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Orthopaedic Proceedings
Vol. 84-B, Issue SUPP_I | Pages - 21
1 Mar 2002
Veihelmann A Hofbauer A Krombach F Refior H Messmer K
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Nitric oxide (NO) production by the inducible NO synthase (iNOS) and enhanced emigration of leukocytes into synovial tissue are suggested to play a crucial role in mediating chronic joint inflammation such as rheumatoid arthritis. The effects of iNOS inhibition in experimental arthritis are dicussed controversally. The aim of our study was to analyze the synovial microcirculation and leukocyte endothelial cell interactions in iNOS-deficient mice with antigen-induced arthritis (AiA) in vivo. 14 homocygote iNOS-deficient (iNOS KO C57BL6/J x 129SvEv; Merck & Co., Rahway, NJ, USA) and 14 iNOS-positive (C57BL6/J x 129SvEv) mice were used for our study. The patella tendon was resected, which allows for visualization of the intraarticular synovial tissue of the knee joint using intravital fluorescence microscopy. Animals were allocated into four groups (iNOS +/+, iNOS +/+ with AiA, iNOS −/− and iNOS −/− with AiA) (n=7 each group). On day 8 after arthritis induction, functional capillary density (FCD), fraction of rolling leukocytes, and the number of adherent leukocytes were quantitatively analyzed in synovial postcapillary venules. Histologic sections were performed to assess leukocyte infiltration of the synovium.

FCD or leukocyte-endothelial cell interaction were not altered in healthy iNOS-deficient mice in comparison to iNOS +/+ animals. However, in iNOS-deficient animals with AiA there was a significant increase in the fraction of rolling (0,510,05) and in the number of adherent leukocytes (729126 mm-2) in comparison to wild type mice with AiA (0,330,07 and 565110 mm-2) (MWSEM, p < 0,05). Histologic sections revealed increased leukocyte infiltration in iNOS-deficient animals with AiA compared to iNOS +/+ arthritic animals.

In our study, there was an enhanced leukocyte accumulation and extravasation in iNOS-deficient mice with antigen-induced arthritis in comparison to iNOS-positive animals with arthritis. Thus, the induction of iNOS appears as critical protective response to AiA possibly by reducing leukocyte adhesion and infiltration.


Orthopaedic Proceedings
Vol. 84-B, Issue SUPP_I | Pages - 21
1 Mar 2002
Veihelmann A Szczesny G Refior H Messmer K
Full Access

Edema and infection represent serious complications of blunt extremity trauma. It is important to differentiate between pathophysiological changes within tissues proximal and within distal to the site of trauma. The aim was to investigate the effects of soft tissue trauma on the microcirculation of the mouse lower limb. Endothelial leakage and leukocyte accumulation proximal and distal to the site of trauma were studied using intravital fluorescence microscopy.

Low-energy trauma to the lower limb was defined in previous experiments as a trauma transferring 50% of the energy required to produce tibial fracture. The trauma was inflicted under general anesthesia by an accelerator, hitting the mid-section of the calf in a perpendicular direction. 5, 90, and 180 minutes after trauma, the following microcirculatory parameters were measured: diameter of arterioles, venules, functional capillary density (FCD), extravasation of FITC-dextrane, and leukocyte-endothelial cell-interactions. Two groups (control and trauma) were studied proximal to, distal to and at the site of trauma. Skin, subcutaneous tissue and muscle were investigated individually in the trauma and the control groups (each group n=7).

At the site of trauma, distinct extravasation and edema formation in all tissues was observed. In subcutaneous and muscle tissue, microvascular thrombosis as well as edema were detected proximal and distal to the trauma. FCD was reduced in muscle and fat tissue. The numbers of rolling and adherent leukocytes were enhanced 5 minutes after trauma and throughout the observational period.

Our results demonstrate endothelial leakage and extravasation early after low-energy soft tissue trauma in all soft tissues proximal and distal to the site of trauma. In addition, we found high accumulation of leukocytes in all locations, especially in soft tissues. The model presented is ideally suited for the in vivo investigation of new therapeutic strategies for edema and thrombosis prevention in animals with soft tissue trauma.