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The Development of Obliterative Airway Disease under the Implication of Epithelium Damage and Proliferation: An Experimental Study Using Heterotopic Tracheal Transplantation in Rats

Sylke Roth-Eichhorn

Katrin Ploetze

Michael Kasper

Stephan Schueler

Cyclosporin A (CsA) and Rolipram, an inhibitor of phosphodiesterase 4 (PDE4), and established as an antiinflammatory drug, were compared examining their immunosuppressive effect. Using an acknowledged heterotopic trachea graft model, 4 groups were investigated: CsA-, Rolipram-, and CsA+Rolipram-treated, and untreated animals. At different time points, the grafts were removed for histology and immunohistochemistry. In untreated and Rolipram-treated animals, the epithelium was completely destroyed by day 28, whereas in CsA-treated rats it was conserved until day 60 (55% ± 39%). A similar protective effect was also seen in the group treated with CsA+Rolipram (50% ± 35%). Rolipram treatment led to decreased proliferation (day 28: 330 ± 130, 370 ± 30, 160 ± 20, 70 ± 20 cells/mm²; untreated, CsA-, Rolipram-, CsA+Rolipram-treated, respectively). Rolipram significantly inhibited the infiltration of monocytes/macrophages but was less effective than CsA (day 5: 4860 ± 420, 2370 ± 210, 3720 ± 280, 2320 ± 30 cells/mm²; untreated, CsA-, Rolipram-, CsA+Rolipram-treated, respectively). This resulted in the lumenal obliteration of 100% ± 1%, 28% ± 2%, 82% ± 6%, 15% ± 6% in control, CsA-, Rolipram-, and CsA+Rolipram-treated animals, respectively (day 60). In isogenic grafts, no changes were observed. The authors' results suggest that PDE4-inhibitor is not suitable for mono-immunosuppressive therapy after lung transplantation. In the acute phase, PDE4-inhibitor is less effective than CsA and does not prevent obliteration. The strong antiproliferating effect of Rolipram, however, is beneficial for the prevention of chronic changes. The combination of immunosuppressive and antiproliferating drugs could be a new strategy for pharmacological intervention of airway obliteration.

Key Words: lung transplantation • BOS • immunosuppression • Rolipram • PDE4-inhibitors • trachea in rat model

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