Oral doxycycline prevents skin-associated adverse effects induced by injectable collagenase in a rodent model of capsular contracture around silicone implants

The collagenase of the bacterium Clostridium histolyticum (CCH) is already an established treatment for fibroproliferative diseases like M. Dupuytren and M. Peyronie Although results are comparable to surgical intervention, skin laceration is a severe and relevant side effect. Doxycycline (DOX) rece...

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Published in:	PloS one Vol. 17; no. 7; p. e0270112
Main Authors:	Diehm, Yannick F, Kotsougiani-Fischer, Dimitra, Porst, Elena, Haug, Valentin, Siegwart, Laura C, Overhoff, Daniel, Kneser, Ulrich, Fischer, Sebastian
Format:	Journal Article
Language:	English
Published:	San Francisco Public Library of Science 06-07-2022 Public Library of Science (PLoS)
Subjects:	Animal experimentation Animals Antibiotics Biology and Life Sciences Chloride Collagen Collagenase Collagenases Collagens Density Doxycycline Engineering and Technology Evaluation Experiments Fibrosis Gene expression Health aspects Health services Histology Immunohistochemistry Implants Matrix metalloproteinase Matrix metalloproteinases Medicine and Health Sciences Physical Sciences Properties Research and Analysis Methods Rodents Silicone resins Silicones Skin Skin diseases Thickness Transplants & implants Zinc Germany United States > US
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Summary:	The collagenase of the bacterium Clostridium histolyticum (CCH) is already an established treatment for fibroproliferative diseases like M. Dupuytren and M. Peyronie Although results are comparable to surgical intervention, skin laceration is a severe and relevant side effect. Doxycycline (DOX) recently rose interest as an inhibitor of matrix-metalloproteinases alongside its capabilities of skin accumulation. It therefore might be a potential skin protective agent in the use of CCH. For simulation of a fibroproliferative disease adjacent to the skin, we utilized a rodent model of capsular fibrosis involving silicone implants and subsequent fibrotic capsule formation. For in-vitro studies, fibrotic capsules were excised and incubated with 0.9 mg/ml CCH and four different doses of DOX. For in-vivo experiments, animals received 0.0, 0.3 or 0.9 mg/ml CCH injections into the fibrotic capsules with or without prior oral DOX administration. Outcome analysis included histology, immunohistochemistry, gene expression analysis, chemical collagen and DOX concentration measurements as well as [mu]CT imaging. In-vitro, DOX showed a dose-dependent inhibition of CCH activity associated with increasing capsule thickness and collagen density and content. In-vivo, oral DOX administration did neither interfere with capsule formation nor in effectiveness of CCH dissolving fibrotic capsule tissue. However, skin thickness and especially collagen density was significantly higher compared to control groups. This led to a reduced rate of clinical skin lacerations after DOX administration. DOX inhibits CCH and accumulates in the skin. Thereby, DOX can effectively reduce skin laceration after CCH treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0270112