128 Lymphology 11 (1978) 128- 132 Anatomy of the Interstitial Tissue H. Haljamae, M.D., Ph. D. Departments of Anesthesiology I and Histology, Universi ty of Goteborg, Goteborg, Sweden - Summary Fibers Aspects on composition and function of the intersti­ Three types of fibers - collagenous, reticular tial tissue have been given. The glycosaminoglycans of and elastic ones, are present in the interstitium. the interstitium have at physiological pH a net nega­ tive charge and are osmotically active. They restrict These fibers are synthetized by mesenchymal free diffussion through the interstitium. The ground cells, fibroblasts, osteogenic and chondrogenic substance phase can be further subdivided in to a cells, and possibly also smooth muscle cells colloid-rich subphase and a colloid-poor subphasc. (elastic fibers; 1). Molecular collagen is secreted The latter seems to constitute the true tissue fluid phase of the interstitium. The functional importance from the cells into the interstitial ground sub­ of the interstitium on exchange processes between the stance, where it is polymerized to collagenous vascular and the cellular compartments is discussed. and reticular fibers (2). The reticular fibers Changes in aggregation and hydration of the ground form thin networks around cells and they are substance change the physico-chemical properties also closely related to basement membranes and the functional characteristics of the interstitium. and the stroma of e.g. lymphoid organs. Colla­ genous fibers of various dimensions are demon­ The interstitial compartment surrounds most strable in the interstitial phase of most tissues cells of the organism. It consists of fibrillar while the networks of elastic fibers are not so structures embedded in a tissue fluid contain­ common. The functional importance of the ing amorphous ground substance. The fluid various fibers is mainly mechanical support. volume of this compartment is approximately The isoelectric points of the fibrillar constituents three times that of plasma and the exchange lie between neutrality and pH 5.0 (3). Therefore, rate of fluid between these two extracellular at physiological pH the number of charged compartments is rapid. All substances that sites is small and the influence of these fibrillar are exchanged between blood and tissue cells structures on the distribution of other ions have to pass through the interstitium. The in­ relatively limited. terstitial content of acid macromolecular com­ ponents may be assumed to affect the com­ Ground substance position of the capillary filtrate reaching the The amorphous ground substance or gellike cells. An evaluation of the true environmen­ matrix of the interstitium is produced by the tal milieu of tissue cells therefore makes it same cell types as the fibrillar components. It necessary to take the physico-chemical proper­ contains several different glycosaminoglycans ties of these various interstitial components (mucopolysaccharides) the more common ones into consideration. Structural and functional of which are hyaluronic acid , chondroitin-4- aspects of the intersti tium will be dealt with sulphate, chondroitin-6-sulphate, dermatan in the following presentation. sulphate and keratan sulphate. The proportions The fundamental structure of the interstitial of the different glycosaminoglycans vary in the phase is schematically shown in Fig. I. The interstitium of various tissues. Hyaluronate is main components are fibers and the interstitial present in most places, while the chondroitin­ ground substance, which may be subdivided sulphates are mainly present in cartilage and into a colloid-rich and a water-rich phase. bone. The glycosaminoglycans are composed of repeat units of two diffe rent saccharides, 0024-7766/78 1600-0128 S 04.00 © 1978 Geo rg Thieme Publishers Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. Anatomy of the Interstitial Tissue 129 COLLOID-RICH THE INTER STIT IAL PH ASE ! ... • . CAPILLARY Fig. 1 Schematic presentation of the . anatomy of the interstitium. usually hexosamine and hexuronic acid. The disaccharide units contain charged anionic groups such as carboxylate and sulphate groups. The density varies from one (hyalurona­ te) to four (heparin) of these anionic groups per disaccharide unit. The mucopolysacchari­ des have low isoelectric points (between pH 2.0 and 3.0) and at physiological pH there is consequently a high density of negative colloidal charge wi thin the interstitial ground substance. It has been suggested, however, that the extent of aggregation of the polymers varies within the interstitium as schematically shown in Fig. 1. On the basis of this concept a colloid­ rich water-poor phase coexists with a water- Fig. 2 Density pf charged coll~id:U m_acromo ~ ecu l es rich colloid-poor phase (4). This hypothesis in the water-rich and the collo1d-nch mterstitial phases. predicts the existence of areas with highly ag­ gregated ground substance and a high negative Important functional effects of th~ coll~id~ charge density alternating with areas which phase are restriction of free diffuswn, bmdmg have a low content of disaggregated ground and immobilization of cations and anions, and su bstance and a low negative charge density involvement in ion-exchange reactions. It is (Figs. 1 and 2). In the highly aggregated areas obvious that the extent of these interstitial the charge density and the large domains of effects is dependent upon the degree of colloi­ the macromolecules will result in steric exclu­ dal aggregation and tissue hydration (Fig. 3). sion of other large molecules (5). Therefore, Oedema causes an increased hydration and it is considered that e.g. plasma proteins pas­ depolymerization of the ground substance. The sing the capillary walls will be mainly restrict­ result will be a decrease in the colloidal-depen- ' ed to a random network of interstitial channels dent restriction of free diffusion as well as in corresponding to the colloid-poor water-rich the binding capacity of cations (9). Tissue areas (6, 7, 8). The relative mobilities and the dehydration, on the other hand, increase~ the distribution of water as well as of small diffusilr colloidal density and thereby restricts free ble cations and anions in the interstitium will diffusion and increases the binding capacity of also be affected by the high negative charge cations ( 10) . density of the g1ycosaminog1ycan aggregates (3, 4). Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 130 H. Haljamae, M.D. Ph. D. CO NTROL OED EM I\ DEHYDRATI O N ----=----/ 4JI) . - ~ - - -· ~ ~ '-------. COL lOIDAl nf N~I lY • • IIH I Dtl , USION OSMOf iC flit CiS • ElECTROlYTES Fig. 3 Changes in inters tilial functio­ · ANION S • nal characteristics in commection with tissue oedema or dehydration. Interstitial tissue fluid Table I The distribution of electrolytes ( K, Na and The existance of an extracellular fluid repre­ Cl) and proteins between plasma (P) and interstitial tissue Ou id (TF ). (From ref. s. 11 , 12, 13 and unpub­ senting a mere dialysate of blood was questio­ lished data) ned already in 1960 by Gersh and Catchpole p ( 4). It seems reasonable to believe that the TF TF- P TF:P free fluid phase i.e. the colloid-poor water­ K mmol/1 4.67 3.78 +0.89 1.25 rich phase is the true interstitial fluid. This Na mmol/1 15 3 142 +11 L.08 Cl mmol/1 91.2 99.5 - 8.2 0.92 fluid phase will receive products from the vas­ Total protein 0.32 cular as well as from the intracellular compart­ Albumin 0.36 ments and its composition will be modified by Globulin 0.24 the equilibrium with the colloid-rich phase. It may be assumed that cellular membranes are tl13.11 1.0 aJld that of ens smaller than 1.0 mainly in contact with this movable fluid (Table 1). This higher content of K and Na in phase and tllis phase, therefo re, represents the tissue fluid is probably due to binding effects true environmental milieu of tissue cells. on cati ons caused by tile colloidal anionic Techniques for direct sampliJlg of nanoliter polyelectrolytes of the interstitium. The low quantities of this interstitial tissue fluid phase Cl con tent is consequently due to the presence have been developed ( 11 ) and the protein ( 12) of t11esc colloidal anionic polyelectrolytes. as well as the electrolyte (I 1, 13) composition The total protein content as well as the albumin: of the flu id has been studied using microme­ globulin ratio of tile sampled fluid are also in tllods (14, 15). agreement wi th hypothetical interstitial fluid The glycosaminoglycan content of this movable concentrations ( 12). tissue fluid phase is shown to be low in com­ Experimental data obtained from direct analy­ parison to that o bserved in fluid obtained from ses of sampled interstitial tissue flu id, therefore, in1planted capsules. The content in such implan­ are in agreement with the hypothesis that the ted capsules may be assumed to represent total coll oid-poor water-rich phase is the true environ­ interstitial content (13). The low content of mental mil ieu of the cells. The nu trients to and glycosaminoglycans in the fluid obtained witl1 metabolites from cells pass mainly through tllis the micropuncture techniques, therefore, phase , but the interplay with the colloid-rich favours the concept that it is a true representa­ phase prevents major fluctuations in the cellular tive for the colloid-poor water-rich interstitial milieu. Extensive loads of e.g. metabolites fluid phase. during tissue hypoxia are buffe red in the in­ The electrolyte content of tl1e interstitial flui d terstitium due to ionic binding to and ion-ex­ is also markedly different from a hypotlletical change reactions with the colloid-rich phase. ultrafiltrate of plasma. The tissue fluid : plasma This interplay between the two interstitial ratios of K+ and Na+ are consi derably large r phases may be considered as an important de- Permission granted for single print for individual use.