Contents:
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1. Article Information, Introduction
2. HYALURONAN-BASED ANTIADHESIVE AGENTS
3. HERNIA REPAIR AND HYALURONAN CONTAINING MESHES
4. THE USE OF HYALURONAN IN INFECTIOUS CONDITIONS
5. MECHANISMS OF ACTION OF HYALURONAN
MECHANISMS OF ACTION OF HYALURONAN
HA-based antiadhesive agents have proved to be effective in reducing intra-abdominal adhesions in both experimental and clinical studies. Although the use of these products is widespread, there is still much debate on the exact mechanisms of action. Mechanical separation of injured peritoneal surfaces is probably the most important. Once these surfaces have healed after a period of approximately five days, no de novo adhesions will form. HA-CMC membranes create a mechanical barrier between the adhesiogenic wound surfaces. This allows the peritoneal lining to heal without adherence to the adjacent structures. HA solutions create a medium in which the bowel floats (the hydroflotation hypothesis), thus separating the intestines and thereby allowing adhesion-free repair of the mesothelial lining. The mechanical mechanism of the action of gels is probably somewhere between acting as a barrier and creating hydroflotation.
Apart from these mechanical mechanisms, biological mechanisms of action may be involved as well. Present in virtually all tissues and body fluids of vertebrates and with a profound role in cell biology, HA might improve peritoneal healing and enhance fibrinolysis.72
The relation between HA synthesis and cell proliferation has been studied thoroughly. The concentration of HA in healing tissues is high.73,74 Furthermore, HA synthesis facilitates cell detachment, mitosis, and locomotion.75–79 An HA-rich environment provides an open, hydrated matrix that facilitates cell migration.80,81 Exogenous HA may be beneficial in wound healing.82,83 Rapid, undisturbed restoration of the mesothelial lining of the traumatized peritoneum after surgery or infection should prevent adhesions, as stated previously. This concept is supported by the adhesion-reducing effect of intraperitoneal seeding of mesothelial cells or mesenchymal stem cells.84,85 Several studies have shown that HA increases the proliferation rate of mesothelial cells in vitro.86,87 This process implies that part of the adhesion-reducing capacity of HA may partly be explained by its ability to improve peritoneal healing due to the stimulation of mesothelial cell proliferation.
Abdominal surgery and peritonitis are known to disturb the equilibrium between the coagulation cascade and the fibrinolytic system, resulting in decreased peritoneal fibrinolytic capacity and subsequently enhanced adhesion formation. The influence of HA on peritoneal fibrinolysis despite several studies is not completely clear. HA increases the fibrinolytic response of human peritoneal mesothelial cells, mainly by decreasing PAI-1 transcription and release but also by increasing the intracellular tPA concentration in vitro.88 However, in vivo HA-based membrane and solution did not affect tissue tPA antigen or its activity in rat peritoneal biopsies after colonic surgery, with and without peritonitis.14 Reijnen et al. discussed several explanations for these contradicting results in an earlier review.89 However, a more recent in vitro study by Sikkink et al. did not show a significant effect of HA on the production of tPA by mesothelial cells either.90 This study showed that cells of the monocyte-macrophage system modulate the fibrinolytic capacity of lipopolysaccharide-treated human peritoneal mesothelial cells by increasing PAI-1 and tPA. HA solution decreased PAI-1 production by mesothelial cells, an effect that was ameliorated by the presence of monocyte-like cells. Two other studies did not add clarity to this subject, as the use of HA showed no effect on tPA and PAI levels in one and even resulted in a decrease of tPA in the other.15,91 Perhaps sequential biopsies from the peritoneum in human studies could further enlighten the role of HA in fibrinolysis, although the harvesting of successive biopsies would not be feasible in humans. Other sampling techniques, including the use of a peritoneal chamber or microdialysis, might overcome this in the near future.92