Effect of simvastatin on development of obliterative airway disease: an experimental study.
BACKGROUND
Obliterative bronchiolitis after lung transplantation is characterized by airway inflammation leading to obliteration of small airways. Statins are known to have lipid-independent immunomodulatory properties. We investigated the effect of simvastatin treatment on innate and adaptive immune responses and the development of obliterative airway disease (OAD).


METHODS
In fully MHC-mismatched rat tracheal allograft recipients, we used simvastatin at different doses (0.1 to 20 mg/kg/day orally) to assess its effect on OAD development. No immunosuppressive treatment was administered. Histologic, immunohistochemical and real-time RT-PCR analyses were performed 3, 10 and 30 days after transplantation.


RESULTS
Simvastatin treatment with doses ranging from 0.5 to 20 mg/kg/day significantly enhanced early epithelial recovery and reduced the development of OAD. No dose response was observed. Simvastatin treatment markedly reduced IL-23 mRNA and lymphocyte chemokine CCL20 production, and the infiltration of CD4(+) and CD8(+) T cells into allografts already at 3 days. At 10 days, simvastatin significantly attenuated the production of pro-inflammatory cytokines, IL-1β, TNF-α, MCP-1 and IP-10, and Th17-polarizing cytokines, IL-6 and IL-17e, and inhibited allograft infiltration by inflammatory cells. The protective effects of simvastatin on inflammation and OAD were partially mediated through nitric oxide synthase.


CONCLUSIONS
Simvastatin treatment inhibited adaptive T-cell alloimmune activation as depicted by reduced expression of lymphocyte chemokine and pro-inflammatory cytokine mRNA and reduced allograft infiltration by inflammatory cells. Importantly, simvastatin inhibits the development of OAD and this effect is partially mediated by increased nitric oxide activity. These results suggest a role for simvastatin in the prevention of obliterative bronchiolitis.
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Jussi O
JO
Ropponen
Simo O
SO
Syrjälä
Maria
M
Hollmén
Raimo
R
Tuuminen
Rainer
R
Krebs
Mikko A
MA
Keränen
Kirsi
K
Vaali
Antti I
AI
Nykänen
Karl B
KB
Lemström
Jussi M
JM
Tikkanen
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D011920:Rats, Inbred WF; D019821:Simvastatin / Q000008:administration & dosage*
D007166:Immunosuppressive Agents; D019821:Simvastatin