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On airway host defence during allergic inflammation

Gela, Anele LU (2016)
Abstract
Asthma is a chronic inflammatory disease of the airways, affecting and disabling
approximately 300 million people worldwide. The inflammatory profile is
characterized by infiltration of eosinophils, which are a rich source of factors that
are implicated in tissue remodeling. The chronic inflammatory response and the
remodeled phenotype create a hospitable environment for secondary bacterial
infections. In recent years, systemic infections caused by Streptococcus
pneumoniae in asthmatics have received global attention. The risk of acquiring
pneumonia in patients suffering from asthma is 2-10 fold increased as compared to
healthy individuals. The cause is not known and in this thesis we hypothesized... (More)
Asthma is a chronic inflammatory disease of the airways, affecting and disabling
approximately 300 million people worldwide. The inflammatory profile is
characterized by infiltration of eosinophils, which are a rich source of factors that
are implicated in tissue remodeling. The chronic inflammatory response and the
remodeled phenotype create a hospitable environment for secondary bacterial
infections. In recent years, systemic infections caused by Streptococcus
pneumoniae in asthmatics have received global attention. The risk of acquiring
pneumonia in patients suffering from asthma is 2-10 fold increased as compared to
healthy individuals. The cause is not known and in this thesis we hypothesized that
the dysregulated allergic response may impair innate host defenses. The
mechanisms being investigated may help to explain how the prolonged and
dysregulated inflammatory response increases the vulnerability of asthmatics to
invasive pneumococcal disease. Initially, the regulation of chemokines, in
particular eotaxins, by mast cell proteases was investigated. From this study, we
were able to map the region of eotaxin-3/CCL26 that harbors antimicrobial
(COOH-terminal) and anti-endotoxin (NH2-terminal) activity following
proteolytic cleavage with mast cell chymase and tryptase, respectively. However,
the receptor activating properties (NH2-terminal) were lost. In a separate study, the
anti-endotoxin fragment derived from CCL26 conferred therapeutic benefits in a
mouse model of LPS-induced inflammation. Furthermore, the interaction of
chemokines, particularly Th-2 chemokines, with osteopontin (OPN) was
investigated. OPN is an anionic glycoprotein that is upregulated in asthma and its
expression increases with the severity of asthma. OPN bound to the COOHterminal
of chemokines and completely abolished their antimicrobial activity
without affecting their NH2-terminal localized functions, including LPSneutralization
and receptor activating properties. To ascertain if whether the
effects of OPN are generic or specific for Th-2 chemokines, we investigated its
interaction with the classical antimicrobial peptides that are constitutively
expressed and upregulated during COPD. Interestingly, OPN bound and
neutralized their antimicrobial activity but did not interfere with the muraminidase
activity and protease inhibitory function of lysozyme and secretory leukocyte
protease inhibitor (SLPI), respectively. These studies suggest that chemokines and
antimicrobial peptides can serve as host defense peptides but their actions are
modulated by mast cell proteases and OPN. Therefore, there is an urgent need for
studies focusing on modification of antimicrobial peptides to become resistant to
proteolytic cleavage, altered pH and various salt conditions. Also, the elucidation
of the novel roles of OPN during allergic inflammation could present potential
pharmaceutical targets. Taken together, this thesis explains several mechanisms
that impair innate host defenses during allergic inflammation.
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Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Simon, Hans-Uwe, Berlin
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Asthma, COPD, Antimicrobial peptide, chemokines, immunology
pages
64 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund
defense date
2016-09-03 09:00
ISBN
978-91-7619-310-5
language
English
LU publication?
yes
id
1368027b-9d1f-4fbc-9716-e18a986be111
date added to LUP
2016-08-01 10:52:16
date last changed
2016-09-19 08:45:20
@misc{1368027b-9d1f-4fbc-9716-e18a986be111,
  abstract     = {Asthma is a chronic inflammatory disease of the airways, affecting and disabling<br/>approximately 300 million people worldwide. The inflammatory profile is<br/>characterized by infiltration of eosinophils, which are a rich source of factors that<br/>are implicated in tissue remodeling. The chronic inflammatory response and the<br/>remodeled phenotype create a hospitable environment for secondary bacterial<br/>infections. In recent years, systemic infections caused by Streptococcus<br/>pneumoniae in asthmatics have received global attention. The risk of acquiring<br/>pneumonia in patients suffering from asthma is 2-10 fold increased as compared to<br/>healthy individuals. The cause is not known and in this thesis we hypothesized that<br/>the dysregulated allergic response may impair innate host defenses. The<br/>mechanisms being investigated may help to explain how the prolonged and<br/>dysregulated inflammatory response increases the vulnerability of asthmatics to<br/>invasive pneumococcal disease. Initially, the regulation of chemokines, in<br/>particular eotaxins, by mast cell proteases was investigated. From this study, we<br/>were able to map the region of eotaxin-3/CCL26 that harbors antimicrobial<br/>(COOH-terminal) and anti-endotoxin (NH2-terminal) activity following<br/>proteolytic cleavage with mast cell chymase and tryptase, respectively. However,<br/>the receptor activating properties (NH2-terminal) were lost. In a separate study, the<br/>anti-endotoxin fragment derived from CCL26 conferred therapeutic benefits in a<br/>mouse model of LPS-induced inflammation. Furthermore, the interaction of<br/>chemokines, particularly Th-2 chemokines, with osteopontin (OPN) was<br/>investigated. OPN is an anionic glycoprotein that is upregulated in asthma and its<br/>expression increases with the severity of asthma. OPN bound to the COOHterminal<br/>of chemokines and completely abolished their antimicrobial activity<br/>without affecting their NH2-terminal localized functions, including LPSneutralization<br/>and receptor activating properties. To ascertain if whether the<br/>effects of OPN are generic or specific for Th-2 chemokines, we investigated its<br/>interaction with the classical antimicrobial peptides that are constitutively<br/>expressed and upregulated during COPD. Interestingly, OPN bound and<br/>neutralized their antimicrobial activity but did not interfere with the muraminidase<br/>activity and protease inhibitory function of lysozyme and secretory leukocyte<br/>protease inhibitor (SLPI), respectively. These studies suggest that chemokines and<br/>antimicrobial peptides can serve as host defense peptides but their actions are<br/>modulated by mast cell proteases and OPN. Therefore, there is an urgent need for<br/>studies focusing on modification of antimicrobial peptides to become resistant to<br/>proteolytic cleavage, altered pH and various salt conditions. Also, the elucidation<br/>of the novel roles of OPN during allergic inflammation could present potential<br/>pharmaceutical targets. Taken together, this thesis explains several mechanisms<br/>that impair innate host defenses during allergic inflammation.<br/>},
  author       = {Gela, Anele},
  isbn         = {978-91-7619-310-5},
  keyword      = {Asthma,COPD,Antimicrobial peptide,chemokines,immunology},
  language     = {eng},
  pages        = {64},
  publisher    = {ARRAY(0xb4a7910)},
  title        = {On airway host defence during allergic inflammation},
  year         = {2016},
}