Lung transplantation remains the only viable option for many patients suffering from a variety of progressive or intractable end-stage lung diseases. Despite significant advances in the prevention of early graft rejection, ischaemia-reperfusion injury and acute management of lung transplant recipients, significant challenges remain in the chronic management of patients after lung transplantation. 1 In this issue of Thorax, Borthwick and colleagues2 provide intriguing new evidence that implicates the airway epithelium directly in the pathogenesis of bronchiolitis obliterans syndrome (BOS), the most significant factor in determining long-term lung graft survival (see page 770). As discussed in the study, the pathological lesion of BOS is obliterative bronchiolitis (OB), which recently has been postulated to be at least partially a disease of aberrant epithelial repair processes. 3 Borthwick and colleagues provide evidence that epithelial to mesenchymal transition (EMT), a process whereby epithelial cells undergo a complete lineage transition to become fibroblasts and/or myofibroblasts, may underlie the dysfunctional airway repair processes that lead to OB. This study, and others like it, attempt to redefine traditional paradigms regarding normal airway epithelial biology and disease pathogenesis, and have the potential to lead to entirely new therapeutic avenues for previously untreatable disease processes such as BOS. OB is characterised by initial inflammation of the small airways followed by airway remodelling, aberrant epithelial regeneration and repair, proliferation of fibroblasts and myofibroblasts, deposition of extracellular matrix (ECM) and eventual airway obstruction. 4 The initial inflammatory response is the result of an allogeneic immune response initiated against donor antigens in the graft endothelial and airway epithelial cells. This response characteristically generates antigen-specific graft-infiltrating destructive lymphocytes. The lymphocytes facilitate activation of macrophages and a variety of other inflammatory cells, with resultant epithelial damage. 5 The critical role of this allogeneic immune response as the initial trigger leading to OB is supported by the fact that the primary risk factors for the development of BOS after lung transplantation are class I and II mismatches between donor and recipient, as well as the number and severity of rejection episodes. 4 Although it has been recognised for over a decade that the airway epithelium is a target of the initial immune response, 6 the pathogenetic pathway that leads to disruption of normal epithelial repair processes, excessive fibroblastic responses and resultant excessive ECM deposition and eventual obliteration of small airways is still incompletely elucidated.

While bronchial epithelial cells (BECs) have been shown to directly present antigen7 and are potentially the primary target of immunological attack during the pathogenesis of OB, 8 their precise link to the proliferation of fibroblasts and the propagation of fibrosis is not entirely clear. It is known that epithelial cell apoptosis and disruption of epithelial integrity probably contributes to subepithelial fibroblastic proliferation, 9 but