bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumour Necrosis Factor‐α Production and Immune Cell Activation in Tuberculous Meningitis
Authors: Mastroianni C. M. , Paoletti F. , Valenti C. , Massetti A. P. , Vullo V. , Delia S.
Published: March 2007

The local production of tumour necrosis factor‐α (TNFα)
was evaluated in the cerebrospinal fluid (CSF) from ten patients
with tuberculous meningitis (TBM). The degree of intrathecal immune
activation was also studied by assessing the CSF levels of
β2‐microglobulin (β2‐M) and
adenosine deaminase activity (ADA). Results indicate that elevated
CSF concentrations of TNFα, β2‐M and ADA were
found in all TBM patients. Moreover, TNFα is produced and
selectively concentrated for a long period of time, while
β2‐M and ADA values progressively decline during the
course of TBM. Our findings suggest that in TBM patients, after an
early activation of immune cells, there is an enhanced and
continuous production of TNFα at the site of infection.
Histamine N‐methyltransferase Modulates Human Bronchial Smooth Muscle Contraction
Authors: Tamaoki J. , Chiyotani A. , Tagaya E. , Isono K. , Konno K.
Published: March 2007

To elucidate the modulatory role of histamine‐degrading enzymes in
airway constrictor responses, human bronchial strips were studied
under isometric conditions in vitro. Pretreatment of tissues with
the histamine N‐methyltransferase (HMT) inhibitor SKF 91488
specifically potentiated the contractile responses to histamine,
causing a leftward displacement of the concentration response curves,
whereas the diamine oxidase inhibitor aminoguanidine had no effect.
This potentiation was attenuated by mechanical removal of the
epithelium. The HMT activity was detected in the human bronchi,
which was less in the epithelium‐denuded tissues than the
epithelium‐intact tissues. These results suggest that HMT localized
to the airway epithelium may play a protective role against
histamine‐mediated bronchoconstriction in humans.
Inhaled Nitric Oxide Counterbalances ET‐1 Dependent Pulmonary Hypertension and Bronchoconstriction in the Pig
Authors: Clement M. G. , Dimori M.
Published: March 2007

In anaesthetized, paralysed, ventilated pigs the ability of
inhaled nitric oxide (80 ppm in 02) to reduce the
haemodynamic and respiratory effects of endothelin‐1
administration (200 pmol/kg, i.v.) was evaluated. The
mechanical properties of the respiratory system were
evaluated by the rapid airway occlusion technique. The
overall respiratory resistance, the interrupter resistance
and the additional resistance that reflects the viscoelastic
properties of tissues and the inequality of the time constant
within the system were also evaluated. The results
show that inhaled nitric oxide can act as a selective
pulmonary vasodilator and as a bronchodilator to counteract
the vasoconstrictor and bronchoconstrictor activity
of endothelin‐1. In the pig, nitric oxide inhaled at 80
ppm for 6 mitt reduced the changes in respiratory‐, interrupter‐
and additional resistance due to endothelin‐1 administration
without significantly changing the static and
dynamic elastance of the respiratory system.
Effects of the Bacterial Extract OM‐85 on Phagocyte Functions and the Stress Response
Authors: Baladi S. , Kantengwa S. , Donati Y. R. A. , Polla B. S.
Published: March 2007

The effects of the bacterial extract OM‐85 on the respiratory burst,
intracellular calcium and the stress response have been investigated
in human peripheral blood monocytes from normal donors. Activation
of the respiratory burst during bacterial phagocytosis has been
previously associated with heat shock/stress proteins synthesis.
Whereas OM‐85 stimulated superoxide production and increased
Ca2+ mobilization, it fared to induce synthesis of
classical HSPs. The lack of stress protein induction was observed
even in the presence of iron which potentiates both oxidative injury
and stress protein induction during bacterial phagocytosis. However
OM‐85 induced a 75–78 kDa protein, which is likely to be a
glucose regulated protein (GRP78), and enhanced intracellular
expression of interleukin‐lβ precursor.
In vitro Superoxide Production by Peripheral Neutrophils from Patients with Inflammatory Bowel Disease
Authors: Nielsen O. H. , Berild D. , Ahnfelt-Rønne I.
Published: March 2007

Activated polymorphonuclear leucocytes, which are accumulated in
inflammatory lesions of inflammatory bowel disease, produce tissue
destructive, oxygen derived free radicals and other inflammatory
mediators. The PMN superoxide production elicited by
formyl‐methionyl‐leucyl‐phenylalanine or the complement split
product 5a were compared in IBD and healthy volunteers.
Significantly reduced superoxide production was found in PMNs from
patients with Crohn′s disease as compared to normal controls,
when fMLP or CSa were used as stimulants (p < 0.001 and p < 0.01, respectively), whereas no differences were found when
ulcerative colitis patients were compared to normal controls (p > 0.05).
The enhanced oxygen derived free radical production
previously reported in active IBD, and especially in CD intestinal
lesions, may either be due to an accumulation of productive
phagocytes or to a change of the inflammatory profile of these cells
when migrating into intestinal lesions, possibly due to interaction
with other mediators (e.g. adhesion molecules and interleukins).
Allergic Rhinoconjunctivitis: the Role of Histamine
Authors: Andersson M. , Greiff L. , Svensson C.
Published: March 2007

Allergic rhinoconjunctivitis is the most common atopic condition
encountered in clinical practice. Analysis of the pathogenesis of
this condition permits identification of optimal therapeutic
targets. The increased knowledge of the underlying pathophysiology
suggests that multiple inflammatory mediators are involved in the
pathogenesis of the allergic reaction in the ocular and nasal
mucosa. However, despite the presence of a wide range of different
mediators, it would appear that histamine plays a key role.
Experimental allergen challenge studies have demonstrated that
histamine is the only mediator which produces the full spectrum of
clinical manifestations of the acute allergic reaction when applied
to the mucosal surface. While both H1‐ and H2‐receptors are present
in the nasal and ocular mucosa, only H1‐receptor antagonists are
capable of inhibiting histamine‐induced symptoms of allergic
rhinoconjunctivitis. Furthermore, although the exact role of
histamine in the immediate and prolonged allergic reaction has not
yet been fully elucidated, these findings do not exclude the
possibility that histamine is involved in these processes. The
available evidence therefore supports current clinical practice for
use of H1‐receptor antagonist as a first‐line therapy in
patients with this atopic condition.
The Effect of Steroid Treatment on Lipocortin Immunoreactivity of Rat Brain
Authors: Go K. G. , Ter Haar J. G. , de Ley L. , Zuiderveen F. , Parente L. , Solito E. , Molenaar W. M.
Published: March 2007

Lipocortin‐1, lipocortin‐2 and lipocortin‐5 were
immunohistochemically assessed in rats. Apart from animals receiving
no treatment, other animals received pretreatment with
methylprednisolone, or the 21‐aminosteroid U‐74389F. Whereas
Hpocortin immunoreactivity was absent in the greater part of the
brain in animals not pretreated with steroid (except in sporadic
microglial cells and choroid plexus), there was obvious
immunostaining of parenchymatous elements in steroid pretreated
animals. In the steroid pretreated animals lipocortin
immunoreactivity of the brain tissue may indicate local formation of
lipocortin under the influence of steroids that had entered the
tissue. The cellular elements which showed immunostaining included
meningeal cells, neurones, ependyma, oligodendroglia and capillary
endotheHum.
Serum Levels of Soluble IL‐2R, CD4 and CD8 in Chronic Active HCV Positive Hepatitis
Authors: Caruso C. , Candore G. , Cigna D. , Tripi S. , Di Gaetano G. , Migneco G. , Montalto G. , Ruggieri I. , Notarbartolo A.
Published: March 2007

The aim of the present study was to compare serum levels of soluble
forms of interleukin‐2 receptor, CD4 and CD8, released by
lymphocytes during activation ofthe immune system, in patients with
histologically verified chronic active hepatitis associated to
hepatitis C virus infection, with those in healthy subjects.
Significantly higher levels of soluble IL‐2R and soluble CD8 were
found in patients with chronic active hepatitis compared with
controls. In contrast no difference was found for soluble CD4 values
in the two groups. No correlations were found for both sIL‐2R and
sCD8 and these two molecules with other parameters of liver
function. These results indicate that in these patients there is a
general activation of the immune system, but the lack of correlation
with parameters of liver function strengthens the suggestion that
this activation does not play a role in the pathogenesis of chronic
type C hepatitis.
Changes and Relationship of PAF and TNF in Rats with Myocardial Ischaemia and Reperfusion Injury
Authors: Han Ya-Ling , Li Shao-Ha , Zheng Qin-Yue , Wang Hong-Bin , Zhang Guo-Yan , Wu Zhong-Gui , Chen Si-Cong
Published: March 2007

In this study it is reported that: (1) the levels of blood
platelet‐activating factor and serum tumour necrosis factor
significantly increased after coronary ligation and reperfusion,
compared with sham‐ligated controls, in an anaesthetized rat model;
(2) compared with vehicle controls, pretreatment with the PAF
antagonist BN 50739 (10 mg/kg, i.v.) produced significant
decreases in infarct size (from 29.6 ± 4.0% to 22.4
± 2.1%, p < 0.05 after 3 h ligation, and from
28.5 ± 9.5% to 10.5 ± 4.5%,
p < 0.01 after 4 h reperfusion) and the level of serum TNF (from 10.4
± 7.7 U/ml to 3.9 ± 4.8 U/ml, p < 0.05); and (3) a significan positive correlation was found between the
level of blood PAF or serum TNF and infarct size. The present
results indicate that PAF and TNF may be important mediators
involved in myocardial ischaemia and reperfusion injury, and that
PAF antagonists may exert a protective effect on ischaemic or
reperfused myocardium by inhibiting the interaction of PAF and TNF.
Possible Involvement of Endothelin Peptides and L‐Arginine‐NitricOxide Pathway on the Effect of Endotoxin in the Rabbit Isolated Perfused Kidney
Authors: Özsan K. , Türker R. K. , Ercan Z. S.
Published: March 2007

Escherichia coli endotoxin (LPS) when infused through the renal
artery of the rabbit isolated perfused kidney prepared as constant
pressure mode, caused a decrease in flow rate and kidney weight
indicating its primary vasoconstrictor effect. This effect was
predominant in kidneys from rabbits pretreated with LPS. Endothelin‐1
at a concentration of 10−10 M and big endothelin‐1 at a concentration
of 10−8 M produced equal vasoconstrictor effects in kidney. Addition
of endotheHn converting enzyme inhibitor, phosphoramidon, to the
perfusion medium at a concentration of 10−6 M caused a reduction in
the effects of both LPS and big ET‐1 without altering the
vasoconstrictor effect of ETol. However, addition of methylene blue
(10−5 M), a soluble guanylate cyclase inhibitor and
NG‐nitro‐L‐arginine‐methyl ester (10−6 M) to the perfusion medium
caused a potentiation in the vasoconstrictor effect of LPS.
Indomethacin at a concentration of 10−6 M did not alter the effect of
LPS. These results were taken as evidence for the participation of
endothelin peptides and the L‐arginine‐nitric oxide pathway in the
effect ofLPS in rabbit isolated perfused kidney.
Serum Concentration and Chemotactic Activity of E‐selectin (CD62E) in Inflammatory Bowel Disease
Authors: Vainerc B. , Nielsen O. H.
Published: March 2007

E‐selectin (CD62E) is an endothelial specific glycoprotein belonging
to the selectin family of adhesion molecules. Because a high
expression of this molecule at intestinal mucosal surfaces in
inflammatory bowel disease (IBD) has been described earlier, the aim
was to assess serum levels of E‐selectin (sE‐selectin) and to
correlate it to disease activity, and further to evaluate its
chemotactic properties at physiological concentrations. Levels of
sEselectin were measured by a sandwich ELISA technique in 31 IBD
patients together with 15 healthy volunteers. In ulcerative colitis
the median value was 0.46 nM (0.16–0.75), in Crohn’s disease
0.47 nM (0.22–1.24), and in healthy controls 0.34 nM
(0.22–0.83). No statistically significant differences in
sE‐selectin were revealed between these groups (p > 0.05). The in vitro chemotactic capabilities of E‐selectin (in the
concentration range of 0.10–31.4 nM) were assessed using the
leading front technique. A significantly increased migratory
response was found at concentrations of 1.00 (p < 0.05) and 3.14 nM (p < 0.02). It is concluded that sE‐selectin in
contrast to sICAM‐1 does not act as a sensitive indicator of local
immune activation in IBD. However, E‐selectin may be important for
recruitment and accumulation of neutrophilic granulocytes and other
phagocytes involved in the inflammatory process seen in IBD. Future
investigations are encouraged in order to reveal its in
vivo effects.
Cytokine Production by Human Colonic Intraepithelial Lymphocytes in Controls and Ulcerative Colitis
Authors: Hoang P. , Dalton H. R. , de Silv H. J. , Jewell D. P.
Published: March 2007

Using an ELISA technique, concentrations of γ‐interferon and
interleukin‐2 were assayed in the supernatants of colonic
intraepithelial lymphocytes cultured with or without
phytohaemagglutinin (PHA). IntraepitheHal lymphocytes produced low
concentrations of γ‐interferon and interleukin‐2 when
stimulated with PHA, but significantly more than when unstimulated
(p < 0.05). There was no difference in production of these
cytokines by IEL from control or inflammatory bowel disease.
Neutrophil‐derived Oxidants and Proteinases as Immunomodulatory Mediators in Inflammation
Authors: Witko-Sarsat V. , Descamps-Latscha B.
Published: March 2007

Neutrophils generate potent microbicidal molecules via the
oxygen‐dependent pathway, leading to the generation of reactive
oxygen intermediates (ROI), and via the non‐oxygen dependent pathway,
consisting in the release of serine proteinases and
metalloproteinases stored in granules. Over the past years, the
concept has emerged that both ROI and proteinases can be viewed as
mediators able to modulate neutrophil responses as well as the whole
inflammatory process. This is well illustrated by the oxidative
regulation of proteinase activity showing that oxidants and
proteinases acts is concert to optimize the microbicidal activity
and to damage host tissues. ROI and proteinases can modify the
activity of several proteins involved in the control of inflammatory
process. Among them, tumour necrosis factor‐α and
interleukin‐8, are elective targets for such a modulation. Moreover,
ROI and proteinases are also able to modulate the adhesion process
of neutrophils to endothelial cells, which is a critical step in the
inflammatory process.
Effect of Platelet‐activating Factor on in vitro and in vivo Interleukin‐6 Production
Authors: Pignol B. , Maisonnet T. , Guinot P. , Mencia-Huertac J. M. , Braquet P.
Published: March 2007

The aim of the present study was to investigate the possible effect
of platelet‐activating factor (PAF), by comparison with
interleukin‐1β and polyriboinositic/polyribocytidylic (poly
I–C) acid, on IL‐6 production by L 929 mouse fibroblasts. At
concentrations above 1 μM PAF, the production of IL‐6 by mouse
fibroblasts was enhanced in a dose dependent fashion. At 5 μM
PAF, the peak increase (60.1 ± 19.4 U/ml) was similar to
that induced by 50 μg/ml poly I–C (60.0 ± 35.0
U/ml) and higher than the one evoked by 100 U/ml IL‐1β
(3.8 ± 1.8 U/ml). The increase of 11‐6 activity induced
by 5 μM PAF was maximal after a 22 h incubation period with L 929
cells. Lyso‐PAF (5 μM) also increased IL‐6 activity from
fibroblasts to a similar extent compared with 5 μM PAF. In
addition, the IL‐6 activity induced by 5 μM PAF was still
observed when the specific PAF antagonist, BN 52021 (10 μM), was
added to the incubation medium of L 929 cells. The result suggests
that the production of IL‐6 by L 929 cells evoked by PAF in
vitro is not receptor mediated. The in vivo
effect of PAF on IL‐6 production was also investigated in the rat.
Two hours after intravenous injection of PAF (2 to 4 μg/kg),
a dramatic increase of IL‐6 activity in rat serum was observed, this
effect being dose dependent. The increase of IL‐6 induced by 3
μg/kg PAF was not observed when the animals were treated with
the PAF antagonist, BN 52021 (1 to 60 mg/kg0. These results
demonstrate that PAF modulates IL‐6 production and that the in
vivo effect is receptor mediated.
Hyaluronic Acid Inhibits Polycation Induced Cellular Responses
Authors: lalenti A. , lanaro A. , Brignola G. , Marotta P. , Di Rosa M.
Published: March 2007

Positively charged macromolecules cause a variety of pathological
events through their electrostatic interaction with anionic sites
present on the membrane of target cells. In the present study we have
investigated the effect of hyaluronic acid, a negatively charged
molecule, on rat paw oedema induced by poly‐L‐lysine as well as on
histamine release from rat mast cells and nitric oxide formation
from rabbit aorta, both induced by this polycation. The results
indicate that hyaluronic acid is able to suppress these
poly‐L‐lysine induced effects with a mechanism which possibly
depends on its negative charges which may balance the effects of
positively charged polycations.
Infection with Toxoplasma gondii does not AlterTNFα and IL‐6 Secretion by A human Astrocytoma Cell Line
Authors: Pelloux H. , Ricard J. , Nissou M.-F. , Renversez J.-C. , Vuillez J.-P. , Meunier A. , Ambroise-Thomas P.
Published: March 2007

The secretion of tumour necrosis factor‐α (TNFα),
interleukin‐1α (IL‐α) and interleukin‐6 (IL‐6) by a
human astrocytoma cell fine was studied 1 h, 3 h, 6 h and 24 h after
infection with tachyzoites from three Toxoplasma gondii
strains (virulent, RH; cystogentc, 76K and Prugniaud strains). The
astrocytoma cell fine constitutively secreted TNFα and IL‐6,
but no IL‐1α. A positive control was obtained by stimulation
with phorbol esters inducing a significant increase (p < 0.05) in TNFα and IL‐ 6 secretion but not in IL‐1α, while
lipopolysaccharide (alone and after priming), interferon gamma,
ionophore A 23187 and sera positive to T. gondii did
not induce any increase in cytokine levels. None of the tachyzoites,
whatever their virulence, induced a significant increase in cytokine
production at any time in the study. Tachyzoites did not inhibit the
secretion induced by phorbol esters.
Cell–Cell Interaction of Macrophages and Vascular Smooth MuscleCells in the Synthesis of Leukotriene B4
Authors: Zou M. , Anges C.
Published: March 2007

Biosynthesis of LTB4 during cell‐cell interaction between
vascular smooth muscle cells (SMC) and alveolar macrophages (AM) has
been investigated by use of both high‐pressure Hquid chromatography
(HPLC) and radtoimmunoassay (RIA). Both interleukin‐β
(IL‐β) and tumour necrosis factor‐α (TNFα) induced
a time‐ and dose‐dependent synthesis of 15‐, and
5‐hydroxyeicosatetraenoic acids (HETEs) from cultured SMC. However,
neither TNFα nor IL‐1β induced a significant
LTB4 production in SMC alone or AM alone after 24 h of
incubation. Addition of IL‐1β and TNFα simultaneously to
SMC resulted in a dose‐dependent synergistic increase of HETEs.
Macrophages dose‐dependently transformed extremely low
concentrations of exogenous LTA4 into LTB4.
Incubation of vascular SMC with various numbers of AM in the
presence of IL‐1β (5 units/ml) and TNFα (10
units/ml) induced a great increase of LTB4 synthesis
in comparison with the detectable levels of LTB4 produced
by macrophages alone. Pretreatment of SMC with NDGA, cycloheximide,
and actinomycin not only inhibited IL‐1 and TNT induced HETEs
synthesis but also abolished LTB4 production when
co‐incubated with macrophages. These results suggest that
LTB4 in a mixture of SMC and macrophages could originate
from a transcellular metabolism, i.e. macrophages transforming
SMC‐derived LTA4 into LTB4.
Oxidized Lipoproteins Suppress Nitric Oxide Synthase in Macrophages:Study of Glucocorticoid Receptor Involvement
Authors: Matthys K. E. , Jorens P. G. , Marescau B. , Rosseneu M. , Bult H. , Herman A. G.
Published: March 2007

Activated cholesterol‐laden macrophages in atherosclerotic lesions
are believed to influence the progression of this disease. The
induction of nitric oxide synthase (iNOS) activity was investigated
in control and cholesterol‐laden J774 macrophages, obtained by
pre‐incubation with oxidized or acetylated low density lipoproteins
(oxLDL, acLDL). Loading with oxLDL caused a small induction of NOS
activity in unstimulated cells, as indicated by nitrite and
citrulline accumulation in the supernatant. However, it suppressed
the iNOS activity resulting from stimulation of the cells with
lipopolysaccharide with or without interferon‐γ. AcLDL had no
inhibitory effect, indicating that cholesterol accumulation as such
was not responsible. Since the induction of NOS in macrophages is
inhibited by glucocorticoids, the possibility that a
glucocorticoid‐like factor, formed during oxidation of LDL, may
cause the inhibition, was investigated. However, addition of the
glucocorticoid receptor antagonist mifepristone did not prevent the
oxLDL‐dependent NOS inhibition, indicating that the glucocorticoid
receptor is not involved in the suppressive effect of oxLDL.
Changes in Eicosanoid and Tumour Necrosis Factor‐α Productionby Rat Peritoneal Macrophages During Carrageenin‐Induced Peritonitis
Authors: Pruimboom W. M. , Verdoold A. , Tak C. J. A. M. , van Dijk A. P. M. , van Batenburg M. , Wilson J. H. P. , Zijlstra F. J.
Published: March 2007

Changes and correlations in cytokine and eicosanoid production by
blood monocytes, non‐purified and purified peritoneal cells during a
carrageenin‐induced peritonitis were investigated for a period of
ten days. The cells were isolated and stimulated in
vitro. Cytokine and eicosanoid production of the non‐purified
fraction increased steadily during peritonitis. During the whole
episode of peritonitis the production capacity of granulocytes was
very low and hardly any effect on the production capacity of
macrophages (Mϕ) was observed. Cytokine and eicosanoid production of the
non‐purified fraction was mainly due to the presence of Mϕ. The production capacity of the peripheral blood monocytes was not
similar to that of the peritoneal Mϕ.
The TNF Receptors p55 and p75 Mediate Chemotaxis of PMN Induced byTNFα and a TNFα 36–62 Peptide
Authors: Rekdal Ø. , Konopski Z. , Svendsen J. S. , Winberg J.-O. , Espevik T. , Østerud B.
Published: March 2007

The present study was performed to examine whether residues
36–62 of TNFα contain the chemotactic domain of
TNFα, and whether the p55 and p75 TNF receptors are involved
in TNFα induced chemotaxis. The chemotactic effect of
TNFα on PMN was inhibited by the mAbs Hrt‐7b and Utr‐1,
against the p55 and p75 TNF receptors, respectively. Both receptors may
therefore be required for mediating the chemotactic effect of TNFcz.
The synthetic TNFα 36–62, similar to TNFα, had
chemotactic effects on both PMN and monocytes. The chemotactic
activity of the TNFα 36–62 peptide on PMN, was inhibited
by Htr‐7b, Utr‐1 and soluble p55 receptor, which shows that the
peptide possessed the ability to induce chemotaxis through the TNF
receptors. In contrast to TNFα, the peptide did not show a
cytotoxic activity against WEHI 164 flbrosarcoma cells. It is
suggested that different domains of the TNFα molecule induce
distinct biological effects.
A pre‐formed Pyrogenic Factor Released by Lipopolysaccharide Stimulated Macrophages
Authors: Zampronio A. R. , Melo M. C. C. , Silva C. A. A. , Pelá I. R. , Hopkins S. J. , Souza G. E. P.
Published: March 2007

The aim of this study was to investigate the pyrogenic activity of
factor(s) released by rat peritoneal macrophages following a brief
stimulation with LPS. The effect of this factor on the number of
circulating leukocytes and serum Fe, Cu and Zn levels, was also
evaluated. The possibility that the content of interleukin
(IL)‐1β, IL‐6 and tumour necrosis factor (TNF) in the
supernatant could explain the observations was investigated.
Supernatant produced over a period of 1 h by peritoneal macrophages,
following a 30 min incubation with LPS at 37°C, was
ultrafiltered through a 10 000 MW cut‐off Amicon membrane,
sterilized, and concentrated 2.5, 5, 10 and 20 times. The
intravenous (i.v.) injection of this supernatant induced a
concentration‐dependent fever in rats with a maximal response at 2
h. The pyrogenic activity was produced by macrophages elicited with
thioglycollate and by resident cells. The supernatants also induced
neutrophilia and reduction in Fe and Zn 6 h after the injection.
Absence of activity in boiled supernatants, or supernatants from
macrophages incubated at 4°C with LPS, indicates that LPS was
not responsible for the activity. In vitro treatment
with indomethacin (Indo), dexamethasone (Dex), or cycloheximide
(Chx) did not modify the release of pyrogenic activity into the
supernatant or its effects on the reduction in serum metal levels.
Although Chx abolished the production of mediator(s) inducing
neutrophilia, and Dex reduced the induction of IL‐1β, TNF and
IL‐6, injection of the highest concentration of these cytokines
detected in the supernatants did not induce fever. In
vivo treatment with Dex, but not Indo, abolished the fever
induced by the supernatant. These results suggest that macrophages
contain pre‐formed pyrogenic mediator(s), not related to IL‐1β,
IL‐6 or TNF, that acts indirectly and independently of
prostaglandtn. It also seems likely that the pyrogenic activity is
related to the factor responsible for the reduction of serum Fe and
Zn levels, but not the neutrophilia.
Effect of Fluticasone propionate Aqueous Nasal Spray Treatment onPlatelet Activating Factor and Eicosanoid Production By nasal Mucosain Patients with A house Dust Mite Allergy
Authors: Garrelds I. M. , de Graaf-in ′t Veld T. , Jansen A. P. H. , van Wijk R. Gerth , Zijlstra F. J.
Published: March 2007

The relationship between the release of platelet activating factor
(PAF), leukotriene C4/D4/EE
(LTC4/D4/E4) and prostaglandin D2 (PGD2)
from nasal mucosa in vivo was examined in 24 rhinitis patients
allergic to the house dust mite (HDM). During a double blind placebo
controlled cross‐over study 200 μg fluticasone propionate aqueous
nasal spray (FPANS) was administered twice daily for two weeks. In
response to allergen provocation (100, 1 000, 10 000 Bu/ml) and
during the 9.5 h after this challenge the nasal fluid was obtained
by washing the nose with saline and the levels of PAF, LTC4/D4/E4 and
PGD2, as indicators of mediator release, were measured at the
following time‐points: baseline (t = − 1/2), allergen provocation with
10 000 Bu/ml (t = 0), 3.5 and 7.5 h (late phase). After allergen
provocation the levels of the mediators increased in the nasal
fluids of placebo treated patients (x‐fold increase to baseline:
PAF, 15; LTC4/D4/E4, 12; PGD2, 1.5). In fluids of patients treated
with FPANS these levels tended to decrease. At the time of
provocation the levels of PAF, LTC4/D4/E4 and PGD2 showed a significant
correlation. The results indicate that these mediators can be used
as markers of allergic reactions against house dust mites and that
fluticasone propionate aqueous nasal spray tended to reduce the
release of mediators of inflammation correlated with beneficial
effects on clinical symptoms in this type of allergic reactions.
The Effect of IFN‐γ, Alum and Complete Freund Adjuvant on TNP‐KLH Induced Ig.G1, IgE and IgG2a Responses in Mice
Authors: van Ommen R. , Vredendaal A. E. C. M. , de Gooyer M. , van Oudenaren A. , Savelkoul H. F. J.
Published: March 2007

Adjuvants are considered to play an important role in directing the
isotype and amount of antibodies produced upon immunization by
conducting the development of either Th‐1 or Th‐2 cells upon T‐cell
stimulation. This is based on the different cytokine production
patterns that were observed after in vitro resttmulation of T cells
isolated from mice immunized with antigen either adsorbed on alum or
emulsified in complete Freund adjuvant (CFA). However, other studies
suggest that primarily the type of antigen determines which isotypes
are produced and to what extent. In these studies, however, IgE was
not determined. Therefore, this study examined whether alum and CFA
influenced the amount and/or ratio of IgG1, IgE and IgG2a produced
after TNP‐KLH immunization. Similar levels of IgG1, IgE and IgG2a
antibodies were found upon immunization with TNP‐KLH either adsorbed
on alum or emulsified in CFA. Moreover, administration of IFN‐γ in
combination with TNP‐KLH adsorbed on alum did not increase the
amount of IgG2a produced. IFN‐γ treatment resulted in an increased
IL‐6 and decreased IFN‐γ production by spleen cells upon Con A
stimulation, whereas it did not change the IL‐4 production in
similar conditions. The presented results suggest that upon
immunization with TNP‐KLH high IL‐4 levels are produced, resulting
in an antibody response that is dominated by IgG1, independent of the
adjuvant employed. The IL‐4 inducing property of TNP‐KLH is
substantiated by the finding that repeated immunization of mice with
TNP‐KI, without adjuvant, increases the serum total IgE level. The
presented data suggest that the carrier part of TNP‐KLH
preferentially results in Th‐2 cell activity after which the
adjuvant merely enhances the antibody responses generated.
Cholinoceptor Activation Subserving the Effects of Interferon Gamma on the Contractility of Rat Ileum
Authors: Borda Enri S. , Sterin-Borda Leonor , Rodriguez Martin , de Bracco Maria M. E.
Published: March 2007

Recombinant rat interferon γ stimulated the contractility of
isolated rat ileum at doses of 4–12 units/ml. Muscarinic
cholinoceptors were involved, as treatment of the tissue with
atropine prevented the contractile response of the ileum.
Furthermore, interferon γ increased the affinity of carbachol for
the cholinoceptors and did not change its maximum effect. Neurogenic
pathways were also involved since pretreatment of ileum with
hexamethonium, hemicholinium or tetrodotoxin impaired the
contractile effect of interferon γ. In contrast to the action of
exogenous carbachol, the effects of interferon γ are indirect. They
appear to involve a G protein regulating phosphoinositide turnover
and cytoskeletal structures since they could not be induced in ileum
strips that were pretreated with pertussis toxin, phospholipase C
inhibitors (2‐nitro‐carboxyphenyl, NN‐diphenyl carbamate and
neomycin), cytochalasine B or colchicine.
The Increased Expression of HLA‐DR and ICAM‐1 Molecules by Human Bronchial EpithelialCells, Induced by Activated Mononuclear Cells, is Downregulated by Nedocromil Sodium
Authors: Sacco O. , Lantero S. , Scarso L. , Frangova V. , Ottolini V. , Rossi G. A.
Published: March 2007

To test the hypothesis that mononuclear cell products could increase
the expression of HLA‐DR and ICAM‐1 molecules in bronchial
epithelial cells (BECs), subconfluent cultures of human BECs,
obtained from surgically resected bronchi, were incubated with
PHA‐activated blood mononuclear cell conditioned media (BCM‐CM) or
recombinant IFN‐γ. The presence of HLA‐DR and ICAM‐1 molecules
on BECs was then evaluated by specific antibody staining and
flow‐cytometry analysis. The addition to BEC cultures of different
concentrations of PHA‐stimulated BMC‐CM, or of IFN‐γ induced a
dosedependent increase of HIA‐DR and ICAM‐1 expression, while no
effect was observed with unstimulated BMC‐CM. The ability of
nedocromil sodium and, as control, of dexamethasone, to prevent the
upregulation of HLA‐DR and ICAM‐1 expression on BECs was then
tested. Increasing concentrations (10−7 to 10−4 M) of nedocromil
significandy inhibited HLA‐DR and ICAM‐1 expression by BECs in a
dose‐dependent fashion. A similarly dose‐dependent inhibitory effect
was also observed with dexamethasone, which, however, was less
active than nedocromil on HL‐ADR expression and more active on
ICAM‐1 expression. Finally, nedocromil and dexamethasone showed a
significant synergistic effect on the expression of both cell
surface molecules at the lowest concentrations tested.
Cromoglycate and Nedocromil: Influence on Airway Reactivity
Authors: Valletta E. A. , Boner A. L.
Published: March 2007

Although basic mechanisms of bronchial hyper‐responsiveness (BHR)
are still incompletely understood, inflammation of airways is likely
to play a fundamental role in modulating BHR in patients with
asthma. The involvement of several inflammatory cells (eosinophils,
mast cells, lymphocytes, neutrophils, macrophages and platelets) and
of bioactive mediators secreted by these cells in the pathogenesis
of asthma is well documented. Sodium cromoglycate and nedocromil
sodium are two pharmacological agents which have anti‐allergic and
anti‐inflammatory properties. Their clinical effectiveness in mild
to moderate asthma, and the capacity to reduce BHR under different
natural and experimental conditions, make them valuable drugs for
maintenance therapy in patients with asthma.
Targeting Drug Delivery to the Lungs by Inhalation
Authors: O′Callaghan C.
Published: March 2007

Most drugs targeted to the respiratory tract are used for their
local action. For example, ephidrine for nasal decongestion, beta‐2
agonists for bronchodilatation, and inhaled steroids to suppress the
inflammation seen in asthmatic airways. Since the drug is delivered
directly to its required site, only a small quantity is needed for
an adequate therapeutic response, and consequently there is a low
incidence of systemic side effects compared with oral or intravenous
administration. More recently, it has become apparent that the
lining of the respiratory tract, from nasal mucosa to airways and
alveoli, may be used for the absorption of a drug for its systemic
effect. This route of administration may be particularly attractive
if it avoids the metabolic destruction encountered when some drugs
are administered by alternative routes (for instance, peptides and
proteins are rapidly destroyed by peptidases when Oven by the oral
route). If there is a lack ofclinical response to an aerosolized
drug, it is important to question whether the drug has failed or
whether delivery to the site of action is inadequate. To deliver
therapeutic agents by inhalation to the lower respiratory tract,
inhaled drug particles must have appropriate aerodynamic
characteristics. In addition, the anatomy and pathophysiology of the
patient′s respiratory tract, mode of inhalation through the
inhaler, and the characteristics of the inhalational device itself,
may significantly affect drug deposition.
Effect of Nedocromil Sodium on Aspecific Bronchial Hyper‐Reactivity in Asthmatic Children
Authors: Fiocchi A. , Signoroni P. , Bruni P. , Galeone M. , DeCet E. , Bogacki S.
Published: March 2007

The purpose of this study was to evaluate whether
nedocromil sodium benefits urban asthmatic children
showing seasonal bronchial hyper‐reactivity to ultrasonic
nebulization of distilled water (UNDW). A prospective,
randomized, placebo‐controlled, parallel‐group,
double‐blind study was carried out at the outpatient
pulmonology service at a tertiary‐care teaching hospital.
Twelve children living in Milan, who were 7–17 years of
age, who were SPT and RAST‐negative to perennial allergens,
who were suffering from episodic asthma, and
showing seasonal bronchial hyper‐reactivity to UNDW
during winter, participated in this study. All the children
received either placebo or nedocromil sodium, 4 mg
every 6 h for 6 weeks. Spirometry and UNDW challenge
were done at the following times: day−7; day 0; day 1; day
7; day 14; day 28; day 42. No differences were found in
the basal spirometric parameters, which were normal in
both nedocromil and placebo groups. Bronchial reactivity
to UNDW was found to be significantly decreased in
the group treated with nedocromtl starting from day 7. It
is therefore concluded that nedocromil sodium can reverse
bronchial hyper‐reactivity caused by seasonal factors
such as cold, viral infections and atmospheric pollutants
in children suffering from asthma.
Apoptosis and inflammation
Authors: Haanen C. , Vermes I.
Published: March 2007

During the last few decades it has been recognized that cell death is not the consequence of accidental injury, but is the expression of a cell suicide programme. Kerr et al. (1972) introduced the term apoptosis. This form of cell death is under the influence of hormones, growth factors and cytokines, which depending upon the receptors present on the target cells, may activate a genetically controlled cell elimination process. During apoptosis the cell membrane remains intact and the cell breaks into apoptotic bodies, which are phagocytosed. Apoptosis, in contrast to necrosis, is not harmful to the host and does not induce any inflammatory reaction. The principal event that leads to inflammatory disease is cell damage, induced by chemical/physical injury, anoxia or starvation. Cell damage means leakage of cell contents into the adjacent tissues, resulting in the capillary transmigration of granulocytes to the injured tissue. The accumulation of neutrophils and release of enzymes and oxygen radicals enhances the inflammatory reaction. Until now there has been little research into the factors controlling the accumulation and the tissue load of granulocytes and their histotoxic products in inflammatory processes. Neutrophil apoptosis may represent an important event in the control of intlamtnation. It has been assumed that granulocytes disintegrate to apoptotic bodies before their fragments are removed by local macrophages. Removal of neutrophils from the inflammatory site without release of granule contents is of paramount importance for cessation of inflammation. In conclusion, apoptotic cell death plays an important role in inflammatory processes and in the resolution of inflammatory reactions. The facts known at present should stimulate further research into the role of neutrophil, eosinophil and macrophage apoptosis in inflammatory diseases.
Macrophage activation by lipopolysaccharide, interferon‐γ and interleukin‐4: effect of fatty acid metabolism
Authors: Darmani H. , Harwood J. L. , Parton J. , Jackson S. K.
Published: March 2007

The aim of this study was to investigate the effects of interferon‐γ and ‐β (IFN‐γ, ‐β), interleukin‐4 and ‐10 (IL‐4, ‐10) and Hpopolysaccharide (LPS) on the metabolism and composition of phospholipid fatty acids in macrophages. Murine J774.2 macrophages were incubated with radiolabelled fatty acids and the appropriate stimulus and the incorporation and composition of the phospholipid classes was determined. IFN‐γ and IL‐4 specifically stimulated enhanced incorporation of [14C]‐linoleic acid into the phosphatidytethanolamine fraction. IL‐4 (in contrast to IFN‐γ and LPS) reduced incorporation of [14C]‐ arachidonic acid into phosphatidylinositol. Incubation of J774.2 cells with linoleic acid significantly increased TNFα and nitric oxide production; arachidonic acid enhanced TNFα production but reduced nitric oxide production. It is concluded that IFN‐γ, IL‐4 and IL‐10 may differentially regulate macrophage activation via effects on the metabolism of polyunsaturated fatty acids.
Elevation of soluble interleukin‐2 receptor levels in nasal allergy
Authors: Hisamatsu K. , Ganbo T. , Nakazawa T. , Horiguchi S. , Shimomura S. , Murakami Y.
Published: March 2007

To investigate soluble IL‐2 receptor (sIL‐2R) levels in nasal allergy, the sera and nasal secretions from patients with nasal allergy and from healthy subjects were subjected to a double‐epitope enzyme‐linked immunosorbent assay. Significant elevation of sIL‐2R concentrations in the sera and nasal secretions was observed in the allergy patients (n = 26) compared with those of healthy subjects (n = 9). IL‐2R‐positive (CD25+) cells were observed in the crust formed in an allergic nasal mucosa. The concentration of sIL‐2R in the sera correlated neither with the eosinophil count of the peripheral blood count nor with clinical severity. The concentration of sIL‐2R in the nasal secretions was significantly higher compared with that in the sera from allergic patients (p < 0.01), whereas no significant difference was observed between sIL‐2R levels in the sera and nasal sections from normal subjects. These findings indicate that sIL‐2R plays an essential role in allergic processes by regulating IL‐2R‐positive cells recruited into the nasal mucosa.
Regulation of electrolyte transport with IL‐1β in rabbit distal colon
Authors: Homaidan F. R. , Desai H. , Zhao L. , Broutman G. , Burakoff R.
Published: March 2007

Interletrkin‐1β levels are elevated in inflammatory bowel disease. In this study the mechanism by which interleukin‐1β affects electrolyte transport in the rabbit distal colon, was investigated. Interleukin‐1β caused a delayed increase in short‐circuit current (Isc) which was attributed to protein synthesis since the effect was inhibited by cycloheximide. The interleukin‐1β induced increase in Isc was not affected by amiloride treatment but was completely inhibited by bumetanide or in chloride‐free buffer and by indomethacin. Prostaglandin E2 levels increased in tissue treated with interleukin‐1β, but this increase was reversed by cycloheximide. These data suggest that interleukin‐1β causes its effect via a yet to be identified second messenger, by increasing chloride secretion through a prostaglandin E2 mediated mechanism.
Tenidap sodium inhibits secretory non‐pancreatic phospholipase A2 synthesis by foetal rat calvarial osteoblasts
Authors: Pruzanski W. , Kennedy B. P. , Bosch H. van den , Stefanski E. , Wloch M. , Vadas P.
Published: March 2007

Tenidap (TD) was initially defined as a dual inhibitor of cyclooxygenase and lipoxygenase. This study was designed to assess its inhibitory activity against proinflammatory phospholipase A2. This study shows that TD inhibits the synthesis of pro‐inflammatory secretory non‐pancreatic phospholipase A2 (sPLA2). Concentrations as low as 0.25 μg/ml (0.725 μM) reduced the release of sPLA2 by 40% from foetal rat calvarial osteoblasts stimulated with IL‐1β and TNFα, whereas a concentration of 2.5 μg/ml (7.25 μM) reduced the release by over 80%. TD also markedly reduced the release of sPLA2 from unstimulated cells. There was no direct inhibition of sPLA2 enzymatic activity by TD in vitro. Northern blot analysis showed that TD did not affect the sPLA2 mRNA levels; however, immunoblotting showed a dose‐dependent reduction in sPLA2 enzyme. These results, together with a marked reduction in sPLA2 enzymatic activity, suggest that TD inhibits sPLA2 synthesis at the post‐transcriptional level. Therefore TD seems to inhibit the arachidonic acid cascade proximally to cyclooxygenase and lipoxygenase and its anti‐inflammatory activity may be related at least in part to the inhibition of sPLA2 synthesis.
Group II phospholipase A2 in human gingiva with periodontal disease
Authors: Shinohara H. , Komatsubara T. , Tojo H. , Okamoto M. , Nishikawa S. , Nagata T. , Ishida H.
Published: March 2007

Fourteen kilodalton phospholipase A2 molecules (PLA2) are classified into two groups, I‐ and II‐PLA2, and only the latter has been considered to play a pathogenetic role in various forms of tissue inflammation. Previously we demonstrated high PLA2 activity in gingival crevicular fluid (GCF) of patients with periodontal disease, without determining the group of the enzyme involved. In this study, the activity, groups and levels of enzyme in gingiva taken from 13 sites of periodontal disease were determined using both biochemical and radioimmunological methods. A linear correlation between the activity and the level of II‐PLA2 was observed. No I‐PLA2 was found in any of the samples tested. These data suggest that the PLA2 activity found in the GCF of patients with periodontal disease does not belong to the I‐PLA2 but to the II‐PLA2 group.
The effects of platelet activating factor and retinoic acid on the expression of ELAM‐1 and ICAM‐1 and the functions of neutrophils
Authors: Chen Si-Feng
Published: March 2007

Preincubation of pulmonary microvascular endothelial cells (PMVECs) with platelet‐activating factor (PAF) for 3.5 h increased the adhesion rate of polymorphonuclear leukocytes (PMNs) to PMVECs from 57.3% to 72.8% (p < 0.01). Preincubation of PMNs with PAF also increased PMN‐PMVEC adhesion rate. All‐trans retinoic acid (RA) blocked the adherence of untreated PMNs to PAF‐pretreated PMVECs but not the adherence of PAF‐pretreated PMNs to untreated PMVECs. PAF increased the expression of intercellular adhesion molecule‐1 (ICAM‐1) and E‐selection (ELAM‐1) on PMVECs, PMN chemotaxis to zymosan‐activated serum and histamine, and PMN aggregation and the release of acid phosphatase from PMNs. Co‐incubation of RA inhibited PAF‐induced PMN aggregation, the release of acid phosphatase from PMNs, and PMN chemotaxis to zymosan‐activated serum and histamine while the expression of ICAM‐1 and ELAM‐1 did not change. Our results suggest that RA can be used to ameliorate PMN‐mediated inflammation.
Modulation of oxazolone‐induced hypersensitivity in mice by selective PDE inhibitors
Authors: Moodley I. , Sotsios Y. , Bertin B.
Published: March 2007

The effects of PDE inhibitors on oxazolone‐induced contact hypersensitivity (CS) were studied in mice. Rolipram, Ro 20‐1724 and theophylline dose dependently inhibited CS but none caused >53% inhibition. ED30 values at 24 h before challenge for rolipram, Ro 20‐1724 and theophylline were 2.1, 5.4 and 30.4 mg/kg, p.o., respectively. Milrinone and SKF 94836 at 30 mg/kg caused a small, but significant inhibition of 13% and 18%, respectively, although the inhibition (8%) caused by zaprinast was not significant. Betamethasone (10 mg/kg, p.o.) caused a marked inhibition (80%) as did indomethacin (65% at 5 mg/kg, p.o.). Rolipram and Ro 20‐1724 inhibited proliferation of mouse lymphoblasts with IC50 values of 0.08 μM and 0.83 μM, respectively. In contrast, zaprinast caused only a weak inhibition (IC50 = 119 μM) of lymphocyte proliferation, whereas SKF 94836 and theophylline failed to cause any significant inhibition at 100 μM (26% and 2%, respectively). These findings suggest that PDE IV isozymes play a principal role in mediating CS by inhibiting lymphocyte activation.
Role of endogenous nitric oxide on PAF‐induced vascular and respiratory effects
Authors: Clement M. , Albertini M.
Published: March 2007

The role of endogenous nitric oxide (NO) on vascular and respiratory smooth muscle basal tone was evaluated in six anaesthetized, paralysed, mechanically ventilated pigs. The involvement of endogenous NO in PAF‐induced shock and airway hyperresponsiveness was also studied. PAF (50 ng/kg, i.v.) was administered before and after pretreatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME, 10 mg/kg, i.v.), an NO synthesis inhibitor. PAF was also administered to three of these pigs after indomethacin infusion (3 mg/kg, i.v.). In normal pigs, L‐NAME increased systemic and pulmonary vascular resistances, caused pulmonary hypertension and reduced cardiac output and stroke volume. The pulmonary vascular responses were correlated with the increase in static and dynamic lung elastances, without changing lung resistance. Inhibition of NO synthesis enhanced the PAF‐dependent increase in total, intrinsic and viscoelastic lung resistances, without affecting lung elastances or cardiac activity. The systemic hypotensive effect of PAF was not abolished by pretreatment with L‐NAME or indomethacin. This indicates that systemic hypotension is not correlated with the release of endogenous NO or prostacyclines. Indomethacin completely abolished the PAF‐dependent respiratory effects.