Mechanisms of asthma and allergic inflammation
Increased TGF-β2 in severe asthma with eosinophilia

https://doi.org/10.1016/j.jaci.2004.09.034Get rights and content

Background

Airway eosinophilia and thickened subepithelial basement membrane have previously been reported to increase with increases in TGF-β expression. However, little is known regarding the expression of specific TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3) in asthma, despite recent evidence suggesting that isoforms may have differing biologic activities.

Objective

This study examined airway tissue expression of the 3 TGF-β 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-β isoforms, their receptors, collagen I deposition, connective tissue growth factor expression, and tissue inhibitor of metalloproteinases 1 levels.

Results

Of the isoforms, only TGF-β2 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-β2. Subjects with severe asthma also had the thickest subbasement membrane and highest tissue inhibitor of metalloproteinases 1 levels. In contrast, TGF-β receptor 1 and connective tissue growth factor were both consistently downregulated in asthma, regardless of severity.

Conclusion

TGF-β2, expressed mainly by eosinophils, is the predominant isoform expressed in severe asthma, and is associated with increased profibrotic responses. Decreased expression of TGF-β receptor 1 and connective tissue growth factor in all asthma severity groups suggests a degree of activation of the TGF-β pathway in airway tissue of all asthmatic compared with normal airways.

Section snippets

Subjects

Severe asthma was defined by: (1) FEV1 of ≤70% predicted on more than 1 occasion over the previous year, (2) 10 mg/d prednisone or equivalent for at least 50% of the previous year while taking other standard asthma medications, (3) >2 urgent care visits for asthma in the previous year, and (4) ongoing symptoms.3 Patients with severe asthma were divided into those with persistent tissue eosinophilia (>22 eosinophils/mm2 tissue, equivalent to ≥2 SDs from the mean value measured in normal

Subject characteristics

Eighty-three subjects, including 24 eosinophil+ (eos+) and 24 eosinophil (eos) subjects with severe asthma, were enrolled in this study (Table I). Control subjects were younger than subjects with asthma (overall P = .03). There was no difference in oral steroid doses between the 2 severe groups, and ∼25% subjects in both groups were only on high-dose inhaled corticosteroids at the time of bronchoscopy.

Tissue expression of TGF-β1, TGF-β2, and TGF-β3

TGF-β1+ and TGF-β3+ cell counts were similar in all groups (Fig 1, A and C). In contrast,

Discussion

The current study, designed to evaluate specifically TGF-β isoforms and TGF-β–related pathways in asthma, is the first to identify TGF-β2 as a prominent TGF-β isoform in severe asthma and its association with eosinophils. TGF-β2 expression in eosinophils was specific to severe asthma, because TGF-β2 could not be colocalized to tissue eosinophils in mild/nonsteroid-treated subjects with asthma or normal subjects. This study further reports evidence for activation of downstream TGF-β–related

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    Supported by National Institutes of Health grants HL-64087, AI-40600, RR-00051, and ALA of Colorado, Oklahoma, and Alaska.

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