Cellular and Molecular Basis of Intestinal and Pancreatic Adaptation R. H. DOWLING Gastroenterology Unit, Guy's Hospital. London. U.K.
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
Dowling RH. Cellular and molecular basis of intestinal and pancreatic adaptation. Scand J Gastroenterol 1992;27 SUPPI 193164-67. This article reviews the structural and functional changes which develop in the intestine and pancreas in response to a variety of stimuli and which characterise adaptive hyper- or hypo-plasia. It then discusses the principal physiological mechanisms controlling this adaptive growth. In the gut, these include luminal nutrition, endocrine, autocrine and paracrine hormonal influences, growth factors, enterotrophic components of pancreatico-biliary secretions, neural factors, changes in blood flow and mesenchymeepithelial interactions. The cell biology of adaptive growth involves cell membrane receptors ( first messengers) and a cascade of intracellular second messengers. the best studied of which is changes in polyamine metabolism and in related enzymes. The effects of ornithine decarboxylase (ODC) blockade with difluoromethyl ornithine (DFMO) and of diamine oxidase (DAO) blockade with aminoguanidine, are described. In general. DFMO inhibits or prevents adaptive hyperplasia while in the small bowel, arninoguanidine treatment induces 'supranormal' adaptation. However, both the gut and the pancreas transport 'exogenous' (ingested in food and circulating in the blood stream) polyamines across their apical and basolateral membranes. The influence of this exogenous polyamine transport on 'endogenous' (enzyme-regulated) intracellular polyamine concentrations, is largely unknown. Finally, the molecular hiology of adaptive growth is described briefly-as illustrated by the use of a growth hormone transgenic model in which mice develop marked intestinal mucosal hyperplasia and increases in the relative abundance of insulin-like growth factor-I (IGF-I) mRNA in the intestine. Key words: Aminoguanidine; diamine oxidase; difluoromethyl ornithine; growth hormone; insulin-like growth factor-I; intestinal and pancreatic adaptive hyper- and hypo-plasia; messenger RNA: ornithine decarboxylase: polyamine metabolism Prof. R. Hermon Dowling, GastroenIerology Unit, 18th Floor. Guy's Tower, Guy's HospiIal, London SEI 9RT. U .K .
THE PHENOMENA O F INTESTINAL ADAPTATION Intestinal adaptation is mainly characterised by changes in crypt cell production rates which lead to hyperplasia (or hypoplasia) of the small bowel villi and crypts. This, coupled with intestinal dilatation, increases the absorptive surface area per unit length of bowel and results in segmental hyperfunction with enhanced absorption and increases in total enzyme activity, per unit length intestine (1). In the case of adaptive hypoplasia which occurs, for example, during total parenteral nutrition and in segments of intestine excluded from continuity as Thirty-Vella fistulae or self-emptying blind loops, the reverse is true. In other words, crypt cell production rates fall and the villi become hypoplastic: at the same time, the calibre of the intestine diminishes and the resultant reduction in absorptive surface area leads to segmental hypofunction. In both adaptive intestinal mucosal hyperplasia and hypoplasia, the size and function of the individual enterocytes changes comparatively little, if at all. The changes in segmental absorption, therefore, are mainly a function of a greater (or lesser) number of enterocytes per unit length of bowel (1). THE PHYSIOLOGICAL MECHANISMS The principal physiological mechanism controlling this
adaptive mucosal growth is luminal nutrition which may have direct topical effects on the small bowel mucosa but which probably acts mainly by stimulating: (i) the synthesis and release of enterotrophic regulatory peptides (such as the gut glucagon family of peptides (2,3) and epidermal growth factor: EGF (4.5)) and (ii) enterotrophic pancreatico-biliary secretions (6,7). Neural factors (8) and changes in mucosal blood flow (9, 10) are also important. Rarely. there may be induction or suppression of specific transport mechanisms in the absence of structural changes (for example, up- or downregulation of active bile acid transport in the ileum by cholestryamine treatment or bile acid feeding) (1 1). Although growth factors, such as insulin-like growth factor-I (IGF-I), transforming growth factors (TGF,,,,,, and TGF,,,,) and fibroblast growth factors (acidic and basic FGF), stimulate increased rates of cell division and growth in cell culture systems (12), as yet, their role as physiological enterotrophins in intestinal adaptation, is uncertain. THE CELLULAR MECHANISMS Enterotrophins, stimulated by luminal nutrition, may have endocrine, paracrine or autocrine effects which are mediated by receptors on enterocyte brush-border (13) or baso-lateral (14) membranes. This signal induction triggers off a cascade
Intestinal and Pancreatic Adaptation
14
P=0.004
150
P=0.0065
P=0.0025
12 120
10 8
P=0.0025
90
6
-
65
60
4
30
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
2 0
T
T+AG
R
0
R+AG
Fig. 1. Results for ileal mucosal DAO activity (means +- SEMs) in transected control rats ( T ) and in animals subjected to80% proximal small-bowel resection (R). The untreated animals were given saline injections only; those given aminoguinadine (AG) were treated with 25 mg kg ' day-'. The studies were carried out 12 days after jejunectomy (or in the corresponding ileal segment from the controls). There were six animals in each group. (Data from Ref. 28.)
of intra-cellular second messengers including changes in membrane phospholipids and protein kinases (15)-neither of which have been adequately studied in intestinal and pancreatic adaptation. Ultimately, these second messenger changes increase either cyclic AMP levels or intracellular free calcium ion activity (possibly with oscillating fluctuations in cytosolic Ca++ (M. J . Berridge, personal communication)), both of which may initiate increases in ornithine decarboxylase (ODC; EC 4.1.1.17) activity. O D C is the first, and rate-limiting, step in the synthesis of growthassociated polyamines-putrescine, spermidine and spermine (16). Occasionally, however, another enzyme involved in polyamine synthesis, S-adenosyl methionine decarboxylase (SAM-DC or adoMET-DC; E C 4.1.1 S O ) may be rate-limiting (17).
T
To date, cell biological studies of intestinal and pancreatic adaptation have mostly been confined to changes in polyamine levels and in the activities of the enzymes controlling polyamine synthesis (ODC and SAM-DC) and degradation (diamine oxidase; D A O ; EC 1.4.3.6). Thus, in several animal models of intestinal adaptation (resection (18, 19), lactation (20) and pancreatico-biliary diversion (21,22)). inhibition of O D C activity with the specific and irreversible blocker, alpha-difluoromethyl ornithine (DFMO), leads to marked reductions in intestinal mucosal putrescine and spermidine (but not in spermine) concentrations, and either significantly reduces or completely prevents the adaptive mucosal growth. Moreover, 'add-back' experiments show
R
R+AG
that the inhibitory effects of DFMO on intestinal adaptation (such as that seen in the ileum following jejunectomy (18, 19)) may be overcome with either putrescine or spermidine given enterally or parenterally (23). Studies such as these suggest that the final common pathway for many growth factors in intestinal adaptation is through changes in polyamine metabolism. In turn, these influence RNA polymerase, D N A , RNA and protein synthesis, cell division and growth. Although they help us to understand the cellular mechanisms controlling growth, in patients with malabsorption/malnutrition secondary to extensive disease/resection of the intestine, the problem is not how to inhibit mucosal growth but how to enhance it and to promote 'supranormal' adaptation (that is, adaptation over and above that which occurs spontaneously). Outside pregnancy (24), D A O activity is almost exclusively confined to the small bowel mucosa, particularly the ileum (25,26). Therefore, manipulation of D A O activity
I 9
T H E CELL BIOLOGY OF INTESTINAL ADAPTATION
T+AG
Fig. 2. Mucosal wet weight per unit/length ileum in the four groups of rats. (See legend to Fig. 1.)
h
c
P=0.004
1
-I
P=0.0025 7
E a.
T
T+AG
R
R+AG
Fig. 3. Mucosal protein (mg/cm per intestine) in the four experimental groups. (See legend to Fig. 1.)
66
R. H. Dowling
P=0.0025 Pe0.05
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
53 *‘OI 1.5
l-
T
T+AG
R
R+AG
Fig. 4. Mucosal DNA (mg/cm per intestine) in the four experimental groups. (See legend to Fig. 1.)
should modify intestinal mucosal polyamine levels and influence intestinal growth. The results of two preliminary studies (27,28) (Figs. 1-4) suggest that inhibition of DAO with aminoguanidine: (i) does indeed prevent the degradation of putrescine (and indirectly, therefore, of the other polyamines), (ii) results in putrescine accumulation in the intestinal mucosa and (iii) induces significantly greater ileal adaptive mucosal hyperplasia, than that which occurs spontaneously after jejunectomy. Extrapolation of these results in animal studies to man are awaited.
MOLECULAR MECHANISMS So far, molecular biological studies of intestinal adaptation have been limited. In the jejunectomy model, ileal mRNA expression of enteroglucagon and ODC increase within hours of resection, whether in fed or in fasted animals (29). and antedates any increase in DNA synthesis or in markers of mucosal growth. The transgenic mouse model has been used to study the effects of growth hormone excess on the gut (30). The growth hormone transgenic animals eat more, grow more and weigh more than their ‘wild-type’normal littermate controls. Their duodenal, jejunal and ileal mucosae show marked and significant increases in wet weight, protein and DNA/cm intestine and in villus height and crypt depth (31). However, the relative abundance of mRNA in the intestine is unchanged for ODC (and probably also for SAM-DC)despite marked increases in ODC activity. This suggests that there must be post-transcriptional changes in the enzyme. Enteroglucagon message is reciprocally related to circulating IGF-I but in keeping with the theory that growth hormone mediates its trophic effects through IGF-I, there was a 2.6 fold increase in mRNA abundance in the hyperplastic small bowel of the transgenic mice.
ACKNOWLEDGEMENTS The author is grateful to many past and present mentors and colleagues whose work formed the basis for this brief review. He was pleased to join in this tribute to Professor Fred Halter-a personal friend for many years who shares his enthusiasm not only in the field of gastrointestinal adaptation but also in the extracurricular pursuit of the trout with the fly. He wishes to thank the Special Trusteesof Guy’s Hospital for their continued help and support and Mrs. Ann Hollington who kindly prepared the manuscript.
REFERENCES 1. Dowling RH. Update on intestinal adaptation. Triangle
1988;27:149-64. 2. Gleeson MH, Bloom SR, Polak JM, Henry K, Dowling RH. Endocrine tumour in kidney affecting small bowel structure, motility and absorptive function. Gut 1971;12:77>82. 3. Jacobs LR, Bloom SR, Dowling RH. Response of plasma and tissue levels of enteroglucagon immunoreactivity to intestinal resection, lactation and hyperphagia. Life Sci 1981;29:20()3-7. 4. Goodlad RA. Wilson TJG, Lenton W, Gregory H, McCullagh KG, Wriaht NA. Intravenous but not intraaastric urogastroneEGF is Gophic to the intestine of parenterally fed Fats. Gut 1987:28:573-82. 5 . Ulshen MH, Lyn-Cook LN, Raasch RH. Effects of intraluminal epidermal growth factor on mucosal proliferation in the small intestine of adult rats. Gastroenterology 1986;91:1134-40. 6. Altmann GG, Influence of bile and pancreative secretions on the size of the intestinal villi in the rat. Am J Anat 1971;132:16778. 7. Miazza BM, Hung L, Vaja S, Dowling RH. Effect of pancreaticobiliary diversion (PBD) on jejunal and ileal structure and function in the rat. In: Robinson JWL, Dowling RH, Riecken EO, editors. Mechanisms of intestinal adaptation. Lancaster, England: MTP Press, 1982: 467-76. 8. Laplace JP. Impairment by vagal deafferentation of the compensatory hypertrophy after enterectomy, at high and low feeding levels. In: Robinson JWL, Dowling RH, Riecken EO, editors. Mechanisms of intestinal adaptation. Lancaster. England: MTP Press Ltd. 1982321-31. 9. Touloukian RJ, Spencer RP. Blood floor in the ileal remnant following massive intestinal resection. Surg Forum 1971 ;22:37& 1. 10. Hollwarth ME, Ullrich-Baker MG, Kvietys PR, Granger DN. Ped Surg Int 1988;4:242-6. 1 1 . Hofmann AF, Crombie DL, Lillienau J. Feedback inhibition of active ileal transport of conjugated bile acids. In: Pathochemistry, pathophysiology and pathomechanics of the biliary system. New strategies for the treatment of hepato-biliarv diseases. Third International Meeting of the Biliary Club, Bologna, March 1992:23. 12. Burgess AW, Sizeland AM. Growth factors and the gut. J Gastroenterol Hepatol 19W;5 Suppl 1 : 1C21. 13. Thompson J . Specific receptors for epidermal growth factor in rat microvillous membranes. Am J Physiol 1988; 264:G42%35. 14. Young GP, Morton CL, Rose IS, Taranto TM, Bhathal PS. Effects of intestinal adaptation on insulin binding to villus cell membranes. Gut 1987;28 Suppl 1:57-62. 15. Gorelick FS. Second messenger systems and adaptation. Gut 1987;28 Suppl 1:79-84. 16. Dowling RH. Polyamines in intestinal adaptation and disease. Digestion 1990;46: Suppl 2:331-44. 17. Seiler N. Polyamine metabolism. Digestion 1990;46 Suppl 2:319-30, 18. Luk GD, Baylin SB. Inhibition of intestinal epithelial and DNA synthesis and adaptive hyperplasia after jejunectomy in the
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
Intestinal and Pancreatic Adaptation
rat by suppression of polyamine biosynthesis. J Clin Invest 1984;74:698-704. 19. Bamba T, Vaja S, Murphy GM, Dowling RH. Role of polyamines in the early adaptive response to jejunectomy in the rat: effect of DFMO on the ileal villus:crypt axis. Digestion 1990;46: Suppl 2:410-23. 20. Yang P, Baylin SB, Luk GD. Polyamines and intestinal growth: absolute requirement for ODC activity in adaptation and lactation. Am J Physiol 1984;247:G553-7. 21. Hosomi N , Lirussi F, Stace NH, Vaja S , Murphy GM, Dowling RH. Mucosal polyamine profile in normal and adapting (hypo and hyperplastic) intestine: effects of DFMO treatment. Gut 1987;28 Suppl 1:10>7. 22. Hosomi M, Stace NH, Lirussi F, Smith SM, Murphy GM, Dowling RH. Role of polyamines in intestinal adaptation in the rat. Eur J Clin Invest 1987;17:375-85. 23. Weser E. Harper AV. Inhibition of ornithine decarboxylase and polyamine biosynthesis abolishes intestinal adaptation after small bowel resection: enteral and intravenous putrescine or spermidine restores adaptive growth. In: Dowling RH, Folsch UR, Loser Chr, editors. Polyamines in the gastrointestinal tract. Dordrecht: Kluwer Academic Publishers, 1992:217-29. 24. lllei G, Morgan DML, Polyamine oxidase activity in human pregnancy serum. Br J Obstet Gynaecol 1979;86:87%881.
67
25. Luk GD, Bayless TM, Baylin SB. Diamine oxidase (histaminase). A circulating marker for rat mucosal maturation and integrity. J Clin Invest 1980;66:66-70. 26. D'Agostino L, D'Argenio G, Ciacci C, et al. Diamine oxidase in rat small bowel: distribution in different segments and cellular location. Enzyme 1984;31:217-20. 27. Erdman SH. Park JHY, Thompson JS, et al. Suppression of mucosal diamine oxidase (DAO) activity enhances postresection ileal proliferation in the rat. Gastroenterology 1989;96:1533-8. 28. Rokkas T, Vaja S, Murphy GM, Dowling RH. Aminoguanidine blocks intestinal diamine oxidase (DAO) activity and enhances the intestinal adaptive response to resection in the rat. Digestion 1990;46: Suppl 2~447-57. 29. Rountree BR, Ulshen MH, Selub S , et al. Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection. Gastroenterology 1992;103: 462-8. 30. Dowling RH, Fuller R, Ulshen MH. Zimmermann E, Lund PK. Small and large bowel mRNA in the intestinal adaptation of growth hormone transgenic mice [abstract]. Gut 1991;32:A1208 31. Ulshen MH, Dowling RH, Fuller CR, Zimmermann EM, Lund PK. Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone. Gastroenterology 1992;102. In press.
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
Dowling RH. Cellular and molecular basis of intestinal and pancreatic adaptation. Scand J Gastroenterol 1992;27 SUPPI 193164-67. This article reviews the structural and functional changes which develop in the intestine and pancreas in response to a variety of stimuli and which characterise adaptive hyper- or hypo-plasia. It then discusses the principal physiological mechanisms controlling this adaptive growth. In the gut, these include luminal nutrition, endocrine, autocrine and paracrine hormonal influences, growth factors, enterotrophic components of pancreatico-biliary secretions, neural factors, changes in blood flow and mesenchymeepithelial interactions. The cell biology of adaptive growth involves cell membrane receptors ( first messengers) and a cascade of intracellular second messengers. the best studied of which is changes in polyamine metabolism and in related enzymes. The effects of ornithine decarboxylase (ODC) blockade with difluoromethyl ornithine (DFMO) and of diamine oxidase (DAO) blockade with aminoguanidine, are described. In general. DFMO inhibits or prevents adaptive hyperplasia while in the small bowel, arninoguanidine treatment induces 'supranormal' adaptation. However, both the gut and the pancreas transport 'exogenous' (ingested in food and circulating in the blood stream) polyamines across their apical and basolateral membranes. The influence of this exogenous polyamine transport on 'endogenous' (enzyme-regulated) intracellular polyamine concentrations, is largely unknown. Finally, the molecular hiology of adaptive growth is described briefly-as illustrated by the use of a growth hormone transgenic model in which mice develop marked intestinal mucosal hyperplasia and increases in the relative abundance of insulin-like growth factor-I (IGF-I) mRNA in the intestine. Key words: Aminoguanidine; diamine oxidase; difluoromethyl ornithine; growth hormone; insulin-like growth factor-I; intestinal and pancreatic adaptive hyper- and hypo-plasia; messenger RNA: ornithine decarboxylase: polyamine metabolism Prof. R. Hermon Dowling, GastroenIerology Unit, 18th Floor. Guy's Tower, Guy's HospiIal, London SEI 9RT. U .K .
THE PHENOMENA O F INTESTINAL ADAPTATION Intestinal adaptation is mainly characterised by changes in crypt cell production rates which lead to hyperplasia (or hypoplasia) of the small bowel villi and crypts. This, coupled with intestinal dilatation, increases the absorptive surface area per unit length of bowel and results in segmental hyperfunction with enhanced absorption and increases in total enzyme activity, per unit length intestine (1). In the case of adaptive hypoplasia which occurs, for example, during total parenteral nutrition and in segments of intestine excluded from continuity as Thirty-Vella fistulae or self-emptying blind loops, the reverse is true. In other words, crypt cell production rates fall and the villi become hypoplastic: at the same time, the calibre of the intestine diminishes and the resultant reduction in absorptive surface area leads to segmental hypofunction. In both adaptive intestinal mucosal hyperplasia and hypoplasia, the size and function of the individual enterocytes changes comparatively little, if at all. The changes in segmental absorption, therefore, are mainly a function of a greater (or lesser) number of enterocytes per unit length of bowel (1). THE PHYSIOLOGICAL MECHANISMS The principal physiological mechanism controlling this
adaptive mucosal growth is luminal nutrition which may have direct topical effects on the small bowel mucosa but which probably acts mainly by stimulating: (i) the synthesis and release of enterotrophic regulatory peptides (such as the gut glucagon family of peptides (2,3) and epidermal growth factor: EGF (4.5)) and (ii) enterotrophic pancreatico-biliary secretions (6,7). Neural factors (8) and changes in mucosal blood flow (9, 10) are also important. Rarely. there may be induction or suppression of specific transport mechanisms in the absence of structural changes (for example, up- or downregulation of active bile acid transport in the ileum by cholestryamine treatment or bile acid feeding) (1 1). Although growth factors, such as insulin-like growth factor-I (IGF-I), transforming growth factors (TGF,,,,,, and TGF,,,,) and fibroblast growth factors (acidic and basic FGF), stimulate increased rates of cell division and growth in cell culture systems (12), as yet, their role as physiological enterotrophins in intestinal adaptation, is uncertain. THE CELLULAR MECHANISMS Enterotrophins, stimulated by luminal nutrition, may have endocrine, paracrine or autocrine effects which are mediated by receptors on enterocyte brush-border (13) or baso-lateral (14) membranes. This signal induction triggers off a cascade
Intestinal and Pancreatic Adaptation
14
P=0.004
150
P=0.0065
P=0.0025
12 120
10 8
P=0.0025
90
6
-
65
60
4
30
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
2 0
T
T+AG
R
0
R+AG
Fig. 1. Results for ileal mucosal DAO activity (means +- SEMs) in transected control rats ( T ) and in animals subjected to80% proximal small-bowel resection (R). The untreated animals were given saline injections only; those given aminoguinadine (AG) were treated with 25 mg kg ' day-'. The studies were carried out 12 days after jejunectomy (or in the corresponding ileal segment from the controls). There were six animals in each group. (Data from Ref. 28.)
of intra-cellular second messengers including changes in membrane phospholipids and protein kinases (15)-neither of which have been adequately studied in intestinal and pancreatic adaptation. Ultimately, these second messenger changes increase either cyclic AMP levels or intracellular free calcium ion activity (possibly with oscillating fluctuations in cytosolic Ca++ (M. J . Berridge, personal communication)), both of which may initiate increases in ornithine decarboxylase (ODC; EC 4.1.1.17) activity. O D C is the first, and rate-limiting, step in the synthesis of growthassociated polyamines-putrescine, spermidine and spermine (16). Occasionally, however, another enzyme involved in polyamine synthesis, S-adenosyl methionine decarboxylase (SAM-DC or adoMET-DC; E C 4.1.1 S O ) may be rate-limiting (17).
T
To date, cell biological studies of intestinal and pancreatic adaptation have mostly been confined to changes in polyamine levels and in the activities of the enzymes controlling polyamine synthesis (ODC and SAM-DC) and degradation (diamine oxidase; D A O ; EC 1.4.3.6). Thus, in several animal models of intestinal adaptation (resection (18, 19), lactation (20) and pancreatico-biliary diversion (21,22)). inhibition of O D C activity with the specific and irreversible blocker, alpha-difluoromethyl ornithine (DFMO), leads to marked reductions in intestinal mucosal putrescine and spermidine (but not in spermine) concentrations, and either significantly reduces or completely prevents the adaptive mucosal growth. Moreover, 'add-back' experiments show
R
R+AG
that the inhibitory effects of DFMO on intestinal adaptation (such as that seen in the ileum following jejunectomy (18, 19)) may be overcome with either putrescine or spermidine given enterally or parenterally (23). Studies such as these suggest that the final common pathway for many growth factors in intestinal adaptation is through changes in polyamine metabolism. In turn, these influence RNA polymerase, D N A , RNA and protein synthesis, cell division and growth. Although they help us to understand the cellular mechanisms controlling growth, in patients with malabsorption/malnutrition secondary to extensive disease/resection of the intestine, the problem is not how to inhibit mucosal growth but how to enhance it and to promote 'supranormal' adaptation (that is, adaptation over and above that which occurs spontaneously). Outside pregnancy (24), D A O activity is almost exclusively confined to the small bowel mucosa, particularly the ileum (25,26). Therefore, manipulation of D A O activity
I 9
T H E CELL BIOLOGY OF INTESTINAL ADAPTATION
T+AG
Fig. 2. Mucosal wet weight per unit/length ileum in the four groups of rats. (See legend to Fig. 1.)
h
c
P=0.004
1
-I
P=0.0025 7
E a.
T
T+AG
R
R+AG
Fig. 3. Mucosal protein (mg/cm per intestine) in the four experimental groups. (See legend to Fig. 1.)
66
R. H. Dowling
P=0.0025 Pe0.05
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
53 *‘OI 1.5
l-
T
T+AG
R
R+AG
Fig. 4. Mucosal DNA (mg/cm per intestine) in the four experimental groups. (See legend to Fig. 1.)
should modify intestinal mucosal polyamine levels and influence intestinal growth. The results of two preliminary studies (27,28) (Figs. 1-4) suggest that inhibition of DAO with aminoguanidine: (i) does indeed prevent the degradation of putrescine (and indirectly, therefore, of the other polyamines), (ii) results in putrescine accumulation in the intestinal mucosa and (iii) induces significantly greater ileal adaptive mucosal hyperplasia, than that which occurs spontaneously after jejunectomy. Extrapolation of these results in animal studies to man are awaited.
MOLECULAR MECHANISMS So far, molecular biological studies of intestinal adaptation have been limited. In the jejunectomy model, ileal mRNA expression of enteroglucagon and ODC increase within hours of resection, whether in fed or in fasted animals (29). and antedates any increase in DNA synthesis or in markers of mucosal growth. The transgenic mouse model has been used to study the effects of growth hormone excess on the gut (30). The growth hormone transgenic animals eat more, grow more and weigh more than their ‘wild-type’normal littermate controls. Their duodenal, jejunal and ileal mucosae show marked and significant increases in wet weight, protein and DNA/cm intestine and in villus height and crypt depth (31). However, the relative abundance of mRNA in the intestine is unchanged for ODC (and probably also for SAM-DC)despite marked increases in ODC activity. This suggests that there must be post-transcriptional changes in the enzyme. Enteroglucagon message is reciprocally related to circulating IGF-I but in keeping with the theory that growth hormone mediates its trophic effects through IGF-I, there was a 2.6 fold increase in mRNA abundance in the hyperplastic small bowel of the transgenic mice.
ACKNOWLEDGEMENTS The author is grateful to many past and present mentors and colleagues whose work formed the basis for this brief review. He was pleased to join in this tribute to Professor Fred Halter-a personal friend for many years who shares his enthusiasm not only in the field of gastrointestinal adaptation but also in the extracurricular pursuit of the trout with the fly. He wishes to thank the Special Trusteesof Guy’s Hospital for their continued help and support and Mrs. Ann Hollington who kindly prepared the manuscript.
REFERENCES 1. Dowling RH. Update on intestinal adaptation. Triangle
1988;27:149-64. 2. Gleeson MH, Bloom SR, Polak JM, Henry K, Dowling RH. Endocrine tumour in kidney affecting small bowel structure, motility and absorptive function. Gut 1971;12:77>82. 3. Jacobs LR, Bloom SR, Dowling RH. Response of plasma and tissue levels of enteroglucagon immunoreactivity to intestinal resection, lactation and hyperphagia. Life Sci 1981;29:20()3-7. 4. Goodlad RA. Wilson TJG, Lenton W, Gregory H, McCullagh KG, Wriaht NA. Intravenous but not intraaastric urogastroneEGF is Gophic to the intestine of parenterally fed Fats. Gut 1987:28:573-82. 5 . Ulshen MH, Lyn-Cook LN, Raasch RH. Effects of intraluminal epidermal growth factor on mucosal proliferation in the small intestine of adult rats. Gastroenterology 1986;91:1134-40. 6. Altmann GG, Influence of bile and pancreative secretions on the size of the intestinal villi in the rat. Am J Anat 1971;132:16778. 7. Miazza BM, Hung L, Vaja S, Dowling RH. Effect of pancreaticobiliary diversion (PBD) on jejunal and ileal structure and function in the rat. In: Robinson JWL, Dowling RH, Riecken EO, editors. Mechanisms of intestinal adaptation. Lancaster, England: MTP Press, 1982: 467-76. 8. Laplace JP. Impairment by vagal deafferentation of the compensatory hypertrophy after enterectomy, at high and low feeding levels. In: Robinson JWL, Dowling RH, Riecken EO, editors. Mechanisms of intestinal adaptation. Lancaster. England: MTP Press Ltd. 1982321-31. 9. Touloukian RJ, Spencer RP. Blood floor in the ileal remnant following massive intestinal resection. Surg Forum 1971 ;22:37& 1. 10. Hollwarth ME, Ullrich-Baker MG, Kvietys PR, Granger DN. Ped Surg Int 1988;4:242-6. 1 1 . Hofmann AF, Crombie DL, Lillienau J. Feedback inhibition of active ileal transport of conjugated bile acids. In: Pathochemistry, pathophysiology and pathomechanics of the biliary system. New strategies for the treatment of hepato-biliarv diseases. Third International Meeting of the Biliary Club, Bologna, March 1992:23. 12. Burgess AW, Sizeland AM. Growth factors and the gut. J Gastroenterol Hepatol 19W;5 Suppl 1 : 1C21. 13. Thompson J . Specific receptors for epidermal growth factor in rat microvillous membranes. Am J Physiol 1988; 264:G42%35. 14. Young GP, Morton CL, Rose IS, Taranto TM, Bhathal PS. Effects of intestinal adaptation on insulin binding to villus cell membranes. Gut 1987;28 Suppl 1:57-62. 15. Gorelick FS. Second messenger systems and adaptation. Gut 1987;28 Suppl 1:79-84. 16. Dowling RH. Polyamines in intestinal adaptation and disease. Digestion 1990;46: Suppl 2:331-44. 17. Seiler N. Polyamine metabolism. Digestion 1990;46 Suppl 2:319-30, 18. Luk GD, Baylin SB. Inhibition of intestinal epithelial and DNA synthesis and adaptive hyperplasia after jejunectomy in the
Scand J Gastroenterol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
Intestinal and Pancreatic Adaptation
rat by suppression of polyamine biosynthesis. J Clin Invest 1984;74:698-704. 19. Bamba T, Vaja S, Murphy GM, Dowling RH. Role of polyamines in the early adaptive response to jejunectomy in the rat: effect of DFMO on the ileal villus:crypt axis. Digestion 1990;46: Suppl 2:410-23. 20. Yang P, Baylin SB, Luk GD. Polyamines and intestinal growth: absolute requirement for ODC activity in adaptation and lactation. Am J Physiol 1984;247:G553-7. 21. Hosomi N , Lirussi F, Stace NH, Vaja S , Murphy GM, Dowling RH. Mucosal polyamine profile in normal and adapting (hypo and hyperplastic) intestine: effects of DFMO treatment. Gut 1987;28 Suppl 1:10>7. 22. Hosomi M, Stace NH, Lirussi F, Smith SM, Murphy GM, Dowling RH. Role of polyamines in intestinal adaptation in the rat. Eur J Clin Invest 1987;17:375-85. 23. Weser E. Harper AV. Inhibition of ornithine decarboxylase and polyamine biosynthesis abolishes intestinal adaptation after small bowel resection: enteral and intravenous putrescine or spermidine restores adaptive growth. In: Dowling RH, Folsch UR, Loser Chr, editors. Polyamines in the gastrointestinal tract. Dordrecht: Kluwer Academic Publishers, 1992:217-29. 24. lllei G, Morgan DML, Polyamine oxidase activity in human pregnancy serum. Br J Obstet Gynaecol 1979;86:87%881.
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25. Luk GD, Bayless TM, Baylin SB. Diamine oxidase (histaminase). A circulating marker for rat mucosal maturation and integrity. J Clin Invest 1980;66:66-70. 26. D'Agostino L, D'Argenio G, Ciacci C, et al. Diamine oxidase in rat small bowel: distribution in different segments and cellular location. Enzyme 1984;31:217-20. 27. Erdman SH. Park JHY, Thompson JS, et al. Suppression of mucosal diamine oxidase (DAO) activity enhances postresection ileal proliferation in the rat. Gastroenterology 1989;96:1533-8. 28. Rokkas T, Vaja S, Murphy GM, Dowling RH. Aminoguanidine blocks intestinal diamine oxidase (DAO) activity and enhances the intestinal adaptive response to resection in the rat. Digestion 1990;46: Suppl 2~447-57. 29. Rountree BR, Ulshen MH, Selub S , et al. Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection. Gastroenterology 1992;103: 462-8. 30. Dowling RH, Fuller R, Ulshen MH. Zimmermann E, Lund PK. Small and large bowel mRNA in the intestinal adaptation of growth hormone transgenic mice [abstract]. Gut 1991;32:A1208 31. Ulshen MH, Dowling RH, Fuller CR, Zimmermann EM, Lund PK. Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone. Gastroenterology 1992;102. In press.
