Skip to main navigation menu Skip to main content Skip to site footer

Research Article

Vol. 2 No. 1 (1996)

Pre-Fibrotic Changes are Induced in the Guinea Pig Liver in Response to Cardiorespiratory, Central Nervous System, and Gastrointestinal Stressors

  • Michael E. Motokata
October 25, 2020


To determine the relationship between stress and the incidence of liver fibrosis, 140 guinea pigs were

exposed to various stressors, and their post-mortem livers were assessed. Four stress groups-
cardiorespiratory (CR), central nervous system (CNS), gastrointestinal (GI), and combined (Cd)were

designated in accordance with the stressor(s) experienced and were compared to unstressed control
subjects. By blood chemistry analysis, the most pervasive findings were decreased glucose and

increased amylase. Stress group blood glucose levels ranged from 22% to 38% below that of non-
stressed controls, and serum amylase was increased by 35% to 68% relative to controls. The reduction

in glucose was significant in the CR and GI groups, and the elevation in amylase was significant in the
CR, GI, and Cd groups. Pathologically, the most frequent finding among the four groups was fatty
change, present in 44% of stressed subjects, followed by passive congestion, observed in 40%. The Cd
group demonstrated a significantly increased incidence of congestion, while both the Cd and GI groups
showed a significantly increased incidence of fatty change. Subjects in whom congestion was detected
showed a 1.7-fold greater fibroblast proliferation than subjects in whom fatty change was seen. The
most extensive pathological changes were manifested in the Cd group, in the form of congestion,
hemorrhage, fatty change, and fibroblast proliferation. Among the three single-stress groups, the
greatest degree of fibroblast proliferation and collagen deposition, and hence the greatest potential for
fibrosis, was evident in the GI group. The fibroblastosis in the GI group was statistically significant,
presenting a direct pathological indication of pre-fibrotic change. These results provide preliminary
evidence that stress is capable of inducing pathological processes in the liver that may lead to fibrosis
and, ultimately, to cirrhosis.


  1. Cotran RS, Kumar V, Robbins SL. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia: WB Saunders Co.; 1994: 834.
  2. Gressner AM, Bachem MG. Cellular communications and cell-matrix interactions in the pathogenesis of fibroproliferative diseases: liver fibrosis as a paradigm. Annales de Biologie Clinique 52(3): 205-226; 1994.
  3. Andus T, Holstege A. Cytokines and the liver in health and disease. Effects on liver metabolism and fibrogenesis. Acta Gastroenterologica Belgica 57(3-4): 236-244; 1994.
  4. Khansari DN, Murgo AJ, Faith RE. Effects of stress on the immune system. Immunology Today 11(5): 170-175; 1990.
  5. Carlson MG, Snead WL, Campbell PJ. Fuel and energy metabolism in fasting humans. American Journal of Clinical Nutrition 60(1): 29-36; 1994.
  6. Friedman SL, Arthur MJ. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. Journal of Clinical Investigation 84: 1780-1785; 1989.
  7. Zerbe O, Gressner AM. Proliferation of fat-storing cells is stimulated by secretion of Kupffer cells from normal and injured liver. Experimental and Molecular Pathology 49(1): 87-101; 1988.
  8. Matsuoka M, Pham NT, Tsukamoto H. Differential effects of interleukin-1-alpha, tumor necrosis factor alpha, and transforming growth factor-beta-1 on cell proliferation and collagen formation by cultured fat-storing cells. Liver 9(2): 71-78; 1989.
  9. Meyer DH, Bachem MG, Gressner AM. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type beta-1 and type alpha. Biochemical and Biophysical Research Communications 171(3): 1122-1129; 1990.
  10. Gressner AM, Zerbe O. Kupffer cell-mediated induction of synthesis and secretion of proteoglycans by rat liver fat-storing cells in culture. Journal of Hepatology 5(3): 299-310; 1987.
  11. Gressner AM, Haarmann R. Regulation of hyaluronate synthesis in rat liver fat storing cell cultures by Kupffer cells. Journal of Hepatology 7(3): 310-318; 1987.
  12. Mak KM, Leo MA, Lieber CS. Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells. Gastroenterology 87(1): 188-200; 1984.
  13. McGee JO, Patrick RS. The role of perisinusoidal cells in hepatic fibrogenesis. An electron microscopic study of acute carbon tetrachloride liver injury. Laboratory Investigation 26(4): 429-440; 1972.
  14. Davis BH. Transforming growth factor beta responsiveness is modulated by the extracellular collagen matrix during hepatic ito cell culture. Journal of Cellular Physiology 136(3): 547-553; 1988.
  15. Bouziane M, Prost J, Belleville J. Dietary protein deficiency affect n-3 and n-6 polyunsaturated fatty acids hepatic storage and very low density lipoprotein transport in rats on different diets. Lipids 29(4): 265-272; 1994.
  16. Bullock BL, Rosendahl PP. Pathophysiology: adaptations and alterations in function. 3rd ed. Philadelphia: J.B Lippincott Co.; 1992.
  17. Sasaki F, Wu P, Rougeau D, et al. Cytochemical studies of responses of corticotropes and thyrotropes to cold and novel environment stress. Endocrinology 127(1): 285-297; 1990.
  18. Chopra S, Griffin PH. Laboratory tests and diagnostic procedures in evaluation of liver disease. American Journal of Medicine 79(2): 221-230; 1985.
  19. Del Olmo Martinez ML, Barba Bermejo M. [Changes in pancreatic secretion in alcoholic liver disease.] Revista Espanola de Enfermedades Digestivas 77(3): 197-204; 1990.
  20. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 95(3): 734-739; 1988.
  21. Yamaguchi H, Kimura T, Nawata H. Does stress play a role in the development of severe pancreatitis in rats? Gastroenterology 98(6): 1682-1688; 1990.
  22. Tanaka T, Ichiba Y, Miura Y. et al. Canine model of chronic pancreatitis due to chronic ischemia. Digestion 55(2): 86-89; 1994.
  23. Freiburghaus AU, Redha F, Ammann RW. Does acute pancreatitis progress to chronic pancreatitis? A microvascular pancreatitis model in the rat. Pancreas 11(4): 374-381; 1995.
  24. Goth L, Meszadros I, Scheller G. Hyperamylasemia and alpha-amylase isozymes in acute liver congestion due to cardiac circulatory failure. Clinical Chemistry 35(8): 1793-1794; 1989.
  25. Shibayama Y, Urano T, Asaka S, et al. Pathogenesis of centrilobular necrosis following congestion of the liver. Journal of Gastroenterology & Hepatology 8(6): 530-534; 1993.
  26. Kissane JM, ed. Anderson's Pathology. 8th ed. St. Louis: CV Mosby Co.; 1985: 1106.
  27. Irita K, Okabe H, Koga A, et al. Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis. Circulatory Shock 42(3): 115-120; 1994.
  28. Schoenberg MH, Buchler M. Pietrzk C, et al. Lipid peroxidation and glutathione metabolism in chronic pancreatitis. Pancreas 10(1): 36-43; 1995.
  29. Luthen R, Niederau C, Grendell JH. Intrapancreatic zymogen activation and levels of ATP and glutathione during caerulein pancreatitis in rats. American Journal of Physiology 268(4 pt 1): G592-G604; 1995.
  30. Takayama F, Egashira T, Yamanaka Y. The multiple hydroperoxides of choline phospholipids occuring in plasma after ischemia-reperfusion in rat liver. Journal of Toxicological Sciences 19(2): 97-106; 1994.


Download data is not yet available.