On airway host defence during allergic inflammation

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)


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.


  • Anele Gela
Enheter & grupper

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicin och hälsovetenskap


Tilldelande institution
Handledare/Biträdande handledare
Tilldelningsdatum2016 sep 3
  • Lund University: Faculty of Medicine
Tryckta ISBN978-91-7619-310-5
StatusPublished - 2016


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