Original Articles
Development of obliterative bronchiolitis after allogeneic rat lung transplantation: implication of acute rejection and the time point of treatment

https://doi.org/10.1016/S1053-2498(98)00009-6Get rights and content

Abstract

Background

Chronic allograft failure represents the major cause of late morbidity and mortality after solid organ transplantation. Despite the pathological and clinical changes of this disease being well-described, the etiology and the causative factors are still under discussion. Several clinical, as well experimental studies, emphasize the significance of acute rejection. In rat model of left lung allo-transplantation (F344-to-WKY) the influence of acute rejection (AR) on the development of chronic rejection (CR) was studied.

Methods

In Group I (n = 25) no immunosuppression was used, while methylprednisolone (MP) (10 mg/kg) was applied in Group II (n = 20) in the early phase of AR on postoperative Days 9, 10, 11 and in Group III (n = 20) during AR on Day 14, Day 15, Day 16. The rats were sacrificed on Day 5, Day 15/20, Day 30, Day 60, Day 100 and following HE-staining the extend of AR as well CR was graded according to the working formulation of The International Society of Heart and Lung Transplantation.

Results

In Group I, AR was found at Day 15 and Day 30 which resolved spontaneously and resulted in CR on Day 60 and Day 100. In Group II, signs of AR were less evident on Day 20, while mild AR persisted on Day 30 and Day 60. On Day 100, normal lung structure was found in all rats. The recipients of Group III showed decreased signs of AR in the early course, however, severe CR was found on Day 60 and Day 100. Extensive airway inflammation with destruction of the subepithelial layer of the smaller airways resulted in severe early obliterative bronchiolitis.

Conclusions

Untreated severe AR in the early course after lung transplantation results in CR in the F344-to-WKY model. Preventive treatment with MP during the early phase of AR clearly diminishes the degree of AR and the graft recovers completely without any evidence of CR. Late application of steroids during the zenith of AR is successful to control the extent of AR, however, it fails to prevent CR.

Section snippets

Material and methods

A total of 80 inbred, male rats underwent allogeneic (F344-to-WKY, n = 65) or syngeneic (WKY-to-WKY, n = 15) orthotopic left lung transplantation (LTX) according to standard technique.9 F344 (RT1lvl) animals served as donors and WKY (RT11) rats as recipients. The rats were obtained from Harlan-Winkelmann Laboratories (Borchen, Germany) and were specific-pathogen-free. The mean weight of the donor rats was 261.26 ± 33.08 g vs 244.00 ± 29.73 g in the recipient group. For anesthesia all animals

Results

Conventional histology showed complete normal lung tissue in the control groups without (Group 0−) or following ECS-perfusion (Group 0+). The same is true for the native right lungs in all instances and for the isografts at Day 100 in all 3 groups. There was no sign of infection or rejection.

At the 5th postoperative day only mild signs of perivascular and peribronchial infiltration without evidence of AR were found (ISHLT-score: A 0.50/B 0.20) (Figure 1). There was no damage to the vascular

Discussion

Early diagnosis and detailed knowledge about the etiology of the underlying process are the most essential preconditions to be successful in the struggle against chronic allograft dysfunction. The pathological findings of chronic lung allograft rejection are characterized by extensive fibrosis and scarring with partial respectively total occlusion of the smaller airways (obliterative bronchiolitis) or fibrointimal thickening of the arteries and veins (vascular sclerosis).10 Treatment of the CR

Conclusion

Chronic allograft dysfunction still represents the major source of late morbidity and mortality after lung transplantation. Functional impairment is based on irreversible structural changes involving the smaller bronchi and vascular structures. Several factors are thought to be of possible influence on the development of the disease. In the model studied, early acute rejection has been identified to be of significant pathogenetic causality for the generation of obliterative bronchiolitis and

Acknowledgements

The authors thank Markus Ernst, PhD for technical assistance during the study and for the statistical review.

References (24)

  • S.A. Yousem et al.

    Does histologic acute rejection in lung allografts predict the development of bronchiolitis obliterans?

    Transplantation

    (1991)
  • Y. Matsumura et al.

    Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation

    Transplantation

    (1995)
  • Cited by (33)

    • Effects of azithromycin and tanomastat on experimental bronchiolitis obliterans

      2015, Journal of Thoracic and Cardiovascular Surgery
      Citation Excerpt :

      Tanomastat was administered orally at a dose of 15 mg/kg body weight21 once per day starting on the first day following transplantation. The orthotopic transplantation of left lung isografts (WKY-WKY) or allografts (F344-WKY) was performed as described.17,22 The heart and lungs were perfused with Perfadex (Vitrolife, Gothenburg, Sweden) with addition of heparin, prednisolone (Solu-Dacortin; Merck, Vienna, Austria), and epoprostenol (Flolan; Glaxo Smith Kline, Uxbridge, United Kingdom) via the right-ventricular outflow tract.

    • Suppression of bronchiolitis obliterans in allogeneic rat lung transplantation-Effectiveness of everolimus

      2013, Experimental and Toxicologic Pathology
      Citation Excerpt :

      The effectiveness of the drug was limited by side effects such as weight loss using continuous application of high doses of everolimus (Hausen et al., 1999; Schuurman et al., 1997). In the present study, we preferred the full organ model in a non-MHC allogeneic rat model (F344-to-WKY) to verify the impact of everolimus on the development of chronic allograft rejection (Matsumura et al., 1995; Hirt et al., 1999). This study included the initial state of the allografts defining different extent of premature damage of epithelial tissue and grading of AR.

    • The need for a new animal model for chronic rejection after lung transplantation

      2011, Transplantation Proceedings
      Citation Excerpt :

      Hirt et al showed that steroid treatment early in AR (days 9, 10, and 11) yielded normal lungs when the rat was humanely killed at day 100. When given later (days 14, 15, and 16), severe CR was noted on days 60 and 100.93 Yasufuku et al reported that rats fed collagen V before LT showed signs of mild AR at 10 weeks, whereas controls showed OB lesions.94

    View all citing articles on Scopus
    View full text