Mast cell activation in response to osmotic and immunological stimulation with focus on release of eicosanoid mediators
Author: Gulliksson, Magdalena
Date: 2007-03-23
Location: Hillarpsalen, Retzius väg 8, Karolinska Institutet
Time: 09.00
Department: Institutet för miljömedicin (IMM) / Institute of Enviromental Medicine
View/ Open:
thesis.pdf (885.8Kb)
Abstract
Mast cells are important in asthma and other inflammatory diseases.
Subjects with asthma have been found to have an increased number of mast
cells in their airway smooth muscle and this was related to airway
sensitivity. Normally harmless stimuli may trigger bronchoconstriction in
subjects with asthma and exercise can generate airway constriction in
subjects with asthma. The mechanism for exercise-induced
bronchoconstriction (EIB) has been suggested to be related to an
increased airway fluid osmolarity. This may activate mast cells with
subsequent release of mediators acting on bronchial smooth muscle leading
to bronchoconstriction. Mannitol inhalation causes bronchoconstriction,
and the mechanism is probably by increasing airway fluid osmolarity. The
aim of this thesis was to establish whether hyperosmolar stimulation
activates human mast cells in vitro and in vivo with focus on the release
of biologically active mediators. Human cord blood derived mast cells
(CBMC) were used for studies on mediator release in response to
immunological and osmotic activation in vitro. Bronchial provocation by
mannitol inhalation was used to mimic EIB for studies in vivo on airway
reactivity and urinary excretion of mediators.
For the first time, mannitol was found to induce the release of PGD2 and
LTC4 in CBMC in vitro. Prostaglandin D2 was formed both via the COX-1 and
COX-2 pathways in CBMC. The late response after stimulation with the
combination of anti- IgE and IL-1beta was more COX-2 dependent. Further,
the pro-inflammatory cytokine IL-1beta induced the expression of COX-2.
In addition to COX derived PGD2, CBMC was found to release TXB2 and
occasionally also PGE2 after stimulation with IL-1beta, anti-IgE or their
combination. Hypoxia (4% O2) was not found to increase the release of
mediators as compared to normoxic (21% O2) conditions. Interleukin-4
induced the expression of 15-LO in CBMC and the main 15-LO derived
metabolite was 15-KETE followed by 15-HETE in IL-4 treated CBMC
stimulated with arachidonic acid. The release of 15-HETE was also induced
by mannitol
Both asthmatic and control subjects had an increased urinary excretion of
the PGD2 metabolite 9alpha,11beta-PGF2 as well as LTE4 after mannitol
challenge in vivo. The increase in 9alpha,11beta-PGF2 was related to
bronchoconstriction since only the asthmatic subjects responded to
mannitol. Further, the mast cell stabiliser sodium cromoglycate (SCG) and
the beta2-agonist formoterol protected from
mannitol-inducedbronchoconstriction in asthmatic subjects with 63% and
95%, respectively. In addition, both inhibitors dampened the
mannitol-induced urinary 9alpha,11beta-PGF2 excretion compared to placebo
treatment.
In conclusion, mast cells release PGD2 after mannitol stimulation in
vitro and in vivo and treatment with a mast cell stabiliser further
supports the mast cell involvement in mannitol-induced
bronchoconstriction in vivo. Both COX-1 and COX-2 enzymes were involved
in PGD2 formation and mast cells were unaffected by hypoxic environmental
changes in vitro. The expression of 15-LO in mast cells in vivo and in
vitro support that these cells can contribute to the formation of novel
metabolites with unknown functions. The mediator formation in mast cells
seems to be important for subjects with EIB since their airways respond
more easily with bronchoconstriction. Inhibition of PGD2 formation
protects from bronchoconstriction in subjects with EIB. The physiological
effect of some mast cell mediators remains to be elucidated however PGD2
appear to have a central role in the airway response to mannitol.
List of papers:
I. Gulliksson M, Palmberg L, Nilsson G, Ahlstedt S, Kumlin M (2004). "Release of prostaglandin D2 and leukotriene C in response to hyperosmolar stimulation of mast cells." Allergy 61(12): 1473-9
Pubmed
II. Gulliksson M, Nold-Petry C, Dahlen SE, Nilsson G, Pfeilschifter J, Palmberg L, Ahlstedt S, Kumlin M (2007). "Cyclooxygenase (COX) isoenzyme participation in release of PGD2 from human cord blood derived mast cells in normoxic and hypoxic environment." (Manuscript)
III. Gulliksson M, Brunnstrom A, Johannesson M, Backman L, Nilsson G, Harvima I, Dahlen B, Kumlin M, Claesson HE (2007). "Expression of 15-lipooxygenase type-1 in human mast cells." (Submitted)
IV. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M (2003). "Evidence of mast cell activation and leukotriene release after mannitol inhalation." Eur Respir J 22(3): 491-6
Pubmed
V. Brannan JD, Gulliksson M, Anderson SD, Chew N, Seale JP, Kumlin M (2006). "Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing." Eur Respir J 27(5): 944-50
Pubmed
I. Gulliksson M, Palmberg L, Nilsson G, Ahlstedt S, Kumlin M (2004). "Release of prostaglandin D2 and leukotriene C in response to hyperosmolar stimulation of mast cells." Allergy 61(12): 1473-9
Pubmed
II. Gulliksson M, Nold-Petry C, Dahlen SE, Nilsson G, Pfeilschifter J, Palmberg L, Ahlstedt S, Kumlin M (2007). "Cyclooxygenase (COX) isoenzyme participation in release of PGD2 from human cord blood derived mast cells in normoxic and hypoxic environment." (Manuscript)
III. Gulliksson M, Brunnstrom A, Johannesson M, Backman L, Nilsson G, Harvima I, Dahlen B, Kumlin M, Claesson HE (2007). "Expression of 15-lipooxygenase type-1 in human mast cells." (Submitted)
IV. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M (2003). "Evidence of mast cell activation and leukotriene release after mannitol inhalation." Eur Respir J 22(3): 491-6
Pubmed
V. Brannan JD, Gulliksson M, Anderson SD, Chew N, Seale JP, Kumlin M (2006). "Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing." Eur Respir J 27(5): 944-50
Pubmed
Issue date: 2007-03-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-091-6
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