Transcriptional profiling of rapamycin-treated fibroblasts from hypertrophic and keloid scars.
Excess scar formation after cutaneous injury can result in hypertrophic scar (HTS) or keloid formation. Modern strategies to treat pathologic scarring represent nontargeted approaches that produce suboptimal results. Mammalian target of rapamycin (mTOR), a central mediator of inflammation, has been proposed as a novel target to block fibroproliferation. To examine its mechanism of action, we performed genomewide microarray on human fibroblasts (from normal skin, HTS, and keloid scars) treated with the mTOR inhibitor, rapamycin. Hypertrophic scar and keloid fibroblasts demonstrated overexpression of collagen I and III that was effectively abrogated with rapamycin. Blockade of mTOR specifically impaired fibroblast expression of the collagen biosynthesis genes PLOD, PCOLCE, and P4HA, targets significantly overexpressed in HTS and keloid scars. These data suggest that pathologic scarring can be abrogated via modulation of mTOR pathways in procollagen and collagen processing.
From the *Division of Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and Science University, Portland, OR; and †Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University, Stanford, CA.
Victor W
VW
Wong
Fanglei
F
You
Michael
M
Januszyk
Geoffrey C
GC
Gurtner
Anna A
AA
Kuang
D000328:Adult; D000368:Aged; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007627:Keloid / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D040081:Protein Array Analysis; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D007166:Immunosuppressive Agents; D003094:Collagen; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus