Lung rejection
Integrity of Airway Epithelium Is Essential Against Obliterative Airway Disease in Transplanted Rat Tracheas

https://doi.org/10.1016/j.healun.2004.04.020Get rights and content

Background

The pathogenesis of obliterative bronchiolitis after lung transplantation requires further elucidation. In this study we used rat trachea transplantation to examine the role of epithelium in the progression of obliterative airway disease.

Methods

Normal and denuded (i.e., epithelium removed) trachea grafts from Lewis (LEW) and Brown Norway (BN) rats were transplanted sub-cutaneously into LEW rats. Viable trachea epithelial cells (to recover epithelium) were seeded into the lumen of some of the denuded tracheas. Grafts were removed at different time-points between 2 days and 8 weeks after transplantation. Histologic analysis was performed to evaluate cellular infiltration of inflammatory cells, loss of epithelium, and obliteration of trachea lumen.

Results

Obliteration was found to occur in trachea transplants after loss of epithelium, caused by rejection in allografts or by enzymatic denudation in isografts. In these situations, fibroblasts started to proliferate and migrate into the lumen in the second week after transplantation. Obliteration could be prevented when epithelial integrity was restored by seeding epithelial cells; no obliteration occurred when denuded trachea isografts were seeded with epithelial cells, whereas non-seeded denuded tracheas were obliterated at Day 6 after transplantation.

Conclusions

We conclude that integrity of airway epithelium is essential for rat trachea transplants to be safeguarded from obliterative airway disease. For clinical lung transplantation the results of our study suggest that protection of the integrity of airway epithelium may be important in preventing the development of obliterative bronchiolitis.

Section snippets

Design of the Study

For the first set of experiments in the study, with the aim to correlate integrity of airway epithelium and luminal obliteration with inflammatory cell infiltration in OAD, trachea isografts and allografts were transplanted subcutaneously from Lewis (LEW) (n = 19) and Brown Norway (BN) (n = 20) donor rats, respectively, into LEW recipient rats (n = 39). Grafts were harvested at 4 days and 1, 2, 3, 4 and 8 weeks after transplantation to assess the integrity of the epithelium, luminal

Transplantation-Induced OAD in Allografts but not Isografts

In trachea iso- and allografts we investigated how the integrity of the tracheal epithelium and the degree of luminal obliteration correlated with inflammatory cell infiltration at 4 days and at 1, 2, 3, 4, and 8 weeks after transplantation. Isografting was not associated with significant cellular infiltration or loss of integrity of the epithelium (Table 2), despite ischemic and surgical injury at the time of transplantation. We did observe a few granulocytes and macrophages in the isografts.

Discussion

From the three experiments in this study it can be concluded that development of OAD in trachea transplants correlates with injury and repair of the airway epithelium. Injury of the epithelium with subsequent luminal obliteration coincided with inflammatory responses in the trachea grafts. In this inflammation-induced injury to airway epithelium we could distinguish 2 injury phases after transplantation of rat tracheas: (1) the “surgical” injury phase (most obvious in isografts immediately

References (35)

  • G.M. Verleden

    Bronchiolitis obliterans syndrome after lung transplantationmedical treatment

    Monaldi Arch Chest Dis

    (2000)
  • M. Estenne et al.

    Bronchiolitis obliterans after human lung transplantation

    Am J Respir Crit Care Med

    (2002)
  • D.J. Hele et al.

    The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis

    Respir Res

    (2001)
  • M.I. Hertz et al.

    Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways

    Am J Pathol

    (1993)
  • I.P. Neuringer et al.

    Immune cells in a mouse airway model of obliterative bronchiolitis

    Am J Respir Cell Mol Biol

    (1998)
  • A. Yamada et al.

    Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model

    Transplantation

    (2000)
  • B.F. Adams et al.

    Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts

    Transplantation

    (2000)
  • Cited by (28)

    • Airway epithelial stem cell chimerism in cystic fibrosis lung transplant recipients

      2021, Journal of Cystic Fibrosis
      Citation Excerpt :

      Many LTx patients develop obstructive allograft dysfunction, a lesion that is limited to small airway segments [3]. However, numerous studies in human patients (reviewed in [4]) and animal models [5,6] indicate that disease is initiated by bronchial epithelial injury. Subsequently, an aberrant repair process decreases the frequency of airway epithelial secretory and ciliated cells and reduces mucociliary function.

    • Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model

      2014, Journal of Thoracic and Cardiovascular Surgery
      Citation Excerpt :

      Our current results further confirm our previous findings that the integrity of epithelial cells is critical for preventing the progression of BO. These results are in agreement with other publications, showing that epithelial cells play an important role in the development of BO26,27 Therefore, PMSCs and PMSCCM may provide a novel therapeutic strategy to reduce BO after lung transplantation by promoting epithelial progenitor cells. Local injection of PMSCs specifically inhibited neutrophil infiltration.

    • Recipient NOD2/CARD15 Variants: A Novel Independent Risk Factor for the Development of Bronchiolitis Obliterans after Allogeneic Stem Cell Transplantation

      2008, Biology of Blood and Marrow Transplantation
      Citation Excerpt :

      Decreased monocyte/macrophage function and altered epithelial defense mechanisms may increase susceptibility to subclinical pulmonary infections, causing dysregulation and prolongation of inflammation [23-26] and possibly resulting in bronchial epithelial injury, obliteration of bronchi and bronchioli, and airway obstruction. Various models have shown a loss of airway epithelium associated with the development of BO [40-42], and the integrity of the airway epithelium seems essential to the prevention of BO [43]. Furthermore, Hill et al. [44] recently demonstrated a preventive role of interferon (IFN)-γ on the development of idiopathic pneumonia syndrome after allo-SCT, mediated through lung parenchymal cells.

    • Techniques for experimental heterotopic and orthotopic tracheal transplantations - When to use which model?

      2007, Transplant Immunology
      Citation Excerpt :

      IgM-to-IgG isotype switching by B cells is tightly regulated by both T cell costimulatory signals and recognition of cognate antigens [21] and had not yet occurred at this early time point. The integrity of the epithelium is widely believed to be essential for the prevention of tracheal allograft rejection [22]. Morris and co-workers demonstrated that airway epithelium removal led to OAD development in denuded tracheal syngrafts and that successful reseeding prevented airway obliteration [23].

    • Pulmonary hypertension and lung transplantation: Thorax publication activity review 2008-2010

      2012, Thorax
      Citation Excerpt :

      Attempted repair responses occurring in the injured epithelium may be critical in the pathophysiology of BOS.31 Animal models have also suggested that epithelial injury and the inability to re-establish an intact epithelium may lead to excessive deposition of ECM.32 Epithelial cells can respond to injury in a number of ways that include repair, necrosis, apoptosis and epithelial to mesenchymal transition (EMT), the latter being a process in which the cells assume the morphological and functional characteristics of mesenchymal cells including increased production of ECM.33

    View all citing articles on Scopus

    Supported in part by a grant from the J. K. de Cock Stichting Foundation and an Ubbo Emmius Scholarship, Groningen University.

    View full text