Purpose: Convective transport of macromolecules from the peritoneal cavity into tumor is determined by its hydraulic permeability and the pressure gradient. Previous studies showed that establishing a pressure gradient into the tumor failed to result in significant penetration. This study addresses the hypothesis that the extracellular matrix is the major resistance to the penetration of an i.p. injected antibody. Experimental Design: Human ovarian tumors (SKOV-3 and OVCAR-3) were established in the abdominal wall of athymic rats. After anesthesia, the tumor serosal surface was treated for 2 hours with Krebs solution (control), collagenase (37.5 unit/mL), or hyaluronidase (10 unit/mL) followed by 3 hours of convective delivery of radiolabeled IgG. Transport of antibody into the tumor was measured with quantitative autoradiography along with the tumor interstitial pressure, concentration of collagen and hyaluronic acid, and IgG volume of distribution. Results: Antibody was excluded from 42% to 53% of tumor extracellular volume. Exposure of tumors to hyaluronidase did not enhance IgG transport despite removal of 90% of the hyaluronan from the exposed tumor. In contrast, collagenase reduced collagen content, lowered tumor interstitial pressure, and markedly enhanced antibody penetration. Conclusions: Reduction of collagen, but not hyaluronan, in the matrix of ovarian xenografts enhanced the transport of i.p. injected antibody. Although high interstitial pressure is a deterrent to convective transport of macromolecules into the tumor parenchyma, the structure of the interstitial matrix provides an inherent resistance, which must be overcome before effective delivery of an antibody.

Most current animal models that are used to study effects of long-term peritoneal exposure to dialysis solutions use an indwelling catheter for daily injections. It was hypothesized that the presence of a foreign body in the peritoneal cavity (PC) might alter the inflammatory response to the solutions and that the response would depend on exposure duration. For addressing these, long-term injections were carried out for 2 to 8 wk in 90 Sprague-Dawley rats: 40 via a subcutaneous port connected to a silicone catheter tunneled to the PC, 40 via direct needle injection, and 10 noninjected, age-control rats. Daily volumes were 30 to 40 ml of filter-sterilized, bicarbonate-buffered solutions that contained 4% dextrose. After 2, 4, 6, and 8 wk, anesthetized rats underwent transport experiments with a chamber affixed to the abdominal wall to determine mass transfer coefficients of mannitol (MTC mannitol ) and albumin (MTC BSA ), osmotic filtration flux (J osm ), and hydrostatic pressure-driven flux. After the rats were killed, tissues were collected for measurement of peritoneal thickness, vascular density, and immunohistochemical staining. ANOVA demonstrated significant (P Ͻ 0.01) differences in thickness, vessel density, MTC mannitol , and MTC BSA among the groups at the various time intervals and in overall means. Differences among the groups were less pronounced for hydrostatic pressure-driven flux and J osm . Vessel density, MTC mannitol , MTC BSA , and J osm were dependent on injection duration (P Ͻ 0.01). There were marked differences between the needle injection and catheter injection groups at various intervals in the expression of three cytokines. It is concluded that the histologic and functional response depends on the duration of injection with animals that are exposed for as little as 2 wk demonstrating alterations. These findings confirm the hypothesis that the presence of a PC catheter increases inflammatory response to sterile solutions as evidenced by the structural and functional changes in the peritoneal barrier. 18: 229418: -230218: , 200718: . doi: 10.1681 Exposure of the peritoneum to sterile solutions that contain glucose results in changes in cellular characteristics, histology, and barrier function. Long-term peritoneal dialysis (PD) without evidence of peritonitis alters the phenotypic appearance of the human peritoneum in 8 to 12 mo. 1 Biopsy studies of longterm (Ͼ3 yr) PD patients have demonstrated marked thickening over time of the subcompact zone, a region between the mesothelial cells and their basement membrane, with corresponding changes in the underlying microvasculature. 2 Exposure of patients to glucose-based dialysis solutions resulted in significant functional changes in transperitoneal transport in a 2-yr study of patients who were treated with automated PD. 3 Studies in animal models parallel these changes and have demonstrated benefit of solutions that are thought to be more biocompatible. 4 -6 Studies in our laboratory using an animal model with a subcutaneous inj...

. Correlating structure with solute and water transport in a chronic model of peritoneal inflammation. Am J Physiol Renal Physiol 290: F232-F240, 2006. First published August 23, 2005 doi:10.1152/ajprenal.00211.2005.-To study the process of chronic peritoneal inflammation from sterile solutions, we established an animal model to link structural changes with solute and water transport. Filtered solutions containing 4% N-acetylglucosamine (NAG) or 4% glucose (G) were injected intraperitoneally daily in 200-to 300-g rats and compared with controls (C). After 2 mo, each animal underwent transport studies using a chamber affixed to the parietal peritoneum to determine small-solute and protein mass transfer, osmotic filtration, and hydraulic flow. After euthanasia, parietal tissues were sampled for histological analysis, which demonstrated significant differences in peritoneal thickness (m; C, 42.6 Ϯ 7.5; G, 80.4 Ϯ 22.3; NAG, 450 Ϯ 104; P Ͻ 0.05). Staining for VEGF correlated with CD-31 vessel counts (no./mm 2 : C, 53.1 Ϯ 16.1; G, 166 Ϯ 32; NAG, 183 Ϯ 32; P Ͻ 0.05 ). Tissue analysis showed treatment effects on tissue hyaluronan (g/g: C, 962 Ϯ 73; G, 1,169 Ϯ 69; NAG, 1,428 Ϯ 69; P Ͻ 0.05) and collagen (g/g: C, 56.9 Ϯ 12.0; G, 107 Ϯ 12; NAG, 97.6 Ϯ 11.4; P Ͻ 0.05) but not sulfated glycosaminoglycan. Transport experiments revealed no significant differences in mannitol transfer or osmotic flow. Changes were seen in hydrostatic pressure-driven flux (l ⅐ min Ϫ1 ⅐ cm Ϫ2 : C, 0.676 Ϯ 0.133; G, 0.317 Ϯ 0.124; NAG, 0.284 Ϯ 0.117; P Ͻ 0.05) and albumin transfer (l ⅐ min Ϫ1 ⅐ cm Ϫ2 : C, 0.331 Ϯ 0.028; G, 0.286 Ϯ 0.026; NAG, 0.229 Ϯ 0.025; P Ͻ 0.04). We conclude that alteration of the interstitial matrix correlates with diminished hydraulic conductivity and macromolecular transport.

Objectives Acute infection in an animal model of chronic peritoneal dialysis (PD) induces structural changes in the peritoneum and alters functional characteristics of transport. These changes may compromise observations of the chronic effects of dialysis solutions. To test the hypothesis that antibiotics would prevent acute infection without affecting transport and structural properties, we characterized the frequency of infection in our rat model of PD and examined whether the inclusion of antibiotics in the dialysis solution altered the transport and structural properties of the peritoneum. Design Female Sprague–Dawley rats were aseptically injected daily under gas anesthesia with 30 – 40 mL of a sterile solution for 2 months via a peritoneal catheter tunneled to a subcutaneous port. Solutions used were Krebs–Ringer bicarbonate (KRB) alone, KRB with antibiotics (cefazolin 200 mg/L and gentamicin 2 mg/L), KRB with 4% glucose, and KRB with both glucose and antibiotics. After 2 months, osmotic filtration and solute transport were assessed in each animal and peritoneal fluid was collected for bacterial culture. Angiogenesis was evaluated by quantitative image analysis of tissue sections stained with CD31. Tissue content of collagen, hyaluronic acid, and sulfated glycosaminoglycan was determined. Results Technique survival (successful PD for 2 months) and infection rate were comparable among all treated groups. There were no differences between the groups in transport properties. Structural changes were comparable between groups, with or without antibiotics. Conclusions Addition of antibiotics to the dialysis solution did not affect the transport characteristics of the peritoneum or the pathologic reaction of the tissue to the PD solution.

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