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Selective Cyclooxygenase-2 Inhibition Reverses Microcirculatory and Inflammatory Sequelae of Closed Soft-Tissue Trauma in an Animal Model
Philip Gierer, MD1; Thomas Mittlmeier, MD1; Reingart Bordel1; Klaus-Dieter Schaser, MD2; Georg Gradl, MD1; Brigitte Vollmar, MD1
1 Departments of Experimental Surgery (P.G., R.B, and B.V.) and Trauma and Reconstructive Surgery (P.G., T.M. and G.G.), University of Rostock, Schillingallee 70, 18055 Rostock, Germany. E-mail address for B. Vollmar: brigitte.vollmar@med.uni-rostock.de
2 Department of Trauma and Reconstructive Surgery, Charité, Campus Virchow, Augustenburger Platz 1, Humboldt University, 13353 Berlin, Germany
View Disclosures and Other Information
The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Department of Experimental Surgery, University of Rostock, Rostock, Germany

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 Jan 01;87(1):153-160. doi: 10.2106/JBJS.C.01510
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Background: Despite the common use of nonsteroidal anti-inflammatory drugs in the treatment of closed soft-tissue injuries, our understanding of the effect of these medications on tissue healing is incomplete. Using high-resolution multifluorescence microscopy, we investigated the efficiency of preinjury and postinjury treatment with the selective cyclooxygenase (COX)-2 inhibitor parecoxib to improve compromised perfusion of traumatized muscle tissue and to minimize secondary tissue damage.

Methods: With use of a pneumatically driven and computer-controlled impact device, closed soft-tissue trauma of the left hindlimb was induced in anesthetized rats that had had intravenous administration of 10 mg/kg of either parecoxib sodium (seven rats) or an equal volume of saline solution (seven rats). Seven additional animals received parecoxib two hours after the trauma, and seven animals without trauma served as controls.

Results: Time-course studies with use of both Western blot protein analysis and immunohistochemistry demonstrated a transient upregulation of COX-2 protein expression with peak levels eight to twelve hours after trauma and a return to near baseline level at eighteen hours. Regardless of whether parecoxib was administered before or after the injury, it completely restored microcirculatory impairment within the injured muscle. This was indicated by the mean values (and standard error of the mean) for nutritive perfusion (434 ± 15 cm/cm2 in animals treated before the injury and 399 ± 8 cm/cm2 in those treated after injury), nicotinamide adenine dinucleotide (NADH) levels (73 ± 2 aU and 74 ± 1 aU, respectively), and inflammatory cell interaction (184 ± 36 and 186 ± 32 n/mm2, respectively, for leukocytes, and 1.0 ± 0.1 and 0.8 ± 0.1 n/mm2, respectively, for platelets) at eighteen hours after trauma, which were not different from those found in noninjured muscle tissue of controls. In contrast, skeletal muscle in saline solution-treated animals revealed persistent perfusion failure (296 ± 30 cm/cm2) with tissue hypoxia (NADH, 100 ± 4 aU), and enhanced endothelial interaction of both leukocytes (854 ± 73 mm-2) and platelets (2.3 ± 0.5 n/mm2) at eighteen hours after trauma.

Conclusions and Clinical Relevance: Treatment of skeletal muscle soft-tissue trauma with parecoxib before as well as after injury is highly effective in restoring disturbed microcirculation. Moreover, a reduced inflammatory cell response helps to prevent leukocyte or platelet-dependent secondary tissue injury. These results deserve further investigation to prove that selective COX-2 inhibitors improve performance and promote healing following closed soft-tissue injury.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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