Selective cyclooxygenase-2 inhibition reverses microcirculatory and inflammatory sequelae of closed soft-tissue trauma in an animal model.
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/cm(2) in animals treated before the injury and 399 +/- 8 cm/cm(2) 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/mm(2), respectively, for leukocytes, and 1.0 +/-0.1 and 0.8 +/- 0.1 n/mm(2), 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/cm(2)) 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/mm(2)) at eighteen hours after trauma.


CONCLUSIONS
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.
Gierer
Philip
P
Departments of Experimental Surgery, University of Rostock, Schillingallee 70, 18055 Rostock, Germany.
Mittlmeier
Thomas
T
Bordel
Reingart
R
Schaser
Klaus-Dieter
KD
Gradl
Georg
G
Vollmar
Brigitte
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015153:Blotting, Western; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D006614:Hindlimb; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017695:Soft Tissue Injuries / Q000188:drug therapy* / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; C409945:parecoxib