From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract.
BACKGROUND
Birch bark has a long lasting history as a traditional medicinal remedy to accelerate wound healing. Recently, the efficacy of birch bark preparations has also been proven clinically. As active principle pentacyclic triterpenes are generally accepted. Here, we report a comprehensive study on the underlying molecular mechanisms of the wound healing properties of a well-defined birch bark preparation named as TE (triterpene extract) as well as the isolated single triterpenes in human primary keratinocytes and porcine ex-vivo wound healing models.


RESULTS
We show positive wound healing effects of TE and betulin in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies elucidate that TE and betulin transiently upregulate pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For COX-2 and IL-6 this increase of mRNA is due to an mRNA stabilizing effect of TE and betulin, a process in which p38 MAPK and HuR are involved. TE promotes keratinocyte migration, putatively by increasing the formation of actin filopodia, lamellipodia and stress fibers. Detailed analyses show that the TE components betulin, lupeol and erythrodiol exert this effect even in nanomolar concentrations. Targeting the actin cytoskeleton is dependent on the activation of Rho GTPases.


CONCLUSIONS
Our results provide insights to understand the molecular mechanism of the clinically proven wound healing effect of birch bark. TE and betulin address the inflammatory phase of wound healing by transient up-regulation of several pro-inflammatory mediators. Further, they enhance migration of keratinocytes, which is essential in the second phase of wound healing. Our results, together with the clinically proven efficacy, identify birch bark as the first medical plant with a high potential to improve wound healing, a field which urgently needs effective remedies.
Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Sandra
S
Ebeling
Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Katrin
K
Naumann
Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Simone
S
Pollok
Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Tina
T
Wardecki
Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Sabine
S
Vidal-Y-Sy
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany ; German Cancer Consortium (DKTK), Heidelberg, Germany.
Juliana M
JM
Nascimento
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany ; German Cancer Consortium (DKTK), Heidelberg, Germany ; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Melanie
M
Boerries
Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Gudula
G
Schmidt
Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Johanna M
JM
Brandner
Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Irmgard
I
Merfort
D000199:Actins / Q000378:metabolism; D000818:Animals; D029662:Betula / Q000737:chemistry*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D024301:Plant Bark / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D014315:Triterpenes / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000094062:Betulinic Acid
D000199:Actins; D051546:Cyclooxygenase 2; D016207:Cytokines; D051959:ELAV Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D010936:Plant Extracts; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins; C002503:betulin; D000094062:Betulinic Acid