Anti-proliferative properties of the phosphodiesterase-4 inhibitor rolipram can supplement immunosuppressive effects of cyclosporine for treatment of obliterative bronchiolitis in heterotopic rat allografts.
BACKGROUND
Potent prevention and therapy of obliterative bronchiolitis may enhance long-term survival after lung transplantation. Phosphodiesterase-4 inhibitors have been established for anti-inflammatory treatment, particularly of pulmonary diseases. Using a heterotopic rat model, the effect of rolipram was investigated and compared with cyclosporine for epithelium disturbance and leukocyte infiltration and proliferation, which are key events in the development of obliterative bronchiolitis.


METHODS
Tracheae were transplanted into the omentum of allo- and syngeneic animals. Four allogeneic groups were investigated: treatment with rolipram; treatment with cyclosporine; treatment with a combination of rolipram and cyclosporine; and untreated (60-day time course). Using histo- and immunohistochemical stainings, epithelium disturbance, leukocyte subsets, proliferating cells and luminal occlusion were quantified by digital morphometry.


RESULTS
In rolipram-treated animals, the epithelium was completely disturbed until Day 14. It was temporarily preserved in rats that received cyclosporine until Day 60. In the acute phase (Day 5), infiltration of monocytes/macrophages was significantly inhibited by rolipram, but less effective than in cyclosporine-treated rats. At later timepoints (Days 28 and 60), rolipram significantly inhibited proliferation, in contrast to enhanced proliferation of fibroblast-like cells after cyclosporine treatment. The combination of rolipram and cyclosporine led to temporary epithelial preservation and effective inhibition of leukocyte infiltration (Day 5) and proliferation (Days 28 and 60). Luminal occlusion was significantly reduced in the combination group compared with the cyclosporine-only group.


CONCLUSIONS
Although cyclosporine temporary protects epithelial integrity by the inhibition of acute rejection, rolipram showed greater potency for long-term inhibition of mesenchymal-cell proliferation. The combination of both drugs may be useful for limiting chronic obliterative changes after lung transplantation.
Roth-Eichhorn
S
S
Cardiovascular Institute University of Dresden, Dresden, Germany. sylke.roth-eichhorn@mailbox.tu-dresden.de
Schade
I
I
Kasper
M
M
Ploetze
K
K
Wunderlich
J
J
Funk
R H
RH
Schueler
S
S
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000628:therapy*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004847:Epithelial Cells / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology*; D014132:Trachea / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D010726:Phosphodiesterase Inhibitors; D016572:Cyclosporine; D020889:Rolipram