Transport of macromolecules across microvascular walls: the two-pore theory

Abstract

In this review we summarized the evidence favoring the concept that the major plasma proteins are passively transported across vascular walls through water-filled pathways by means of convection and diffusion. With regard to solute transport, a majority of microvascular walls seems to show a bimodal size selectivity. This implies the presence of a high frequency of functional small pores, restricting proteins, and an extremely low number of non-size-selective pathways, permitting the passage of macromolecules from blood to tissue, here denoted large pores. We discussed the general behavior of such a heteroporous system. A major consequence of two-pore heteroporosity is that large-solute transport must mainly occur due to convection through large pores at low filtration rates, that is, at normal or even zero lymph flows. Indeed, convection must be the predominating transport mode for most solutes across large pores when the net filtration rate is zero. Under these (transient) conditions, the convective leak of macromolecules across large pores will be counterbalanced by absorption of essentially protein-free fluid through protein-restrictive pores. In a heteroporous membrane, proteins can thus be transported by solvent drag across vascular walls in the absence of a net convection. Normally the steady-state transcapillary fluid flow (lymph flow) is about equally partitioned among small and large pores, which makes lymph essentially a "half and half" mixture of protein-free ultrafiltrate and plasma. With increasing fluid flows, however, the plasma filtrate will be progressively diluted, eventually reaching a protein concentration largely in proportion to the fractional hydraulic conductance accounted for by the large pores (alpha L). Under these high lymph flow conditions, not only the large-pore transport but also the small-pore transport (of smaller macromolecules) will become convective. At low lymph flows, however, the small-pore transport of smaller macromolecules is usually mostly diffusive. An important implication of capillary heteroporosity is that single-pore formalism is inadequate for correctly evaluating the capillary sieving characteristics. With the use of homoporous transport formalism, the "lumped" macromolecular PS and sigma will therefore vary as a function of transcapillary fluid flow (Jv). However, it is approximately correct to use single-pore formalism for conditions when Jv is very high during steady state. Thus, if minimal sieving coefficients can be measured for macromolecules, then these values will accurately reflect (1 - sigma).(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma volume expansion of 5% albumin, 4% gelatin, 6% HES 130/0.4, and normal saline under increased microvascular permeability in the rat

“…An increase in transcapillary leakage of macromolecules at increased permeability is compatible with the 2-pore theory of transcapillary fluid exchange [21]. According to this theory, fluid and smaller solutes pass the capillary membrane through all pores along the entire microvascular bed, whereas macromolecules pass the capillary membrane only through the 10-30 ×10 3 times less common larger pores present in venules and at the venous side of the capillary network.…”

“…According to this theory, fluid and smaller solutes pass the capillary membrane through all pores along the entire microvascular bed, whereas macromolecules pass the capillary membrane only through the 10-30 ×10 3 times less common larger pores present in venules and at the venous side of the capillary network. The transcapillary/transvenular hydrostatic pressure is the only force responsible for fluid flow through the large pores, as the oncotic pressure across these pores is virtually zero [21]. This means that the macromolecules are lost to the interstitium mainly through convection by following the large-pore fluid flux, while the diffusion force is of less importance [21].…”

“…The transcapillary/transvenular hydrostatic pressure is the only force responsible for fluid flow through the large pores, as the oncotic pressure across these pores is virtually zero [21]. This means that the macromolecules are lost to the interstitium mainly through convection by following the large-pore fluid flux, while the diffusion force is of less importance [21]. This hypothesis means that there is always a continuous leakage of macromolecules (normal transcapillary escape rate) and even a minute increase in total pore area via the large pores may cause a substantially greater loss of macromolecules.…”

“…However, the plasma expanding effect of colloids is transient due to a continuous clearance from the circulation related to the rate of degradation, renal and gastrointestinal losses, and due to a continuous leakage of macromolecules into the interstitial space [16]. According to the modern 2-pore theory of transvascular exchange [21], transcapillary leakage of macromolecules occurs through the large pores of the capillary/venular membrane and is compatible with the view that it is greater at increased permeability than at normal permeability. Except size and number of the large pores, transcapillary leakage may also be influenced by charge of the molecules and their interaction with glycocalyx and other endothelial structures [22,23].…”

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

“…Sizeselective properties can be described by using a two-pore model with experimental fractional clearances for Ficolls with a molecular radius range of 12-70 Å. In brief, the exchange was estimated using the following parameters: the functional small-and large-pore radii, the large-pore fraction of the glomerular filtrate, and the unrestricted area divided by diffusion distance [33]. By using a non-linear regression analysis and a previously defined set of physiological equations [8], model parameters were fitted to the experimental fractional clearances for neutral Ficolls (12-70 Å).…”