Sirolimus impairs wound healing.
OBJECTIVE
Clinically, the immunosuppressive drug sirolimus, used in organ transplantation, appears to impair wound healing. Little is known about the mechanisms of action. We investigated the effect of sirolimus on wound healing, and we analyzed the expression of stimulating mediators of angiogenesis (VEGF, vascular endothelial growth factor) and collagen synthesis (nitric oxide) in wounds.


METHODS
Groups of ten rats underwent dorsal skin incision, and polyvinyl alcohol sponges were implanted subcutaneously. Beginning at the day of wounding, rats were treated with 0.5, 2.0, or 5.0 mg sirolimus/kg/day. Animals were killed 10 days later to determine wound breaking strength and reparative collagen deposition. Expression of VEGF and nitric oxide was studied in wounds.


RESULTS
Splenic lymphocyte proliferative activity was significantly decreased by sirolimus (p < 0.05). Sirolimus levels in wound fluid were found to be approximately two- to fivefold higher than blood levels (p < 0.01). Sirolimus (2.0 and 5.0 mg kg(-1) day(-1)) reduced wound breaking strength (p < 0.01) and wound collagen deposition (p < 0.05). This was paralleled by decreased expression of VEGF and nitric oxide in wounds.


CONCLUSIONS
Experimentally, our data show that sirolimus impairs wound healing, and this is reflected by diminished expression of VEGF and nitric oxide in the wound.
Schäffer
Michael
M
Department of Surgery, Chirurgische Universitätsklinik, Knappschaftskrankenhaus Bochum-Langendreer, In der Schornau 23-25, 44892 Bochum-Langendreer, Germany. michael.schaeffer@kk-bochum.de
Schier
Robert
R
Napirei
Markus
M
Michalski
Stefan
S
Traska
Thilo
T
Viebahn
Richard
R
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000032:analysis; D007166:Immunosuppressive Agents / Q000032:analysis / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D023421:Models, Animal; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000032:analysis / Q000494:pharmacology*; D012867:Skin / Q000293:injuries; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects*
D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D003094:Collagen; D052247:Nitric Oxide Synthase Type II; D006909:Hydroxyproline; D020123:Sirolimus