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Renin-angiotensin in preascitic cirrhosis: Evidence for primary peripheral arterial vasodilatation
August 1998
EDITORIALS
IDX-1 is certainly a major culprit, the accomplices in the case of the missing cecum remain at large. PETER G. TRABER Department of Medicine University of Pennsylvania Philadelphia, Pennsylvania
References 1. McGinnis W. A century of homeosis, a decade of homeoboxes. Genetics 1994;137:607–611. 2. Traber PG, Wu GD. Intestinal development and differentiation. In: Rustgi AK, ed. Gastrointestinal cancers: biology, diagnosis, and therapy. Philadelphia: Lippincott-Raven, 1995:21–43. 3. Yokouchi Y, Sakiyama J, Kuroiwa A. Coordinated expression of Abd-B subfamily genes of the HoxA cluster in the developing digestive tract of chick embryo. Dev Biol 1995;169:76–89. 4. Pollock RA, Jay mG, Bieberich CJ. Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell 1992;71:911–923. 5. Wolgemuth DJ, Behringer RR, Molstoller MP, Brinster RL, Palmiter RD. Transgenic mice overexpressing the mouse homeoboxcontaining gene Hox-1.4 exhibit abnormal gut development. Nature 1989;337:464–467. 6. Traber PG. Epithelial cell growth and differentiation V: transcriptional regulation, development, and neoplasia of the intestinal epithelium. Am J Physiol 1997;273:G979–G981. 7. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BLM, Wright CVE. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996;122:983–995. 8. Ahlgren U, Jonsson J, Edlund H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 1996;122: 1409–1416. 9. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor
10.
11.
12.
13.
14.
15.
16.
17.
489
1 is required for pancreas development in mice. Nature 1994;371: 606–609. Larsson L-I, Madsen OD, Serup P, Jonsson J, Edlund H. Pancreaticduodenal homeobox 1—role in gastric endocrine patterning. Mech Dev 1996;60:175–184. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–110. Heller RS, Stoffers DA, Hussain MA, Miller CP, Habener JF. Misexpression of the pancreatic homeodomain protein IDX-1 by the Hoxa-4 promoter associated with agenesis of the cecum. Gastroenterology 1998;115:381–387. Halder G, Callaerts P, Gehring WJ. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 1995;267:1788–1792. Behringer RR, Crotty DA, Tennyson VM, Brinster RL, Palmiter RD, Wolgemuth DJ. Sequences 58 of the homeobox of the Hox-1.4 gene direct tissue-specific expression of lacZ during mouse development. Development 1993;117:823–833. Beck F, Erler T, Russell A, James R. Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes. Dev Dyn 1995;204:219–227. Timchenko NA, Harris TE, Wilde M, Bilyeu TA, Burgess-Beusse BL, Finegold MJ, Darlington GJ. CCAAT/enhancer binding protein alpha regulates p21 protein in hepatocyte proliferation in newborn mice. Mol Cell Biol 1997;17:7353–7361. Dubnau J, Struhl G. RNA recognition and translational regulation by a homeodomain protein. Nature 1996;379:694–699.
Address requests for reprints to: Peter G. Traber, M.D., Department of Medicine, University of Pennsylvania, 100 Centrey, 3400 Spruce Street, Philadelphia, Pennsylvania 19104-4283. Fax: (215) 614-0160. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Renin-Angiotensin in Preascitic Cirrhosis: Evidence for Primary Peripheral Arterial Vasodilatation See article on page 397.
n this issue of GASTROENTEROLOGY, Wong et al.1 report studies comparing the responses to lower body negative pressure (LBNP) in preascitic cirrhotic patients and matched healthy controls. It is known that renal sodium and water retention and expanded total plasma volume occur in cirrhotic patients before ascites formation. Moreover, the presence of portal hypertension is associated with splanchnic arterial vasodilation early in the course of cirrhosis before the occurrence of ascites. Grossman2 showed, in rats, a decrease in systemic vascular resistance within 24 hours and an increase in
I
total body sodium level within 48 hours after prehepatic portal hypertension caused by portal vein constriction. Unfortunately, Wong et al.1 did not measure plasma volume in their cirrhotic patients. Cardiac output was also not measured; therefore, systemic vascular resistance could not be calculated. It is interesting, however, that the cirrhotic patients had significantly lower mean arterial pressures (MAP) in response to LBNP of 215 and 220 mm Hg than the matched control subjects. Furthermore, plasma renin activity (PRA) increased at 215 mm Hg LBNP in cirrhotic, but not in control, subjects. At 220 mm Hg, LBNP was associated with significantly increased renin and angiotensin II secretory rates in the cirrhotic patients but not the control subjects. These are
490
EDITORIALS
the changes expected with LBNP in preascitic cirrhotic patients with splanchnic arterial vasodilation causing arterial underfilling. There is now considerable evidence that the major determinant of renal sodium and water excretion is the relative fullness of the arterial circulation rather than total blood volume or pressures on the venous side of the circulation.3–5 It is not surprising that renal sodium retention was observed at 220 mm Hg LBNP when MAP was decreased in the cirrhotic, but not healthy, subjects; this sodium retention occurred despite a higher central venous pressure (CVP) in the cirrhotic patients. In cirrhosis, splanchnic arterial vasodilation and renal sodium retention lead to an increase in fluid retention in the splanchnic circulation that is translocated to the central venous circulation on assuming the supine position. In the present study, the cirrhotic patients were presumably investigated in the supine position, no doubt explaining their higher CVP. When studying renal sodium and water retention in cirrhosis and other edematous disorders, it is important to be explicit about the posture and location of the body fluid volume expansion. Approximately 85% of the intravascular fluid resides on the venous side of the circulation, and the remaining 15% is in the arterial circulation. Arterial underfilling caused by a decrease in cardiac output, such as with low-output heart failure, or arterial vasodilation as occurs with cirrhosis, pregnancy, arteriovenous fistula, or arterial vasodilators (e.g., hydralazine, minoxidil) may lead to avid renal sodium and water retention in the presence of an expanded total plasma volume and an elevated CVP on the venous side of the circulation. The lower MAP (and thus renal arterial pressure), increased PRA, and enhanced renal renin and angiotensin II secretion rates in the cirrhotic patients during LBNP are very compatible with the peripheral arterial vasodilation hypothesis of renal sodium retention in cirrhosis.6 It is well known that baroreceptors in the renal afferent arterioles modulate renal renin release independent of any effect on renal nerves7; thus the absence of an effect on renal sympathetic norepinephrine is not problematic in explaining the increased activity of the renin-angiotensin system and the renal sodium retention in the cirrhotic patients during 220 mm Hg LBNP. On the other hand, evidence for an hepatorenal reflex has generally been shown to involve stimulation of renal nerves.8 Thus, the LBNP in the present study, which was not associated with any detectable alteration in renal nerve stimulation, is somewhat problematic for a hepatorenal reflex. Wong et al., somewhat surprisingly, conclude the discussion of their results by citing several findings that
GASTROENTEROLOGY Vol. 115, No. 2
they infer are against the peripheral arterial vasodilation hypothesis of renal sodium and water retention in cirrhosis. First, they mention the failure of prehepatic portal hypertension to lead to ascites formation. Recently the portal vein ligation model of portal hypertension was found to be associated with significantly less arterial vasodilation than the carbon tetrachloride model of cirrhosis.9 Moreover, the most likely mediator of the splanchnic arterial vasodilation, up-regulation of nitric oxide synthase leading to increased NO, was significantly greater in cirrhotic than portal vein–ligated animals.9 Second, reports of decreased plasma renin and aldosterone levels in preascitic cirrhotic patients are cited. We first suggested in the article that formalized the peripheral arterial vasodilation hypothesis that suppressed plasma renin and aldosterone concentrations in preascitic cirrhosis were probably a result of making the measurements while the patients were in the supine position, when the excess splanchnic fluid volume is translocated to the central circulation.6 Subsequent studies in cirrhotic patients by Bernardi et al.10 of the neurohumoral and renal responses in the supine vs. upright position are supportive of this proposal. Third, Wong et al. mention a study by Bernardi et al.10 in which the hyperdynamic circulation, which is characteristic of cirrhosis, was found only in the supine position. If the translocation of fluid from the splanchnic to the central circulation in the supine position were the only factor causing the hyperdynamic circulation in cirrhosis, then cirrhotic patients would be either normotensive or hypertensive. However, it is known that a decrease in MAP, which worsens with progression of the cirrhotic state from compensated (no ascites) to decompensated (ascites) to the hepatorenal syndrome, characterizes cirrhotic patients. A recent study in experimental cirrhosis showed that when the hyperdynamic circulation was reversed by NO synthesis inhibition, this was accompanied by reversal of the elevated PRA, plasma aldosterone, arginine vasopressin, and arterial natriuretic peptide concentrations, hyponatremia, and ascites formation.11 These findings, which support the peripheral arterial vasodilation hypothesis of sodium retention and ascites formation in cirrhosis, need to be confirmed in clinical studies in patients with cirrhosis. The results of the present study by Wong et al. are supportive of a role of renin-angiotensin, and presumably aldosterone, in the early renal sodium retention in preascitic cirrhotic patients. ROBERT W. SCHRIER Department of Medicine University of Colorado School of Medicine Denver, Colorado
August 1998
EDITORIALS
References 1. Wong F, Sniderman K, Blendis L. The renal sympathetic and renin-angiotensin response to lower body negative pressure in well-compensated cirrhosis. Gastroenterology 1998;115:397– 405. 2. Groszmann RJ. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences. Hepatology 1994;20:1359–1363. 3. Schrier RW. Pathogenesis of sodium and water retention in high and low output cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. N Engl J Med 1988;319:1065–1072 (Part 1) and 1988;319:1127–1134 (Part 2). 4. Schrier RW. Body fluid volume regulation in health and disease: a unifying hypothesis. Ann Intern Med 1990;113:155–159. 5. Schrier RW. A unifying hypothesis of body fluid volume regulation. J R Coll Physicians Lond 1992;26:295–3–6. 6. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rode´s J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151–1157. 7. Henrich WL, Berl T, McDonald KM, Anderson RJ, Schrier RW. Angiotensin II, renal nerves, and prostaglandins in renal hemodynamics during hemorrhage. Am J Physiol 1978;235:F46–F51.
491
8. Anderson RJ, Cronin RE, McDonald KM, Schrier RW. Mechanisms of portal hypertension induced alternations in renal hemodynamics, renal water excretion and renin secretion. J Clin Invest 1976;58:964–970. 9. Niederberger M, Gines P, Martin P-Y, Tsai P, Morris K, McMurtry I, Schrier RW. Comparison of vascular nitric oxide production on systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. Hepatology 1996;24:947–951. 10. Bernardi M, Di Marco M, Trevisani F, Fornale L, Andreone P, Cursaro C, Baraldini M, et al. Renal sodium retention during upright posture in preascitic cirrhosis. Gastroenterology 1993; 105:188–193. 11. Martin P-Y, Ohara M, Gines P, Xu DL, St John J, Niederberger M, Schrier RW. Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest 1998;101:235–242.
Address requests for reprints to: Robert W. Schrier, M.D., Department of Medicine, University of Colorado School of Medicine, , 4200 East Ninth Avenue, Denver, Colorado 80262. Fax: (303) 315-7702. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Pancreatic Stellate Cells: The New Stars of Chronic Pancreatitis? See article on page 421.
he identification of hepatic stellate cells (HSC) as the primary source of matrix components in hepatic fibrosis provided a tremendous impetus for understanding the development of fibrosis in chronic liver disease.1,2 Now, with the isolation of structurally and functionally similar cells from the pancreas (termed pancreatic stellate cells [PSC]3), our understanding of pancreatic fibrosis should move forward substantially. The report of the existence of PSC raises fundamental issues regarding the cellular anatomy of the pancreas, the pathogenesis of chronic pancreatitis, and the activation and proliferation of fibrogenic cells within the pancreas. Reports of vitamin A–storing cells in the pancreas date only to 1982, when they were observed in mice fed an excess of vitamin A.4 The first description of these cells in the human pancreas appeared in 1990.5 Likewise, the description of a possible cell source of the excess matrix observed in pancreatic fibrosis came only recently, with the isolation of myofibroblast-like cells from human pancreas.6 The article by Bachem et al.3 in this issue suggests that the vitamin A–storing cells and the myofibroblasts are one and the same: vitamin A–contain-
T
ing cells isolated from the pancreas were shown to differentiate in primary culture into myofibroblast-like cells expressing a-smooth muscle actin and producing collagen types I and III, laminin, and fibronectin. What are the implications of this report for chronic pancreatitis, a disease whose pathogenesis remains obscure? At the very least, the demonstration of a highly fibrogenic cell type in the pancreas suggests a likely source for the increased extracellular matrix observed in chronic pancreatitis. The matrix components produced by the cells isolated by Bachem et al.,3 including collagens I and III and fibronectin, mimic those observed in the fibrotic pancreas,7,8 and the similarities between HSC and PSC suggest analogous roles in fibrosis. More speculative is a possible role for these cells in the initiation of chronic pancreatitis. Many investigators believe that chronic pancreatitis is the sum of multiple episodes of acute pancreatitis,9,10 and microvascular insufficiency has been proposed as a potential cause of ischemic injury to acinar cells in acute pancreatitis.11 Activated HSC have features of smooth muscle cells and show contractile behavior that may be important in the regulation of the hepatic microvasculature and therefore hepatic ischemia.12,13 To the extent that PSC resemble their contractile counterparts in the liver and occupy a perivascular position,5 the possibility must be considered
EDITORIALS
IDX-1 is certainly a major culprit, the accomplices in the case of the missing cecum remain at large. PETER G. TRABER Department of Medicine University of Pennsylvania Philadelphia, Pennsylvania
References 1. McGinnis W. A century of homeosis, a decade of homeoboxes. Genetics 1994;137:607–611. 2. Traber PG, Wu GD. Intestinal development and differentiation. In: Rustgi AK, ed. Gastrointestinal cancers: biology, diagnosis, and therapy. Philadelphia: Lippincott-Raven, 1995:21–43. 3. Yokouchi Y, Sakiyama J, Kuroiwa A. Coordinated expression of Abd-B subfamily genes of the HoxA cluster in the developing digestive tract of chick embryo. Dev Biol 1995;169:76–89. 4. Pollock RA, Jay mG, Bieberich CJ. Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell 1992;71:911–923. 5. Wolgemuth DJ, Behringer RR, Molstoller MP, Brinster RL, Palmiter RD. Transgenic mice overexpressing the mouse homeoboxcontaining gene Hox-1.4 exhibit abnormal gut development. Nature 1989;337:464–467. 6. Traber PG. Epithelial cell growth and differentiation V: transcriptional regulation, development, and neoplasia of the intestinal epithelium. Am J Physiol 1997;273:G979–G981. 7. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BLM, Wright CVE. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996;122:983–995. 8. Ahlgren U, Jonsson J, Edlund H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 1996;122: 1409–1416. 9. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor
10.
11.
12.
13.
14.
15.
16.
17.
489
1 is required for pancreas development in mice. Nature 1994;371: 606–609. Larsson L-I, Madsen OD, Serup P, Jonsson J, Edlund H. Pancreaticduodenal homeobox 1—role in gastric endocrine patterning. Mech Dev 1996;60:175–184. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–110. Heller RS, Stoffers DA, Hussain MA, Miller CP, Habener JF. Misexpression of the pancreatic homeodomain protein IDX-1 by the Hoxa-4 promoter associated with agenesis of the cecum. Gastroenterology 1998;115:381–387. Halder G, Callaerts P, Gehring WJ. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 1995;267:1788–1792. Behringer RR, Crotty DA, Tennyson VM, Brinster RL, Palmiter RD, Wolgemuth DJ. Sequences 58 of the homeobox of the Hox-1.4 gene direct tissue-specific expression of lacZ during mouse development. Development 1993;117:823–833. Beck F, Erler T, Russell A, James R. Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes. Dev Dyn 1995;204:219–227. Timchenko NA, Harris TE, Wilde M, Bilyeu TA, Burgess-Beusse BL, Finegold MJ, Darlington GJ. CCAAT/enhancer binding protein alpha regulates p21 protein in hepatocyte proliferation in newborn mice. Mol Cell Biol 1997;17:7353–7361. Dubnau J, Struhl G. RNA recognition and translational regulation by a homeodomain protein. Nature 1996;379:694–699.
Address requests for reprints to: Peter G. Traber, M.D., Department of Medicine, University of Pennsylvania, 100 Centrey, 3400 Spruce Street, Philadelphia, Pennsylvania 19104-4283. Fax: (215) 614-0160. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Renin-Angiotensin in Preascitic Cirrhosis: Evidence for Primary Peripheral Arterial Vasodilatation See article on page 397.
n this issue of GASTROENTEROLOGY, Wong et al.1 report studies comparing the responses to lower body negative pressure (LBNP) in preascitic cirrhotic patients and matched healthy controls. It is known that renal sodium and water retention and expanded total plasma volume occur in cirrhotic patients before ascites formation. Moreover, the presence of portal hypertension is associated with splanchnic arterial vasodilation early in the course of cirrhosis before the occurrence of ascites. Grossman2 showed, in rats, a decrease in systemic vascular resistance within 24 hours and an increase in
I
total body sodium level within 48 hours after prehepatic portal hypertension caused by portal vein constriction. Unfortunately, Wong et al.1 did not measure plasma volume in their cirrhotic patients. Cardiac output was also not measured; therefore, systemic vascular resistance could not be calculated. It is interesting, however, that the cirrhotic patients had significantly lower mean arterial pressures (MAP) in response to LBNP of 215 and 220 mm Hg than the matched control subjects. Furthermore, plasma renin activity (PRA) increased at 215 mm Hg LBNP in cirrhotic, but not in control, subjects. At 220 mm Hg, LBNP was associated with significantly increased renin and angiotensin II secretory rates in the cirrhotic patients but not the control subjects. These are
490
EDITORIALS
the changes expected with LBNP in preascitic cirrhotic patients with splanchnic arterial vasodilation causing arterial underfilling. There is now considerable evidence that the major determinant of renal sodium and water excretion is the relative fullness of the arterial circulation rather than total blood volume or pressures on the venous side of the circulation.3–5 It is not surprising that renal sodium retention was observed at 220 mm Hg LBNP when MAP was decreased in the cirrhotic, but not healthy, subjects; this sodium retention occurred despite a higher central venous pressure (CVP) in the cirrhotic patients. In cirrhosis, splanchnic arterial vasodilation and renal sodium retention lead to an increase in fluid retention in the splanchnic circulation that is translocated to the central venous circulation on assuming the supine position. In the present study, the cirrhotic patients were presumably investigated in the supine position, no doubt explaining their higher CVP. When studying renal sodium and water retention in cirrhosis and other edematous disorders, it is important to be explicit about the posture and location of the body fluid volume expansion. Approximately 85% of the intravascular fluid resides on the venous side of the circulation, and the remaining 15% is in the arterial circulation. Arterial underfilling caused by a decrease in cardiac output, such as with low-output heart failure, or arterial vasodilation as occurs with cirrhosis, pregnancy, arteriovenous fistula, or arterial vasodilators (e.g., hydralazine, minoxidil) may lead to avid renal sodium and water retention in the presence of an expanded total plasma volume and an elevated CVP on the venous side of the circulation. The lower MAP (and thus renal arterial pressure), increased PRA, and enhanced renal renin and angiotensin II secretion rates in the cirrhotic patients during LBNP are very compatible with the peripheral arterial vasodilation hypothesis of renal sodium retention in cirrhosis.6 It is well known that baroreceptors in the renal afferent arterioles modulate renal renin release independent of any effect on renal nerves7; thus the absence of an effect on renal sympathetic norepinephrine is not problematic in explaining the increased activity of the renin-angiotensin system and the renal sodium retention in the cirrhotic patients during 220 mm Hg LBNP. On the other hand, evidence for an hepatorenal reflex has generally been shown to involve stimulation of renal nerves.8 Thus, the LBNP in the present study, which was not associated with any detectable alteration in renal nerve stimulation, is somewhat problematic for a hepatorenal reflex. Wong et al., somewhat surprisingly, conclude the discussion of their results by citing several findings that
GASTROENTEROLOGY Vol. 115, No. 2
they infer are against the peripheral arterial vasodilation hypothesis of renal sodium and water retention in cirrhosis. First, they mention the failure of prehepatic portal hypertension to lead to ascites formation. Recently the portal vein ligation model of portal hypertension was found to be associated with significantly less arterial vasodilation than the carbon tetrachloride model of cirrhosis.9 Moreover, the most likely mediator of the splanchnic arterial vasodilation, up-regulation of nitric oxide synthase leading to increased NO, was significantly greater in cirrhotic than portal vein–ligated animals.9 Second, reports of decreased plasma renin and aldosterone levels in preascitic cirrhotic patients are cited. We first suggested in the article that formalized the peripheral arterial vasodilation hypothesis that suppressed plasma renin and aldosterone concentrations in preascitic cirrhosis were probably a result of making the measurements while the patients were in the supine position, when the excess splanchnic fluid volume is translocated to the central circulation.6 Subsequent studies in cirrhotic patients by Bernardi et al.10 of the neurohumoral and renal responses in the supine vs. upright position are supportive of this proposal. Third, Wong et al. mention a study by Bernardi et al.10 in which the hyperdynamic circulation, which is characteristic of cirrhosis, was found only in the supine position. If the translocation of fluid from the splanchnic to the central circulation in the supine position were the only factor causing the hyperdynamic circulation in cirrhosis, then cirrhotic patients would be either normotensive or hypertensive. However, it is known that a decrease in MAP, which worsens with progression of the cirrhotic state from compensated (no ascites) to decompensated (ascites) to the hepatorenal syndrome, characterizes cirrhotic patients. A recent study in experimental cirrhosis showed that when the hyperdynamic circulation was reversed by NO synthesis inhibition, this was accompanied by reversal of the elevated PRA, plasma aldosterone, arginine vasopressin, and arterial natriuretic peptide concentrations, hyponatremia, and ascites formation.11 These findings, which support the peripheral arterial vasodilation hypothesis of sodium retention and ascites formation in cirrhosis, need to be confirmed in clinical studies in patients with cirrhosis. The results of the present study by Wong et al. are supportive of a role of renin-angiotensin, and presumably aldosterone, in the early renal sodium retention in preascitic cirrhotic patients. ROBERT W. SCHRIER Department of Medicine University of Colorado School of Medicine Denver, Colorado
August 1998
EDITORIALS
References 1. Wong F, Sniderman K, Blendis L. The renal sympathetic and renin-angiotensin response to lower body negative pressure in well-compensated cirrhosis. Gastroenterology 1998;115:397– 405. 2. Groszmann RJ. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences. Hepatology 1994;20:1359–1363. 3. Schrier RW. Pathogenesis of sodium and water retention in high and low output cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. N Engl J Med 1988;319:1065–1072 (Part 1) and 1988;319:1127–1134 (Part 2). 4. Schrier RW. Body fluid volume regulation in health and disease: a unifying hypothesis. Ann Intern Med 1990;113:155–159. 5. Schrier RW. A unifying hypothesis of body fluid volume regulation. J R Coll Physicians Lond 1992;26:295–3–6. 6. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rode´s J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151–1157. 7. Henrich WL, Berl T, McDonald KM, Anderson RJ, Schrier RW. Angiotensin II, renal nerves, and prostaglandins in renal hemodynamics during hemorrhage. Am J Physiol 1978;235:F46–F51.
491
8. Anderson RJ, Cronin RE, McDonald KM, Schrier RW. Mechanisms of portal hypertension induced alternations in renal hemodynamics, renal water excretion and renin secretion. J Clin Invest 1976;58:964–970. 9. Niederberger M, Gines P, Martin P-Y, Tsai P, Morris K, McMurtry I, Schrier RW. Comparison of vascular nitric oxide production on systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. Hepatology 1996;24:947–951. 10. Bernardi M, Di Marco M, Trevisani F, Fornale L, Andreone P, Cursaro C, Baraldini M, et al. Renal sodium retention during upright posture in preascitic cirrhosis. Gastroenterology 1993; 105:188–193. 11. Martin P-Y, Ohara M, Gines P, Xu DL, St John J, Niederberger M, Schrier RW. Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest 1998;101:235–242.
Address requests for reprints to: Robert W. Schrier, M.D., Department of Medicine, University of Colorado School of Medicine, , 4200 East Ninth Avenue, Denver, Colorado 80262. Fax: (303) 315-7702. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Pancreatic Stellate Cells: The New Stars of Chronic Pancreatitis? See article on page 421.
he identification of hepatic stellate cells (HSC) as the primary source of matrix components in hepatic fibrosis provided a tremendous impetus for understanding the development of fibrosis in chronic liver disease.1,2 Now, with the isolation of structurally and functionally similar cells from the pancreas (termed pancreatic stellate cells [PSC]3), our understanding of pancreatic fibrosis should move forward substantially. The report of the existence of PSC raises fundamental issues regarding the cellular anatomy of the pancreas, the pathogenesis of chronic pancreatitis, and the activation and proliferation of fibrogenic cells within the pancreas. Reports of vitamin A–storing cells in the pancreas date only to 1982, when they were observed in mice fed an excess of vitamin A.4 The first description of these cells in the human pancreas appeared in 1990.5 Likewise, the description of a possible cell source of the excess matrix observed in pancreatic fibrosis came only recently, with the isolation of myofibroblast-like cells from human pancreas.6 The article by Bachem et al.3 in this issue suggests that the vitamin A–storing cells and the myofibroblasts are one and the same: vitamin A–contain-
T
ing cells isolated from the pancreas were shown to differentiate in primary culture into myofibroblast-like cells expressing a-smooth muscle actin and producing collagen types I and III, laminin, and fibronectin. What are the implications of this report for chronic pancreatitis, a disease whose pathogenesis remains obscure? At the very least, the demonstration of a highly fibrogenic cell type in the pancreas suggests a likely source for the increased extracellular matrix observed in chronic pancreatitis. The matrix components produced by the cells isolated by Bachem et al.,3 including collagens I and III and fibronectin, mimic those observed in the fibrotic pancreas,7,8 and the similarities between HSC and PSC suggest analogous roles in fibrosis. More speculative is a possible role for these cells in the initiation of chronic pancreatitis. Many investigators believe that chronic pancreatitis is the sum of multiple episodes of acute pancreatitis,9,10 and microvascular insufficiency has been proposed as a potential cause of ischemic injury to acinar cells in acute pancreatitis.11 Activated HSC have features of smooth muscle cells and show contractile behavior that may be important in the regulation of the hepatic microvasculature and therefore hepatic ischemia.12,13 To the extent that PSC resemble their contractile counterparts in the liver and occupy a perivascular position,5 the possibility must be considered