The epidermal growth factor receptor mediates allergic airway remodelling in the rat.
The chronicity of bronchial asthma is attributed to persistent airway inflammation and to a variety of structural changes, or remodelling, that includes smooth muscle and goblet cell hyperplasia. To investigate the mechanisms of airway remodelling, the current authors used an established allergen (ovalbumin; OVA)-driven rodent model (the Brown Norway rat). Brown Norway rats were sensitised to OVA and challenged three times at 5-day intervals to evoke airway remodelling. The effects of an epidermal growth factor (EGF) receptor inhibitor, AG1478, and a cysteinyl leukotriene-1 receptor antagonist, montelukast, on epithelial and airway smooth muscle (ASM) cell proliferation in vivo in response to repeated OVA challenge were tested. Three challenges with leukotriene (LT)D(4) were given, to examine their effects on remodelling with and without AG1478 pretreatment. OVA challenges caused ASM hyperplasia, with an increase in mass, epithelial cell proliferation and goblet cell proliferation. AG1478 prevented the changes, as did montelukast. Multiple OVA challenges increased heparin-binding EGF-like growth factor but not EGF expression by airway epithelium. LTD(4) reproduced the changes in remodelling induced by OVA and this was blocked by AG1478. Allergen-induced airway epithelial and airway smooth muscle remodelling is mediated by cysteinyl leukotrienes via the cysteinyl leukotriene-1 receptor with downstream effects on the epidermal growth factor receptor axis.
Tamaoka
M
M
Meakins-Christie Laboratories, Dept of Medicine, McGill University, 3626 St Urbain Street, Montreal, QC, H2X 2P2, Canada.
Hassan
M
M
McGovern
T
T
Ramos-Barbón
D
D
Jo
T
T
Yoshizawa
Y
Y
Tolloczko
B
B
Hamid
Q
Q
Martin
J G
JG
D000485:Allergens / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D003545:Cysteine / Q000737:chemistry; D066246:ErbB Receptors / Q000502:physiology*; D020869:Gene Expression Profiling; D020397:Goblet Cells / Q000473:pathology*; D006965:Hyperplasia / Q000473:pathology; D007249:Inflammation; D017998:Leukotriene D4 / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D010047:Ovalbumin / Q000378:metabolism; D011799:Quinazolines; D051381:Rats; D018077:Receptors, Leukotriene / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D000485:Allergens; D011799:Quinazolines; D018077:Receptors, Leukotriene; D020032:Tyrphostins; C101044:RTKI cpd; D017998:Leukotriene D4; D010047:Ovalbumin; D066246:ErbB Receptors; D003545:Cysteine