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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29DK048479-04S1
Application #
2834885
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Eggers, Paul Wayne
Project Start
1998-07-15
Project End
1999-05-31
Budget Start
1998-07-15
Budget End
1999-05-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Flessner, M F; Lofthouse, J; Zakaria, E R (2001) Improving contact area between the peritoneum and intraperitoneal therapeutic solutions. J Am Soc Nephrol 12:807-13
Flessner, M F (2001) Transport of protein in the abdominal wall during intraperitoneal therapy. I. Theoretical approach. Am J Physiol Gastrointest Liver Physiol 281:G424-37
Flessner, M F; Lofthouse, J; Williams, A (2001) Increasing peritoneal contact area during dialysis improves mass transfer. J Am Soc Nephrol 12:2139-45
Zakaria, E R; Lofthouse, J; Flessner, M F (2000) Effect of intraperitoneal pressures on tissue water of the abdominal muscle. Am J Physiol Renal Physiol 278:F875-85
Flessner, M F (1999) Changes in the peritoneal interstitium and their effect on peritoneal transport. Perit Dial Int 19 Suppl 2:S77-82
Zakaria, E R; Lofthouse, J; Flessner, M F (1999) In vivo effects of hydrostatic pressure on interstitium of abdominal wall muscle. Am J Physiol 276:H517-29
Demissachew, H; Lofthouse, J; Flessner, M F (1999) Tissue sources and blood flow limitations of osmotic water transport across the peritoneum. J Am Soc Nephrol 10:347-53
Flessner, M F; Lofthouse, J (1999) Blood flow does not limit peritoneal transport. Perit Dial Int 19 Suppl 2:S102-5
Flessner, M F; Dedrick, R L (1998) Tissue-level transport mechanisms of intraperitoneally-administered monoclonal antibodies. J Control Release 53:69-75
Kim, M; Lofthouse, J; Flessner, M F (1997) A method to test blood flow limitation of peritoneal-blood solute transport. J Am Soc Nephrol 8:471-4

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