Within the interstitial matrix of muscle, hyaluronan (HA) is a macromolecule which imbibes water, excludes solutes from its space, and plays a role in the inflammatory response. The hypothesis of the proposed research is that HA concentration ((HA)) is a major factor determining interstitial transport properties of the barrier between the blood and therapeutic dialysis solutions in the peritoneal cavity. To address the hypothesis, both acute and chronic studies will be carried out in which animals will be treated with intraperitoneal solutions to alter tissue (HA) from control levels. After the (HA) change, mathematical modeling will be combined with in vivo experimentation to quantify solute diffusion and convection in the subperitoneal muscle of anesthetized rats during peritoneal dialysis. The in vivo model permits control of the tissue pressure forces and measurement of the pressure profile with a micropipette-servo-null device. This data will be coupled with quantitative autoradiographic measurements of tissue concentrations of iv- or ip-injected radiolabeled marker molecules to determine the following transport coefficients: diffusivity, hydraulic conductivity, interstitial volume, intracellular volume, and solute void volume. At the conclusion of an experiment, an extensive histopathologic analysis and measurement of interstitial matrix components, including HA, collagen, and glycosaminoglycan will be carried out on subperitoneal tissue. At the conclusion of the chronic experiments, inflammatory mediators will be determined within the tissue and in the residual peritoneal fluid. Analysis of variance will test the hypothesis that changes in (HA) or another matrix component significantly affects each transport coefficient. Correlations of each coefficient with interstitial pressure and the averaged tissue (HA) will be inserted into the mathematical model to create a quantitative tool capable of predicting transport of water and solute across the peritoneum with a range of tissue HA levels. Chronic experiments will test whether (HA)-induced changes over a longer time affect tissue structure, inflammatory mediators, and transport function. The long-term goal is to gain an integrative understanding of transport through the interstitium, which includes its molecular constituents and their interactions with cells to form a tissue barrier. The results of this research project will provide a basis for future work designed to preserve or enhance the transport characteristics of peritoneal tissue during chronic dialysis.
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