The aim of the study was to investigate the long-term effects of postoperative immobilization as opposed to mobilization on the biomechanical attributes of healing Achilles tendons in a new experimental mouse model. Postoperative mobilization resulted in a continuous and significantly more rapid restoration of load to failure in comparison to the immobilization group. Tendon deflection was decreased by postoperative mobilization, whereas under immobilization it paradoxically increased still further in the later course. After 112 days the tendons of the mobilization group had regained their original tendon stiffness, whereas the tendons after immobilization reached only about half the values seen in the control tendons. Histologically, postoperative mobilization led to increased immigration of inflammatory cells in the early phase. In the late phase, as compared to immobilization, tendon structure was more mature, with fibre bundles arranged in parallel and interposed tendocytes.Tensile loading of the healing tendon by postoperative mobilization leads to fundamental changes in the biological process of tendon healing resulting in accelerated restoration of load to failure and reduced tendon deflection.
The gum resin extract from Boswellia serrata (H15), an herbal product, was recently shown to have positive therapeutic effects in inflammatory bowel disease (IBD). However, the mechanisms and constituents responsible for these effects are poorly understood. This study examined the effect of the Boswellia extract and its single constituent acetyl-11-keto-beta-boswellic acid (AKBA) on leukocyte-endothelial cell interactions in an experimental model of IBD. Ileitis was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) in Sprague-Dawley rats 24 h apart. Rats also received oral treatment with the Boswellia extract (H15) or AKBA at two different doses (low and high) equivalent to recommendations in human disease over 2 days. Controls received only the carriers NaHCO3 (subcutaneously) and tylose (orally). Effects of treatment were assessed by intravital microscopy in ileal submucosal venules for changes in the number of rolling and adherent leukocytes and by macroscopic and histological scoring. Increased leukocyte-endothelial cell adhesive interactions and severe tissue injury accompanied indomethacin-induced ileitis. Treatment with the Boswellia extract or AKBA resulted in a dose-dependent decrease in rolling (up to 90%) and adherent (up to 98%) leukocytes. High-dose Boswellia extract as well as both low- and high-dose AKBA significantly attenuated tissue injury scores. Oral therapy with the Boswellia extract or AKBA significantly reduces macroscopic and microcirculatory inflammatory features normally associated with indomethacin administration, indicating that the anti-inflammatory actions of the Boswellia extract in IBD may be due in part to boswellic acids such as AKBA.
Knowledge of sepsis is growing rapidly and new pathogenetic concepts and therapeutic strategies evolve. The animal models of sepsis catalyze this development. Any model of this complex disease is inevitably a compromise between clinical realism and experimental simplification. Against the background of current pathogenetic concepts this review tries to analyze the validity and clinical relevance of each model. Endotoxemia and bacteremia represent models without an infectious focus. They reproduce many characteristics of sepsis and are highly controlled and standardized. However, they reflect a primarily systemic challenge and create neither an infectious focus nor the protracted immune reaction that characterizes sepsis. In this respect, any model with an infectious focus is decisively closer to clinical reality. In these models the peritoneal cavity is contaminated either by bacteria or inoculated feces or perforation of the bowel wall. Both the bolus injection and the implantation of carriers loaded with bacteria or feces are used. In fecal spesis and perforation models the complete spectrum of enteric pathogens is present in the septic focus and infective selection is undisturbed. Here the pathophysiologic and immunologic features of clinical sepsis are successfully reproduced. However, presumably due to inadequate control of the bacterial challenge, only poor interlaboratory standardization is possible. As to optimize models for the clinical reality the choice of an appropriate class of models is crucial. Moreover the incorporation of clinical therapy such as volume resuscitation, antibiotic therapy and surgical treatment of the septic focus is indispensable. Finally, the importance of simulation of comorbidities cannot be overemphasized.
This study provides evidence that the effects of low-dose TP differ from those of AVP, not only as TP has a longer half life, but also because of different mechanisms of action. Although low-dose TP infusion may be superior to sole norepinephrine or AVP therapy in septic shock, the safety of this therapeutic approach should be determined in more detail.
Cell transplantation-induced hepatic ischemia and recruitment of vasoconstrictors, e.g., endothelin-1, leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan, which potently blocks endothelin-1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without darusentan in dipeptidyl peptidase IV-deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells, neutrophils or hepatic stellate cells. The retrorsine-partial hepatectomy model was used for liver repopulation studies. Whether darusentan was directly cytoprotective was examined in cultured rat hepatocytes or CFSC-8B rat hepatic stellate cells. We found darusentan induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage versus drug-untreated controls. Moreover, in darusentan-treated animals, cell transplantation-induced activation of Kupffer cells, albeit not of neutrophils, decreased, and fewer hepatic stellate cells expressed desmin. In darusentan-treated rats, improvements in cell engraftment led to greater extent of liver repopulation compared with drug-untreated controls. In cell culture assays, darusentan did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from hepatic stellate cells. Moreover, darusentan did not protect hepatocytes from TNF-α- or oxidative stress-induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. We concluded that systemic administration of darusentan decreased hepatic ischemia-related events and thus indirectly improved cell engraftment and liver repopulation. This vascular mechanism will permit development of combinatorial drug-based regimens to help optimize cell therapy.
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