Eosinophil-associated TGF- β₁mRNA Expression and Airways Fibrosis in Bronchial Asthma

Abstract

The histopathology of bronchial asthma is associated with structural changes within the airways, including subepithelial fibrosis, as well as chronic eosinophilic inflammation. The mechanisms responsible for this tissue remodeling, and in particular the role of inflammatory cells, remain to be established. Transforming growth factor-beta (TGF-beta) is a potent profibrotic cytokine which may contribute to the thickening of the reticular lamina by the deposition of collagen fibers. To investigate the molecular mechanisms underlying these structural changes, we have investigated the expression of TGF-beta1 mRNA and immunoreactivity within the bronchial mucosa of mild to severe asthmatic individuals and normal control subjects using the techniques of in situ hybridization and immunocytochemistry. As eosinophils are prominent within the asthmatic airway and are known to synthesize pro-inflammatory cytokines, the presence of TGF-beta1 mRNA and immunoreactive protein in eosinophils was also examined. Asthmatic individuals exhibited a greater expression of TGF-beta1 mRNA and immunoreactivity in the airways submucosa than normal control subjects (P < 0.05), and these increases were directly related to the severity of the disorder. The extent of airways fibrosis, as detected histochemically, was also increased in asthmatics compared with normal control subjects (P < 0.005). In asthmatic subjects, the presence of subepithelial fibrosis was associated with the severity of the disease and correlated with the decline in forced expiratory volume in 1 s (r2 = 0.78; P < 0.05). Within the asthmatic airways, EG2-positive eosinophils represented the major source of TGF-beta1 mRNA and immunoreactivity. These results provide evidence that TGF-beta1 may play a role in the fibrotic changes occurring within asthmatic airways and that activated eosinophils are a major source of this cytokine.

Peroxisome proliferator–activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model☆

“…2,6,7,33 Smad proteins, c-Jun NH2-terminal kinase, and mitogen-activated protein kinase are reported to be involved in TGF-b signaling. 33,34 These factors are targets for PPAR-c regulation.…”

“…1,2 Much evidence suggests that bronchial fibrosis correlates with airway function. [2][3][4] Various mediators, such as TGF-b, GM-CSF, and epidermal growth factor, were reported to regulate airway remodeling. 1,3 Among these factors, TGFb is an important profibrotic cytokine.…”

“…5 In most studies TGF-b expression correlates with basement membrane thickness, fibroblast numbers, and disease severity. 2,6,7 Nuclear receptors are ligand-activated transcription factors. 8 The glucocorticoid receptor a (GR-a) mediates the anti-inflammatory effects of corticosteroids.…”

Airway Hyperresponsiveness, Late Allergic Response, and Eosinophilia Are Reversed with Mycobacterial Antigens in Ovalbumin-Presensitized Mice

“…This cytokine has been implicated in the profibrotic changes occurring in airway remodeling (37). Investigators have further linked expression of TGF-␤ 1 with eosinophils (38,39) and have found significantly increased levels in BAL fluid after allergen challenge (40) in humans. Our finding of unaffected TGF-␤ 1 concentrations in murine BAL samples was an unexpected result in light of the suppressed eosinophil numbers.…”

The −403 G→A promoter polymorphism in the RANTES gene is associated with atopy and asthma

“…This view is supported by data showing that production of profibrotic cytokines such as TGF␤1 by eosinophils correlates with airway thickening and a reduction in FEV 1 . 27 Thus, RANTES may be important in determining the severity of the persistent inflammation leading to airway remodeling and bronchial response to inhaled aeroallergen.…”