bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of vascular and respiratory effects of endothelin‐1 in the pig
Authors: Clement M. G. , Dimori M. , Albertini M.
Published: March 2007

The haemodynamic and respiratory responses caused by i.v. administration of endothelin‐1 (ET‐1) (20–100 pmol/kg) were studied in anaesthetized spontaneously breathing pigs. Intravenous bolus administration of synthetic ET‐1 (40–100 pmol/kg) caused a transient decrease followed by a long‐lasting increase in mean pulmonary arterial pressure and dose dependent vasoconstriction both in the systemic and pulmonary circulations. The effect on pulmonary arterial pressure was biphasic, with an initial transient fall followed by a long‐lasting dose dependent increase. A biphasic response of the systemic mean arterial pressure was demonstrated only at a high dose of ET‐1 (100 pmol/kg). ET‐1 administration did not significantly change breathing pattern or phasic vagal input, but caused a significant decrease in passive compliance. Passive resistances or active compliance and resistances of the respiratory system were not modified. These results suggest that in the pig ET‐1 is a more potent constrictor of vascular than of bronchial smooth muscle. The vasoconstrictor activity was greater in the pulmonary than the systemic circulations.
Anti‐inflammatory agents and substance P depletion in experimental ileitis
Authors: Miller M. J. S. , Sadowska-Krowicka H. , Chotinaruemol S. , Wong M. , Clark D. A. , Jeng A. Y.
Published: March 2007

To understand the interactions between substance P and gut inflammation, changes in substance P levels were evaluated in a chronic model of ileitis in response to three anti‐inflammatory agents with distinct mechanisms of action. The agents were the prostaglandin E1 analogue misoprostol (30 μg/kg, s.c., b.i.d.), the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μg/ml in drinking water) and the leumedin, N‐(fluorenyl‐9‐methoxycarbonyl)‐L‐leucine (NPC 15199, 10 mg/kg, s.c.). Ileitis was induced by a transmural injection of trinitrobenzene sulphonic acid (TNBS 30 mg/kg in 50% ethanol) into the distal ileum of guinea‐pigs. All anti‐inflammatory therapies were introduced after TNBS administration and continued until day 7, when guinea‐pigs were killed. Ileal substance P levels were measured by radioimmunoassay, and granulocyte infiltration was quantified by myeloperoxidase (MPO) activity. Protein and nitrite (an index of nitric oxide formation) levels in a luminal saline lavage were quantified in all groups. TNBS ileitis caused a marked reduction in ileal substance P content and increased MPO activity, protein and nitrite secretion. The nitric oxide synthase inhibitor, L‐NAME, completely restored all parameters to baseline. Misoprostol attenuated the granulocyte infiltration and exacerbated protein leak but had no effect on substance P levels. In contrast, NPC 15199 had no effect on granulocyte infiltration but normalized substance P levels and protein leak. Only L‐NAME and NPC 15199 blocked the TNBS induced increase in nitrite levels. These results suggest that the regulation of granulocyte infiltration in this model is unrelated to changes in substance P levels. Inhibition of nitric oxide synthase was the most effective therapeutic strategy in TNBS ileitis but the precise interactions between nitric oxide and the enteric nervous system during inflammatory states remain to be defined.
Phosphoinositide hydrolysis mediated by H1 receptors in autoimmune myocarditis mice
Authors: Goren Nora , Leiros Claudia Perez , Sterin-Borda Leonor , Borda Enri S.
Published: March 2007

Stimulation of phosphoinositide hydrolysis in myocardium from autoimmune myocarditis mice by ThEA and histamine was assayed. Myocardium from autoimmune heart, but not the normal forms, specifically increased phosphoinositide turnover in the presence of histaminergic agonists. This increment was blocked by a specific H1 antagonist mepyramine and to the same extent by the phospholipase C inhibitor NCDC. By using a binding assay H1 histaminergic receptors were detected in autoimmune heart membrane preparations, but this was not observed in normal heart. These data suggest that autoimmune myocardium expressed a functional H1 receptor that could involve a distinctive mechanism operating in the disease.
Investigation of intracellular signals generated by γ‐interferon and IL‐4 leading to the induction of class II antigen expression
Authors: Vassiliadis S. , Kyrpides N. , Stravopodis D. , Grigoriou M. , Athanassakis I. , Papamatheakis J.
Published: March 2007

Signal transduction plays a vital role in cellular behaviour as cells respond to various stimuli in different ways and utilize diverse pathways for accomplishing their task. Determination of the pathway followed by various cytokines can be achieved using specific inhibitors which include theophylline (TPH), TMB‐8 and W7 that hinder calmodulin binding to Ca2+; sphingosine (SPH), H7 and staurosporine that inhibit protein kinase C (PKC) activation; and mevalonate (MEV) or the anti‐p21ras antibody which block G‐proteins. This study shows that the immunologically important class II antigens in human cells are up‐regulated predominately via the same pathway after gamma‐interferon (γ‐IFN) treatment, whereas murine cells are activated by other signalling routes. Thus, the calcium/calmodulin (Ca2+/Cam) pathway is preferentially selected for human cells whereas the PKC pathway is more often chosen for murine cells. These findings are firmly supported by other reports and show, in addition, a unique action exerted by γ‐IFN, since IL‐4, another inducer of class II antigen expression, uses different pathways. This diversity of activation reveals the existence of a previously unknown complicated network of intracellular interactions able to regulate the same phenotype or cellular event. As major histocompatibility complex antigens (MHC) or human leukocyte antigens (HLA), are important in immune recognition and response, the results show that for human cells a more coherent method of HLA‐DR antigen induction is followed after γ‐IFN administration, as calcium participation seems to be the first step in signal transduction. The same T‐cell derived lymphokine, however, follows a totally different route when applied to murine cells.
Calcium ionophore (A‐23187) induced peritoneal eicosanoid biosynthesis: a rapid method to evaluate inhibitors of arachidonic acid metabolism in vivo
Authors: Rao T. S. , Currie J. L. , Shaffer A. F. , Isakson P. C.
Published: March 2007

The present investigation characterizes calcium ionophore (A‐23187) induced peritoneal eicosanoid biosynthesis in the rat. Intraperitoneal injection of A‐23187 (20 μg/rat) stimulated marked biosynthesis of 6‐keto‐PGF1α (6‐KPA), TxB2, LTC4 and LTB4, with no detectable changes on levels of PGE2. Levels of all eicosanoids decreased rapidly after a peak which was seen as early as 5 min. Enzyme markers of cellular contents of neutrophils and mononuclear cells, MPO and NAG respectively, decreased rapidly after ionophore injection; this was followed by increases after 60 min. Indomethacin, a selective cyclooxygenase inhibitor, and zileuton and ICI D‐2138, two selective 5‐lipoxygenase inhibitors attenuated prostaglandin and leukotriene pathways respectively. Oral administration of zileuton (20 mg/kg, p.o.) inhibited LTB4 biosynthesis for up to 6 h suggesting a long duration of pharmacological activity in the rats consistent with its longer half‐life. The rapid onset and the magnitude of increases in levels of eicosanoids render the ionophore induced peritoneal eicosanoid biosynthesis a useful model to evaluate pharmacological profiles of inhibitors of eicosanoid pathways in vivo.
Protein tyrosine kinase but not protein kinase C inhibition blocks receptor induced alveolar macrophage activation
Authors: Pollock K. , Withnall M. T.
Published: March 2007

The selective enzyme inhibitors genistein and Ro 31‐8220 were used to assess the importance of protein tyrosine kinase (PTK) and protein kinase C (PKC), respectively, in N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) induced generation of superoxide anion and thromboxane B2 (TXB2) in guinea‐pig alveolar macrophages (AM). Genistein (3–100 μM) dose dependently inhibited FMLP (3 nM) induced superoxide generation in non‐primed AM and TXB2 release in non‐primed or in lipopolysaccharide (LPS) (10 ng/ml) primed AM to a level > 80% but had litle effect up to 100 μM on phorbol myristate acetate (PMA) (10 nM) induced superoxide release. Ro 31‐8220 inhibited PMA induced superoxide generation (IC50 0.21 ± 0.10 μM) but had no effect on or potentiated (at 3 and 10 μM) FMLP responses in non‐primed AM. In contrast, when present during LPS priming as well as during FMLP challenge Ro 31‐8220 (10 μM) inhibited primed TXB2 release by > 80%. The results indicate that PTK activation is required for the generation of these inflammatory mediators by FMLP in AM. PKC activation appears to be required for LPS priming but not for transducing the FMLP signal; rather, PKC activation may modulate the signal by a negative feedback mechanism.
Mechanism of pentoxifylline mediated down‐regulation of killer lineage cell functions
Authors: Parhar R. S. , Ernst P. , Sheth K. , Einspenner M. , Al-Sedairy S.
Published: March 2007

The authors reported recently that endotoxaemia mediated elevated levels of tumour necrosis factor (TNF‐α) and interleukin‐1α (IL‐1α) were involved in the pathophysiology of acute heat stroke patients. Pentoxifylline (PTX) is known to modulate neutrophil functions. In the present study the effects of PTX on lipopolysaccharide (LPS) and cytokine induced T‐cell and macrophage (ΦM) activation, and on natural killer (NK) cell and lymphokine activated killer (LAK) cell mediated cytotoxicity were examined. Finally, the effect of PTX on the expression of adhesion molecules (LFA‐1, Mac‐1 and ICAM‐1), and cytokine (IL‐1α, IL‐2, TNF‐α, IL‐6 and IFN‐γ) production and their surface receptor expression in response to LPS activation was investigated. PTX free cultures served as a control. Results revealed that PTX can down‐regulate all the above‐mentioned immunological parameters in a dosedependent manner. These findings might have far reaching clinical implications.
Interleukin‐6 stimulates gene expression of extracellular matrix components in bovine mesangial cells in culture
Authors: Zoja C. , Benigni A. , Piccinini G. , Figliuzzi M. , Longaretti L. , Remuzzi G.
Published: March 2007

The effect of interleukin‐6 (IL‐6) on gene expression of extracellular matrix components in bovine mesangial cells in culture has been investigated. IL‐6 (100 U/ml) time dependently increased the steady state expression of mRNAs coding for α1 collagen III and fibronectin, both transcripts being 1.5‐ and 2.5‐fold higher than basal level at 24 and 48 h, respectively. In contrast, IL‐6 stimulated laminin mRNA expression only after 48 h incubation (2.5‐fold upon basal level). These results suggest that IL‐6 could favour glomerular matrix accumulation thus contributing to the development of glomerulosclerosis.
Low molecular weight thymic factor inhibits histamine release from basophils
Authors: Yalkut S. I. , Gulling E. V. , Gots T. Yu. , Kotova S. A. , Belova O. B. , Premyslov V. Ch.
Published: March 2007

Low molecular weight thymic factor stimulates the suppressor function of T‐lymphocytes, increases cAMP content (but not cGMP) in lymphocytes and inhibits histamine release from sensitized basophils. The mechanisms of LTF action are discussed.
Immunoregulatory biological response modifiers: effect of cytokines on septic shock
Authors: Chirigos Michael A. , De Simone Claudio
Published: March 2007

Whole bacteria or bacterial components or their extracts were employed to restore or augment the immune system. Beneficial effects were attained with these agents in treating various diseases. These agents were named biological response modifiers (BRMs) because they regulated certain cellular components of the immune system. The cellular regulation induced by these BRMs was found to be due to cytokines. The cytokines were shown to act directly on the various cellular components and to provide therapeutic benefit in various autoimmune and immune deficiency diseases. Overproduction of specific cytokines however leads to a deleterious effect on the host. Overproduction of tumour necrosis factor (endotoxin, lipopolysaccharide) leads to septic shock. Bacteraemia is the leading cause of overproduction of tumour necrosis factor (TNF). Septic shock in many cases leads to death. Several monoclonal antibodies to lipopolysaccharide (LPS) and anticytokines have demonstrated protection against septic shock.
Immunological responses in patients with tuberculosis and in vivo effects of acetyl‐L‐carnitine oral administration
Authors: Jirillo Emilio , Altamura Maria , Marcuccio Carlo , Tortorella Cosimo , De Simone Claudio , Antonaci Salvatore
Published: March 2007

Tuberculosis (TBC) is characterized by a complex immune response which parallels the clinical course of the disease. In this respect, acquired resistance, delayed hypersensitivity reaction and anergy are the main types of immune reactivity to mycobacterial antigens. In view of the presence of nonspecific and specific immune deficits in TBC patients, a clinical trial was carried out in a group of 20 individuals with active pulmonary TBC by oral administration of acetyl‐L‐carnitine (ALC). This drug, which has been shown to possess immunomodulating activities, was able to upregulate the T‐dependent antibacterial activity in TBC patients after 30 days′ treatment, while the same activity decreased in patients receiving placebo only. On the other hand, ALC did not modify serum levels of tumour necrosis factor‐α, in the same individuals. This cytokine plays a detrimental rather than beneficial role in TBC pathogenesis. In the light of these data, ALC seems to be a powerful immunomodulator in the course of Mycobacterium tuberculosis infection and other mycobacteriosis.
Vulnerability of vascular endothelium in lipopolysaccharide toxicity: effect of (acyl) carnitine on endothelial stability
Authors: Hülsmann W. C.
Published: March 2007

The literature presented illustrates that lipopolysaccharide (LPS), from bacterial cell walls, induces tumour necrosis factor (TNF) synthesis in macrophages. TNF affects a number of cell types, amongst which are endothelial cells, within a few hours. Its injection has been shown to produce all symptoms of the toxic syndrome. In the present communication the vulnerability of endothelial cells will be stressed. These cells require carnitine not only for fatty acid oxidation but also for membrane protection and repair. As endothelial cells lose carnitine during hypoperfusion, it is speculated that the supply of carnitine during the early phase of LPS toxicity in rats might delay or avoid loss of endothelial functions. Earlier it was observed that hearts from rats, injected 3 h previously with LPS, showed strongly increased interstitial fluid production compared to hearts from control rats, even when TNF was present during a 3 h in vitro perfusion. It showed that LPS in vivo generates factors other than TNF, such as platelet activating factor (PAF), that are responsible for the increased capillary permeability.
L‐carnitine: a partner between immune response and lipid metabolism ?
Authors: Famularo Giuseppe , Tzantzoglou Sonia , Santini Gino , Trinchieri Vito , Moretti Sonia , Koverech Aleardo , De Simone Claudio
Published: March 2007

The authors demonstrated that in vivo administered L‐carnitine strongly ameliorated the immune response in both healthy individuals receiving Intralipid and ageing subjects with cardiovascular diseases, as shown by the enhancement of mixed lymphocyte reaction. Notably, in the latter group L‐carnitine treatment also resulted in a significant reduction of serum levels of both cholesterol and triglycerides. Therefore, the hypothesis is that L‐carnitine supplementation could ameliorate both the dysregulated immune response and the abnormal lipid metabolism in several conditions.
Anaesthetics modulate tumour necrosis factor α: effects of L‐carnitine supplementation in surgical patients. Preliminary results.
Authors: Delogu Giovanna , De Simone Claudio , Famularo Giuseppe , Fegiz Alessandra , Paoletti Francesca , Jirillo Emilio
Published: March 2007

Both anaesthetics and surgical trauma could strongly affect the production of tumour necrosis factor α (TNFα). During in vitro experiments the authors found that anaesthetics modulate the production of TNFα by peripheral blood mononuclear cells. Notably, Pentothal strongly increased the production of the cytokine as compared to both lipopolysacchride treated and control mononuclear cells, whereas in supernatants from Leptofen driven mononuclear cells TNFα was strongly reduced. On the other hand, Pavulon did not significantly affect the cytokine production. In the in vivo study, in an attempt to ameliorate the metabolic response to surgical trauma, L‐carnitine was administered to 20 surgical patients, then the circulating TNFα was measured. The results indicate that the levels of circulating TNFα were strongly increased following surgery and that L‐carnitine administration resulted in a strong reduction of TNFα. Thus, the data suggest that L‐carnitine could be helpful in protecting surgical patients against dysmetabolism dependent on dysregulated production of TNFα.
Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNFα
Authors: Garrelds Ingrid M. , Elliott Graham R. , Pruimboom Wanda M. , Zijlstra Freek J. , Bonta Iván L.
Published: March 2007

THE acyl carrier coenzyme A (CoA) is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long‐chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L‐carnitine, acetyl Lcarnitine and propionyl L‐carnitine on the basal and calcium ionophore (A23187) stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN) leucocytes. The basal release of prostaglandin E2 (PGE2), 6‐ketoprostaglandin F1α (6‐keto‐PGF1α) and leukotriene B4 (LTB4) was stimulated by all treatments. The A23187 stimulated release of 6‐keto‐PGF1α and LTB4 was increased by all three compounds. The 6‐keto‐PGF1α:TxB2 and 6‐keto‐PGF1α:LTB4 ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (>95% macrophages) and none of the compounds fed to the rats caused a change of either eicosanoid or TNFα formation. Moreover the 6‐keto‐PGF1α:TxB2 and 6‐keto‐PGF1α:LTB4 ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6‐keto‐PGF1α:TxB2 and 6‐keto‐PGF1α:LTB4 reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages.
The Role of Cytokines in Inflammatory Bowel Disease
Authors: Radford-Smith G. , Jewell D. P.
Published: March 2007

Cytokines play an important role in the development and persistence
of the inflammatory lesions seen in Crohn′s disease and ulcerative
colitis. This review discusses the current thinking of the role of
cytokines in chronic intestinal inflammation including the
involvement of immunoregulatory cytokines within the Th1 and Th2
subsets.
Mechanism for the Increased Permeability in Endothelial Monolayers Induced by Elastase
Authors: Suzuki N. , Ishii Y. , Kitamura S.
Published: March 2007

The aim of this study was to investigate the mechanism for the
increase in endothelial permeability induced by human neutrophil
elastase (HNE). Pretreatment of bovine pulmonary artery endothelial
cells (BPAEC) with HNE(0‐30 μg/ml) for 1 h produced a concentration
dependent increase in 125I‐albumin clearance. The effect was
reversible and was not due to cytolysis. Pretreatment of BPAEC with
sodium tungstate, which depletes xanthine oxidase, or with
oxypurinol, did not prevent HNE induced increased permeability.
Heparin, which neutralizes the cationic charge of HNE, also had no
protective effect. Pretreatment with heat inactivated HNE, which
still had positive charge sites, did not result in increased
endothelial permeability. Also, ONO‐5046, a novel specific inhibitor
of HNE, did prevent increased permeability. These results suggest
that elastase increases endothelial permeability mainly through its
proteolytic effects.
Interferon‐γ Stimulates Monocyte Chemotactic Protein‐1 Expression by Monocytes
Authors: Liebler J. M. , Kunkel S. L. , Allen R. M. , Burdick M. D. , Strieter R. M.
Published: March 2007

Monocyte chemotactic protein (MCP‐1) is a specific monocyte
chemoattractant and activating factor produced by both immune cells
(mononuclear phagocytes and lymphocytes) and non‐immune cells
(parenchymal and stromal cells). In order to define the conditions
under which human monocytes express MCP‐1, monocytes were exposed to
IFN‐γ, IL‐ lβ, TNF‐α, IL‐4 or PHA under serum free
conditions. There was no significant MCP‐1 production by monocytes
following exposure to IL‐lβ, TNF‐α or IL‐4. In contrast,
stimulation with IFN‐γ resulted in a dose dependent increase
in MCP‐1 protein and mRNA expression. Simultaneous stimulation with
IFN‐γ and IL‐1β or TNF‐α resulted in no further
increase in MCP‐1 production. It is concluded that IFN‐γ,
primarily a product of TH1 T lymphocytes, stimulates the expression
of MCP‐1 by monocytes.
Cytokine Detection and Modulation in Acute Graft vs. Host Disease in Mice
Authors: Knulst A. C. , Tibbe G. J. M. , Bril-Bazuin C. , Breedland E. G. , van Oudenaren A. , Benner R. , Savelkoul H. F. J.
Published: March 2007

A murine model for acute lethal graft vs. host disease (GVHD) was
used to study the role that a number of cytokines play in the development of lethal GVHD. In this study we focused on the role of IL‐1, IL‐2, IL‐4, IL‐6, IFN‐γ and TNF‐α. Lethally irradiated (C57BL × CBA)F1 mice were reconstituted either with 107 allogeneic BALB/c spleen cells or with a similar number of syngeneic cells, as a control. A significant rise in serum levels of IL‐6, TNF‐α and IFN‐γ levels was found in allogeneically reconstituted mice. This is in contrast to the
syngeneic control group in which no rise was seen. Serum IL‐2 and IL‐4 levels were below the detection limit. In the supernatant of Con A stimulated spleen cells from allogeneically reconstituted mice
IL‐6, IFN‐γ and TNF‐α concentrations were increased. The
expression of mRNA for cytokines as detected by reverse
transcription PCR was studied in spleen cells. In the allogeneic
reconstituted mice the mRNA expression of IL‐1α, IL‐2, IL‐6,
IFN‐γ and TNF‐α displayed faster kinetics compared with
that in syngeneic reconstituted mice. The effect of treatment with
recombinant cytokines, antibodies to cytokines and to cytokine
receptors on the development of GVHD was investigated.
Administration of recombinant IL‐2 to allogeneically reconstituted
mice strongly increased the morbidity and mortality whereas
injection of IL‐1α and TNF‐α did not influence survival.
Administration of antibodies against IL‐2 or the IL‐2 receptor
decreased the morbidity and mortality. Anti‐IL‐6, anti‐IFN‐γ,
and anti‐TNF‐α mAB, on the other hand, did not affect the
morbidity and mortality of GVHD. The results of this study suggest
successive waves of cytokine‐secreting cell populations consistent
with the induction of an inflammatory response in the development of
acute GVH disease.
Interleukin‐5 Potentiates Sulfidopeptide Leukotriene Production by Human Eosinophils
Authors: Van Oosterhout A. J. M. , Van Der Poel A. , Koenderman L. , Roos D. , Nijkamp F. P.
Published: March 2007

Interleukin‐5 (IL‐5) has been shown to be a selective eosinophil
growth and differentiation factor. In the present study, the effect
of recombinant human IL‐5 on human eosinophil sulfidopeptide
leukotriene production was investigated. IL‐5 did not affect
leukotriene synthesis in unstimulated eosinophils. However, IL‐5
potentiated leukotriene synthesis by eosinophils stimulated with
serum treated zymosan (STZ) or the calcium ionophore A23187 by
69% and 135%, respectively. The priming effect of IL‐5
was dose dependent, with significant stimulation occurring at 1 000
U/ml for STZ and 100‐1 000 U/ml for A23187. Pre‐incubation with IL‐5
did not increase leukotriene synthesis further.
A novel Mutein of TNFα Containing the Arg‐Gly‐Asp Sequence Shows Reduced Toxicity in Intestine
Authors: Shikama H. , Miyata K. , Sakae N. , Kuroda K. , Nishimura K. , Yotsuya S. , Kato M.
Published: March 2007

The effects of human tumour necrosis factor‐α (TNFα), or its
mutein (F4168) having the cell adhesive Arg‐Gly‐Asp sequence at the
N‐terminus, on intestinal injury, were examined. Histopathological
examination revealed that an intravenous injection of TNFα
resulted in marked haemorrhage or oedema in the caecum of rats,
whereas F4168 showed no such effects even at the same therapeutic
dose. Moreover, the number of neutrophils that adhered to
endothelial cells or infiltrated the mucosal tissue was much higher
after TNFα injection compared with F4168 in vivo.
The enhanced adhesion of neutrophils on to human umbilical vein
endothelial cells also occurred when the latter were pre‐stimulated
with TNFα but not with F4168 in vitro. The
expression of the cell adhesion molecules including endothelial
leukocyte adhesion molecule‐1 or intercellular adhesion molecule‐1
on F4168‐ stimulated human umbilical vein endothelial ceils was
significantly lower than that stimulated with TNFα. These
results suggest that the Arg‐Gly‐Asp sequence introduced into the
TNFα molecule abrogates the side effect of this cytokine such
as tissue injury or shock, and that F4168 could be useful for
systemic therapy.
Inactivation of α2‐Macroglobulin by Activated Human Polymorphonuclear Leukocytes
Authors: Deby-Dupont G. , Croisier J.-L. , Camus G. , Brumioul D. , Mathy-Hartert M. , Sondag D. , Deby C. , Lamy M.
Published: March 2007

The proteolytic activity of trypsin releases the dye Remazol
Brilliant Blue from its high molecular weight substrate, the skin
powder (Hide Powder Azure, Sigma), with an increase in absorbance at
595 nm. Active α2‐ macroglobulin (80 μg/ml) totally inhibits the
proteolytic activity of trypsin (14 μg/ml) by trapping this
protease. But after a 20 min incubation of α2‐macroglobulin at 37°C
with 2 × 106 human polymorphonuclear leukocytes activated by
N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine
(10−7 M) and cytochalasin B (10−8 M), 100% of trypsin
activity was recovered, indicating a total inactivation of
α2‐macroglobuHn. Incubation with granulocyte myeloperoxidase also
inactivates α2‐macroglobulin. Hypochlorous acid, a by‐product of
myeloperoxidase activity, at a concentration of 10−7 M also
inactivates α2‐macroglobulin, which indicates that an important
cause of α2‐macroglobulin inactivation by activated
polymorphonuclear leukocytes could be the activity of myeloperoxidase.
Modulation of Leishmania (L.) amazonensis Growth inCultured Mouse Macrophages by Prostaglandins and Platelet Activating Factor
Authors: Lonardoni M. V. C. , Barbieri C. L. , Russo M. , Jancar S.
Published: March 2007

The role of endogenously synthesized PAF and prostaglandins on the
infection of mouse macrophages by Letsbmanta (L.) amazonensis was
investigated, as well as the possible correlation between the
effects of these inflammatory mediators with nitric oxide
production. It was found that pretreatment of macrophages with 10−5 M
of the PAF antagonists, BN‐52021 or WEB‐2086, increased
macrophage infection by 17 and 59%, respectively. The
cyclooxygenase inhibitor, indomethacin (10 μg/ml), induced a
significant inhibition which was reversed by addition of PGE (10‐3
M) to the culture medium. These results suggested that the infection
of macrophages by leisbmanla is inhibited by PAF and enhanced by
prostaglandins and that these mediators are produced by macrophages
during this infection. This was confirmed by addition of these
mediators to the culture medium before infection; PAF (10−6, 10−9
and 10−12M) reduced significantly the infection whereas PGE2 (10−5 M)
induced a marked enhancement. This effect of exogenous PAF on
macrophage infection was reversed by the two PAF antagonists used in
this study as well as by the inhibitor of nitric oxide synthesis,
L‐arginine methyl ester (100 mM). Taken together the data suggest
that endogenous production of PAF and PGE2 exert opposing effects on
Lesbmana–macrophage interaction and that nitric oxide may be
involved in the augmented destruction of parasites induced by PAF.
Thromboxane Modulates Endothelial Permeability
Authors: Klausner J. M. , Abu-Abid S. , Alexander J. S. , Hanshke-Mineau R. , Goldman G. , Morel N. , Valeri C. R. , Shepro D. , Hechtman H. B.
Published: March 2007

The study tests the role of thromboxane in modulating microvascular
permeability in vitro. Cultured monolayers of bovine
aortic endothelial cells were challenged with the thromboxane (Tx)
mimic U46619. This led to disassembly of actin microfilaments, cell
rounding, border retraction and interendotheHal gap formation.
Pretreatment with the Tx receptor antagonist SQ 29,548 prevented the
Tx mimic‐induced cytoskeletal changes. The Tx mimic also altered
endothelial cell barrier function. Increased permeability was
indicated by the increased passage of labelled albumin across
monolayers cultured on microcarriers, relative to untreated
endothelial cells (p < 0.05). Furthermore, electron microscopy
of endothelial cells cultured on the basement membrane of human
placental amnion indicated increased permeability based on wide,
interendotheHal gap formation and transit of the tracer horseradish
peroxidase. Quantification of interendothelial gaps revealed an
eleven‐fold increase with the Tx mimic relative to untreated
endothial cells (p < 0.05) and prevention by pretreatment with
the Tx receptor antagonist (p < 0.05). These data indicate that
Tx directly modulates the permeability of endothelial cell in
vitro.
Endothelin‐1 Stimulates Monocytes in vitro to ReleaseChemotactic Activity Identified as Interleukin‐8 and Monocyte Chemotactic Protein‐1
Authors: Helset E. , Sildnes T. , Konopski Z. S.
Published: March 2007

In the present study we examined whether endothelin‐1 stimulation of
human monocytes causes release of chemotactic factors. It was found
that monocytes released neutrophil‐ and monocyte‐chemotactic
activity in a dose‐ and time‐dependent manner in response to ET‐1.
ET‐1 did not show any chemotactic activity by itself. NCA was
detected in monocyte supernatants in response to ET‐1
(0.01–100 nM) after 1, 4, 8 and 24 h stimulation. MCA was
detected only after 24 h stimulation with ET‐1 (0.1–100 nM).
Preincubation of the monocyte cultures with the lipoxygenase
inhibitors nordihydroguaiaretic acid (10−4 M) or
diethylcarbamazine (10−9 M) completely abolished
the appearance of NCA and MCA. NCA was neutralized by >
75% using a polyclonal antibody against human interleuktn‐8.
The ET‐1 induced release of IL‐8 was confirmed by IL‐8 ELISA. A
monoclonal antibody against human monocyte chemotactic protein‐1
neutralized MCA by > 80%. It is concluded that ET‐1
stimulation of monocytes in vitro causes release of
neutrophil‐ and monocyte‐chemotactic activity identified as IL‐8 and
MCP‐I respectively. An intact lipoxygenase pathway is crucial for
this effect of ET‐1 to occur.
Effects of Ursolic Acid and its Analogues on Soybean 15‐LipoxygenaseActivity and the Proliferation Rate of A human Gastric Tumour Cell Line
Authors: Es-Saady D. , Najid A. , Simon A. , Denizot Y. , Chulia A. J. , Delage C.
Published: March 2007

The authors have previously isolated and purified ursolic acid from
heather flowers (Calluna vulgarts). This terpene was found to
inhibit HL‐60 leukaemic cell proliferation and arachidonic acid
oxidative metabolism in various cell species. The effects of ursolic
acid and its analogues on soybean 15‐lipoxygenase activity and on
the proliferation of a human gastric tumour cell line (HGT), have
been assessed. These triterpenes inhibited soybean 15‐lipoxygenase
at its optimal activity (pH 9). The proliferation ofHGT was
decreased in a dose‐dependent manner. At 20 μM the rank order is:
ursolic acid > uvaol > oleanolic acid > methyl ursolate. The
carboxylic group at the C28 position of ursolic acid appears to be
implicated in the inhibition of both lipoxygenase activity and cell
proliferation. Thus methylation of this group decreases these two
inhibitory properties. Oleanolic acid, which differs by the position
of one methyl group (C20 instead of C19) is less inhibitory than
ursolic acid. The lipophilicity of the terpene is also implicated
since uvaol appears to be more inhibitory than methyl ursolate.
Neurogenic Inflammation of Guinea‐Pig Bladder
Authors: Bjorling D. E. , Saban M. R. , Saban R.
Published: March 2007

Capsaicin, substance P, and ovalbumin, instilled into the bladders
of naive and ovalbumin (OVA) sensitized guineapigs caused
inflammation, as indicated by increased vascular permeability.
Histological changes after exposure to these compounds progressed
with time from intense vasodilatation to marginalization of
granulocytes followed by interstitial migration of leukocytes. In
vitro incubation of guinea‐pig bladder tissue with substance P and
ovalbumin stimulated release of prostaglandin D2 and leukotrienes. In
vitro incubation of bladder tissue with capsaicin, OVA,
prostaglandin D2, leukotriene C4, histamine, or calcium ionophore
A‐23587 all stimulated substance P release. These data suggest that
bladder inflammation initiated by a variety of stimuli could lead to
a cyclic pattern of release of inflammatory mediators and
neuropeptides, which could result in amplification and persistence
of cystitis after the inciting cause has subsided.
Changes in Mobility of the Golden Hamster with Induction of an IL‐1‐Induced Arthritis
Authors: Otterness I. G. , Bliven M. L. , Milici A. J.
Published: March 2007

Many studies in animals have examined biochemical, immune and
histological changes during arthritis; however, the study of the
effects of arthritis on mobility has been largely neglected.
Interleukin‐1, administered by the intraarticular route into hamster
knee joints, resulted in inhibition of spontaneous wheel running
activity; however, the effect was transient, lasting only through
the evening following IL‐1 administration. A further injection of
IL‐1 2 days later showed still greater inhibition of running. The
effect again did not extend beyond the first evening after
injection. IL‐1α and IL‐1β showed equivalent effects on
mobility, and no evidence was seen for cooperative interaction
between them. A 50% inhibition of running occurred at a dose
of approximately 10 ng/knee of IL‐1α. The effect appeared
not to be systemic since intraperitoneal injection required
microgram amounts of IL‐1 for an equivalent inhibition. At the time
mobility had been restored to normal, histological examination
showed the continued presence of inflammatory cells, soft tissue
swelling and cartilage proteoglycan loss. These results suggest a
lack of correlation between inhibition of mobility and
histopathological changes in cartilage and soft tissue.
In vitro Release of Eosinophil Proteins in Allergic and Atopic Dermatitis Patients
Authors: Poulsen L. K. , Reimert C. M. , Bindslev-Jensen C.
Published: March 2007

To investigate whether eosinophils are stimulated in
vivo or have acquired an increased susceptibility to stimuli
from the coagulation cascade, the release of eosinophil proteins was
compared for three groups of donors with different levels of serum
IgE. (1) with atopic dermatitis (s‐IgE > 5000 IU/ml, n = 11);
(2) with inhalant allergy (200 < s‐IgE < 2 000 IU/ml,
n = 10); and (3) non‐allergic (s‐ IgE < 100 IU/ml, n = 10). The
levels of eosinophil cationic protein and eosinophil protein X (ECP,
EPX) were determined in serum (clotting time = 2.0 h) and plasma.
Serum and plasma ECP in normal donors demonstrated large
intra‐personal variations (C.V. 50–80%), but serum‐ECP
(mean 8.1 ng/ml) was clearly distinguishable from plasma ECP
(mean 1.0 ng/ml) by a factor of 8 (range: 5.6–11.6). The
ECP released during clotting was markedly increased in the atopic
dermatitis group (serum:plasma ratio 13.5, p < 0.003) compared with the other groups (6.7 and 5.6). EPX, having a higher plasma
level, demonstrated a less pronounced release (serum: plasma ratios
2.0, 1.7 and 1.4), with no statistical difference between donor
groups. Considering all donors together the levels of ECP and EPX in
plasma and in serum were correlated to the number of eosinophils
(coefficients of correlation 0.54‐0.58, p < 0.002).
A study of the Interaction Between Cetirizine and Plasma Membrane ofEosinophils, Neutrophils, Platelets and Lymphocytes using A fluorescence Technique
Authors: Kantar A. , Oggiano N. , Giorgi P. L. , Rihoux J-P.
Published: March 2007

The effect of cetirizine on plasma membrane fluidity and
heterogeneity of human eosinophils, neutrophils, platelets and
lymphocytes was investigated using a fluorescence technique.
Membrane fluidity and heterogeneity were studied by measuring the
steady‐state fluorescence anisotropy and fluorescence decay of 1‐(4‐
trimethylammonium‐phenyl)‐6‐phenyl‐1, 3, 5‐hexatriene (TMA‐DPH)
incorporated in the membrane. The results demonstrate that
cetirizine (1 μg/ml) induced a significant increase in the
Hpid order in the exterior part of the membrane and a decrease in
membrane heterogeneity in eosinophils, neutrophils and platelets.
Moreover, cetirizine blocked the PAF induced changes in membrane
fluidity in these cells. Cetirizine did not influence significantly
the plasma membrane of lymphocytes. These data may partially explain
the effect ofcetirizine on inflammatory cell activities.
Cytokine Reduction in the Treatment of Joint Conditions
Authors: Sipe J. D. , Martel-Pelletier J. , Otterness I. G. , Pelletier J.-P.
Published: March 2007

The destruction of joints caused by rheumatoid arthritis and
osteoarthritis is characterized by an imbalance of enzyme catalysed
cartilage breakdown and regeneration. A complex cytokine network
perpetuates joint conditions by direct regulation of
metalloproteases, by indirect recruitment of cells that secrete
degradative enzymes, and by inhibition of reparative processes. The
destructive action of cytokines such as interleukin‐1, interleukin‐6
and tumour necrosis factor‐α can be modulated at multiple
points associated either with cytokine production or with cytokine
action. Potential agents for cytokine reduction include selective
anti‐cytokine antibodies, anticytokine receptor antibodies, cytokine
receptor antagonist proteins, and soluble and chimeric cytokine
receptor molecules. Pharmacologic regulation of IL‐1 and TNFα
remain primary targets for treatment of arthritis, and results of
early clinical trials are promising. However, the results of
long‐term clinical trials will be required to support the value of
anti‐cytokine therapy in treatment of arthritis.
In vivo Mononuclear Phagocyte Migration: Paradoxical Effect of Adrenalectomy
Authors: Heluy-Neto N. E. , Cunha F. Q. , Ferreira S. H.
Published: March 2007

The effect of adrenalectomy on neutrophil and monocyte migration
into rat peritoneal and pleural cavities was investigated.
Carrageenin‐ or thioglycollate‐induced neutrophil emigration into
both cavities was enhanced by adrenalectomy. In contrast, monocyte
migration into peritoneal cavities induced by these two stimuli was
significantl decreased. In pleural cavities, adrenalectomy enhanced
the monocyte migration induced by carrageenin but had no effect on
that induced by thioglycollate. Administration of physiological
doses of glucocorticoids reversed the effect of adrenalectomy on
monocyte migration by both stimuli into both cavities. The results
support the hypothesis that endogenous glucocorticotds negatively
control neutrophil migration independently of the site or type of
stimulus. Their role in monocyte migration is, however, dependent on
the site of injury and on the type of inflammatory stimulus. There
is no obvious explanation for the divergent influence of endogenous
glucocorticoids on the monocyte emigration into peritoneal and
pleural cavities observed with different stimuli.
A reasonable Approach for the Treatment of HIV Infection in the Early Phase with Ozonetherapy(Autohaemotherapy). How ‘Inflammatory’ Cytokines may have A therapeutic Role
Authors: Bocci V.
Published: March 2007

Immunoregulatory cytokines produced by the TH1 subset and by
CD8+ T lymphocytes appear to brake naturally and
sometimes arrest the progress of HIV infection in the early phase.
It appears reasonable to assume that a mild and equilibrated
stimulation of the immune system may prevent or delay the fatal
transition towards the prevalent production of TH2‐type cytokines.
The problem is how to stimulate the immune system in a physiological
fashion. In the last 7 years we have clarified the main mechanisms
of action of an unorthodox immunotherapeutic method first used 40
years ago. Optimized autohaemotherapy after a brief exposure ofblood
to ozone may today afford the trick of reprogramming the immune
system to keep HIV at bay. The autohaemotherapeutic procedure is
simple, safe, inexpensive and most likely is more effective than
conventional approaches.
Anti‐ Schistosomular Activity of Human Monocytes/Macrophagesin Response to Interleukin‐3 and Granulocyte‐Macrophage Colonystimulating Factor Stimulation
Authors: Gold D. , Nissimov L. , Lengy J. , Keisari Y.
Published: March 2007

Human monocytes, co‐incubated for 7 days in culture with GM‐CSF or
IL‐3 but not with IFN‐γ, exerted a variable
schistosotnulicidal effect on Schistosoma mansoni
parasites when grown in 96‐well round‐bottomed plates but not in
flat‐bottomed plates. Addition of LPS or IFN‐γ or both, for
the last 48 h did not enhance the cidal effect. Addition of LPS but
not IFN‐γ to the pre‐incubated cells with GM‐CSF or IL‐3
markedly stimulated TNF‐α production by the cells but not
their cidal activity. The variable cidal effects obtained with the
monocytes/macrophages from different donors suggest that these
effects may be genetically predetermined and are possibly linked to
blood group markers or to MHC class I or II antigens.
Autologous Enhancement by Interferon of Natural Killer Activity ofHuman Peripheral Blood Lymphocytes
Authors: Cheknev S. B. , Ashmanova Y. G. , Pritsker A. D. , Latysheva O. L. , Yershov F. I. , Kulberg A. J.
Published: March 2007

The in vitro action of interferon (IFN)‐α and
IFN‐γ from six healthy donors and ten patients with multiple
sclerosis (MS) on natural killer (INK) activity of peripheral blood
lymphocytes (PBL) was studied in an autologous system. The NK
activity of PBL was detected by a cytotoxic test using
3H‐uridine human erythromyeloblast K562 cells. Autologous
IFN‐α and IFN‐γ did not augment NK activity of PBL from
healthy donors in vitro, whereas in samples from MS
patients the IFNs strongly stimulated NK cell cytotoxic function.
This stimulation suggests the existence of an inhibitor of
regulatory IFN action, that is produced in healthy donors
simultaneously with IFN in response to IFN induction, but which is
lacking in commercial IFN preparations. The factor‐containing
supernatants from healthy donors reduced the stimulatory action of
autologous IFNs in patients with MS almost until complete blockade.
Because this inhibitor was absent in patients with MS, deficiency of
an inhibitor of IFN regulatory action in MS could open the way to
treatment of this compartment of the immune system.
Anti‐IgE Response in Human Airways: Relative Contribution of Inflammatory Mediators
Authors: Gorenne I. , Labat C. , Norel X. , Alaoui H. Sosse , Gascard J.-P. , Brink C.
Published: March 2007

Heman airway preparations at resting tone were relaxed with either
the leukotriene synthesis inhibitor BAY x1005 (3 μM),
chlorpheniramine (1 μM) or the thromboxane receptor antagonist
BAY u3405 (0.1 μM). The response to anti‐IgE (1:1000) was 58
± 8% of acetylcholine pre‐contraction (2.19 ±
0.28 g). Indomethacin (3 μM) enhanced the anti‐IgE‐induced
contraction by 28%. The anti‐IgE maximal response was not
modified by either chlorpheniramine, BAY x1005 or BAY u3405. When
the tissues were treated with either BAY xl005/indomethacin or
BAY x1005/chlorpheniramine, the anti‐IgE‐induced contraction was
reduced. In addition, in presence of BAY
xl005/indomethacin/chlorpheniramine the response was
completely blocked. These results suggest that mediatots released
during anti‐IgE challenge cause airway contraction which may mask
the evaluation of the leukotriene component.
FK506 and Cyclosporin A Enhance IL‐6 Production in Monocytes: A single‐Cell Assay
Authors: Murayama K. , Sawamura M. , Murakami H. , Tamura J. , Naruse T. , Tsuchiya J.
Published: March 2007

The effect of FK506 and cyclosporin A (CsA) on the production of
interleukin 6 (IL‐6) in adherent monocytes was studied at a
single‐cell level by the avidinbiotin‐ peroxidase complex methods.
The percentage of IL‐6‐producing monocytes increased when stimulated
with lipopolysaccharide (LPS) at concentrations between 10 ng/ml and
10 μg/ml, in a dose dependent manner. Both FK506 and CsA
enhanced the percentage of IL‐6‐ producing monocytes stimulated with
100 pg/ml‐1 μg/ml of LPS up to values near those
obtained with 10 μg/ml of LPS. The enhancement by FK506 and
CsA was not seen when monocytes were stimulated with a high
concentration of LPS (10 μg/ml). When monocytes were
stimulated with a low concentration of LPS (10 ng/ml), FK506 and
CsA enhanced IL‐6 production in a dose dependent manner, at a drug
concentration of 0.12 nM–1.2 μM (0.1–1 000 ng/ml)
for FK506 and 0.83 nM–8.3 μM (1–10 000 ng/ml) for
CsA. The optimal effect of FK506 was achieved at a concentration
7‐fold lower than that of CsA. In contrast, production of turnout
necrosis factor‐α (TNFα and interleukin 1β
(IL‐1β) was slightly suppressed by FK506 and CsA at the
concentrations tested. Moreover, pretreatment of monocytes with
FK506 and CsA had a significant enhancing effect on LPS‐induced IL‐6
production, while treatment with FK506 or CsA after LPS stimulation
had no effects on IL‐6 production, suggesting that the enhancing
effect of each drug is exerted before LPS stimulation or at an early
stage of the post‐receptor pathway after LPS stimulation. These
experiments demonstrate that FK506 and CsA can selectively enhance
IL‐6 production in monocytes under certain conditions in
vitro and, possibly, also in vivo.
Platelet Activating Factor Synthesis and Metabolism in Intestinal Ischaemia‐Reperfusion Injury
Authors: Mangino M. J. , Murphy M. , Bohrer A. , Turk J.
Published: March 2007

The object of this study was to characterize the synthesis and
metabolism of platelet activating factor (PAF) by intestinal mucosa
subjected to ischaemia–reperfusion injury. Canine intestinal mucosa
produced 16:0‐PAF, 18:0‐PAF, and high levels of the corresponding
lyso‐ PAF metabolites. Three h of intestinal ischaemia and ischaemia
followed by 1 h of reperfusion did not affect the synthesis or
metabolism of PAF by intestinal mucosa. Intestinal mucosa elaborated
a factor that rapidly hydrolyzes PAF to lyso‐PAF. The observed
hydrolysis rate was not altered by ischaemia or ischaemia and
reperfusion. In conclusion, this study suggests that intestinal
mucosa produces PAF and rapidly hydrolyzes PAF. The PAF synthesis
and metabolism rates of intestinal mucosa is not altered by
ischaemia reperfusion in this model under the imposed conditions.