Blood-tissue Barriers Research Articles

Convection and permeation of albumin between plasma and interstitium

Nonequilibrium thermodynamics is combined with compartmental analysis to interpret albumin sieving and tracer experiments in terms of a permeability-surface product PS (permeation) and a solvent drag reflection coefficient σ f (convection) for various blood-tissue barriers. The human whole-body albumin data of Lassen, Parving, and Rossing ( Lassen, Parving, and Rossing, Microvasc. Res. 7, i–iv (1974) ), modified for nonliver tissues by Johnson and Levitt ( Johnson & Levitt, Microvasc. Res. 9, 141 (1975) ) lead to P ∼ 1.8 × 10 −8 cm sec −1 (based on a surface area per unit plasma volume of 700 cm −1) and to σ f ∼ 0.9, which imply, in agreement with Johnson and Levitt, that permeation is the dominant nonliver blood-tissue transport mechanism for albumin in the normal resting human. Similar values are derived from the dog paw muscle data of Garlick and Renkin ( Garlick and Renkin, Amer. J. Physiol. 219, 1595–1605 (1970) ). The Casley-Smith ( Casley-Smith, Microvasc. Res. 9, 43–48 (1975) ) mechanism of uphill albumin transport is verified as possible. It is tentatively inferred that lymph formation in resting tissue does not result from a small difference between a large fluid (volumetric) filtration and an almost equally large fluid reabsorption, either in the same capillary (Starling) or between different capillaries (Zweifach) ( Zweifach, Circ. Res. 34, 858–866 (1974) ). Rather, reabsorption is negligibly small relative to filtration, and lymph flow is comparable to volumetric filtration.

A theoretical study of restricted convection-diffusion as applied to blood-tissue barrier exchange.

This paper handles a model of the capillary function in the exchange of uncharged molecules between the blood and the tissue. The capillary system is subdivided into a filtering and a reabsorbing part. The exchange is assumed to occur through channels which are described in operational terms as pores. Through these pores there is a transport of solutes by concomitantly acting convection and diffusion influenced by a steric hinderance (restricted convection-diffusion). The outflux of glucose and raffinose is enhanced in the filtering pores, raffinose relatively more than glucose. In the reabsorbing pores the outward diffusion is hindered to some extent, raffinose relatively more than glucose. It is shown that the net effect of filtration and reabsorption is to increase the outflux of raffinose as compared to that of glucose. This mechanism may explain why glucose and raffinose and other small molecules appear to pass across capillary walls in proportion to their free diffusion coefficients and not in proportion to their restricted diffusion coefficients.

Delayed equilibrium of pituitary triiodothyronine (T3) following an acute T3 administration.

To reconcile the knowledge on tissue T3 concentration with cellular metabolism regulatory mechanism of thyroid hormone secretion, the pattern of the change of tissue T3 concentration following an acute administration of T3 was studied in mice. Basal T3 concentration in serum, liver, brain and pituitary was 61, 173, 198 and 1630ng/100g, respectively. After 0.5 mug T3 dose, T3 concentration in serum and liver reached the maximum level 1 to 3 hrs following the administration and decreased exponetially thereafter, thus, maintaining almost constant tissue/plasma T3 ratio. In contrast, T3 increase in brain or pituitary was far delayed, not until 7 to 12 hrs following T3 injection, and then decreased parallel to that in serum. Furthermore, the magnitude of increase in pituitary T3 was limited when compared to that in liver. Thus, tissue/plasma T3 ratio in pituitary decreased markedly after the dose of T3. This finding suggests the possibility that there is blood-brain barrier or blood-tissue barrier for the transport of T3 in pituitary or brain, resulting in delayed equilibrium with that in serum. These results may also explain the delay of inhibition of TRH-induced TSH release after single dose of T3 as recently reported by Azizi et al. (1975).

Electron microscopic study on the hepatic sinusoidal wall and the fat-storing cells in the normal human liver.

In normal human livers obtained in surgical operations the sinusoidal wall has been observed with the electron microscope.The “endothelial cells” and the “Kupffer cells” lining the sinusoid are regarded as two functional states of the same cell lineage and show alike the ultrastructures suggesting phagocytic activity. They differ from each other especially in that the endothelial cells consist of two distinct portions, the perikaryon and the sheet-like cytoplasmic extension, the latter occupying the major part of the sinusoidal lining, while the Kupffer cells are of simple rounded-up form bulking into the sinusoidal lumen; the endothelial cell sheets extend to the Kupffer cell body to contact with the latter. On the other hand, the marginal ends on the neighboring endothelial sheets may overlap like roof tiles. In both connections there occur no functional structures like terminal bars and desmosomes.The endothelial lining of the sinusoid which is discontinuous because of the presence of intracellular gaps or pores and lacking in general in continuous basement membrane, is as a rule a simple layer. Frequent figures of stratified endothelial sheets are caused for the most part by the occurrence of subendothelial fat-storing cells which extend thin processes as if to reinforce the endothelial lining. The perisinusoidal or Disse's space is filled with blood plasm filtered through the discontinuous endothelial lining of the sinusoid. This space which represents the blood-tissue barrier of the liver contains, besides abundant microvilli of the hepatocytes and collagen or reticular fibers and fibrils, fat-storing cells, unmyelinated nerve fibers with their Schwann cells and occasional round, probably hemopoietic cells. The fat-storing cells are constant residents in the Disse's space and frequently extend into the recesses between the hepatocytes. They are lacking in their own basement membrane and contact directly with the collagen fibers, which are sometimes embraced in the invaginations of their plasma membrane. They send out a considerable number of cytoplasmic processes in the Disse's space which interlace with the microvilli of the hepatocytes. Close contacts between the even surfaces of the fat-storing cells and of the hepatocytes are occasionally encountered.The fat-storing cells possess relatively well-developed Golgi complex containing a diplosome, sparse small mitochondria, fairly well-developed elements of granular endoplasmic reticulum, small lysosomes, glycogen particles and, occasionally, a single cilium into the Disse's space which arises from one of the paired centrioles of the diplosome. Though the fat-storing cells exhibit no cytological signs indicating a phagocytic activity, many invaginations of the plasma membrane and vesicles including the bristle-coated ones are found along their free surfaces suggesting a vigorous pinocytotic activity. As constant and characteristic cytoplasmic inclusion bodies, the fat-storing cells contain small fat droplets, each of which (about 2μ in diameter) is bounded by a weak limiting membrane and does not fuse with each other into larger ones. The fat-storing cells may occasionally contain no fat droplets; the “pericytes” observed by some authors in the Disse's space, probably correspond to these empty fat-storing cells.The following possible functions of the fat-storing cells are proposed: 1) Fat synthesis and fat-droplet formation, 2) the storing of fat droplet and fat-soluble vitamin A, 3) the participation in intralobular fibrilogenesis and 4) the reinforcement of the endothelial lining of the sinusoid by sending subendothelial processes.

The role of PMN-leukocyte lysosomes in tissue injury, inflammation and hypersensitivity: I. The vascular changes and the role of PMN-leukocytes in the reversed passive arthus reaction

The vascular changes in the reversed passive Arthus reaction were examined with light, immuno-fluorescent, and electron microscopy. A comparison with the direct Arthus reaction showed both similarities and dissimilarities. In the reversed passive reaction, the primary site of antigen-antibody interaction is in the wall of venules, and PMN-leukocytes accumulate at these sites. Intravascular changes consist of platelet aggregation thrombosis and stasis, but immune complexes are rarely seen intravascularly. The significant pathogenetic factor in the reversed Arthus reaction, as in the direct one, is the accumulation of PMN-leukocytes at sites where antigen-antibody complexes precipitate, followed by phagocytosis of the complexes and degranulation of the leukocytes. Considerable indirect evidence indicates that hydrolytic enzymes, primarily proteases, released from the granules (lysosomes) of the PMN-leukocytes mediate the delayed-prolonged phase of increased vascular permcability, as well as the edema and the hemorrhage. The significance of the liberation of these lysosomal hydrolases at a strategic site, namely at the blood tissue barrier, is stressed. Circumstantial evidence points to an early, humoral “anaphylactic” phase which precedes the delayed-prolonged or “Arthus” phase.

Self and Not-Self a Clonal Induction Approach to Immunology

This new approach to immunology engenders a unified conception of embryogenesis, cellular differentiation, mitotic- and growth-control, carcinogenesis, autoimmunity, and aging. The primary and intrinsic function of the complex lymphoid system is postulated to be the central regulation of the growth and size of target tissues throughout the body. Where tissues are normally freely infiltrated by small lymphocytes, these cells, bearing specific "mitotic control proteins" (MCPs), constitute the effectors of symmetrical mitosis; where target tissues are located behind a blood-tissue barrier, specific humoral MCPs (possibly a2 -macroglobulins) constitute the mitogenic effectors. The protein component of "tissue coding factors" (TCFs) on cell membranes identifies the target tissue, while the secretion of TCFs from target cells, and their passage to regional lymph nodes via afferent lymphatics, constitutes the afferent signal in the feedback control circuit. Symmetrical mitosis is normally inhibited by the specific contact relations between stem or parent cells of similar differentiation bearing similar TCFs. These views are supported by an analysis of spontaneous disturbed-tolerance autoimmunity. This analysis indicates that the molecular basis of "self-recognition" is the identity of some or all of the polypeptide chains of lymphoid MCPs and their corresponding target tissue TCFs. London-van der Waal's "self-recognition" forces account for the specificity of interactions in the central feedback control of symmetrical mitosis. In spontaneous autoimmunity, a special form of gene "mutation" in lymphoid mitotic control stem cells converts an MCP into a autoantibody (cell-bound or humoral) with a complementary and pathogenic relationship to its associated TCF. The connection between lymphoid MCPs and immunoglobulins is discussed, and a new theory is presented of the classical immune response, and of immunological paralysis.

Autoradiography of whole animals as an experimental tool in pharmacological research.

Pharmacology is the study of drugs and their action on living systems. Elucidation of the mechanism of drug action frequently requires information on distribution patterns, metabolic fate, and excretion. The widely used method for the study of these processes involves sacrificing the animal by exsanguination or otherwise, dissecting out the organs of interest at room temperature, and homogenization, followed by assay for the drug and its metabolites by appropriate method. This approach suffers from certain limitations. The technique of whole-body autoradiography developed in Sweden by Ullberg and colleagues [1] seems to offer several advantages over the conventional method and is particularly suited for the study of the fate of radioisotopically labeled substances in experimental animals in the following respects: (1) It makes it possible to study the relative distribution of the drug in all the areas of the body rather than in just a few conveniently isolable organs, which is the case with the conventional method. (2) The secondary changes that may result in the period of dissection at room temperature are considerably minimized. (3) Short-time studies which cannot be done with any degree of assurance using the conventional method can easily be performed by the method of whole-body autoradiography. (4) It shows the blood-tissue barriers to drugs when such barriers exist and indicates the various excretory pathways. (5) Most important of all is the fact that it brings out facets which are often not apparent when conventional methods are employed, since all areas are revealed in the same experiment with or without conscious selection.

On the theory of blood-tissue exchange of inert gases: VI. Validity of approximate uptake expressions

It is shown that the equation of inert gas uptake by a distinct parallel tissue-blood arrangement coincides, under certain conditions, with two formulations which neglect the possible existence of a blood-tissue barrier. The first of these approximations is the classic von Schrotter equation in continuous form, whereas the second is the empirical one frequently used by contemporary authors. The condition for coincidence is that the product of permeability and blood-tissue exchange surface greatly exceed the rate of blood flow to the tissue. It is difficult to examine this condition at present because of a dearth of gas permeability measurement and because apparently there exist no measurements of surface and flow on the same tissue. A compilation is made of such values as are available, and it is found that on the assumption that gas permeabilities are of the order of 1×10−3 cm sec−1, the conditions for neglecting the blood-tissue barrier may be met in many cases and certainly not met in many others. It is concluded that under these circumstances the more exact equations, taking into account the barrier, should be employed, at least until precise independent measurements justifying the approximations become available.