BACKGROUND: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS: We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta 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-beta was immunolocalized in the airways and lung parenchyma. TGF-beta 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-beta 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-beta 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-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.
BACKGROUND: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS: We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta 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-beta was immunolocalized in the airways and lung parenchyma. TGF-beta expression was greater in OBpatients (median score 8, range 5-12) in comparison to patients without OB (median score 4, range 1-13), p < .0001. Positive TGF-beta 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-beta 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-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.
Authors: A DerHovanessian; S S Weigt; V Palchevskiy; M Y Shino; D M Sayah; A L Gregson; P W Noble; S M Palmer; M C Fishbein; B M Kubak; A Ardehali; D J Ross; R Saggar; J P Lynch; R M Elashoff; J A Belperio Journal: Am J Transplant Date: 2015-10-13 Impact factor: 8.086
Authors: C Ward; I A Forrest; D M Murphy; G E Johnson; H Robertson; T E Cawston; A J Fisher; J H Dark; J L Lordan; J A Kirby; P A Corris Journal: Thorax Date: 2005-06-21 Impact factor: 9.139
Authors: Z Xu; D Nayak; W Yang; G Baskaran; S Ramachandran; N Sarma; A Aloush; E Trulock; R Hachem; G A Patterson; T Mohanakumar Journal: Am J Transplant Date: 2015-02-03 Impact factor: 8.086
Authors: Takeshi Nakajima; Vyachesav Palchevsky; David L Perkins; John A Belperio; Patricia W Finn Journal: Semin Immunopathol Date: 2011-01-27 Impact factor: 9.623