can release MPO into the extracellular environment and then may cause tissue injury through direct endothelial cells lysis. We showed that human umbilical vein endothelial cells (HUVEC) were capable of taking up active MPO. In presence of H2O2 (10−4 M), this uptake was accompanied by cell lysis. The cytolysis was estimated by the release of 51Cr from HUVEC and expressed as an index of cytotoxicity (IC). Dose dependent protection was obtained for CAZ concentrations ranging from 10−5 to 10−3 M;this can be attributed to inactivation of HOCl by the drug. This protection is comparable to that obtained with methionine and histidine, both of which are known to neutralize HOCl. This protection by CAZ could also be attributed to inactivation of H2O2, but when cytolysis was achieved with H2O2 or generating enzymatic systems, no protection by CAZ was observed. Moreover, the peroxidation activity of MPO (action on H2O2) was not affected by CAZ, while CAZ prevented the chlorination activity of MPO (chlorination of monochlorodimedon). So, we concluded that CAZ acts via HOCl inactivation. These antioxidant properties of CAZ may be clinically useful in pathological situations where excessive activation of neutrophils occurs, such as in sepsis.
Clostridium difficile suppresses colonic vasoactive intestinal peptide associated with altered motility
Authors: Nassif A. , Longo W. E. , Sexe R. , Stratton M. , Standeven J. , Vernava A. M. , Kaminski D. L.
Published: March 2007

We investigated whether Clostridium difficile toxin alters colonic tissue levels of vasoactive intestinal peptide (VIP) at the expense of changes in colonic motility in the isolated perfused rabbit left colon. Colonic inflammation was induced by the intracolonic administration of 10−8 M C. difflcile toxin. Strain gauge transducers were sewn onto the serosal surface of the colon to evaluate colonic motility. C. difflcile administration produced histologic changes consistent with epithelial damage. This was associated with an increased production of prostaglandin E2 and thromboxane B2. Tissue levels of VIP but not substance P were significantly reduced. This was associated with an increased number of contractions per minute and an average force of each colonic contraction. These results suggest that tissue levels of VIP are suppressed by C. difflcile and may participate in colonic dysmotility during active inflammation.
Tumour necrosis factor‐α and adenosine in endotoxin shockleading related cardiovascular symptoms
Authors: Sipka S. , Seres T. , Dinya Z. , Szekanecz Z. , Szentmiklósi J. , Bodolay E. , Szegedi G.
Published: March 2007

We have observed uncontrollable cardiogenic shock as a cardiovascular manifestation of systemic inflammatory response syndrome (SIRS) leading to death in a 62‐year‐old woman. The diagnosis of SIRS was based on the demonstration of endotoxinaemia, and highly elevated plasma levels of tumour necrosis factor (TNF)‐α, and interleukin (IL)‐10. We suggest that these cytokines may contribute to the terminal SIRS‐related arrythmias, impaired myocardial contractility, as well as increased vascular permeability. In addition, the increased production of adenosine, a counter‐regulatory mediator of inflammation, may also play a role in cardiodepression. We suggest a relationship between the action of TNF‐α , IL‐10 and adenosine in the pathogenesis of circulatory symptoms described above.
Efficacy and tolerability of levocabastine and azelastine nasal sprays for the treatment of allergic rhinitis
Authors: Mösges Ralph , Spaeth Joachim , Klimek Ludger
Published: March 2007

Levocabastine and azelastine are currently the only antihistamines available as nasal sprays for the topical therapy of seasonal allergic rhinitis. The present study was undertaken to compare the onset of action, efficacy and tolerability of these two agents in a total of 242 patients with this condition. This was an international, multicentre, open‐label, randomized, parallel‐group trial with 123 patients treated with levocabastine (0.5 mg/ml, two puffs per nostril twice daily) and 119 with azelastine (1 mg/ml, one puff per nostril twice daily). Onset of action was comparable for the two drugs with over 50% of patients in each group reporting significant symptomatic relief within 30 min of administration of the first dose of study medication. Therapeutic efficacy was also found to be comparable in the two groups with no statistically significant intergroup differences reported for any of the parameters evaluated, although assessments of global therapeutic efficacy revealed a trend favouring levocabastine. Levocabastine appeared to be better tolerated than azelastine (p = 0.06), with the incidence of the most common adverse experiences, application site reactions and taste disturbances, significantly higher on azelastine than with levocabastine (5% versus 1%; p = 0.05 and 5% versus 0%; p = 0.01, respectively). In conclusion, levocabastine nasal spray appears to be at least as effective as, but better tolerated than, azelastine nasal spray for the treatment of seasonal allergic rhinitis.
Levocabastine eye drops are effective and well tolerated for the treatment of allergic conjunctivitis in children
Authors: Wüthrich Brunello , Gerber Martin
Published: March 2007

This open‐label, prospective, multicentre, 4‐week trial was undertaken to assess the efficacy and tolerability of twice daily levocabastine eye drops (0.5 mg/ml), with sodium cromoglycate nasal spray for the relief of concurrent nasal symptoms if required, in a total of 233 children with seasonal allergic conjunctivitis. No correlation between efficacy, tolerability and age was found. Investigator assessments revealed that the total severity of ocular symptoms decreased by 84 ± 34% in patients < 12 years and 85 ± 30% in those ≥ 12 years, with corresponding reductions in the total severity of ocular findings of 84% in both patient groups over the 4‐week treatment period. Global assessments of therapeutic efficacy revealed the effect of therapy on ocular symptoms to be excellent or good in 81% of patients < 12 years and 82% of those ≥ 12 years after 2 weeks of treatment, with corresponding values at the end of the trial of 88% and 82% in the two groups, respectively. Treatment tolerability was considered to be excellent or good by 94% of patients overall. Application site reactions were the most common adverse event associated with ocular levocabastine, occurring in 13% of patients < 12 years and 9% of those ≥ 12 years. Twice daily levocabastine eye drops therefore appear to be effective and well tolerated for the treatment of seasonal allergic conjunctivitis in children.
Topical levocabastine—a review of therapeutic efficacy compared with topical sodium cromoglycate and oral terfenadine on days with high pollen counts
Authors: Azevedo Marianela de
Published: March 2007

Levocabastine is a new H1‐receptor antagonist specifically developed for the topical treatment of seasonal allergic rhinoconjunctivitis. Clinical experience to date clearly demonstrates that levocabastine eye drops and nasal spray are effective and well tolerated for the treatment of this allergic disorder. Analysis of data from a number of comparative trials reveals that topical levocabastine is at least as effective as sodium cromoglycate and the oral antihistamine terfenadine, even on days with high pollen counts (≥ 50 pollen particles/m3 ) when symptoms are severe. Coupled with a rapid onset of action and twice daily dosing, these findings make topical levocabastine an attractive alternative to other therapeutic approaches as a first‐line therapy for the treatment, of this common condition.
The venom of South American rattlesnakes inhibits macrophage functions and is endowed with anti‐inflammatory properties
Authors: Silva Maria C. C. de Sousa e , Gonçalves Luis R. C. , Mariano Mario
Published: March 2007

The injection of Crotalus durissus terrificus venom into the foot pad of mice did not induce a significant inflammatory response as evaluated by oedema formation, increased vascular permeability and cell migration. The subcutaneous injection of the venom, or its addition to cell cultures, had an inhibitory effect on the spreading and phagocytosis of resident macrophages, without affecting the viability of the cells. This effect was not observed when the venom was added to cultures of thioglycollate elicited macrophages, but it was able to inhibit these macrophage functions when the cells were obtained from animals injected simultaneously with the venom and thioglycollate. These observations suggest that the venom interferes with the mechanisms of macrophage activation. Leukocyte migration induced by intraperitoneal injection of thioglycollate was also inhibited by previous venom injection. This down‐regulatory activity of the venom on macrophage functions could account for the mild inflammatory response observed in the site of the snake bite in Crotalus durissus terrificus envenomation in man.
Role of transforming growth factor‐β1 in down‐regulating TNF production by alveolar macrophages during asbestos‐induced pulmonary fibrosis
Authors: Lemaire Irma , Ouellet Sophie
Published: March 2007

Activation of alveolar macrophages (AM) for tumour necrosis factor production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF suppression, notably the role of other AM‐derived mediators including prostaglandin E2 (PGE2), transforming growth factor‐β1 (TGF‐β1), and interleukin 6 (IL‐6). The action of PGE2 and TGF‐β1, on AM was different. At physiologically relevant doses (25–300 pg/ml), PGE2 did not cause significant inhibition of Hpopolysaccharide (Lps)‐induced TNF release by AM in vitro but stimulated IL‐6 (up to six fold), an inhibitor of AM‐derived TNT. In contrast, TGF‐β1 (0.5–50 ng/ml) inhibited both LPS‐induced TNT and IL‐6 release by 50% but had no effect on PGE2 production by AM. To determine the respective contribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for weeks were treated with neutralizing antibody against TGF‐β1 or indomethacin, an inhibitor of PGE2 synthesis. Treatment of rat AM with anti‐TGF‐β1 but not indomethacin, abrogated the observed TNT suppression. These results suggest that an autocrine, TGF‐β1‐dependent mechanism is involved in the down‐regulation of TNF production by rat AM from animals with lung fibrosis.
Plasma levels of immunosuppressive mediators during cardiopulmonary bypass
Authors: Borrelli E. , Giomarelli P. , Naldini A. , Luzzi E. , Silvestri S. , Gardinali M. , Bocci V.
Published: March 2007

The aim of this study was to evaluate plasma levels of two mediators with immunosuppressive properties, complement fraction C3a (C3a) and transforming growth factor‐β1 (TGF‐β1), during extracorporeal circulation. The proliferation index after phytohaemagglutinin (PHA) stimulation of isolated peripheral blood mononuclear cells was also investigated. Sixteen patients undergoing hypothermic (n = 8, group 1) and normothermic (n = 8, group 2) cardiopulmormry bypass (CPB) were enrolled in this study. As a control, we evaluated four patients undergoing thoracovascular operations without CPB. Blood samples were collected before CPB but after anaesthesia, every 30 min during CPB, at the end of CPB and 10 min after protamine administration. Both C3a and TGF‐β1 increased significantly during CPB and after protamine administration in the hypothermic as well as the normothermic group. In the latter case the increase of C3a and TGF‐β1, although more prominent, was not significantl higher than in the former group. Conversely, the proliferation, index of peripheral mononuclear cells had already decreased 30 min after CPB was started and remained depressed throughout the CPB time. These results suggest a possible role of C3a and TGF‐β1 in the immunological changes occurring during extracorporeal circulation.
Adhesion‐independent synergy of monocytes and endothelial cells in cytokine production: regulation of IL‐6 and GM–CSF production by PAF
Authors: Lacasse C. , Turcotte S. , Gingras D. , Rola-Pleszczynski M.
Published: March 2007

Co‐Cultures of monocytes (MO) and endothelial cells (EC) were studied for their capacity to synergize in the production of interleukin‐6 (IL‐6) and granulocyte‐macrophage colony‐stimulating factor (GM–CSF), two cytokines potentially important in vascular physiopathology. Resting monocytes produced detectable amounts of IL‐6 but no GM–CSF, whereas confluent EC produced significant quantities of GM–CSF, but minimal IL‐6. In co‐cultures without stimuli, additive synthesis of both cytokines was observed. When EC were pretreated, however, with either PAF, TNF or both stimuli, before addition of MO, synergistic production of IL‐6 was observed. In contrast, GM–CSF production was not enhanced by coculture of monocytes with activated EC. When either cell population was fixed with paraformaldehyde or killed by freeze‐thawing before addition to the co‐culture, cytokine levels reverted to those produced by the unaffected population alone. On the other hand, separating the two cell populations by a cell‐impermeable membrane in transwell cultures did not affect the synergistic production of the cytokines. Taken together, our data suggest that EC and MO can synergize in response to stimuli by producing IL‐6 and that this synergy is dependent on the integrity of both cell populations, but independent of cell‐cell contact.
Endothelium‐dependent relaxation of rat aorta to a histamine H3 agonist is reduced by inhibitors of nitric oxide synthase, guanylate cyclase and Na+,K+‐ATPase
Authors: Djuric D. M. , Nesic M. T. , Andjelkovic I. Z.
Published: March 2007

The possible involvement of different effector systems (nitric oxide synthase, guanylate cyclase, β‐adrenergic and muscarinic cholinergic receptors, cyclooxygenase and lipoxygenase, and Na+,K+‐ATPase) was evaluated in a histamine H3 receptor agonist‐induced ((R)α‐methylhistamine, (R)α‐MeHA) endothelium‐dependent rat aorta relaxation assay. (R)α‐MeHA (0.1 nM – 0.01 mM) relaxed endothelium‐dependent rat aorta, with a pD2 value of 8.22 ± 0.06, compared with a pD2 value of 7.98 ± 0.02 caused by histamine (50% and 70% relaxation, respectively). The effect of (R)α‐MeHA (0.1 nM – 0.01 mM) was competitively antagonized by thioperamide (1, 10 and 30 nM) (pA2 = 9.21 ± 0.40; slope = 1.03 ± 0.35) but it was unaffected by pyrilamine (100 nM), cimetidine (1 μM), atropine (10 μM), propranolol (1 μM), indomethacin (10 μM) or nordthydroguaiaretic acid (0.1 mM). Inhibitors of nitric oxide synthase, L‐NG‐monomethylarginine (L‐NMMA, 10 μM) and NG‐nitro‐L‐arginine methylester (L‐NOARG, 10 μM) inhibited the relaxation effect of (R)α‐MeHA, by approximately 52% and 70%, respectively). This inhibitory effect of L‐NMMA was partially reversed by L‐arginine (10 μM). Methylene blue (10 μM) and ouabain (10 μM) inhibited relaxation (R)α‐MeHA‐induced by approximately 50% and 90%, respectively. The products of cyclooxygenase and lipoxygenase are not involved in (R)α‐MeHA‐induced endothelium‐dependent rat aorta relaxation nor are the muscarinic cholinergic and β‐adrenergic receptors. The results also suggest the involvement of NO synthase, guanylate cyclase and Na+,K+‐ATPase in (R)α‐MeHA‐induced endothelium‐dependent rat aorta relaxation.
Effects of copper and zinc on proteoglycan metabolism in articular cartilage
Authors: Pasqualicchio M. , Gasperini R. , Velo G. P. , Davies M. E.
Published: March 2007

Co‐Cultures of porcine articular cartilage and synovium or synovial conditioned medium were used as an in vitro model to mimic inflammatory events at the cartilage/synovial junction in degenerative joint disease. This model provides a useful tool to assess the anti‐inflammatory and antiarthritic properties of pharmacological agents. In this study the effects of copper and zinc on (i) PG synthesis by cartilage and (ii) synovial‐induced PG depletion have been investigated. Copper sulphate at a concentration of 0.01 mM did not stimulate PG synthesis significantly in cultured cartilage explants but completely abrogated the inhibitory effects of synovial tissue in co‐culture experiments. This finding was supported by the histological demonstration of copper‐dependent reversal of the PG depletion in cartilage exposed to synovial conditioned medium. Zinc sulphate at 0.01 mM had no effect on PG synthesis and was unable to protect cartilage against synovialinduced PG depletion. These results reveal possible mechanisms by which copper exerts its anti‐inflammatory and anti‐arthritic actions.
Inhibition of the production of mediators of inflammation by corticosteroids is a glucocorticoid receptor‐mediated process
Authors: Madretsma G. S. , Dijk A. P. M. van , Tak C. J. A. M. , Wilson J. H. P. , Zijlstra F. J.
Published: March 2007

In order to find an explanation for corticosteroid resistance we assessed whether inhibition by dexamethasone (DEX) of the stimulated production of TNF‐∝, IL‐6, PGE2 and LTB4 by peripheral blood mononuclear cells (MNC) depends on binding to the glucocorticoid receptor (GR), and whether it is determined by the number or the affinity of the GR of these cells. GR number and affinity of MNC were determined by means of a whole cell DEX binding assay. MNC were incubated with DEX and LPS or A23187 in the absence or presence of RU486, a potent steroid antagonist. DEX caused a concentration dependent inhibition of TNF‐∝, IL‐6 and PGE2 production but had no effect on LTB4 production. RU486 significantly blocked the effect of DEX, but no correlations were found between the inhibition of mediator release and the Kd or receptor number.
Opposite effects of interleukin‐4 and interleukin‐10 on nitric oxide production in murine macrophages
Authors: Maru A. , Jackson S. K.
Published: March 2007

Interleukin‐4 (IL‐4) and interleukin‐10 (IL‐10) were evaluated for their ability to inhibit the production of nitric oxide (NO) by interferon‐γ (IFN‐γ)‐ or lipopolysaccharide (LPS)‐activated murine macrophages (RAW 264.7 and J774.2). Macrophages pre‐treated with IL‐4 and then stimulated with IFN‐γ or LPS showed significant inhibition in their ability to produce NO as measured by nitrite production. Simultaneous treatment of IL‐4 pre‐incubated cells with IFN‐γ and LPS together augmented nitrite accumulation. On the other hand, similar exposures of the macrophages to IL‐10 followed by IFN‐γ or LPS treatments resulted in significantly increased NO production. Thus IL‐10 failed to suppress IFN‐γ or LPS‐induced NO production and showed opposite effects in these experiments to IL‐4. We conclude that the two lymphokines have differing roles in the control of production of NO and might act to control the secretion of nitric oxide in vivo.
Blood eosinophils and serum eosinophil cationic protein in patients with acute and chronic urticaria
Authors: Lorenzo G. Di , Mansueto P. , Melluso M. , Candore G. , Cigna D. , Pellitteri M. E. , Salvo A. Di , Caruso C.
Published: March 2007

We have analysed the relationship of blood eosinophil count and serum eosinophil cationic protein (ECP) levels in patients with acute and chronic idiopathic urticaria. The ECP levels and eosinophil counts were measured in the peripheral blood of 15 patients with acute urticaria, 25 with chronic idiopathic urticaria and 10 normal healthy subjects. Blood eosinophil counts and serum ECP levels increased in all patients with acute urticaria. Concerning patients affected by chronic urticaria, taking into account the recrudescence of the disease at the moment of taking the blood sample, only symptomatic patients showed increased eosinophil blood values whereas serum ECP levels were increased both in symptomatic and asymptomatic patients. Furthermore, serum ECP levels in chronic urticaria did not correlate with the peripheral eosinophil counts, as they did in acute urticaria. The results of the present study indicate that eosinophils may play a role in the inflammatory mechanisms in patients with acute and chronic urticaria showing a positive correlation between serum ECP levels and disease activity.
Macrophage‐derived neutrophil chemotactic factor is involved in the neutrophil recruitment inhibitory activity present in the supernatants of LPS‐stimulated macrophages
Authors: Tavares-Murta B. M. , Cunha F. Q. , Dias-Baruffi M. , Roque-Barreira M. C. , Ferreira S. H.
Published: March 2007

In a previous study, we demonstrated the presence of a neutrophil recruitment inhibitory factor (NRIF) in the supernatants of LPS‐stimulated macrophages. Recently, the purification of a 54 kDa protein, identified as the macrophage‐derived neutrophil chemotactic factor (MNCF) was reported. Since NRIF and MNCF are obtained under the same conditions, and, since the intravenous administration of TNF‐α and IL‐8 inhibits neutrophil migration, we have investigated whether MNCF could be responsible for this inhibitory activity. After affinity chromatography of the macrophage supernatants on a D‐galactose column, the inhibitory activity was recovered in both the unbound (D‐gal−) and bound (D‐gal+) fractions, with MNCF being found in the D‐gal+ fraction. Further gel filtration of the latter on Superdex 75 yielded a single peak containing both activities. In a cytotoxicity assay, most of the TNF found in the crude supernatants was recovered in the D‐gal− fraction. Furthermore, the incubation of the D‐gal− fraction with anti‐TNF‐α plus anti‐IL‐8 antisera partially prevents its inhibitory effect on neutrophil migration, but had no effect on the D‐gal+ activity. Overall, these results suggest that the D‐gal− inhibitory effect is partially mediated by TNF‐α and IL‐8, and that MNCF accounts for the inhibition of neutrophil migration in vivo by the D‐gal+ fraction.
The contribution of the immune system to parturition
Authors: Jongh R. De , Jorens Ph. , Student I. , Heylen R.
Published: March 2007

The immune system plays a central role before and during parturition, including the main physiological processes of parturition: uterine contractions and cervical ripening. The immune system comprises white blood cells and their secretions. Polymorphonuclear cells and macrophages invade the cervical tissue and release compounds, such as oxygen radicals and enzymes, which break down the cervical matrix to allow softening and dilatation. During this inflammatory process, white blood cells undergo chemotaxis, adherence to endothelial cells, diapedesis, migration and activation. Factors that regulate white blood cell invasion and secretion include cytokines such as tumour necrosis factor and interleukins. Glucocorticoids, sex hormones and prostaglandins, affect cytokine synthesis. They also modulate the target cells, resulting in altered responses to cytokines. On the other hand, the immune system has profound effects on the hormonal system and prostaglandin synthesis. In animals, nitric oxide has marked effects on uterine quiescence during gestation. At the same time, it plays an important role in regulating the vascular tone of uterine arteries and has anti‐adhesive effects on leukocytes. Cytokines are found in amniotic fluid, and in maternal and foetal serum at term and preterm. Several intrauterine cells have been shown to produce these cytoldnes. Since neither white blood cells, cytokines nor nitric oxide seem to be the ultimate intermediate for human parturition, the immune system is an additional but obligatory and underestimated component in the physiology of delivery. Scientists, obstetricians and anaesthesiologists must thus be aware of these processes.
Effects of anti‐inflammatory drugs on fever and neutrophilia induced by Clostridium difficile toxin B
Authors: Cardoso R. A. , Filho A. A. Melo , Melo M. C. C. , Lyerly D. M. , Wilkins T. D. , Lima A. A. M. , Ribeiro R. A. , Souza G. E. P.
Published: March 2007

This study investigated the ability of Clostridium difficile toxin B, isolated from the VPI 10463 strain, to induce fever and neutrophilia in rats. Intravenous injection of toxin B (0.005–0.5 μg/kg) evoked a dose‐dependent increase in body temperature. The febrile response to 0.5 μg/kg of the toxin started in 2.5 h, peaked at 5 h, and subsided fully within 24 h. Toxin B also induced a dosedependent neutrophilia. Pretreatment with indomethacin (2 mg/kg, i.p.) did not affect the neutrophilia induced by toxin B, but significantly reduced the febrile response measured 4 to 8 h after toxin B injection. Dexamethasone (0.5 mg/ kg) also markedly diminished the febrile response induced by toxin B. These results show that Clostridium difficile toxin B induced a febrile response susceptible to inhibition by dexamethasone and indomethacin. Furthermore, they suggest that prostaglandins are not involved in the neutrophilia caused by this toxin.
The effect of lipocortin 1 on neutrophil deformability
Authors: Drost E. M. , MacNee W. , Smith S. F.
Published: March 2007

Lipocortn 1 (Lc1) is an anti‐inflammatory protein, which, given systemically, inhibits polymorphonuclear neutrophil (PMN) emigration from the circulation to sites of inflammation; delivery of Lc1 to the inflamed site is ineffective. We have examined the effect of Lc1 on changes in PMN deformability, and observed a consistent improvement in the deformability of unstimulated PMN; N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐activated cell deformability was unaltered. A Lc1‐induced increase in cell deformability may reduce PMN sequestration so contributing to the anti‐migratory effects of systemic Lc1 previously demonstrated in vivo.
Expression of lipocortins in human bronchial epithelial cells: effects of IL‐1β , TNF‐α, LPS and dexamethasone
Authors: Verheggen M. M. , Bont H. I. M. de , Adriaansen-Soeting P. W. C. , Goense B. J. A. , Tak C. J. A. M. , Hoogsteden H. C. , Hal P. Th. W. van , Versnel M. A.
Published: March 2007

In this study, we investigated the expression of lipocortin I and II (annexin I and I in the human bronchial epithelium, both in vivo and in vitro. A clear expression of lipocortin I and II protein was found in the epithelium in sections of bronchial tissue. In cultured human bronchial epithelial cells we demonstrated the expression of lipocortin I and II mRNA and protein using Northern blotting, FACScan analysis and ELISA. No induction of lipocortin I or II mRNA or protein was observed after incubation with dexamethasone. Stimulation of bronchial epithelial cells with IL‐1β, TNF‐α or LPS for 24 h did not affect the lipocortin I or II mRNA or protein expression, although PGE2 and 6‐keto‐PGF1α production was significantly increased. This IL‐1β‐ and LPS‐mediated increase in eicosanoids could be reduced by dexamethasone, but was not accompanied by an increase in lipocortin I or II expression. In human bronchial epithelial cells this particular glucocorticoid action is not mediated through lipocortin I or II induction.
TNF‐induced IL‐8 and MCP‐1 production in the eosinophilic cell line, EOL‐1
Authors: Goldstein L. A. , Strieter R. M. , Evanoff H. L. , Kunkel S. L. , Lukacs N. W.
Published: March 2007

The role of eosinophils in inflammation and their mode of activation is not well understood. Eosinophil accumulation and subsequent expression of cytokines at the site of inflammation may play a role in exacerbation of inflammatory responses. In the present study, we have examined the role of TNF‐α in eosinophil activation and chemokine production using a human leukaemic eosinophil cell line, EOL‐1. Initial studies demonstrated that TNF‐α induced the upregulation of IL‐8 and MCP‐1 mRNA and protein. Kinetic studies indicated production of chemokines, IL‐8 and MCP‐1, as early as 4 h post‐activation, with peak levels of chemokine produced at 8 h, and decreasing by 24 h post‐TNF‐α activation. When IL‐10, a suppressive cytokine, was incubated with TNF‐α and EOL‐1 cells, no effect was observed on IL‐8 and MCP‐1 production. However, dexamethasone, a glucocorticoid, demonstrated potent inhibitory effects on the EOL‐1‐derived chemokines. These studies indicate that eosinophils may be a significant source of chemokines capable of participating in, and maintaining, leukocyte recruitment during inflammatory responses, such as asthma.
Effects of fluticasone propionate on arachidonic acid metabolites in BAL‐fluid and methacholine dose‐response curves in non‐smoking atopic asthmatics
Authors: Overbeek S. E. , Bogaard J. M. , Garrelds I. M. , Zijlstra F. J. , Mulder P. G. H. , Hoogsteden H. C.
Published: March 2007

Hyperresponsiveness of the airways to nonspecific stimuli is a characteristic feature of asthma. Airway responsiveness is usually characterized in terms of the position and shape of the dose–response curve to methacholine (MDR). In the study we have investigated the influence of fluticasone propionate (FP), a topically active glucocorticoid, on arachidonic acid (AA) metabolites in broncho‐alveolar lavage (BAL) fluid (i.e. TxB2, PGE2, PGD2, 6kPGF1α and LTC4) on the one hand and MDR curves on the other hand. The effect of FP was studied in a randomized, double‐blind, placebo‐controlled design in 33 stable nonsmoking asthmatics; 16 patients received FP (500 μg b.i.d.) whereas 17 patients were treated with placebo. We found that the forced expiratory volume in 1s (FEV1 % predicted) increased, the log2PC20 methacholine increased and the plateau value (% fall in FEV1) decreased after a 12 week treatment period. No changes in AA‐metabolites could be determined after treatment except for PGD2 which decreased nearly significantly (p = 0.058) within the FP treated group, whereas the change of PGD2 differed significantly (p = 0.05) in the FP treated group from placebo. The levels of the other AA metabolites (i.e. TxB2, PGE2, 6kPGF1α and LTC4) remained unchanged after treatment and were not significantly different from the placebo group. Our results support the hypothesis that although FP strongly influences the position, the shape and also the maximum response plateau of the MDR curve, this effect is not mainly achieved by influence on the level of AA metabolites. Other pro‐inflammatory factors may be of more importance for the shape of the MDR curve. It is suggested that these pro‐inflammatory factors are downregulated by FP.
Inhibition of NO‐synthase and degranulation of rat omental mast cells in vitro
Authors: Northover A. M. , Northover B. J.
Published: March 2007

Mast cell amines, platelet‐activating factor (PAF), thromboxanes and leukotrienes have been shown to be released during nitric oxide‐synthase inhibition in the rat intestine. Mast cells in rat isolated omentum (OMCs) or isolated from the rat peritoneal cavity (PMCs) have been used here to investigate the relationship(s) between these agents. N‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) caused some degranulation of OMCs, but no enhancement of histamine release from PMCs. PAF (5 μM) and U46619 (1 μM) degranulated OMCs and enhanced histamine release from PMCs. Pre‐treatment of the omentum with BN52021 (10 μM) inhibited degranulation of OMCs in response to L‐NAME, PAF or U46619. Pretreatment with 1‐benzylimidazole (5 or 50 μM) inhibited the effect of L‐NAME but not that of PAF. Indomethacin (1 μM) or sodium nitroprusside (10 μM) also inhibited the effects of L‐NAME, but nordihydroguaiaretic acid (30 μM) did not. In PMCs BN52021 inhibited PAF‐induced, but not U46619‐induced, release of histamine. These results suggest that inhibition of nitric oxidesynthase in the omentum by L‐NAME allows thromboxanes to release PAF, which in turn degranulates and releases histamine from OMCs.
Detection of serum soluble markers of immune activation in rheumatoid arthritis
Authors: Kogure T. , Itoh T. , Shimada Y. , Shintani T. , Ochiai H. , Terasawa K.
Published: March 2007

The mutual correlation among soluble CD4 (sCD4), soluble CD8 (sCD8), and soluble CD23 (sCD23) has not yet been studied in patients with rheumatoid arthritis (RA), although previous studies have demonstrated that certain soluble markers of immune activation are elevated in RA. Thus, we examined this correlation based on the serum levels of sCD4, sCD8 and sCD23, and that of their levels with other serum markers such as immunoglobulin (Ig) subtypes (IgG, IgM and IgA), IgM‐rheumatoid factor (IgM‐RF) and C‐reactive protein (CRP) in 25 RA patients, sCD4 was not elevated, whereas both sCD8 and sCD23 increased in RA patients compared with the healthy controls; a majority of RA patients, in particular, showed a high sCD23 level. The level of sCD23 showed a correlation with that of IgM‐RF, but not with those of IgG, IgM, IgA and CRP. Importantly, a high level of sCD23 was not always accompartied with that of sCD8. The independent change between sCD23 and sCD8 levels was also observed in a one‐year follow‐up study of the two RA patients. These findings indicate that B cells might be generally activated in RA, whereas T‐cell activation in variable in each patient with RA, suggesting that sCD23 is a more indicative marker for the immune status of RA patients than sCD8 from the clinical aspects.
Levels of soluble VCAM‐1, soluble ICAM‐1, and soluble E‐selectin in patients with tuberculous pleuritis
Authors: Hamzaoui A. , Hamzaoui K. , Kahan A. , Chabbou A.
Published: March 2007

Tuberculosis is characterized by the presence of activated mononuclear cells both in the peripheral circulation and in pleural fluid. Expression and up‐regulation of adhesion molecules is the basis of cell‐cell adhesion in granuloma formation and in leukocyte migration to the inflammatory site. Soluble isoforms of adhesion molecules have been described, and their expression at high levels indicated an activated state. The purpose of this study was to evaluate levels of soluble adhesion molecules in serum and pleural fluid from patients with tuberculous pleural effusions, compared with non‐tuberculous pleural effusions. We analysed levels of soluble vascular cell adhesion molecule‐1 (s.VCAM‐1), soluble intercellular adhesion molecule‐1 (s.ICAM‐1), and soluble E‐selectin (sE‐selectin) in serum and pleural fluid from patients with tuberculous pleuritis, by sandwich ELISA. Serum levels of s.ICAM‐1 and s.VCAM‐1 in patients with tuberculosis were higher than those in healthy controls (p < 0.001). Levels of sE‐selectin levels were in the normal range compared with control groups. In pleural fluid, levels of s.VCAM‐1 and s.ICAM‐1 were increased in pleural effusions. Patients with tuberculous pleural effusion exhibited high levels of s.ICAM‐1 compared with patients with neoplastic pleural involvement. Up‐regulation of s.VCAM‐1 and s.ICAM‐1 in serum, along with increased levels of sE‐selectin in pleural effusions from tuberculous patients, may result in transmigration of activated inflammatory cells inducing pleural damage, which may contribute to the pathological processes involved.
Anti‐inflammatory effects of Stephania tetrandra S. Moore on interleukin‐6 production and experimental inflammatory disease models
Authors: Kang H-S. , Kim Y-H. , Lee C-S. , Lee J-J. , Choi I. , Pyun K-H.
Published: March 2007

Deregulation of interleukin‐6 (IL‐6) expression caused the synthesis and release of many inflammatory mediators. It is involved in chronic inflammation, autoimmune diseases, and malignancy. Stephania tetrandra S. Moore is a Chinese medicinal herb which has been used traditionary as a remedy for neuralgia and arthritis in China. To investigate the anti‐inflammatory effects of S. tetrandra S. Moore in vitro and in vivo, its effects on the production of IL‐6 and inflammatory mediators were analysed. When human monocytes/macrophages stimulated with silica were treated with 0.1–10 μg/ml S. tetranda S. Moore, the production of IL‐6 was inhibited up to 50%. At these concentrations, it had no cytotoxicity effect on these cells. It also suppressed the production of IL‐6 by alveolar macrophages stimulated with silica. In addition, it inhibited the release of superoxide anion and hydrogen peroxide from human monocytes/macrophages. To assess the anti‐fibrosis effects of S. tetrandra S. Moore, its effects on in vivo experimental inflammatory models were evaluated. In the experimental silicosis model, IL‐6 activities in the sera and in the culture supernatants of pulmonary fibroblasts were also inhibited by it. In vitro and in vivo treatment of S. tetrandra S. Moore reduced collagen production by rat lung fibroblasts and lung tissue. Also, S. tetrandra S. Moore reduced the levels of serum GOT and GPT in the rat cirrhosis model induced by CCL4, and it was effective in reducing hepatic fibrosis and nodular formation. Taken together, these data indicate that it has a potent anti‐inflammatory and antifibrosis effect by reducing IL‐6 production.
Regulation by anti‐inflammatory cytokines (IL‐4, IL‐10, IL‐13, TGFβ)of interleukin‐8 production by LPS‐ and/ or TNFα‐activated human polymorphonuclear cells
Authors: Marie C. , Pitton C. , Fitting C. , Cavaillon J-M.
Published: March 2007

The capacity to down‐regulate the production of IL‐8 by LPS‐activated human polymorphonuclear cells (PMN) has been demonstrated for IL‐4, IL‐10, and TGFβ. We compared their relative capacities and further extended this property to IL‐13. We report a great heterogeneity among individuals related to the responsiveness of PMN to the IL‐4 and IL‐13 inhibitory effects while their response to the IL‐10 effect was homogenous. The inhibitory activities were observed at the transcriptional level. IL‐8 induction by TNFα was, unlike its induction by LPS, resistant to the inhibitory effects of IL‐10, IL‐4, IL‐13 and TGFβ. Furthermore, IL‐10 and IL‐4 inhibitory activity were less effective when TNFα was acting synergistically with LPS to induce IL‐8 production by PMN. LPS‐induced cell‐associated IL‐8, detected in the PMN cultures, could be marginally inhibited by IL‐4 and IL‐10. Altogether, our data demonstrate that IL‐13 is able to inhibit LPS‐induced IL‐8 production by human PMN, although IL‐10 remains the most active anti‐inflammatory cytokine. Despite the capacity of IL‐4, IL‐10, and IL‐13 to limit the production of TNFα‐induced IL‐8 in a whole blood assay, none was able to inhibit this production when studying isolated human polymorphonuclear cells.
Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate
Authors: Slieker W. A. T. , Hal P. Th. W. van , Wijkhuijs J. M. , Hopstaken-Broos J. P. M. , Noordhoek J. A. , Overbeek S. E. , Mulder P. G. H. , Postma D. S. , Hoogsteden H. C.
Published: March 2007

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down‐modulation of HLA‐DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long‐term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non‐smoking patients with allergic asthma who were treated for 2.5 years with a β2‐receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long‐term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two‐fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA‐DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long‐term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.
Phosphodiesterase 4 inhibitors and db‐cAMP inhibit TNF‐α release from human mononuclear cells. Effects of cAMP and cGMP‐dependent protein kinase inhibitors
Authors: Hichami A. , Boichot E. , Germain N. , Berdyshev E. , Coqueret O. , Lagente V.
Published: March 2007

We investigated the effects of specific inhibitors of cAMP‐dependent protein kinase (PKA) and cGMP‐dependent protein kinase (PKG) on the inhibitory activity of phosphodiesterase (PDE) type 4 inhibitors and of the cell permeable analogue of cAMP, db‐cAMP on LPS‐induced TNF‐α release from human mononuclear cells. Incubation from 30 min of mononuclear cells with dbcAMP (10−5 to 10−3 M), rolipram (10−9 M to 10−5 M) or Ro 20‐1724 (10−9 M to 10−5 M) significantly inhibited LPS‐induced TNF‐α release. When mononuclear cells were preincubated for 30 min with the selective PKA inhibitor, H89 (10−4 M), but not with the selective PKG inhibitor, Rp‐8‐pCPT‐cGMPs (10−4 M), a significant reduction of the inhibitory effect of db‐cAMP was noted. Thirty min incubation of mononuclear cells with Rp‐8‐pCPT‐cGMPs induced a significant reduction of the inhibitory activities of both rolipram and Ro 20‐1724 (10−9 to 10−5 M) on LPS‐induced TNF‐α release, whereas H89 elicited a moderate, but significant inhibition. The present data indicate that db‐cAMP inhibits TNF‐α release from human mononuclear cells through a PKA‐dependent mechanism. In contrast, PDE 4 inhibitors elicit their in vitro anti‐inflammatory activities via a PKG‐dependent rather than PKA‐dependent activation.