The contribution of transforming growth factor-  and epidermal growth factor signalling to airway remodelling in chronic asthma

Abstract

Asthma is increasing in prevalence in the developing world, affecting ,10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time.Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-b is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma.This review highlights the role of transforming growth factor-b in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome. In vivo, however, it is the balance between transforming growth factor-b and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways.A fuller comprehension of the actions of transforming growth factor-b, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.

Asthma: where is it going?

“…TGF-ß, FGF-2 and endothelin-1 have been demonstrated to be increased in asthma, while both epithelial EGFR expression and TGF-ß production are refractory to corticosteroid treatment. This suggests that the combined effects of these signaling pathways on the epithelial mesenchymal trophic unit (EMTU) could be involved in tissue remodeling, explaining the incomplete resolution of lung function with anti-inflammatory treatment in chronic asthma (9,(53)(54)(55). In severe asthma, however, a high level of EGFR expression is not followed by increased proliferation.…”

“…Collagen, reticular and elastic fibers, proteoglycans and glycoproteins, all of which contribute to lung remodeling, can be produced by mesenchymal cells influenced by epithelial cells. Thus, epithelial-mesenchymal interactions play an important role in extracellular matrix production and deposition (52,53). Furthermore, the Th2-type cytokines IL-4 and IL-13, signaling via the transcription factor STAT-6, are able to induce myofibroblast transformation and submucosal remodeling through a TGF-ß-depending mechanism.…”

“…Communication between epithelium and the underlying epithelial fibroblast sheet is reminiscent of the process that drives branching morphogenesis, whereas epithelium and mesenchyme act as a trophic unit. Intermittent EGF and TGF-ß dominance produces alternating linear and branching of the developing airways, in a process similar to that observed in asthmatic airways (53). EGFRs = epidermal growth factor receptors; TGF-ß = transforming growth factor-ß; ECM = extracellular matrix.…”

“…Although it was initially suggested that the instructive signaling was unidirectional, with the pulmonary mesenchyme producing signaling molecules such as NF-κB, TGF-ß and FGF to induce normal epithelial development, it is now known that the epithelium also produces signaling molecules such as EGF, TGF-ß, Sonic Hedgehog (Shh) and Wnt proteins that are important for normal mesenchymal differentiation and proliferation (57). Moreover, the majority of transcription factors, growth factors and other signaling molecules involved in branching morphogenesis are also implicated in airway remodeling (53,57). The observation that overexpression or inhibition of key elements of the EMTU results in dysfunctional repair has led to the proposal that remodeling in asthma could be a result of the EMTU remaining active after birth or becoming reactivated in susceptible asthmatics (57).…”

Effects of Arkadia on airway remodeling through enhancing TGF-β signaling in allergic rats

“…1 Transforming growth factor b (TGF-b), a fibrogenic cytokine, has been implicated in the development of airway remodeling in asthma on the basis of its strong capacity to induce the production of extracellular matrix factors including type 1 collagen (COL-I). 2 It is, therefore, possible that regulators of TGF-b activity might also have important role in the modulation of the airway remodeling process in asthma.…”