Exchange of macromolecules between plasma and peritoneal cavity in ascites tumor-bearing, normal, and serotonin-injected mice.
Fluorescein-labeled dextrans (FITC-D) from 3 to 5000 kDa (Stokes' radii from 1 to 40 nm) were used to study influx from the plasma into the peritoneum and efflux from the peritoneal cavity into the plasma in normal and ascites tumor-bearing mice and in mice whose peritoneal vessels had been rendered hyperpermeable by serotonin. Two syngeneic transplantable murine ascites tumors were studied: mouse ovarian tumor and the TA3/St breast adenocarcinoma. To control for effects of peritoneal fluid volume, influx and efflux were also analyzed in mice that had received 5 ml of 5% bovine serum albumin i.p. as "artificial ascites." Following i.v. or i.p. injection, levels of FITC-D in the plasma and peritoneal fluid were quantitated by fluorimetry at successive time intervals from 5 to 360 min posttracer injection. Influx and efflux data were analyzed with a model consisting of three compartments (plasma, peritoneal cavity, and the extravascular space of all other organs) to yield kinetic parameters that characterized macromolecular transport. Depending on the size of the FITC-D tracer, from 3- to 50-fold more FITC-D accumulated in mouse ovarian tumor or TA3/St tumor ascites fluid, and 3- to 10-fold more FITC-D accumulated in the peritoneum of serotonin-treated than normal mice, all of it intact by gel exclusion chromatography. Influx of the FITC-D from plasma into the peritoneum, as characterized by the rate constant k1, was 2- to 40-fold greater in ascites tumor-bearing animals and 2- to 10-fold greater in serotonin-treated animals than in controls. Control animals with artificial ascites showed at most a 4-fold increase in the value of k1. As judged by fluorescence microscopy, the permeability of peritoneal-lining vessels in ascites tumor-bearing animals was greatly increased to FITC-D of 70 to 5000 kDa. Efflux of FITC-D, characterized by the rate constant k2, was reduced from 5- to 50-fold in ascites tumor-bearing animals but was unchanged or actually somewhat enhanced following serotonin treatment. Efflux in animals that had received artificial ascites was reduced 2.5- to 12.5-fold, correlating increased peritoneal fluid volume with decreased efflux. We conclude that tracer accumulation in malignant ascites fluid results from both increased influx as well as impaired efflux. Influx, and to a lesser extent efflux, were significantly affected by tracer size. However, within the range of FITC-D tested, we found no absolute size barrier to macromolecular transport from plasma to the peritoneal cavity, or vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)
Nagy
J A
JA
Department of Pathology, Beth Israel Hospital, Boston, Massachusetts 02215.
Herzberg
K T
KT
Masse
E M
EM
Zientara
G P
GP
Dvorak
H F
HF
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism; D000818:Animals; D001201:Ascites / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D003911:Dextrans / Q000097:blood / Q000378:metabolism*; D005260:Female; D019793:Fluorescein; D005452:Fluoresceins; D051379:Mice; D008970:Molecular Weight; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism; D010529:Peritoneal Cavity / Q000378:metabolism*; D010537:Peritoneum / Q000098:blood supply / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology
D003911:Dextrans; D005452:Fluoresceins; D012701:Serotonin; D019793:Fluorescein