The movement of fluid and protein through the interstitium is not only critical to mammalian tissue homeostasis but also of major importance in therapeutic procedures such as macromolecular drug delivery or peritoneal dialysis. Recently proposed mathematical models of interstitial fluid and protein transport include theories of convection which are potentially capable of calculating interstitial pressure forces, changes in the extracellular space, flow rates within the interstitium, and the solvent drag effect on solutes. The investigator has formulated a mathematical model which combines elements of several theories to simulate diffusion, convection, and capillary exchange within tissue. However, existing data represent the averaged properties of whole organs and cannot be used to implement these theories or test their assumptions. In vivo experiments are proposed to obtain intratissue data to test the following hypotheses which form the basis of these theories: (a) that fluid movement into tissue can be correlated with the hydrostatic pressure gradient within the tissue; (b) that the extracellular space changes with variations in local interstitial pressure; (c) that convection moves protein through the tissue at a velocity proportional to the water velocity. To carry this out, a unique animal preparation has been chosen: the rat anterior abdominal wall during peritoneal dialysis. Prior research with this animal model has established: that protein acts as a marker of convection from the peritoneal cavity, that the rate of convection is directly proportional to the intraperitoneal (i.p.) pressure, and that the abdominal wall is the major site of absorption. The pressure difference across the abdominal wall (the driving force for convection) can be manipulated by raising or lowering the i.p. pressure. The abdominal wall is accessible to servo-null micropressure device for measurement of the interstitial pressure profile. Dual-label quantitative autoradiography can be used to measure the concentration profiles of markers of the interstitial space during transport experiments. By matching the concentration profiles with the pressure gradients, the following will be determined within the tissue: hydraulic conductivity, the interstitial void fraction and its dependence on interstitial pressure (compliance), the protein void fraction, and the solvent drag coefficient. These parameters and the accompanying data will be used to test the hypotheses. With respect to transport physiology, the results will lay a foundation for the validation of current theories of interstitial convection. A quantitative understanding of the driving forces and parameters which govern large solute and fluid transport through tissue may lead to strategies to improve clinical procedures which depend on convection.
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