EPITHELIAL CHU-JENG
LESIONS IN LOW FLOW STATES: A UNIFYING
CONCEPT
CHIU, Associate Professor of Surgery, McGill University Faculty of Medicine.
Reprint requests to: Dr. Chu-Jeng Chiu, McGill University Surgical Clinic, The Montreal General Hospital, Montreal, Canada.
SUMMARY Several epithelium-lined organs are highly vulnerable in low flow states, and may lead to lesions such enteritis, stress ulcer, renal tubular necrosis, acalculous cholecystitis and “shock lung”. A hypothesis is postulates that the redistribution of the subepithelial microcirculatory blood flow and the subsequent epithelial barrier are the crucial processes in their pathogenesis. Presently available evidence in support summarized.
Why is it that after a short period of total cessation of blood flow, as in cardiac arrest, the brain is irreversibly damaged, while after prolonged low flow states, such as in shock, trauma, sepsis and cardiac failure, the brain may be spared but renal shutdown occurs? A number of organs are known to be particularly vulnerable to serious damage as a result of low flow states. The lesions which appear in the gastrointestinal tract, kidney, gall bladder and lung are known respectively as hemorrhagic enteritis, stress ulcer, renal tubular necrosis, acalculous cholecystitis and “shock lung”. Each of these clinical entities has been studied extensively by various specialities, and for each lesion pathogenetic pathways have been postulated and mazes of diagrams drawn depicting the interactions of numerous factors. As in other scientific endeavours, however, the accumulation of observations and collection of data, when advanced to a certain stage, allows the formulation of a unifying principle or hypothesis, which in turn may stimulate further investigation and experimentation. Thus the following attempt to present a unifying concept is not intended to replace a complex situation with a simplistic view, but to try to discern or to suggest what common denominators may underlie these apparently diverse pathological processes. In brief, this unifying concept postulates the following events as the crucial processes common to these organ lesions: 1) Redistribution of blood flow at the level of the microcirculation, often based on a unique anatomical arrangement of the sub-epithelial capillaries, leads to hypoperfusion of the epithelium. 2) Consequently, the epithelium, which is metabolically highly active, is deprived of oxygen and other substrates and therefore is subject to biochemical deterioration and morphological disruption (Fig. 1). 3) Epithelial lesions occur, destroying vital barrier and exchange functions, and often leading to further tissue damage. A. Hemorrhagic enteritis, most dramatic in canine shock, is characterized by hemorrhagic necrosis of the intestinal mucosa. In low flow states the tips of the villi may be deprived of diffusible substrates such as oxygen as a result
as hemorrhagic presented which damage to the of this thesis is
of the counter-current arrangement which exists in the microcirculation of the villi (1). This phenomenon is based on the unique hair-pin loop configuration of arterioles, capillaries and venules in the intestinal villi. Sympathetic stimulation which accompanies shock and stress also diverts blood flow away from the superficial layer of mucosa (2). Subsequent metabolic deterioration of the overlying epithelium with depression of oxygen utilization and nucleotide phosphate synthesis (3), results in an orderly progression of morphological damage, which is flow dependent and advances from the tips toward the crypts of the villi (4). With the loss of their epithelial “barrier”, the denuded villi become vulnerable to tryptic digestion, and finally ulceration and hemorrhagr ensue (5). Further evidence to support this thesis can be found in the protective effects of intraluminally administered glucose, which the epithelium can utilize as a metabolic substrate during low flow states (6). Also, removal or inhibition of intraluminal tryptic enzymes prevents the development of hemorrhagic necrosis (7). B. Stress ulcers have been observed with a gastroscope during the course of their development in patients, and it was noted that the initial shallow erosions of the mucosa were preceded by focal areas of pallor and hyperemia (8). Experimentally, “stress” and sympathetic stimulation not only produce gastric mucosal &hernia (9), but also a redistribution of blood flow within the mucosa (10). Recent quantitative studies using flow dependent isotopes, chromium-5 1 tagged erythrocytes and cryostatic sectioning of the gastric mucosa confirmed that there is a redistribution of blood flow. with marked “congestive hypoperfusion” of the superficial layer of the mucosa underneath the epithelium. Subsequent metabolic depression of the epithelium (11) and damage to the mucosal barrier function (12) may lead to the development of mucosal ulcerations. Intraluminal acid, enzymes and toxins may play major roles in causing tissue damage once the defence mechanism represented by the epithelial barrier is compromised (13). C. Renal tubular necrosis is characterized by the degeneration of the renal tubular epithelium. In low flow 159
states, cortical nucleotide phosphate is depleted (14) and tissue oxygen extraction is reduced (15). The vulnerability of the renal tubular epithelium can also be attributed to the peculiar microcirculatory arrangement of the vessels which supply these cells with their metabolic substrates. In the kidney, two sets of capillaries, the glomerular and the peritubular capillaries, are connected in series, rendering the latter highly vulnerable in low flow states (16). D. Two other epithelium-lined organs may also share similar pathophysiologic processes and suffer damage in low flow states, although in these cases much still remains speculative. Acalculous cholecystitis,which may occur after shock, trauma and surgery (17), could be initiated by epithelial barrier damage. Epithelial lesions similar to those described in the intestine and stomach have been observed in canine and porcine shock experiments (Fig. 1). They are rather rare, perhaps because the microcirculation in the gall bladder is less vulnerable (18). In the so-called “shocklung” syndrome, obliteration of the alveolar space due to collapse or fluid exudate is known to cause the redistribution of pulmonary blood flow away from these alveoli, so that the unoxygenated “shunt” flow is minimized (19). The affected alveolar epithelium, here considered as a metabolizing tissue, is consequently deprived of oxygen not only from the alveolar space, but also from the capillary side. Although the lungs are endowed with another blood supply, from the bronchial circulation, this arterial blood fails to reach the alveolar level. Whether pulmonary denervation, recently shown to prevent the “shock lung” syndrome (20), may 160
exert its protective effect by abolishing this blood flow redistribution would be an interesting area for further study. It appears, therefore, that the microcirculation beneath the epithelial layer of a number of organs responds to low flow states with redistribution of blood flow, aggravating local hypoperfusion. Many other factors may further interact to produce epithelial lesions. Epithelium constitutes the barrier between the living organism and his often hostile environment, while at the same time providing the portal of exchange of substances required for the metabolism and survival of the organism. In this sense, phylogenetically it is akin to the all-important cell membrane in more primitive forms of life, and its destruction may herald a major catastrophe for the whole organism. Acknowledgements
I wish to thank Drs. F. N. Gurd and E. J. Hinchey, and the John A. Hartford Foundation for their support in the studies which led to the concept presented. These studies were carried out during my tenure as a Scholar of the Medical Research Council of Canada.
REFERENCES Lundgren 0. Acta Physiol Stand, suppl. 303, 1967. Folkow B, Lewis DH, Lundgren 0, Mellander S, Wallentin I. Acta Physiol Stand. 61, 458, 1964 Bounous G, Hampson LG, Gurd FN, AM Surg. 160, 650, 1964 Chiu CJ, McArdle AH, Brown RA, Scott HJ, Gurd FN. Arch Surg. 101, 478, 1970 Gurd FN. Amer J Surg. 110, 333, 1965 McArdle AH, Chiu CJ, Gurd FN. Arch Surg. 105, 441, 1972
7.
Bounous G, Brown RA, Mulder DS, Hampson LG, Gurd FN. Arch Surg. 91, 371, 1965 8. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ. Arch Surg. 102, 266, 1971 9. Arabehety JT, Dolcini H, Gray SJ. Amer J Physiol. 197: 4, 915, 1959 10. Bulkley G, Goldman H, Trencis L, SiIen W. Surg Forum 21, 27, 1970 11. Chiu CJ, McArdle AH, Brown RA, Scott HJ, Gurd FN. Arch Surg. 103, 147, 1971 12. Skillman JJ, Gould SA, Chung RSK, Silen W. Ann Surg. 175 564, 1970
13. Mersereau WA, Hinchey EJ. Gastroenterology 64, 1130, 1973 14. LePage GA, Amex J Physiol. 147, 446, 1946 15. Dole VP, Emerson K Jr, Philhps RA, Hamilton PB, VanSlyke DD. Amer J Physiol. 145, 337, 1946 16. Trueta J, Barclay AE, Daniel PM, Franklin KJ, Prichard MML. Studies of the renal circulation. Oxford, Blackwell, 1947. 17. Lindberg EF, Grinnan GLB, Smith L. Ann Surg. 171, 152, 1970 18. Howard JM, Milford MT’, DeBakey M. Surgery 32, 251, 1952 19. Aviado DM. The lung circulation. Per amon Press NY, 1965. 20. Sug WL, Webb WR, Ecke-r RR. Surg s ynecol obstet. 127, 1005, 1968
161
LESIONS IN LOW FLOW STATES: A UNIFYING
CONCEPT
CHIU, Associate Professor of Surgery, McGill University Faculty of Medicine.
Reprint requests to: Dr. Chu-Jeng Chiu, McGill University Surgical Clinic, The Montreal General Hospital, Montreal, Canada.
SUMMARY Several epithelium-lined organs are highly vulnerable in low flow states, and may lead to lesions such enteritis, stress ulcer, renal tubular necrosis, acalculous cholecystitis and “shock lung”. A hypothesis is postulates that the redistribution of the subepithelial microcirculatory blood flow and the subsequent epithelial barrier are the crucial processes in their pathogenesis. Presently available evidence in support summarized.
Why is it that after a short period of total cessation of blood flow, as in cardiac arrest, the brain is irreversibly damaged, while after prolonged low flow states, such as in shock, trauma, sepsis and cardiac failure, the brain may be spared but renal shutdown occurs? A number of organs are known to be particularly vulnerable to serious damage as a result of low flow states. The lesions which appear in the gastrointestinal tract, kidney, gall bladder and lung are known respectively as hemorrhagic enteritis, stress ulcer, renal tubular necrosis, acalculous cholecystitis and “shock lung”. Each of these clinical entities has been studied extensively by various specialities, and for each lesion pathogenetic pathways have been postulated and mazes of diagrams drawn depicting the interactions of numerous factors. As in other scientific endeavours, however, the accumulation of observations and collection of data, when advanced to a certain stage, allows the formulation of a unifying principle or hypothesis, which in turn may stimulate further investigation and experimentation. Thus the following attempt to present a unifying concept is not intended to replace a complex situation with a simplistic view, but to try to discern or to suggest what common denominators may underlie these apparently diverse pathological processes. In brief, this unifying concept postulates the following events as the crucial processes common to these organ lesions: 1) Redistribution of blood flow at the level of the microcirculation, often based on a unique anatomical arrangement of the sub-epithelial capillaries, leads to hypoperfusion of the epithelium. 2) Consequently, the epithelium, which is metabolically highly active, is deprived of oxygen and other substrates and therefore is subject to biochemical deterioration and morphological disruption (Fig. 1). 3) Epithelial lesions occur, destroying vital barrier and exchange functions, and often leading to further tissue damage. A. Hemorrhagic enteritis, most dramatic in canine shock, is characterized by hemorrhagic necrosis of the intestinal mucosa. In low flow states the tips of the villi may be deprived of diffusible substrates such as oxygen as a result
as hemorrhagic presented which damage to the of this thesis is
of the counter-current arrangement which exists in the microcirculation of the villi (1). This phenomenon is based on the unique hair-pin loop configuration of arterioles, capillaries and venules in the intestinal villi. Sympathetic stimulation which accompanies shock and stress also diverts blood flow away from the superficial layer of mucosa (2). Subsequent metabolic deterioration of the overlying epithelium with depression of oxygen utilization and nucleotide phosphate synthesis (3), results in an orderly progression of morphological damage, which is flow dependent and advances from the tips toward the crypts of the villi (4). With the loss of their epithelial “barrier”, the denuded villi become vulnerable to tryptic digestion, and finally ulceration and hemorrhagr ensue (5). Further evidence to support this thesis can be found in the protective effects of intraluminally administered glucose, which the epithelium can utilize as a metabolic substrate during low flow states (6). Also, removal or inhibition of intraluminal tryptic enzymes prevents the development of hemorrhagic necrosis (7). B. Stress ulcers have been observed with a gastroscope during the course of their development in patients, and it was noted that the initial shallow erosions of the mucosa were preceded by focal areas of pallor and hyperemia (8). Experimentally, “stress” and sympathetic stimulation not only produce gastric mucosal &hernia (9), but also a redistribution of blood flow within the mucosa (10). Recent quantitative studies using flow dependent isotopes, chromium-5 1 tagged erythrocytes and cryostatic sectioning of the gastric mucosa confirmed that there is a redistribution of blood flow. with marked “congestive hypoperfusion” of the superficial layer of the mucosa underneath the epithelium. Subsequent metabolic depression of the epithelium (11) and damage to the mucosal barrier function (12) may lead to the development of mucosal ulcerations. Intraluminal acid, enzymes and toxins may play major roles in causing tissue damage once the defence mechanism represented by the epithelial barrier is compromised (13). C. Renal tubular necrosis is characterized by the degeneration of the renal tubular epithelium. In low flow 159
states, cortical nucleotide phosphate is depleted (14) and tissue oxygen extraction is reduced (15). The vulnerability of the renal tubular epithelium can also be attributed to the peculiar microcirculatory arrangement of the vessels which supply these cells with their metabolic substrates. In the kidney, two sets of capillaries, the glomerular and the peritubular capillaries, are connected in series, rendering the latter highly vulnerable in low flow states (16). D. Two other epithelium-lined organs may also share similar pathophysiologic processes and suffer damage in low flow states, although in these cases much still remains speculative. Acalculous cholecystitis,which may occur after shock, trauma and surgery (17), could be initiated by epithelial barrier damage. Epithelial lesions similar to those described in the intestine and stomach have been observed in canine and porcine shock experiments (Fig. 1). They are rather rare, perhaps because the microcirculation in the gall bladder is less vulnerable (18). In the so-called “shocklung” syndrome, obliteration of the alveolar space due to collapse or fluid exudate is known to cause the redistribution of pulmonary blood flow away from these alveoli, so that the unoxygenated “shunt” flow is minimized (19). The affected alveolar epithelium, here considered as a metabolizing tissue, is consequently deprived of oxygen not only from the alveolar space, but also from the capillary side. Although the lungs are endowed with another blood supply, from the bronchial circulation, this arterial blood fails to reach the alveolar level. Whether pulmonary denervation, recently shown to prevent the “shock lung” syndrome (20), may 160
exert its protective effect by abolishing this blood flow redistribution would be an interesting area for further study. It appears, therefore, that the microcirculation beneath the epithelial layer of a number of organs responds to low flow states with redistribution of blood flow, aggravating local hypoperfusion. Many other factors may further interact to produce epithelial lesions. Epithelium constitutes the barrier between the living organism and his often hostile environment, while at the same time providing the portal of exchange of substances required for the metabolism and survival of the organism. In this sense, phylogenetically it is akin to the all-important cell membrane in more primitive forms of life, and its destruction may herald a major catastrophe for the whole organism. Acknowledgements
I wish to thank Drs. F. N. Gurd and E. J. Hinchey, and the John A. Hartford Foundation for their support in the studies which led to the concept presented. These studies were carried out during my tenure as a Scholar of the Medical Research Council of Canada.
REFERENCES Lundgren 0. Acta Physiol Stand, suppl. 303, 1967. Folkow B, Lewis DH, Lundgren 0, Mellander S, Wallentin I. Acta Physiol Stand. 61, 458, 1964 Bounous G, Hampson LG, Gurd FN, AM Surg. 160, 650, 1964 Chiu CJ, McArdle AH, Brown RA, Scott HJ, Gurd FN. Arch Surg. 101, 478, 1970 Gurd FN. Amer J Surg. 110, 333, 1965 McArdle AH, Chiu CJ, Gurd FN. Arch Surg. 105, 441, 1972
7.
Bounous G, Brown RA, Mulder DS, Hampson LG, Gurd FN. Arch Surg. 91, 371, 1965 8. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ. Arch Surg. 102, 266, 1971 9. Arabehety JT, Dolcini H, Gray SJ. Amer J Physiol. 197: 4, 915, 1959 10. Bulkley G, Goldman H, Trencis L, SiIen W. Surg Forum 21, 27, 1970 11. Chiu CJ, McArdle AH, Brown RA, Scott HJ, Gurd FN. Arch Surg. 103, 147, 1971 12. Skillman JJ, Gould SA, Chung RSK, Silen W. Ann Surg. 175 564, 1970
13. Mersereau WA, Hinchey EJ. Gastroenterology 64, 1130, 1973 14. LePage GA, Amex J Physiol. 147, 446, 1946 15. Dole VP, Emerson K Jr, Philhps RA, Hamilton PB, VanSlyke DD. Amer J Physiol. 145, 337, 1946 16. Trueta J, Barclay AE, Daniel PM, Franklin KJ, Prichard MML. Studies of the renal circulation. Oxford, Blackwell, 1947. 17. Lindberg EF, Grinnan GLB, Smith L. Ann Surg. 171, 152, 1970 18. Howard JM, Milford MT’, DeBakey M. Surgery 32, 251, 1952 19. Aviado DM. The lung circulation. Per amon Press NY, 1965. 20. Sug WL, Webb WR, Ecke-r RR. Surg s ynecol obstet. 127, 1005, 1968
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