bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of triazolodiazepine on the production of interleukin‐6 from murine spleen cells and rabbit synovial cells in vitro
Authors: Ju Dian-Wen , Zheng Qin-Yue , Cao Xue-Tao , Zheng Qing-Hua , Guan Xiao-Jun , Wang Hong-Bin
Published: March 2007

Interleukin‐6 (IL‐6) is a multifunctional cytokine that regulates the immune response, acute phase anaphylactic reaction, and haematopoiesis. Lipopolysaccharide (6–24 μg/ml) significantly induced IL‐6 release from murine spleen cells. In cultured rabbit synovial cells interleukin‐1 (IL‐1, 1–10 U/ml) induced IL‐6 production in a concentration‐dependent manner. Triazolodiazepine (Tri) is a hetrazepine platelet‐activating factor antagonist. In this study we found that Tri (0.1–10 μmol/l) exerted strong inhibitory effects on LPS stimulated IL‐6 production in murine spleen cells. Kinetic studies showed that the inhibition of IL‐6 release was time‐independent. In rabbit synovial cells Tri also reduced IL‐6 release induced by IL‐1 and tumour necrosis factor. Inhibition of cytokine production by Tri may partially explain its wide and strong anti‐inflammatory effects.
CD25+ T‐lymphocytes induce CD11b on eosinophils in allergic nasal mucosa
Authors: Horiguchi S. , Hisamatsu K. , Tasaka K.
Published: March 2007

In the allergic mucosa, there is a significant increase in numbers of CD25+ cells and activated eosinophils. To determine whether a link exists between the activated T‐lymphocytes and tissue eosinophils in nasal allergy, we studied CD25+ cells in the nasal mucosa and compared the levels of soluble IL‐2 receptor (sIL‐2R) both in the serum and the nasal secretions, and further investigated expression of CD11b on eosinophils in the nasal lavage fluids and peripheral blood of patients with nasal allergy. We also examined the effects of the culture supernatant of Con A‐ and IL‐2‐activated T‐lymphocytes on CD11b expression on eosinophils in the present study. The concentration of sIL‐2R in the nasal secretions from patients with Japanese cedar pollinosis (JCP) was significantly higher than that from normal subjects (p < 0.01). The sIL‐2R level was significantly higher in the nasal secretions than in the sera in patients (p < 0.01), and CD11b expression on eosinophils from nasal hvage fluid was significandy higher than that of eosinophils from peripheral blood of the same individuals (p < 0.01). The activated T‐lymphocytes promoted eosinophil activation with upregulation of CD11b in vitro, and eosinophils in the nasal secretions from patients significantly expressed more CD11b in vivo. These results indicate that activation of T‐lymphocytes is linked to eosinophil activation in nasal allergy.
Influence of sensitization and allergen provocation procedures on the development of allergen‐induced bronchial hyperreactivity in conscious, unrestrained guinea‐pigs
Authors: Santing R. E. , Olymulder C. G. , Diepen B. van , Meurs H. , Zaagsma J.
Published: March 2007

The effects of different sensitization and allergen provocation regimens on the development of allergen‐induced bronchial hyperreactivity (BHR) to histamine were investigated in conscious, unrestrained guinea‐pigs. Similar early and late phase asthmatic reactions, BHR for inhaled histamine after the early (6 h) as well as after the late reaction (24 h), and airway inflammation were observed after a single allergen provocation in animals sensitized to produce mainly IgG or IgE antibodies, respectively. Repeating the allergen provocation in the IgE‐sensitized animals after 7 days, using identical provocation conditions, resulted in a similar development of BHR to histamine inhalation. Repetition of the allergen provocation during 4 subsequent days resulted in a decreased development of BHR after each provocation, despite a significant increase in the allergen provocation dose necessary to obtain similar airway obstruction. The number of inflammatory cells in the bronchoalveolar lavage was not significantly changed after repeated provocation, when compared with a single allergen provocation. Finally, we investigated allergen‐induced bronchial hyperreactivity by repetition of the sensitization procedure at day 7 and 14 (booster), followed by repeated allergen provocation twice a week for 5 weeks. Surprisingly, no BHR to histamine could be observed after either provocation, while the number of inflammatory cells in the bronchoalveolar lavage fluid after 5 weeks was enhanced compared with controls. These data indicate that both IgE and IgG sensitized guinea‐pigs may develop bronchial hyperreactivity after a single allergen provocation. Repeated allergen exposure of IgE sensitized animals causes a gradual fading of the induced hyperreactivity despite the on‐going presence of inflammatory cells in the airways, indicating a mechanism of reduced cellular activation.
Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective
Authors: Vamvakopoulos Nicholas V.
Published: March 2007

This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue‐specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2) a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system.
Sequential release of cytokines, lipid mediators and nitric oxide in experimental colitis
Authors: van Dijk A. P. M. , Keuskamp Z. J. , Wilson J. H. P. , Zijlstra F. J.
Published: March 2007

The object of this study was to establish whether different pro‐ and anti‐inflammatory mediators were formed in colonic tissue from experimental colitis depending on the course of the disease. Concentrations of mediators of inflammation were examined in colonic tissue in dextran induced colitis in mice. Initial inflammation was produced by 5 days treatment of 10% dextran sodium sulfate (DSS) in drinking water, followed by a further 9 day period of 2% DSS in an attempt to produce a milder chronic inflammation. The degree of inflammation was scored by a standardized macroscopic and histological examination. Initially, a 60% maximum inflammation score was observed at day 4. At this time inflammation was associated with the release of interleukin‐lβ (IL‐1β) and tumour necrosis factor‐α (TNFα), whereas both prostaglandins 6kPGF1α and PGE2 and nitric oxide (NO) markedly decreased. Then a 25% inflammation score was reached which coincided with an increased production of platelet‐activating factor (PAF). No significant changes were observed in leukotriene B4 and C4 formation. In conclusion, pro‐inflammatory cytokines IL‐1β and TNFα are considered to be primary mediators, whereas PAF, eicosanoids and NO may reflect secondary mediators in experimental colitis.
Analysis of cyt0kine gene expression in stimulated T cells of small children by semi‐quantitative PCR
Authors: Koning H. , Baert M. R. M. , Groot R. de , Neijens H. J. , Savelkoul H. F. J.
Published: March 2007

Only limited amounts of peripheral blood samples can be obtained from small children. Therefore, a polymerase chain reaction (PCR) aided analysis of cytokine gene expression by PBMC or T cells is a valuable tool. We present a combination of procedures to obtain an accurate estimation of the expression of the cytokines IL‐4 and IFN‐γ. This can be performed on T cells purified from blood samples of up to 5 ml in volume from children aged 0–4 years with allergic asthma and atopic dermatitis. This procedure includes multiple sampling of PCR products to determine the linear phase of the PCR; inter‐experiment correction using a helper T‐cell clone, expressing both IL‐4 and IFN‐γ; interpatient correction by comparing the expression of a housekeeping gene (HPRT); and finally the development of specific software to analyse densitometric data obtained by scanning photographs of agarose gels, separating PCR products. In this way it is possible to study cytokine gene expression from a very small amount of material.
An increase in nitric oxide produced by rat peritoneal neutrophils is not involved in cell apoptosis
Authors: Fierro I. M. , Barja-Fidalgo C. , Canedo R. M. , Cunha F. Q. , Ferreira S. H.
Published: March 2007

Polymorphonuclear neutrophils (PMN) obtained from carrageenin‐stimulated peritoneal cavities of rats, but not blood PMN, spontaneously produced nitric oxide (NO) when incubated in vitro. Incubation of the cells with the NO synthase inhibitors, L‐imino‐ethyl‐L‐ornithine (L‐NIO) or NG‐monomethyl‐L‐arginine (L‐NMMA), inhibited NO production. This inhibition could be reversed by L‐arginine. Incubation of PMN with lipopolysaccharide (LPS) failed to enhance NO production. Pretreatment of the rats with dexamethasone (DEXA) prior to carrageenin injection or incubation of PMN with the glucocorticoid in vitro partially inhibited the spontaneous release of NO. On the other hand, when PMN obtained from DEXA pretreated rats were incubated in vitro with DEXA, NO synthase activity and hence NO generation were almost abolished. A similar inhibition was also observed following the addition of L‐NIO or cycloheximide to cultures of carrageenin‐elicited PMN. The NO production by PMN did not appear to be related to cell viability or apoptosis. Indeed, neither the blockade of NO generation by L‐NIO nor the incubation of the neutrophils with a NO donor, S‐nitroso‐acetylpenicillamine (SNAP) modified the pattern of LDH release or DNA fragmentation. In summary, it appears that PMN migration triggers a continuous NO synthesis, and that NO produced by these cells is not related to their apoptosis.
Nitric oxide induces apoptosis in a human colonic epithelial cell line, T84
Authors: Sandoval M. , Liu X. , Oliver P. D. , Zhang X.-J. , Clark D. A. , Miller M. J. S.
Published: March 2007

Chronic inflammation is associated with inducible nitric oxide synthase expression in infiltrating and resident cells (epithelia, neurons) and an exaggerated release of nitric oxide. NO can induce apoptosis in macrophages and tumour cell lines. We investigated whether NO induced cell death in an epithelial (T84) cell fine via apoptosis. Culture T84 cells were exposed to a bolus of NO (40 or 80 μM) dissolved in Hank′s balanced salt solution (HBSS) supplemented with 10% fetal calf serum (FCS). After incubation for 4 h at 37°C in 5% CO2, cells were either stained for DNA fragmentation with the TdT‐mediated dUTP–biotin nick end labelling (TUNEL) method, or cytosolic DNA fragments quantified by a cell death detection ELISA assay. Nitric oxide induced apoptosis in a dose‐dependent manner which preceded frank cell death (failure to exclude Trypan blue). These data suggest that epithelial cell death may be NO dependent and via apoptosis, in states of gut inflammation.
Effects of systemic glucocorticosteroids on peripheral neutrophil functions in asthmatic subjects: an ex vivo study
Authors: Paggiaro P. L. , Bancalari L. , Giannessi D. , Bernini W. , Lazzerini G. , Sicari R. , Bacci E. , Dente F. L. , Vagaggini B. , Caterina R. De
Published: March 2007

In 21 asthmatic subjects, several functions of isolated peripheral neutrophils (chemokinesis and chemotaxis toward 10% E. coli; superoxide anion generation after PMA; leukotriene B4 (LTB4) release from whole blood and isolated neutrophtls, before and after different stimuli) were evaluated during an acute exacerbation of asthma, and after 14 – 54 days of treatment with systemic glucocorticosteroids (GCS). During acute exacerbation, superoxide anion generation was higher in asthmatics than in eleven normal subjects (39.2 ± 14.1 vs. 25.2 ± 7.3 nmol, p < 0.05); there was a significant correlation between FEV1 (% of predicted) and neutrophil chemotaxis (r = −0.52, p = 0.04). After treatment, there was no significant change in all neutrophil functions, except for a decrease in neutrophil chemotaxis in subjects who showed an FEV1 increase > 20% after GCS treatment (from 131 ± 18 to 117 ± 21 μm, p = 0.005). Chemokinesis sicantly decreased in all subjects, and the changes significantly correlated with an arbitrary score of the total administered dose of GCS (r = 0.57, p < 0.05). These data suggest that neutrophil activation plays a minor role in asthma, and that treatment with GCS is not able to modify most functions of peripheral neutrophils in asthmatic subjects; chemotaxis seems to be related only to the severity of the asthma and it could reflect the improvement of the disease.
A change of IL‐2 and IL‐4 production in patients with Helicobactor pylori infection
Authors: Fan X. G. , Yakoob J. , Fan X. J. , Keeling P. W. N.
Published: March 2007

Helicobactor pylori is the most common cause of gastroduodenal inflammation. However, the exact immune pathogenesis is not fully understood. To look for evidence of the immunological mechanism in H. pylori associated disease, we measured cytokine interleukin‐2 (IL‐2) and IL‐4 levels produced by peripheral blood lymphocytes (PBL) and gastric biopsies in 20 subjects with or without H. pylori infection. H. pylori can stimulate IL‐2 and IL‐4 production from PBL in H. pylori negative as well as H. pylori positive individuals. The spontaneous IL‐2 production by PBL and gastric biopsies was greater (p < 0.0025, <0.001)in H. pylori negative individuals than that in H. pylori infected patients. Increased IL‐4 levels from PBL in H. pylori infected patients were found in the presence of H. pylori (p < 0.0025). An increased spontaneous production of IL‐4 from gastric biopsies was also observed in H. pylori infected patients (p < 0.025). In conclusion, an enhanced type 2 cytokine production was observed in H. pylori infected patients, which may be responsible for H. pylori chronic infection.
The breakdown of the cytokine network subsequent to human immunodeficiency virus infection
Authors: Clerici M. , Villa M. L. , Trabattoni D. , Shearer G. M.
Published: March 2007

The acquired immunodeflciency syndrome (AIDS) is a clinically multifaceted disease induced by infection with the human immunodeficiency virus (HIV). HIV infection results in a complex pattern of immunologic alterations that leads to the development of AIDS in the majority of HIV seropositive (HIV+) individuals. The reduction in CD4 T lymphocyte counts is the hallmark of HIV infection; nevertheless, long before the reduction in CD4 counts reaches critical levels, a series of profound and complex defects that impair the function of CD4 T lymphocytes can be detected. Thus, HIV infection is characterized by quantitative and qualitative defects affecting CD4 T lymphocytes. It was suggested recently that programmed cell death (PCD) is an important mechanism leading to CD4 depletion in HIV infection, and that susceptibility of peripheral lymphocytes to PCD is differentially regulated by diverse cytokines. Thus, type 1 cytokines would protect CD4 lymphocytes against PCD, whereas type 2 cytokines would not protect against, and could augment, PCD. We suggest that the qualitative alterations of the immune response provoke the CD4 depletion characteristic of HIV disease via type 2 cytokinemediated augmentation of PCD, and are therefore ultimately responsible for the progression of HIV infection. Finally, we summarize recent data showing that three correlates of disease progression: emergence of HIV strains with syncitium‐inducing ability (SI), type 1‐to‐type 2 cytokine shift, and CD4 depletion, are significantly associated, suggesting a complex interconnected virologic‐immunologic pathogenesis of HIV infection.
Histamine as a marker for hydroxyl radicals
Authors: Ching T.-L. , Hee R. M. van der , Bhoelan N. M. , Blauw J. , Menge W. M. P. B. , de Jong J. , Bast A.
Published: March 2007

During inflammation an influx of neutrophils and release of mediators from mast cells (such as histamine) take place. The stimulated neutrophils can produce reactive oxygen species (ROS). One of these ROS is the highly reactive hydroxyl radical (OH.). It would be interesting to be able to quantify the extent of ROS formation. We investigated if histamine which is present at the inflammation site can serve as an endogenous marker for the formation of OH.. We found that histamine after incubation with OH. gave two distinct products in our HPLC system. One of the products gave the same characteristics as the synthesized 2‐imidazolone derivative of histamine. This suggests that this derivative will be formed when histamine is incubated with OH..
Detection of soluble interleukin‐2 receptor and soluble intercellular adhesion molecule‐1 in the effusion of otitis media with effusion
Authors: Ganbo T. , Hisamatsu K.-I. , Inoue H. , Kikushima K. , Mizukoshi A. , Murakami Y.
Published: March 2007

We measured sIL‐2R, TNF‐α and sICAM‐1 in the sera and middle ear effusions (MEEs) of patients with otitis media with effusion (OME). Although there was no signmcant difference between the sIL‐2R levels of the serous and mucoid MEEs, they were significantly higher than serum sIL‐2R levels of OME patients and healthy controls. TNF‐α levels of the mucoid MEEs were significantly higher than those of the serous type. However, TNF‐α was rarely detected in the sera of OME patients or healthy controls. We observed significant differences between the serous and mucoid MEEs with respect to their sICAM‐1 levels, which were also higher than serum slCAM‐1 levels of OME patients and healthy controls. Our findings suggested that IL‐2, TNF‐α and ICAM‐1 could be significantly involved in the pathogenesis of OME through the cytokine network.
Lobenzarit disodium inhibits the constitutive NO–cGMP metabolic pathways. Possible involvement as an immunomodulatory drug
Authors: Padrón J. , Rojas A. , Glaría L. , Caveda L. , Delgado R. , Torres M. , Martínez O. , López E. , Beltrán A. , Palacios M.
Published: March 2007

Lobenzarit disodtulIl (CCA) is a novel immunomodulatory drug useful in the treatment of chronic inflammations. Its principal mechanism of action seems to be through enhancing the T suppressor/T helper lymphocyte ratio. However, the molecular basis for these actions remains unclear. In this study it was found that CCA inhibits the production of guanosine 3′,5′‐cyclic monophosphate almost completely when present in concentrations of 1 mM. Further results demonstrated that such inhibition could also be explained by interference in constitutive nitric oxide generation. In addition to previous findings, more insight into the molecular mechanism of action of CCA is provided.
Nitric oxide as a mediator of inflammation?—You had better believe it
Authors: Miller Mark J. S. , Grisham Matthew B.
Published: March 2007

Nitric oxide has enigmatic qualities in inflammation. In order to appreciate the precise contributions of nitric oxide to a pathophysiological process, one must account for enzyme source, coproduction of oxidants and antioxidant defences, time, rate of nitric oxide production, cellular source, peroxynitrite formation and effects on DNA (mutagenesis/apoptosis). We contend that there is ample evidence to consider nitric oxide as a molecular aggressor in inflammation, particularly chronic inflammation. Therapeutic benefit can be achieved by inhibition of inducible nitric oxide synthase and not the donation of additional nitric oxide. Furthermore, there is growing appreciation that nitric oxide and products derived thereof, are critical components linking the increased incidence of cancer in states of chronic inflammation.
Nitric oxide as a mediator of gastrointestinal mucosal injury?—Say it ain′t so
Authors: Kubes Paul , Wallace John L.
Published: March 2007

Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down‐regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury.
Phagocytosis of mast cell granules results in decreased macrophage superoxide production
Authors: Shah Bobby A. , Li Yuai , Stechschulte Daniel J. , Dileepan Kottarappat N.
Published: March 2007

The mechanism by which phagocytosed mast cell granules (MCGs) inhibit macrophage superoxide production has not been defined. In this study, rat peritoneal macrophages were co‐incubated with either isolated intact MCGs or MCG‐sonicate, and their respiratory burst capacity and morphology were studied. Co‐incubation of macrophages with either intact MCGs or MCG‐sonicate resulted in a dose‐dependent inhibition of superoxide‐ mediated cytochrome c reduction. This inhibitory effect was evident within 5 min of incubation and with MCG‐sonicate was completely reversed when macrophages were washed prior to activation with PMA. In the case of intact MCGs, the inhibitory effect was only partially reversed by washing after a prolonged co‐incubation time. Electron microscopic analyses revealed that MCGs were rapidly phagocytosed by macrophages and were subsequently disintegrated within the phagolysosomes. Assay of MCGs for superoxide dismutase (SOD) revealed the presence of significant activity of this enzyme. A comparison of normal macrophages and those containing phagocytosed MCGs did not reveal a significant difference in total SOD activity. It is speculated that, although there was no significant increase in total SOD activity in macrophages containing phagocytosed MCGs, the phagocytosed MCGs might cause a transient increase in SOD activity within the phagolysosomes. This transient rise in SOD results in scavenging of the newly generated superoxide. Alternatively, MCG inhibition of NADPH oxidase would explain the reported observations.
Nitric oxide synthase inhibition decreases tolerance to hyperoxia in newborn rats
Authors: Pierce M. R. , Voelker C. A. , Sosenko I. R. S. , Bustamante S. , Olister S. M. , Zhang X.-J. , Clark D. A. , Miller M. J. S.
Published: March 2007

We evaluated the effects of sustained perinatal inhibition of NO synthase (NOS) on hyperoxia induced lung injury in newborn rats. NG‐nitro‐Larginine‐methyl‐ester (L‐NAME) or untreated water was administered to pregnant rats for the final 7 days of gestation and during lactation; followed by postnatal exposure to hyperoxia (>95% O2) or room air. The survival rate of L‐NAME treated pups when placed in > 95% O2 at birth was significantly lower than controls from day 4 (L‐NAME, 87%; control pups, 100%, p < 0.05) to 14 (L‐NAME, 0%; control pups, 53%, p < 0.05). Foetal pulmonary artery vasoconstriction was induced by L‐NAME with a decrease in internal diameter from 0.88 ± 0.03 mm to 0.64 ± 0.01 mm in control vs. L‐NAME groups (p < 0.05), respectively. We conclude that perinatal NOS inhibition results in pulmonary artery vasoconstriction and a decreased tolerance to hyperoxia induced lung injury in newborn rats.
Abrogation of mercuric chloride‐induced nephritis in the Brown Norway rat by treatment with antibodies against TNFα
Authors: Molina A. , Sánchez-Madrid F. , Bricio T. , Martín A. , Escudero E. , Alvarez V. , Mampaso F.
Published: March 2007

HgCl2 induces an autoimmune disease in the Brown Norway rat characterized by synthesis of autoantibodies (mainly, anti‐GBM Abs), severe proteinuria and interstitial nephritis. Also, HgCl2‐ injected rats develop glomerular cell infiltrates consisting of ED1+ cells (monocyte/macrophage), starting on day 4 and reaching a maximum on day 8. Treatment with anti‐TNF‐α antiserum had preventative effects as it reduced the urinary protein levels to close to the normal range and also blocked the influx of inflammatory cells in the renal glomeruli and interstitium, but circulating anti‐GBM and lineal glomerular IgG deposits were unmodified. In addition, whole isolated glomeruli from HgCl2‐induced nephritis secreted TNF‐α commencing on day 8, being maximally detected on day 11 and preceding, between 2 to 3 days, the development of proteinuria. The administration of anti‐TNF‐α antiserum or anti‐α4 integrin mAb completely abrogated the synthesis of TNF‐α in glomeruli isolated from the respective treated groups of animals, in addition to the proteinuria. Taken together our results confirm that TNF‐α plays an important role in the induction and development of HgCl2‐induced nephritis and highlights the pathogenic importance of the local release of TNF in those renal diseases in which prominent glomerular macrophage accumulation is a constant feature.
Faster onset of action with topical levocabastine than with oral cetirizine
Authors: Drouin Michel A. , Yang William H. , Horak Frederick
Published: March 2007

This international multicentre, open‐label, parallel‐group trial was undertaken to compare the therapeutic efficacy and tolerability of topical levocabastine and oral cetirizine in patients with perennial allergic rhinoconjunctivitis, with particular reference to the comparative onset of action of the two drugs. A total of 207 patients were randomized to receive either levocabastine nasal spray (0.5 mg/ml, two sprays in each nostril twice daily) plus levocabastine eye drops as required (0.5 mg/ml, one drop in each eye twice daily p.r.n.) or cetirizine orally (10 mg once daily) with a treatment duration of 2 weeks. Onset of action was found to be significantly more rapid with levocabastine than with cetirizine for both nasal and ocular symptoms (p < 0.001). Within 15 min of study drug administration, 36% of levocabastine‐treated patients reported relief from nasal symptoms and 32% relief from ocular symptoms compared with 10% and 17% of patients on cetirizine, respectively. At 1 h, the percentages of patients reporting relief were 76% and 38% for nasal symptoms, and 81% and 48% for ocular symptoms in the levocabastine and cetirizine treatment groups, respectively. At 8 h there were no differences between the two treatments. Overall therapeutic efficacy was found to be comparable in the two treatment groups over the 2‐week study period with no significant intergroup differences in symptom severity or global therapeutic efficacy. Both drugs were well tolerated with no significant differences in the incidence or type of adverse reactions between the two groups. In conclusion, levocabastine eye drops and nasal spray are as effective and well tolerated as oral cetirizine for the treatment of perennial allergic rhinoconjunctivitis with the advantage of a significantly faster onset of action for both nasal and ocular symptoms.
A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management
Authors: Howarth Peter H.
Published: March 2007

Levocabastine is a highly potent and selective H1‐receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo‐treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.
Treatment of allergic rhinoconjunctivitis: a review of the role of topical levocabastine
Authors: Wijk R. Gerth van
Published: March 2007

Lcocabastine is an extremely potent and highly selective H1‐receptor antagonist which has been specifically developed as eye drops and nasal spray for the treatment of allergic rhinoconjunctivitis. Clinical experience to date suggests that this topical antihistamine is at least as effective as other current first‐line therapeutic approaches for the treatment of this condition, including oral H1‐receptor antagonists and sodium cromoglycate. Onset of action is rapid, with clinical effects apparent within minutes of instillation. Moreover, duration of action is sufficiently long to permit a convenient twice‐daily dosing regimen. Topical levocabastine is well tolerated with an adverse‐effect profile comparable with that of placebo and sodium cromoglycate. As might be expected from the route of drug administration, application site reactions are the most frequent adverse effect associated with levocabastine eye drops and nasal spray with an incidence comparable with that seen in placebotreated controls. The availability of effective and well‐tolerated topical antihistamines, such as levocabastine, is an important advance which broadens the range of therapeutic approaches available for the clinical management of allergic rhinoconjunctivitis. Levocabastine appears to be an attractive alternative to oral antihistamines as a first‐line therapeutic option for the treatment of this atopic condition.
The evolution of inflammatory mediators
Authors: Rowley Andrew F.
Published: March 2007

Invertebrates do not display the level of sophistication in immune reactivity characteristic of mammals and other ‘higher’ vertebrates. Their great number and diversity of forms, however, reflect their evolutionary success and hence they must have effective mechanisms of defence to deal with parasites and pathogens and altered self tissues. Inflammation appears to be an important first line defence in all invertebrates and vertebrates. This brief review deals with the inflammatory responses of invertebrates and fish concentrating on the cell types involved and the mediators of inflammation, in particular, eicosanoids, cytokines and adhesion molecules.
Modulation of macrophage activation by prostaglandins
Authors: Sautebin L. , Carnuccio R. , D′Acquisto F. , Rosa M. Di
Published: March 2007

The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor‐α release in J774 macrophages has been studied. Both prostaglandin E2 and iloprost inhibited, in a concentration‐dependent fashion, the lipopolysaccharide‐induced generation of nitric oxide and tumour necrosis factor‐α. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO‐20‐1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E2 and iloprost in lipopolysaccharide‐activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor‐α generation, which in turn is likely to be mediated by cAMP.
IL‐5 drives eosinophils from bone marrow to blood and tissues in a guinea‐pig model of visceral larva migrans syndrome
Authors: Faccioli L. H. , Mokwa V. F. , Silva C. L. , Rocha G. M. , Araujo J. I. , Nahori M. A. , Vargaftig B. B.
Published: March 2007

This study was undertaken to evaluate the role of IL‐5 in eosinophil migration and in the maintenance of eosinophilia in a guinea‐pig model of visceral larva migrans syndrome. The results show that the infection of animals with Toxocara canis induced an early increase in serum IL‐5 levels that might be essential for eosinophil differentiation and proliferation and for the development of eosinophilia. When infected guinea‐pigs were treated with mAb anti‐IL‐5 (TRFK‐5) given at the same time or 1 or 3 days after infection, there was a high percentage of reduction of eosinophil counts 18 days after infection. However, when the mAb was administered during the peak of eosinophilia, there was high inhibition in blood, no inhibition in bronchoalveolar lavage fluid (BALF) or peritoneum and an increase in eosinophil numbers in bone marrow. Thus, a basic level of IL‐5 may be essential to drive eosinophils from bone marrow to blood and tissues, and for the maintenance of eosinophilia in infected animals. We may also conclude that when eosinophils have already migrated to the lungs, TRFK‐5 has no power to inhibit eosinophilia, which is also under control of local lung cells producing IL‐5. In this way, only one later TRFK‐5 treatment may not be sufficient to modify the lung parenchyma microenvironment, since T. canis antigens had already stimulated some cell populations to produce IL‐5.
Rat intestinal mast cell amines are released during nitric oxide synthase inhibition in vitro
Authors: Northover A. M. , Northover B. J.
Published: March 2007

Inhibition of nitric oxide synthase increases microvascular permeability in rat small intestinal villi. To determine the mechanism(s) whereby this occurs we have perfused the vasculature of rat isolated small intestines with a gelatin‐containing physiological salt solution. Inclusion of N‐nitro‐L‐argintne methyl ester (L‐NAME, 100 μM) or indomethacin (1 μM) in the perfusate increased leakage of injected colloidal carbon into microvessel walls. Pre‐treatment with sodium nitroprusside (10 μM) significantly reduced the effects of both L‐NAME and indomethacin, whereas carbacyclin (1 μM) only reduced the effects of indomethacin. PD151242 (1 μM) showed some antagonism towards the effects of L‐NAME, but nordihydroguaiaretic acid (3 μM) was inactive. Pre‐tment with cyproheptadine (10 μM) reduced the effects of both L‐NAME and indomethacin, and also significantly reduced background (control) colloidal carbon leakage. Small intestines from polymixin B‐treated rats showed significantly reduced colloidal carbon leakage in response to L‐NAME. This suggests that the leakage‐enhancing effects of both L‐NAME and indomethacin in this preparation may be mediated by mast cell‐derived amines.
Serum levels of total IgE and soluble CD23 in bronchial asthma
Authors: Lorenzo G. Di , Mansueto P. , Melluso M. , Morici G. , Cigna D. , Candore G. , Caruso C.
Published: March 2007

The aim of the present study was to compare, during the pollen season, serum levels of total IgE and soluble CD23 (sCD23) from patients with allergic bronchial asthma, with those from healthy subjects. Significantly higher levels of total IgE and sCD23 were found in patients with asthma compared to the control group. Both in normal controls and in asthmatic patients, a significant correlation was shown between the levels of these two molecules. In asthmatic patients, significant correlations were found for both total IgE and sCD23, with lung function measured as bronchial responsiveness to inhaled methacholine. These results suggest that in asthmatic patients, in addition to the study of total serum IgE levels, the assessment of sCD23 serum levels may be helpful in the evaluation of disease activity.
Time‐resolved fluoroimmunoassay for bactericidal/permeability‐increasing protein
Authors: Häggblom J.-O. , Jokilammi-Siltanen A. B. , Peuravuori H. , Nevalainen T. J.
Published: March 2007

Bactericidal/permeability‐increasing protein (BPI) is a cationic antimicrobial protein produced by polymorphonuclear leukocytes, that specifically interacts with and kills Gram‐negative bacteria. BPl competes with lipopolysaccharide‐binding protein (LBP) secreted by liver cells into blood plasma for binding to lipopolysaccharide (LPS) and thus reduces the proinflammatory effects of LPS. We have developed a time‐resolved fluoroimmunoassay for BPI and measured the concentration of BPI in human serum and plasma samples. The assay is based on a rabbit antibody against recombinant BPI. This antibody specifically adheres to polymorphonuclear leukocytes in immunostained human tissues. The difference in the serum concentration of BPI between unselected hospitalized patients with and without an infection was statistically significant. The mean concentration of BPI in serum samples was 28.3 μg/l (range 1.64–132, S.D. 26.8, n = 83). In contrast, there was no difference between the two groups in the BPI levels in plasma samples. For all individuals tested, BPI levels were consistently higher in plasma samples compared to the matched serum samples. The mean concentration of BPI in plasma samples was 52.3 μg/l (range 0.9–403, S.D. 60.6, n = 90). There was a positive correlation between the concentration of BPI and the white blood cell count as well as between the BPI concentration and C‐reactive protein (CRP) in serum samples. In conclusion, the present study demonstrates that BPI can be quantified reliably by time‐resolved fluoroimmunoassay in human serum samples.
Nitric oxide production in murine spleen cells: role of interferons and prostaglandin E2 in the generation of cytotoxic activity
Authors: Vaillier Dominique , Daculsi Richard , Gualdel Norbert
Published: March 2007

The production of nitric oxide (NO) was measured in cultures of spleen cells stimulated by lipopolysaccharide (LPS), IL‐2 or LPS + IL‐2. We observed that NO synthesis is increased by IFN‐γ but inhibited by IFN‐α/β. This is not the case when IL‐2 is present in the cultures, since interferons play a minor role in the regulation of the NO production. When IL‐2 and LPS were associated in the cultures, the IFN‐α/β role seems more important than that of IFN‐γ. PGE2 inhibits NO production in LPS supplemented cultures but has a slight effect in the presence of IL‐2 and no effect with IL‐2 + LPS. 3‐isoButyl‐1‐methylxanthine (IBMX), an inhibitor of phosphodiesterases, induces a decrease of IFN production. In the presence of H‐7, an inhibitor of protein kinase C (PKC), NO production is reduced when the cultures are supplemented by LPS or IL‐2 but not when IL‐2 and LPS are both added. H‐7 also reduced IFN production. In the presence of NG‐monomethyl‐L‐arginine (N‐MMA), an inhibitor of NO synthesis, IFN production was increased, with no change in the cytotoxic activity. Hence, interferons regulate NO production by mouse spleen cells and, in return, NO modulates the generation of IFN.
Dimeric and polymeric IgA, but not monomeric IgA, enhance the production of IL‐6 by human renal mesangial cells
Authors: Reterink T. J. F. , Schroeijers W. E. M. , Es L. A. van , Daha M. R.
Published: March 2007

Depositions of IgA in the renal glomerular mesangial area are a hallmark of IgA nephropathy, and are thought to be crucial for the onset of inflammation processes in IgA nephropathy. In this report we show that human mesangial cells (MC) in vitro bind IgA and that binding of IgA enhances the production of IL‐6 by MC. Furthermore we show that the size of IgA is crucial in its capability to enhance IL‐6 production. Monomeric IgA does not affect basic IL‐6 production, whereas dimeric and polymeric IgA enhance IL‐6 production up to 3‐ to 9‐fold respectively. Additional studies demonstrate that enhanced IL‐6 production by MC is not accompanied by increased proliferation of human mesangial cells, a finding which is distinct from that found with rat mesangial cells. Taken together, these fmdings suggest that deposition of dimeric and polymeric IgA in the mesangial area of human kidneys in IgA nephropathy may amplify local inflammation.
Inhibition of the activity of pro‐inflammatory secretory phospholipase A2 by acute phase proteins
Authors: Pruzanski W. , Stefanski E. , Vadas P.
Published: March 2007

Pro‐Inflammatory non‐pancreatic phospholipase A2 (sPLA2) is markedly over‐expressed in acute systemic and chronic local inflammatory processes. Since in acute phase reaction sPLA2 is often over‐expressed simultaneously with acute phase proteins (APP), it is important to determine whether APP interacts with sPLA2. We tested ten APPs for interaction with sPLA2 using as a substrate multilamellar Hposomes composed either of PC:Lyso PC or PE:Lyso PE. Using PC:Lyso PC substrate, CRP, lactoferrin and SAP were found to inhibit sPLA2 activity with an IC50 of 25 μg/ml, 7.5 μg/ml and 50 μg/ml, respectively, corresponding to 0.21 μM, 0.1 μM and 0.21 μM respectively. Using PE:Lyso PE substrate only SAP was inhibitory, with an IC50 of 10 μg/ml (0.04 μM). Phosphorylcholine abolished the inhibitory activity of CRP but not of SAP or lactoferrin. Addition of phosphorylethanolamine or of excess calcium had no effect on the inhibitory activity of APP. Limulin, lysozyme, transferrin, β2‐microglobulin, α2‐macroglobulin, human and bovine albumins had no effect on sPLA2 activity. Therefore neither the structure of pentraxins, or ironbinding, bacteriostatic property or amyloidogenic property preclude whether APP modulates sPLA2 activity. Inhibition of pro‐inflammatory sPLA2 by APP may be one of the protective mechanisms of the acute phase reaction.
Intra‐pancreatic release of bradykinin during the course experimental pancreatitis in rat
Authors: Jönsson P. , Ohlsson K.
Published: March 2007

Kallikrein/Kininogn activation is an important pathophysiological event in acute pancreatitis, leading to microcirculatory changes within the gland. Hitherto, only indirect measurements of pancreatic bradykinin formation have been performed, monitoring the peptide in the circulation and in the peritoneal exudate. In the present study, intra‐pancreatic bradykinin release was assessed using microdialysis during experimental acute pancreatitis in rat. In mild, oedematous pancreatitis, induced by caerulein hyperstimulation, the levels of bradykinin within the gland were not elevated compared with those of control rats. However, in necrotic pancreatitis, induced by retrograde injection of taurocholate into the pancreatic duct, significantly elevated levels of intraglandular bradykinin were seen. Several rats in this group died whilst in a state of circulatory shock.
Development and some applications of enzyme‐linked immunosorbent assay system for murine macrophage inflammatory protein‐2 (MIP‐2)
Authors: Ochiai H. , Sakai S. , Kogure T. , Hirabaytashi T. , Nakajima K. , Terasawa K.
Published: March 2007

We attempted to establish an enzyme‐linked immunosorbent assay (ELISA) system by preparation of recombinant murine MIP‐2 and its rabbit antibodies. A fusion construct of MIP‐2 to protein A was used to enable easy purification as well as the generation of a sufficiently large antibody response. The specificity of antibody was confirmed by Western blotting analysis of 20‐h conditioned medium from lipopolysaccharide (LPS)‐stimulated RAW264.7 cells, a murine macrophage cell line; antibody gave a single band with a molecular weight of approximately 6000, which is identical to that of murine MIP‐2 reported previously. Biotin–streptavidin sandwich ELISA could detect quantitatively MIP‐2 at concentration range of 20 to 1000 pg/ml. In some applications of this ELISA system, time‐related production of MIP‐2 and inhibitory effect of dexamethasone on its production have been demonstrated in LPS‐stimulated RAW264.7 cells. Thus, ELISA system established in this study is considered to be a useful tool to study MIP‐2 response in various inflammation models in mice.
Piroxicam fails to reduce myocellular enzyme leakage and delayed onset muscle soreness induced by isokinetic eccentric exercise
Authors: Croisier J-L. , Camus G. , Monfils T. , Deby-Dupon G. , Fafchamps M. , Venneman I. , Crielaard J-M. , Juchmès-Ferir A. , Lhermerout C. , Lamy M. , Deby C.
Published: March 2007

To test the hypothesis that delayed onset muscular soreness (DOMS) following intense eccentric muscle contraction could be due to increased production of prostaglandin E2 (PGE2), ten healthy male subjects were studied. Using a double‐blind randomized crossover design, each subject performed two isokinetic tests separated by a period of at least 6 weeks: once with placebo, and once with piroxicam (Feldene®). They were given one capsule containing either placebo or piroxicam (20 mg) per day for 6 days with initial doses given starting 3 days prior to isokinetic testing. Exercise consisted of eight stages of five maximal contractions of the knee extensor and flexor muscle groups of both legs separated by 1 min rest phases, on a Kin Trex device at 60°/s angular velocity. The subjective presence and intensity of DOMS were evaluated using a visual analogue scale immediately after, and 24 and 48 h after each test. The mean plasma concentration of PGE2 measured at rest and after exercise was significantly lower in the group treated with piroxicam (p < 0.05). However, statistical analysis (two‐way ANOVA test) revealed that exercise did not cause any significant change of mean plasma PGE2 over time in either of the two groups. Eccentric work was followed by severe muscle pain in extensor and flexor muscle groups. Maximal soreness was noted 48 h postexercise. Serum creatine kinase activity and the serum concentration of myoglobin increased significantly, and reached peak values 48 h after exercise in both experimental conditions (p < 0.001). By paired t‐test, it appeared that there were no significant differences in the serum levels of these two markers of muscle damage between the two groups at any time point. We conclude that: (1) oral administration of piroxicam fails to reduce muscle damage and DOMS caused by strenuous eccentric exercise; and (2) the hypothetical role of increased PGE2 production in eccentric exercise‐induced muscle damage, DOMS, and reduced isokinetic performance is not substantiated by the present results.
α2‐macroglobulin and α1‐inhibitor‐3 mRNA expression in the rat liver after slow interleukin‐1 stimulation
Authors: Gudmundsson T. , Björk P. , Ohlsson K.
Published: March 2007

In this study we have investigated total fiver RNA and the expression of mRNA in the rat fiver in vivo after a slow stimulation of interleukin‐1. A total dose of 4 μg interleukin‐1β was administered via a subcutaneously implanted osmotic minipump over a period of 7 days. Plasma concentrations of α2‐macroglobulin manifested a rapid increase, reaching a peak on day 2, while α1‐inhibitor‐3 manifested a marked initial decrease to 50% of the baseline level, followed by a tendency to increase again. For measurement of total RNA and specific mRNAs from the fiver, rats were sacrificed at different times during the experimental period. Total RNA peaked at 6 h, the level being approximately 60% higher than baseline value. Specific mRNA from the liver for α2‐macroglobulin and α1‐inhibitor‐3 were quantified using laser densitometry on slot blots. The amounts measured during the experimental period agreed with the pattern of corresponding plasma protein levels. From barely detectable amounts at baseline, α2‐macroglobulin mRNA peaked on day 1, and then declined. Levels of α1‐inhibitor‐3 mRNA manifested an initial increase at 3 h, but then declined and remained low until day 5 when there was a tendency towards an increase. It was concluded that the levels of plasma concentrations of α2‐macroglobulin and α1‐inhibitor‐3 are mainly regulated at the protein synthesis level, and that long‐term interleukin‐1β release could not override the initial acute phase protein counteracting mechanism triggered.