Increased TGF-beta2 in severe asthma with eosinophilia.
BACKGROUND
Airway eosinophilia and thickened subepithelial basement membrane have previously been reported to increase with increases in TGF-beta expression. However, little is known regarding the expression of specific TGF-beta isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) in asthma, despite recent evidence suggesting that isoforms may have differing biologic activities.


OBJECTIVE
This study examined airway tissue expression of the 3 TGF-beta isoforms and several downstream pathway elements in 48 patients with severe asthma with or without persistent eosinophilia, 14 patients with mild asthma, and 21 normal subjects.


METHODS
Immunochemistry/immunofluorescence, quantitative real-time PCR and enzyme immunoassay were used to evaluate the 3 TGF-beta isoforms, their receptors, collagen I deposition, connective tissue growth factor expression, and tissue inhibitor of metalloproteinases 1 levels.


RESULTS
Of the isoforms, only TGF-beta2 was different among the groups and increased in severe asthma (overall P < .0001). The increase was due to severe asthma tissue eosinophils which, unlike eosinophils in other groups, expressed high amounts of TGF-beta2. Subjects with severe asthma also had the thickest subbasement membrane and highest tissue inhibitor of metalloproteinases 1 levels. In contrast, TGF-beta receptor 1 and connective tissue growth factor were both consistently downregulated in asthma, regardless of severity.


CONCLUSIONS
TGF-beta2, expressed mainly by eosinophils, is the predominant isoform expressed in severe asthma, and is associated with increased profibrotic responses. Decreased expression of TGF-beta receptor 1 and connective tissue growth factor in all asthma severity groups suggests a degree of activation of the TGF-beta pathway in airway tissue of all asthmatic compared with normal airways.
Balzar
Silvana
S
Department of Medicine, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver 80206, USA. balzars@njc.org
Chu
Hong Wei
HW
Silkoff
Phillip
P
Cundall
Meghan
M
Trudeau
John B
JB
Strand
Matthew
M
Wenzel
Sally
S
D000328:Adult; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001980:Bronchi / Q000276:immunology; D003238:Connective Tissue / Q000378:metabolism; D004802:Eosinophilia / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000276:immunology; D020033:Protein Isoforms / Q000032:analysis / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis*; D053781:Transforming Growth Factor beta2
D006133:Growth Substances; D020033:Protein Isoforms; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2