Rapamycin-induced impaired wound healing is associated with compromised tissue lactate accumulation and extracellular matrix remodeling.

Abstract

INTRODUCTION:

Extracellular matrix (ECM) remodeling involving matrix metalloproteinases (MMPs) and wound lactate accumulation are essential elements of tissue repair. The aim of this study was to investigate whether rapamycin-induced impaired healing is associated with compromised wound fluid lactate accumulation and altered ECM remodeling.

METHODS:

Polyvinyl alcohol sponges were subcutaneously implanted in male C57/BL6 mice. Animals were randomized to daily intraperitoneal treatment with either vehicle or 1.5 mg/kg rapamycin. After 7 or 14 days, sponges were harvested to collect wound fluid for subsequent analyses. Wounds were excised for assessment of tensile strength.

RESULTS:

After 7 days, wound hydroxyproline content was significantly decreased due to rapamycin therapy, whereas the observed difference in tensile strength marginally failed to show statistical significance. In addition, rapamycin reduced wound lactate accumulation and enhanced MMP-2 protein expression, and both MMP-2 and MMP-9 activity. At day 14, wound tensile strength and hydroxyproline content were significantly lower along with an increase in MMP-2 and MMP-9 activity in rapamycin-treated mice. Similarly, wound fluid lactate concentration and MMP-2 protein expression were found to be persistently decreased and increased, respectively.

CONCLUSIONS:

Rapamycin affects tissue repair by interfering with fundamental mechanisms involved in healing, namely lactate accumulation and ECM remodeling.

• Authors: J Weinreich, S Löb, M Löffler, I Königsrainer, D Zieker, A Königsrainer, S Coerper, S Beckert
• Journal: European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes (Eur Surg Res) Vol. 47 Issue 1 Pg. 39-44 ( 2011) ISSN: 1421-9921 [Electronic] Switzerland
• PMID: 21597297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 S. Karger AG, Basel.

Chemical References

• Immunosuppressive Agents
• Lactic Acid
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Hydroxyproline
• Sirolimus

Topics

• Animals
• Extracellular Matrix (drug effects, physiology)
• Hydroxyproline (metabolism)
• Immunosuppressive Agents (adverse effects)
• Lactic Acid (metabolism)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Sirolimus (adverse effects)
• Tensile Strength (drug effects)
• Tissue Distribution
• Wound Healing (drug effects, immunology, physiology)