Benefit of phosphodiesterase 4 inhibitors as supplemental therapy after lung transplantation concerning their antiproliferative effects: an experimental study using a heterotopic rodent model.
BACKGROUND
Recent advances in the understanding of immunomodulatory properties of phosphodiesterase 4 (PDE4) inhibitors recommend these drugs for immunosuppressive therapy after lung transplantation. The potency of three PDE4 inhibitors was tested using an established model of heterotopic tracheal transplantation in rats.


METHODS
Five allogenic groups were investigated and treated with the PDE4 inhibitors: rolipram, cilomilast (Ariflo, SB-207499, SmithKline Beecham, Munich, Germany), roflumilast (Altana Pharmacia, Bad Homburg, Germany) or cyclosporine A (CsA), or left without immunosuppression. The grafts were quantitatively analyzed for epithelial integrity, monocyte/macrophage content, cell proliferation, and tracheal obliteration by histology/immunohistochemistry (days 1, 5, 7, 21, 28; n=4-7).


RESULTS
In animals treated with the PDE4 inhibitors, the epithelium was completely lost until day 21. The epithelium was partially preserved in the rats receiving CsA until day 28. In the acute phase (days 5 and 7) the infiltration of monocytes and macrophages was significantly inhibited similarly (cilomilast) or less effective (rolipram, roflumilast) as in CsA-treated rats. In the chronic phase (day 28) the significant increase of monocytes and macrophages after CsA-treatment was not found in PDE4 inhibitor-treated rats. The PDE4 inhibitors showed lower (rolipram) or higher (cilomilast, roflumilast) potency as CsA to inhibit the cell proliferation. Only treatment with PDE4 inhibitor (Ariflo) significantly inhibited the obliteration, but to a lesser degree as CsA.


CONCLUSIONS
The PDE4 inhibitors tested in our study are not suitable on their own for immunosuppressive therapy after lung transplantation because of the limited protection against the epithelial disturbance, infiltration of immune cells, and luminal obliteration. The strong anti-proliferative effect of the second-generation PDE4 inhibitors, cilomilast and roflumilast, suggest a benefit for the effective inhibition of immune cell and fibroblast proliferation contributing to the development of obliterative bronchiolitis.
Schade
Ina
I
Cardiovascular Institute, University of Dresden, Germany. Monika.Weber.hkz_dd@t-online.de
Roth-Eichhorn
Sylke
S
Kasper
Michael
M
Kuss
Hildegard
H
Plötze
Katrin
K
Funk
Richard H W
RH
Schüler
Stephan
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D016572:Cyclosporine / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020889:Rolipram / Q000627:therapeutic use*; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000502:physiology
D003509:Cyclohexanecarboxylic Acids; D007166:Immunosuppressive Agents; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D016572:Cyclosporine; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram