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

Paper presented in the ISHLT 17th Annual meeting, April 2–5th, 1997, London, UK.
https://doi.org/10.1016/S1053-2498(99)00047-9Get rights and content

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.

Section snippets

Patients and sample

Specimens from 93 consecutive lung transplantations performed on 91 patients in the Wythenshawe Lung Transplant Program between January 1990 and March 1996 were analyzed retrospectively. In addition 380 fixed unstained transbronchial biopsies from our histologic archives were stained for TGF-β. We also reviewed 780 transbronchial biopsies from all the recipients to classify and score rejection, infection, and fibrosis of our patients. Technical aspects of lung transplantation operative

Results

Procedures were heart and lung (n = 32), double lung (n = 18), and single lung transplantation (n = 41). Descriptive statistics of different variables are shown in Table III. The incidence of OB in this group was 28.5% (n = 26/91). All satisfied the functional decline accepted as a definition for BOS, of whom 20 had positive histology at the time of OB diagnosis and 6 were confirmed at postmortum. BOS grades are presented in Figure 1. Overall 30-day mortality was 10.9% (n = 10/91), and 90-day

Discussion

Since the first long-term success of human lung transplant in 1983 (Toronto Lung Transplant Group, 1986) remarkable progress has been achieved. The operative mortality rate is now in the range of 10%. One- and 2-year survival rates are 80% and 70%, respectively.21 However, problems remain, most notably chronic rejection, which is manifested in the pulmonary allograft as OB.

TGF-β is an important member of a family of cytokines involved in controlling the differentiation and proliferation of a

References (43)

  • S.A Yousem et al.

    Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation

    Ann Thorac Surg

    (1990)
  • C Chaparro et al.

    Causes of death in lung transplant recipients

    J Heart Lung Transplant

    (1994)
  • X.H.R.H Huang et al.

    Heterotopic tracheal allograft transplantationa new model to study the molecular events causing obliterative airway disease (OAD) in rats

    J Heart Lung Transplant

    (1995)
  • G Al-Dossari et al.

    Pathogenesis of obliterative bronchiolitis. Possible roles of PDGF and bFGF

    Transplantation

    (1995)
  • S Stewart

    Pathology of lung transplantation

    Semin Diag Pathol

    (1992)
  • S Hasegawa et al.

    Expression of class II major histocompatibility complex antigens (HLA-DR) and lymphocyte subset immunotyping in chronic pulmonary transplant rejection

    Arch Pathol Lab Med

    (1995)
  • P Vaillant et al.

    The role of cytokines in human lung fibrosis

    Monaldi Arch Chest Dis

    (1996)
  • J.D Cooper

    The evolution of techniques and indications for lung transplantation

    Ann Surg

    (1990)
  • J.D Cooper et al.

    A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation

    J Heart Lung Transplant

    (1993)
  • A Voller et al.

    Enzyme immunoassays in diagnostic medicine. Theory and practice

    Bull World Health Organ

    (1976)
  • A Lendrum

    The staining of esoinophil, polymorph and enterochromassin cells in histology sections

    J Pathol Bacteriol

    (1944)
  • Cited by (170)

    View all citing articles on Scopus
    View full text