Læknablaðið : fylgirit - 01.08.2002, Side 27

ABSTRACTS / 21 ST NORDIC CONGRESS OF ALLERGOLOGY
2. Glucocorticoid sensitive ví resistcint asthmatics
Inhaled glucocorticoids (GCs) are widely used to control moderate
to severe asthma. Asthma prevalence in Iceland is 5-6% and over
40% of patients use inhaled GCs on a daily basis. The effective dose
for each patient can vary as much as 10 fold, however little is known
about the molecular mechanisms that underlie these differences in
GC sensitivity. In this set of experiments, we used affymetrix
technology; performed on RNA samples from PBMCs collected
from 50 asthmatic patients. Patients were classified as GC resistant
(n=25) if dependent on a GC inhalation dose of 1600 mg per day or
higher and GC sensitive (n=25) if dependent on a daily GC dose
between 200-800 mg. The two groups were adjusted by age and sex.
Asthma disease severity was assessed by PFTs and Mch challenge
tests and prevalence of atopy was confirmed by skin prick test and
total serum IgE values. The PBMCs were treated in an in vitro
setting with IL-ip/TNFa in the absence (woGC) and presence
(wGC) of pre-treatment with GC. Total RNA was extracted from
the treated PBCM and gene expression was examined by Affy-
hu95A chips which each has 12607 genes. RNA expression was
analysed by comparing the mean difference change of signal
intensity of wGC to woGC in each group. Asthma and atopy scores
for the resistant and sensitive asthmatics were were comparable.
We found forty genes to be significantly differently expressed
between the GCSAs and GCRAs. These genes included various
cytokines/chemokines, their receptors, transcription factors and
regulators of signal transduction and apoptosis. Examples of such
genes are IL-6, IL-8, CD44, NF-kappa-B and jun-B which are all
more significantly downregulated by GC in the GCSAs compared
to GCRAs.
A group of genes involved in interferon pathways, transcription
factors and IL-10 that separated atopics from nonatopics -
irrespective of asthma status. Also a group of proinflammatory
genes, cytokines and chemokines - in addition to factors associated
with airway remodelling that separarted asthmatics from non-
asthmatics - irrespective of atopic status.
Where will the future take us? Global gene profiling may give us
the possibility to confirm current hypothesis on differences in gene
expression and inflammatory pathways already known in asthma.
This could in turn improve our understanding of yet unknown
disease mechanisms and factors and the possibility of target direc-
ted therapy.
R 3 - Does dietary fish-oil improve health?
Haraldsson A
In many countries, dietary fish-oil is considered healthy and is
claimed to diminish infections, decrease autoimmune reactions and
improve health in general. The reason for this remains unclarified.
In recent years, we have conducted several animal studies in
order to investigate the possible effect of dietary fish-oil on the
immune system.
The effect of dietary fish-oil supplementation on survival after
infection was first investigated. The study revealed that the survival
of NMRI mice after Klebsiella Pneumoniae intramuscular infection
was significantly better in the group fed fish-oil enriched diet as
compared to control groups (P=0.0034).
These results raised the question whether the dietary fish-oil
might have any direct effect on bacterial growth in vivo. We
therefore conducted a study where bacteria were counted in blood
and in the infected muscle at various time intervals after infection
with Klebsiella Pneumoniae. The bacterial count was not signifi-
cantly different between the groups. Our conclusion therefore was
that the fish-oil did not affect the bacterial growth in vivo.
Subsequently, we studied the effect of dietary fish-oil on TNF-a
and IL-1 production and were not able to detect significant
difference in these cytokine productions between the animals fed
fish-oil enriched diet or not.
If the beneficial effect of dietary fish-oil is due to influence on
the immune response it should be more or Iess independent of the
infection site. Consequently, we studied the survival of mice after
pulmonary infections with Klebsiella Pneumoniae. Again, the sur-
vival of the mice fed the fish-oil enriched diet and infected in the
lungs with Klebsiella pneumoniae was significantly better compared
to the survival of mice fed the corn-oil enriched diet (p=0,0001 and
p=0,0013). We therefore concluded that the beneficial effect of
dietary fish-oil on infection was independent of the site of infection.
These results are in accordance with the hypothesis that dietary
fish-oil influences the immune response.
Most of the infection studies have been done using the Gram
negative bacteria Klebsiella pneumoniae as an infective agent.
However, Gram positive bacteria, such as Streptococcus pneu-
moniae, are a very common microbes, in particular in children. The
immune response against Gram positive bacteria is somewhat
different to the response to Gram negative agents. Subsequently,
we evaluated the effect of dietary fish-oil on infections due to Gram
positive or Gram negative bacteria, by studying the survival of mice
infected in the lungs with either Klebsiella pneumoniae or Strepto-
coccus pneumoniae. The data for the groups infected with Klebsi-
ella pneumoniae confirmed our earlier results (p=0.0001 and
0.0013) but, interestingly, there was no difference in the survival of
mice infected with Streptococcus pneumoniae serotype 3, receiving
either fish-oil or corn-oil enriched diets (p=0.74 and p=0.15). These
results indicate that dietary fish-oil has beneficial effect on survival
of mice after experimental infection with Klebsiella pneumoniae
but not after infection with Streptococcus pneumoniae serotype 3.
It indicates a more specific effect on the immune system than
anticipated.
It has been postulated that fish-oil,in particular the omega-3
fatty acids, alter the leukotrien metabolism, shifting the production
from the more active substances, LTB4, PGE2, and TXA2, to the
less active, LTB5, PGE3, and TXA3. Consequently, we studied the
effect of dietary fish-oil on the leukotriene metabolism by feeding
the mice fish-oil or corn-oil with or without a leukotrien inhibitor
(5-LO inhibitor, Zileuton® Abott). Interestingly, the beneficial
effect of fish-oil was prevented by the leukotriene inhibitor. Our
results thus indicates that the beneficial effects of fish oil are, at
least in part, due to altered leukotriene metabolism.
Taken together, our studies indicate that fish-oil in fact alters the
immune response and increases survival after some infections in
experimental animals. Our hypothesis is that the fish-oil is slightly
immunosuppressive, possibly due to the altered leukotriene meta-
bolism, shifting towards less active substances. This immunosup-
pression would diminish the overwhelming septic shock syndrome
Læknablaðið/Fylgirit 46 2002/88 27