Transforming growth factor beta (TGF-β) and obliterative bronchiolitis following pulmonary transplantation

Abstract

Background: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-β has been implicated in the pathogenesis of fibrosis. Methods We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-β polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. Results Procedures were heart and lung ( n = 32), bilateral sequential lung ( n = 18), and single lung transplantation ( n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-β was immunolocalized in the airways and lung parenchyma. TGF-β expression was greater in OB patients (median score 8, range 5–12) in comparison to patients without OB (median score 4, range 1–13), p < .0001. Positive TGF-β staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus ( p = .02); recurrent acute rejection episodes ( p < .0005); lymphocytic bronchiolitis ( p = .0001); and tissue eosinophilia, regardless of the rejection grade ( p < .0001). Conclusions Increased expression of TGF-β is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-β production following allograft injury. Hence, modulation of TGF-β levels or function by antagonists may represent an important approach to control OB.