Plasma-lymph exchange and interstitial distribution volumes of charged macromolecules in the lung

Abstract

The plasma-lymph exchange of two lactate dehydrogenase (LDH) isozymes (4.2 nM) of different molecular charge between plasma (CP) and lung lymph (CL), their initial clearances across the capillary wall, and their extravascular distribution volumes were studied in dog lungs at control and increased left atrial pressures (Pla = 23.3 +/- 2.1 cmH2O). The anionic LDH 1 [isoelectric point (pI) = 5.0] exhibited a more rapid plasma decay compared with cationic LDH 5 (pI = 7.9) after bolus injection but was maintained relatively constant in several experiments using a constant infusion. The mean 10- to 12-min lung tissue clearances were 40% higher for LDH 5 than LDH 1 at control Pla and 120% higher at increased Pla. The CL/CP ratios of the anionic LDH 1 were consistently higher at 4-5 h after simultaneous injection than those of cationic LDH 5. However, the extravascular distribution volumes of LDH 5 were significantly higher in lymph equivalents than those of LDH 1 at 4 h in both Pla groups. Fixed negative charges located on endothelial cells, basement membrane, and interstitial matrix could explain the observed differences between LDH isozymes in CL/CP ratios, tissue uptake, and extra-vascular distribution volumes by the ionic interaction of LDH 5 with these negative change sites which would retard the plasma-lymph transport and enhance the extravascular distribution volume and initial clearance of these cationic macromolecules.

True

“…The charge-dependence in vascular permeability in tumours is consistent with observations in normal tissues (Jain, 1997;Curry et al, 1987;Turner et al, 1983;Vehaskari et al, 1984;Deen et al, 1980;Baldwin et al, 1991;Dermietzel et al, 1983;Adamson et al, 1988;Barrowcliffe et al, 1990;Gandhi and Bell, 1992;Gilchrist and Parker, 1985;Haraldsson et al, 1983;Khaw et al, 1991;Leypoldt and Henderson, 1993;Michel and Phillips, 1985;Öjteg et al, 1987;Parker et al, 1985;Rasio and Goresky, 1985;Triguero et al, 1989), suggesting the luminal surface of tumour vascular endothelium is negatively charged as well.…”

“…Thus, it restricts the extravasation of anionic macromolecules, as has been demonstrated in cultured endothelial cell monolayer (Sahagun et al, 1990) and various normal tissues (Jain, 1997;Curry et al, 1987;Turner et al, 1983;Vehaskari et al, 1984;Deen et al, 1980;Baldwin et al, 1991;Dermietzel et al, 1983;Adamson et al, 1988;Barrowcliffe et al, 1990;Gandhi and Bell, 1992;Gilchrist and Parker, 1985;Haraldsson et al, 1983;Khaw et al, 1991;Leypoldt and Henderson, 1993;Michel and Phillips, 1985;Öjteg et al, 1987;Parker et al, 1985;Rasio and Goresky, 1985;Triguero et al, 1989). Adamson et al (1988) have demonstrated that the microvascular permeability to α-lactalbumin (M r = 14 176, net charge -10) is approximately 50% of that to ribonuclease (M r = 13 683, net charge +4), suggesting that the microvascular permeability to the positively charged molecules is higher than the permeability to the negative ones.…”

Effects of polycations on pulmonary vascular permeability in conscious sheep.

“…Glomerular capillaries appear to clear anionic molecules more slowly than cationic molecules of very similar hydrodynamic radii (1). In contrast, in pulmonary mi-tated when compared with neutral dextran (2)(3)(4)(5). Since electron microscopic examinations have shown a distribution of anionic sites on the endothelial surface in both glomeruli and pulmonary microvessels (5-7), differences in transport of macromolecules based on molecular charge between these organs might be attributed to the charge and construction of the basement membranes and interstitium (4).…”

“…However, there are mounting data suggesting that molecular filtration is also influenced by the interaction of charges on the endothelial surface with charged circulating molecules (1)(2)(3)(4). Glomerular capillaries appear to clear anionic molecules more slowly than cationic molecules of very similar hydrodynamic radii (1).…”

Fate of aerosolized recombinant DNA-produced alpha 1-antitrypsin: use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance.

“…Second, when proteins are infused intravenously to experimental animals, they are readily detected in lung lymph and ELF (20,21,28,30,36). Furthermore, when a1-antitrypsin is infused intravenously to humans, the a1-antitrypsin is readily detectable in the lower respiratory tract ELF at levels -15% that achieved in plasma (37).…”