Modulation de l'activation des protéases chez les éosinophiles
|Advisor:||Laviolette, Michel; Rola-Pleszczynski, Marek|
|Abstract:||Infiltration of eosinophils into the bronchial mucosa is a key feature in asthma pathology. With the influence of mediators, eosinophils have the capacity to interact with structural cells, modulate their functions, promote airway remodelling, and activate and recruit other inflammatory cells. Proteases are essential to promote cell migration from blood into tissue and interactions with tissue structural cells and extracellular matrix components. This work presents some of the mechanisms modulating eosinophil protease activity, more specifically the production of MMP-9 and plasmin. Herein, we evaluated the mechanism of action of two lipid mediators, the cysteinyl-leukotrienes (cysLTs) and the 5-oxo-ETE, in eosinophil recruitment. 5-Oxo-ETE elicits eosinophil migration by activating MMP-9 secretion, plasmin generation and by increasing uPAR expression. The cysLTs are also implicated in eosinophil migration but not in protease activation. On the other hand, montelukast, a cysLT type 1 receptor antagonist, decreases uPAR expression, MMP-9 secretion and plasmin generation. These results suggest that montelukast is not a neutral antagonist, but an inverse agonist in eosinophils, although this hypothesis needs to be validated. Thereafter, we were interested in signalling induced by 5-oxo-ETE. Our results demonstrated that protein kinase C (PKC)-δ, PKC-ζ, extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) play a major role in eosinophil migration. The implication of ERK-1/2 seems to depend on plasminogen presence in the medium. Plasmin generated from plasminogen activates ERK-1/2 and stimulates MMP-9 secretion. These results demonstrate the complex regulation of eosinophil proteases and the essential implication of PKC and MAPK in this process.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||16 April 2018|
|Collection:||Thèses et mémoires|
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