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Is the extracellular matrix an integral and dynamic component of the sodium and water homeostatic system?
Medical Hypotheses 0306
Medical fiyporheses (1990) 33, 197- 199 0 Longman Group UK Ltd 1990
9877/90/0033
- 0197/110.00
Is the Extracellular Matrix an Integral and Dynamic Component of the Sodium and Water Homeostatic System? I.J. LLOYD Department
of Chemical
Pathology,
Old Medical
School,
University
of Leeds,
Leeds LS2 9JT,
UK
Abstract - This hypothesis questions the validity of Starling’s hypothesis regarding the distribution of water and electrolytes between the intravascular and interstitial compartments. It emphasises the potential importance of the gel state of the extracellular matrix in determining interstitial compliance and the distribution of water and electrolytes between the intravascular and interstitial compartments. Because the physicochemical properties of the extracellular matrix can change rapidly in response to numerous stimuli, it is suggested that the extracellular matrix is an integral and dynamic component of the sodium homeostatic system.
Introduction
Recently three papers appeared in one issue of the Lancet
but is imbibed by a heterogenous gel-like matrix of collagen, elastin proteoglycans and glycoproteins (see 4) has grown up. It seems surprising that Starling’s hypothesis still exerts such an influence on our thinking and that so little attention has been paid to the involvement of the extracellular matrix (ECM) in sodium and water metabolism.
The extracellular matrix (ECM) The ECM consists of a highly organised network of collagen and elastin fibres embedded in the interfibrillar matrix (IFM), and it appears that the properties of these three components are interdependent (see 5). It is relevant that these properDate received 28 December 1989 Date accepted 19 January 1990
197
198 ties will have a profound effect on the compliance of the ECM, which in turn will influence the distribution of water and electrolytes between the intra and extravascular compartments (6). The IFM consists largely of proteoglycan aggregates, hyaluronate and glycoproteins (7). It is also considered to be heterogeneous, consisting of colloidrich-water-poor and colloid-poor-water-rich regions (8). The proteoglycan aggregates form hydrated gels which show a high degree of order. The system is also highly dynamic (6, 8, 9), the phases being able to respond rapidly, presumably to physiological demands, through changes in the degree of aggregation and conformational changes in the component macromolecules. There is no doubt that the glycosaminoglycan (GAG) composition of the proteoglycan aggregates and the degree of aggregation determine many of the hydrodynamic properties of the IFM. These sulphated polysaccharides, by virtue of their high negative charge and ion selectivity, will influence the ionic composition of the IFM (8). For example, it has been shown that the potassium content of the ECM of cartilage is fourteen times higher than that of plasma and similar differences have been demonstrated for sodium, calcium and magnesium (8). Similarly, the sodium content of arterial tissue is considerably higher than that of plasma (10). It has also been shown that the binding of cations and organic molecules can cause large changes in free energy and result in changes in tonic balance (8). It is evident therefore that the ECM, and the IFM in particular, must be a major determinant of the total body capacity for sodium and water and the distribution of fluid and electrolytes between the intravascular and interstitial compartments (for further general discussion of the ECM and references see 1 1 - 13).
Sodium and GAG metabolism Work in this laboratory has recently demonstrated: 1) that increasing dietary sodium in rats increases (+ 48%, P <0.05) the urinary excretion of GAG’s (a marker of the metabolism of the IFM), and also the incorporation of 35S04 (+ 38% P <0.02) into skin (14). (35SO4 incorporation is a marker of the rate of synthesis of sulphated GAG’s); 2) that doubling the dietary sodium in man also causes a significant increase (+ 88%, P <0.05) in urinary GAG’s (15, 16); 3) that in congestive cardiac failure there is an increased (+ 37% P <0.05) urinary excretion of GAG’s and
MEDICAL
HYPOTHESES
an alteration in the electrophoretic pattern of the excreted GAG’s (15, 16); 4) that Atriopeptin II reduces the incorporation of 3sSO4 into aortic tissue in long term (-15% P <0.02) in vitro incubations using tissue culture techniques (to be published). From the above discussion it would appear that there is a high probability that the ECM is an integral and dynamic component of sodium and water homeostatic mechanism in which the GAG’s have a prominent function. It could be argued that physiological and pathological influences which affect sodium and water homeostasis bring about physicochemical changes in the ECM. It is known that physical forces, haemodynamic pressure changes, alterations in the micro-ion and micromolecular environment, growth factors, systemic hormones and neurohumoral transmitters influence the properties of the ECM. This may explain the observation that oedema has been seen in some patients with car pulmonale without weight gain and little sodium retenti,ni (17). A change in the properties of the IFM could have resulted in the release of sodium and water that had previously been bound to the macromolecule components of the IFM. Likewise, it may explain why in some models of cirrhosis sodium retention antedates the formation of ascites and oedema (18). Firth et al (3) have pointed out the difficulty of explaining how increased renal interstitial pressure secondary to raised venous pressure can in some circumstances lead to increased, and in other circumstances to decreased, sodium excretion. The extracellular electrolyte environment influences a number of different electrolyte transport pathways and hence the intracellular ion composition (19, 20). The ECM would be expected to modulate the extracellular electrolyte environment through its ion-binding, ion-exchange characteristics and the resnonse of the macromolecular complex (which-determines these) to physiological controlling influences. Joseph et al (21) have proposed that the distribution of cations at any charged interface depends upon the distribution of colloid charge, on the dielectric constants of the various phases (extra- and intracellular) and on the hydration energies and sizes of the ions. Redistribution of ions would depend upon changes of colloid charge, on the states of aggregation and on the changes of concentrations of various metabolites. Thus differences in the physicochemical properties of the renal interstitium (ECM) may help to explain the difficulty outlined by Firth.
THE EXTRACELLULAR
MATRIX AS A COMPONENT OF THE SODIUM AND WATER HOMEOSTATIC SYSTEM
Harris (2) drew attention to the fact that the same neuro-renal-endocrine systems are being pursued with equal enthusiasm by those investigating the pathogenesis of oedema formation and of arterial hypertension. It is pertinent that some workers have drawn attention to the possibility that the ECM may be playing an important pathophysiological role in the development and maintenance of arterial hypertension (6, 22). From the above discussion on the role of the ECM in sodium metabolism it could be reasoned that the ECM is the link between sodium and hypertension. It may now be worth considering whether we should include this additional factor, the ECM and the IFM in particular, into our model of electrolyte and water homeostasis and include it in our conceptual thinking about the subject.
7.
8.
9.
10.
11.
12. 13.
14.
Conclusion It is suggested that Starling’s hypothesis (1886) is no longer adequate to explain the distribution of water and electrolytes between the intravascular and interstitial compartments. The interstitial space under most circumstances is in the gel and not the sol state. The physicochemical properties of this gel must be expected to play a major role in determining the distribution of water and electrolytes between these two compartments. In addition the physicochemical properties of the gel change rapidly in response to many physiological stimuli. Thus it is likely that this gel, ie. the ECM and in particular the IFM, is an integral and dynamic component of the electrolyte and water homeostatic mechanisms.
15.
16.
17.
18.
References 1. Anonymous.
2. 3.
4.
5.
6.
What causes oedema (Editorial). Lancet 1988; i: 1028 - 1030. Harris P. Role of arterial pressure in the oedema of heart disease. Lancet 1988; i: 1036- 1038. Firth JD, Raine AEG, Ledingham JGG. Raised venous pressure: a direct cause of sodium retention in oedema. Lancet 1988: i: 1033 - 1035. Brace RA. Progress towards resolving the controversy of positive Vs. negative interstitial fluid pressure. Circ Res 1981; 41: 281-297. Minns RJ, Steven FS. The effect of calcium on the mechanicaf behaviour of aorta media efastin and collagen. Brit J Exp Path 1977; 58: 572- 579. Ffoyer MA, Lucas J, Morris DV. Interstitial tissue compfi-
19.
20.
21.
22.
199
ante in the genesis of hypertension. Contr Nepherof 1977; 8: 95-99. Hay ED. Extracellular Matrix. J Cell Biol 1981; 91: 2055 - 2235. Gersh I, Catchpole HR. The nature of ground substance of connective tissue. Perspectives in Biology and Medicine 1960; 3: 282-319. Catchpole HR. Capillary permiability. In inflammatory nrocess vol 2. Eds Zweifach et al. Acad Press NY 1982; i21-127. Pafaty V, Gustafson BK, Friedman SM. Sodium binding in the arterial wall. Canad J Physiof Pharmacol 1969; 47: 763 - 770. Comper WD, Laurent TC. Physiological function of connective tissue polysaccharides. Physiol Rev 1978; 1: 255-315. Iozzo RV. Proteogfycans: structure, function and role in neoplasia. Lab Invest 1985; 4: 373 - 396. B&elf MJ, Barcellos-Hoff. The influence of extracellular matrix on gene expression: is structure the message? J Cell Sci 1987; suppf 8 327-343. Lloyd IJ, Weston R. Dietary sodium and glycosaminoglycan metabolism: is the extracellular matrix involved in sodium homeostasis. In Kimchi A, Lewis BS Eds. Abstracts 1st International Symposium on Heart Failure Mechanisms and Management. Jerusalem. International Society and Federation of Cardiology. 1989, 3 I. Lloy IJ, Weston R, Henderson AH, Mulligan I. Pickering B. Urinary glycosaminogfycan extretion in man during altered sodium intake and during congestive cardiac failure. Is the extracellular matrix involved in sodium metabolism. In Kimchi K, Lewis BS Eds. Heart Failure - Mechanisms and Management. Springer-Verlag FRG (In Press). Lloyd IJ, Weston R, Henderson AH, Mulligan I. Urinary gfycosaminogfycan excretion in man during altered sodium intake and during congestive cardiac failure. Is the extracellular matrix involved in sodium metabolism. In Kimchi A, Lewis BS Eds. Abstracts 1st International Symposium on Heart Failure - Mechanisms and Managements. Jerusalem. International Society and Federation of Cardiology. 1989. 46. Campbell RHA, Brand HL, Cox JR, Howard P. Body weight and body water in chronic car pufmonale. Clin Sci Mof Med 1975; 49: 323 - 335. Levy M, Affotey JBK. Temporal relationship between urinary salt retention and altered systemic haemodynamics in dogs with experimental cirrhosis. J Lab Clin Med 1978; 92: 560 - 569. VanBreeman C, Aaronson P, Lontzenfiser R. Sodium-calcium interactions in smooth muscle. Pharma Rev 1979; 30: 167 - 208. Bfaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension. A reassessment and hypothesis. Amer J Physiol 1977; 232: cl65 - 173. Joseph NR, Engef MB, Catchpole HR. Distribution ot sodium and potassium in certain cells and tissues. Nature 1961; 4794: 1175-1178. Lloyd IJ. Extracellular matrix in hypertension: the link between renal function, anteregulation and sodium metabolism: a review and hypothesis. Med Hypothesis 1985; 18: 169- 187.
Medical fiyporheses (1990) 33, 197- 199 0 Longman Group UK Ltd 1990
9877/90/0033
- 0197/110.00
Is the Extracellular Matrix an Integral and Dynamic Component of the Sodium and Water Homeostatic System? I.J. LLOYD Department
of Chemical
Pathology,
Old Medical
School,
University
of Leeds,
Leeds LS2 9JT,
UK
Abstract - This hypothesis questions the validity of Starling’s hypothesis regarding the distribution of water and electrolytes between the intravascular and interstitial compartments. It emphasises the potential importance of the gel state of the extracellular matrix in determining interstitial compliance and the distribution of water and electrolytes between the intravascular and interstitial compartments. Because the physicochemical properties of the extracellular matrix can change rapidly in response to numerous stimuli, it is suggested that the extracellular matrix is an integral and dynamic component of the sodium homeostatic system.
Introduction
Recently three papers appeared in one issue of the Lancet
but is imbibed by a heterogenous gel-like matrix of collagen, elastin proteoglycans and glycoproteins (see 4) has grown up. It seems surprising that Starling’s hypothesis still exerts such an influence on our thinking and that so little attention has been paid to the involvement of the extracellular matrix (ECM) in sodium and water metabolism.
The extracellular matrix (ECM) The ECM consists of a highly organised network of collagen and elastin fibres embedded in the interfibrillar matrix (IFM), and it appears that the properties of these three components are interdependent (see 5). It is relevant that these properDate received 28 December 1989 Date accepted 19 January 1990
197
198 ties will have a profound effect on the compliance of the ECM, which in turn will influence the distribution of water and electrolytes between the intra and extravascular compartments (6). The IFM consists largely of proteoglycan aggregates, hyaluronate and glycoproteins (7). It is also considered to be heterogeneous, consisting of colloidrich-water-poor and colloid-poor-water-rich regions (8). The proteoglycan aggregates form hydrated gels which show a high degree of order. The system is also highly dynamic (6, 8, 9), the phases being able to respond rapidly, presumably to physiological demands, through changes in the degree of aggregation and conformational changes in the component macromolecules. There is no doubt that the glycosaminoglycan (GAG) composition of the proteoglycan aggregates and the degree of aggregation determine many of the hydrodynamic properties of the IFM. These sulphated polysaccharides, by virtue of their high negative charge and ion selectivity, will influence the ionic composition of the IFM (8). For example, it has been shown that the potassium content of the ECM of cartilage is fourteen times higher than that of plasma and similar differences have been demonstrated for sodium, calcium and magnesium (8). Similarly, the sodium content of arterial tissue is considerably higher than that of plasma (10). It has also been shown that the binding of cations and organic molecules can cause large changes in free energy and result in changes in tonic balance (8). It is evident therefore that the ECM, and the IFM in particular, must be a major determinant of the total body capacity for sodium and water and the distribution of fluid and electrolytes between the intravascular and interstitial compartments (for further general discussion of the ECM and references see 1 1 - 13).
Sodium and GAG metabolism Work in this laboratory has recently demonstrated: 1) that increasing dietary sodium in rats increases (+ 48%, P <0.05) the urinary excretion of GAG’s (a marker of the metabolism of the IFM), and also the incorporation of 35S04 (+ 38% P <0.02) into skin (14). (35SO4 incorporation is a marker of the rate of synthesis of sulphated GAG’s); 2) that doubling the dietary sodium in man also causes a significant increase (+ 88%, P <0.05) in urinary GAG’s (15, 16); 3) that in congestive cardiac failure there is an increased (+ 37% P <0.05) urinary excretion of GAG’s and
MEDICAL
HYPOTHESES
an alteration in the electrophoretic pattern of the excreted GAG’s (15, 16); 4) that Atriopeptin II reduces the incorporation of 3sSO4 into aortic tissue in long term (-15% P <0.02) in vitro incubations using tissue culture techniques (to be published). From the above discussion it would appear that there is a high probability that the ECM is an integral and dynamic component of sodium and water homeostatic mechanism in which the GAG’s have a prominent function. It could be argued that physiological and pathological influences which affect sodium and water homeostasis bring about physicochemical changes in the ECM. It is known that physical forces, haemodynamic pressure changes, alterations in the micro-ion and micromolecular environment, growth factors, systemic hormones and neurohumoral transmitters influence the properties of the ECM. This may explain the observation that oedema has been seen in some patients with car pulmonale without weight gain and little sodium retenti,ni (17). A change in the properties of the IFM could have resulted in the release of sodium and water that had previously been bound to the macromolecule components of the IFM. Likewise, it may explain why in some models of cirrhosis sodium retention antedates the formation of ascites and oedema (18). Firth et al (3) have pointed out the difficulty of explaining how increased renal interstitial pressure secondary to raised venous pressure can in some circumstances lead to increased, and in other circumstances to decreased, sodium excretion. The extracellular electrolyte environment influences a number of different electrolyte transport pathways and hence the intracellular ion composition (19, 20). The ECM would be expected to modulate the extracellular electrolyte environment through its ion-binding, ion-exchange characteristics and the resnonse of the macromolecular complex (which-determines these) to physiological controlling influences. Joseph et al (21) have proposed that the distribution of cations at any charged interface depends upon the distribution of colloid charge, on the dielectric constants of the various phases (extra- and intracellular) and on the hydration energies and sizes of the ions. Redistribution of ions would depend upon changes of colloid charge, on the states of aggregation and on the changes of concentrations of various metabolites. Thus differences in the physicochemical properties of the renal interstitium (ECM) may help to explain the difficulty outlined by Firth.
THE EXTRACELLULAR
MATRIX AS A COMPONENT OF THE SODIUM AND WATER HOMEOSTATIC SYSTEM
Harris (2) drew attention to the fact that the same neuro-renal-endocrine systems are being pursued with equal enthusiasm by those investigating the pathogenesis of oedema formation and of arterial hypertension. It is pertinent that some workers have drawn attention to the possibility that the ECM may be playing an important pathophysiological role in the development and maintenance of arterial hypertension (6, 22). From the above discussion on the role of the ECM in sodium metabolism it could be reasoned that the ECM is the link between sodium and hypertension. It may now be worth considering whether we should include this additional factor, the ECM and the IFM in particular, into our model of electrolyte and water homeostasis and include it in our conceptual thinking about the subject.
7.
8.
9.
10.
11.
12. 13.
14.
Conclusion It is suggested that Starling’s hypothesis (1886) is no longer adequate to explain the distribution of water and electrolytes between the intravascular and interstitial compartments. The interstitial space under most circumstances is in the gel and not the sol state. The physicochemical properties of this gel must be expected to play a major role in determining the distribution of water and electrolytes between these two compartments. In addition the physicochemical properties of the gel change rapidly in response to many physiological stimuli. Thus it is likely that this gel, ie. the ECM and in particular the IFM, is an integral and dynamic component of the electrolyte and water homeostatic mechanisms.
15.
16.
17.
18.
References 1. Anonymous.
2. 3.
4.
5.
6.
What causes oedema (Editorial). Lancet 1988; i: 1028 - 1030. Harris P. Role of arterial pressure in the oedema of heart disease. Lancet 1988; i: 1036- 1038. Firth JD, Raine AEG, Ledingham JGG. Raised venous pressure: a direct cause of sodium retention in oedema. Lancet 1988: i: 1033 - 1035. Brace RA. Progress towards resolving the controversy of positive Vs. negative interstitial fluid pressure. Circ Res 1981; 41: 281-297. Minns RJ, Steven FS. The effect of calcium on the mechanicaf behaviour of aorta media efastin and collagen. Brit J Exp Path 1977; 58: 572- 579. Ffoyer MA, Lucas J, Morris DV. Interstitial tissue compfi-
19.
20.
21.
22.
199
ante in the genesis of hypertension. Contr Nepherof 1977; 8: 95-99. Hay ED. Extracellular Matrix. J Cell Biol 1981; 91: 2055 - 2235. Gersh I, Catchpole HR. The nature of ground substance of connective tissue. Perspectives in Biology and Medicine 1960; 3: 282-319. Catchpole HR. Capillary permiability. In inflammatory nrocess vol 2. Eds Zweifach et al. Acad Press NY 1982; i21-127. Pafaty V, Gustafson BK, Friedman SM. Sodium binding in the arterial wall. Canad J Physiof Pharmacol 1969; 47: 763 - 770. Comper WD, Laurent TC. Physiological function of connective tissue polysaccharides. Physiol Rev 1978; 1: 255-315. Iozzo RV. Proteogfycans: structure, function and role in neoplasia. Lab Invest 1985; 4: 373 - 396. B&elf MJ, Barcellos-Hoff. The influence of extracellular matrix on gene expression: is structure the message? J Cell Sci 1987; suppf 8 327-343. Lloyd IJ, Weston R. Dietary sodium and glycosaminoglycan metabolism: is the extracellular matrix involved in sodium homeostasis. In Kimchi A, Lewis BS Eds. Abstracts 1st International Symposium on Heart Failure Mechanisms and Management. Jerusalem. International Society and Federation of Cardiology. 1989, 3 I. Lloy IJ, Weston R, Henderson AH, Mulligan I. Pickering B. Urinary glycosaminogfycan extretion in man during altered sodium intake and during congestive cardiac failure. Is the extracellular matrix involved in sodium metabolism. In Kimchi K, Lewis BS Eds. Heart Failure - Mechanisms and Management. Springer-Verlag FRG (In Press). Lloyd IJ, Weston R, Henderson AH, Mulligan I. Urinary gfycosaminogfycan excretion in man during altered sodium intake and during congestive cardiac failure. Is the extracellular matrix involved in sodium metabolism. In Kimchi A, Lewis BS Eds. Abstracts 1st International Symposium on Heart Failure - Mechanisms and Managements. Jerusalem. International Society and Federation of Cardiology. 1989. 46. Campbell RHA, Brand HL, Cox JR, Howard P. Body weight and body water in chronic car pufmonale. Clin Sci Mof Med 1975; 49: 323 - 335. Levy M, Affotey JBK. Temporal relationship between urinary salt retention and altered systemic haemodynamics in dogs with experimental cirrhosis. J Lab Clin Med 1978; 92: 560 - 569. VanBreeman C, Aaronson P, Lontzenfiser R. Sodium-calcium interactions in smooth muscle. Pharma Rev 1979; 30: 167 - 208. Bfaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension. A reassessment and hypothesis. Amer J Physiol 1977; 232: cl65 - 173. Joseph NR, Engef MB, Catchpole HR. Distribution ot sodium and potassium in certain cells and tissues. Nature 1961; 4794: 1175-1178. Lloyd IJ. Extracellular matrix in hypertension: the link between renal function, anteregulation and sodium metabolism: a review and hypothesis. Med Hypothesis 1985; 18: 169- 187.