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Glucocorticoid delays intestinal epithelial restitution by inhibiting endogenous prostaglandin synthesis
A268
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 108, No. 4
GLUCOCORTICOID DELAYS INTESTINAL EPITHELIAL R E S T I T U T I O N BY I N H I B I T I N G E N D O G E N O U S PROSTAGLANDIN SYNTHESIS. S.Zushi, Y.Shinomura, T.Kiyohara, S.Kanayama, T.Minami, M.Sugimachi, Y.Matsuzawa. Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan
Corticosteroids and NSAIDs are commonly used drugs for their strong anti-inflammatory activity. However, these drugs are recently known to cause intestinal inflammation in many cases. !npairment of epithelial barrier function may play some role, though the precise mechanism is not clear. The aim of the present study is to examine the effect of these drugs on intestinal epithelial restitution. Methods: By using two intestinal cell lines of IEC-6 and Caco-2, we assessed the effect o f dexamethasone and piroxicani on intestinal epithelial cell restitution. Wounds were created in confluent monolayers and restitution was estimated by the area of migrated ceils covered:over denuded area in 24hours. Cell viability and proliferation were assessed by MTT assay, and prostaglandin syntbesis was examined by ELISA~ Results: Dexamethasone suppressed FCS-accerelated restitution in a dosedependent manner up to 60.0% in IEC-6 cells, and 69.2% in Caco-2 cells, respectively. Dexamethasone also abolished the increase in prostaglandin synthesis stimulated by FCS in both cells. A specific cyclooxygenase inhibitor piroxicam mimicked the effects of dexamethasone. No additive effect of dexamethasone and piroxicam was observed. Conclusions: Inhibition of FCS-accerelated restitution by dexamethasone and piroxicam suggests the important role of endogenous eicosanoids in restitution process of intestinal epithelial cells.
,testinal Disorde,
THE RELEASE OF ENTERIC NEUROPEPTIDES FOLLOWING SMALL BOWEL RESECTION, WITH AND WITHOUT BYPASS OF THE ILEOCECAL JUNCTION. T.E. Adrian, J.S. Thompson, E.M.M. Quigley, P. Staab. Department of Biomedical Sciences, Creighton University School of Medicine, and Surgery and Medicine, VAMC and University of Nebraska Medical Center, Omaha, NE. The mechanisms responsible for the slowing of transit and improved absorption which occurs over time after bowel resection are largely unknown, but retention of the ileocecal junction (ICJ) appears to promote a better nutritional outcome. Bacterial overgrowth, due to loss of this sphincteric region, may influence neuropeptide function through production of volatile fatty acids or by disrupting digestion: The influence of the ICJ on resection-induced changes in neuropeptide release were investigated in dogs. The portal release of neuropeptides and hormones by perfusion (40ml/10 min) with mixed volatile fatty acids (MVFA, 145mM), or fat (26 % corn oil, Lipomul) into a loop of intestine was investigated in 12 dogs with 50% distal bowel resection, 6 with and 6 without ileocolonic anastomosis,and in 5 controls (transection). MVFA caused a marked release of VIP in control dogs but not in either resection group (P < 0.05). In contrast, MVFA-stimulated substance P release was similar in all three groups. Fat substantially increased VIP and substance P release in control dogs but the VIP rise was virtually abolished by resection (P<0.05) and the substance P increase was obtunded. CGRP levels were unchanged by MVFA and fat and were similar between the groups. Basal PYY levels were increased in the resection groups, but a fat-indflced increase was only seen in the control group. Similarly, M V F ~ and fat induced release o f neurotensin was significant only in the cmttrol group. Control perfusions with lactic acid and saline had no effect in any group. Small boweL, resection is associated with marked changes in neuropeptide and hormone release in response to luminal volatile fatty acids and fat; and features a striking blunting of the responses of VIP~' substance P, PYY, and neurotensin to luminal fat and volatile fatty acids. While changes in release of these regulatory peptides may be involved in motor and secretory adaptation to resection, they are unlikely to account for the malabsorption seen after loss of the ileocecal junction.
• EFFECTS OF ACUTE AND CHRONIC NITRIC OXIDE SYNTHASE (NOS) I N H I B m O N ON SPLANCHNIC ORGAN BLOOD FLOW: IMPLICATIONS IN GUT AND LIVER PATHOPHYSIOLOGY. S. Aiko. J. Davis, J.N. Banoit, M.B. Grisham, Dept. of Physiology and Biophysics, LSU Medical Center, Shreveport, LA 71130. Recent studies from our laboratory as well as others have demonstrated that oral administration of certain NOS inhibitors attenuates tissue inju~ and inflammation in several different models of gut and liver pathdbiolngy. Although these data have been interpreted to suggest that NO-may directly or indirectly play an important role in promoting gut inflammation and dysfunction, it is possible that inhibition of vascular-NOS may pro.tect gut by promoting vasoconstriction wnich would decrease blood flow mereay limiting the defivery of inflammatory cells and media.to.rs to the tissue, Therefore, the objective of this study was to quanti~ blood flow t? the splaochnlc organs before and after acute or chronic administration of two different NOS inldbitors. A total of 46 male Sprague-Dawley ~ts (300= 325g) were randomized_ into 5 grou.ps,consisting ot one untreated control grpup (n=15), two N~-nitro-L-argmine methyIester (L-NAME) groups ~vhich were treated for 1 or 21 days with 15/~mnies/kg/day (p.o.; nffie rer each group) and two aminoguanidine (AG) groups w~ich were treated for 1 or 21 days with 15 ~xonles~g/day (p.o.; n=7 for 1 day and n=8 for 21 day group~. L-NAME and AG were chosen as the NOS.mhibitors be~.use of their relative selectivities for me constitutive ano inouciole Nu~, respf,ctively. The radiolabeled micrnspbere/reference organ metho¢[, was used to ~terrnine tissue blood flo.ws in the splanclmic organs and pmsma nitrate and nitrite levels were qcantined using the Grieas reaction following reduction of all nitrate to fiitrite. We found that acute and chronic administration of L-NAME but not AG enhanced mean arterlalpressure (134 vs 163 and 170 mmHg for 1 and 21 day, rnspoctivaly~ p~:0.005). Plasma levels of nitrate and nitrite were signi6cantly inldbit~ omy in the 21 .day L-NAME group (14+1 vs 20+I #M; p<~0.05). Acute (1 day) administration L-NAME produced a significant decrease m hepatic arterml blood flow (28+3 vs 54+5 ml/min/100g wet wt; p<0.05) Whereas acute administration of AG reduced blood flow in the stomach 0 9 + 5 vs 64+7 ml/mirdl00 g wet wt;.p<0.05), p~creas_ (66+8 vs 105~10^ml/min/100 g wet wt; p<0.05) one mesentery (43+~; vs 80+10 m!/mm/lw g. wet ~ ; p<0.05). Blood flow to all other splanchnic org.~ (including me smad intestine and colon) was unaffected by acute administration of either LNAME or AG. Interesfingly~chronic (21 day.) administration of L-NAME reauced hepatic arterial blood flow Dy approximately 70% (154-3 vs 544-5 ml/min/100 g wet wt; p<0.05) whereas chronic administration of AG Od not affect blood flow to any splaocbeic organ/We conclude that the protective effects of L-NAME or AG in models of intestinal or colonic injury and inflammation are not due to reductions in blood flow to these organs. However, L-NAME does reduce hepatic arterial BF and thus this ettact may be important in models of hepatic pathophysiology. (Supported by DK47663)
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 108, No. 4
GLUCOCORTICOID DELAYS INTESTINAL EPITHELIAL R E S T I T U T I O N BY I N H I B I T I N G E N D O G E N O U S PROSTAGLANDIN SYNTHESIS. S.Zushi, Y.Shinomura, T.Kiyohara, S.Kanayama, T.Minami, M.Sugimachi, Y.Matsuzawa. Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan
Corticosteroids and NSAIDs are commonly used drugs for their strong anti-inflammatory activity. However, these drugs are recently known to cause intestinal inflammation in many cases. !npairment of epithelial barrier function may play some role, though the precise mechanism is not clear. The aim of the present study is to examine the effect of these drugs on intestinal epithelial restitution. Methods: By using two intestinal cell lines of IEC-6 and Caco-2, we assessed the effect o f dexamethasone and piroxicani on intestinal epithelial cell restitution. Wounds were created in confluent monolayers and restitution was estimated by the area of migrated ceils covered:over denuded area in 24hours. Cell viability and proliferation were assessed by MTT assay, and prostaglandin syntbesis was examined by ELISA~ Results: Dexamethasone suppressed FCS-accerelated restitution in a dosedependent manner up to 60.0% in IEC-6 cells, and 69.2% in Caco-2 cells, respectively. Dexamethasone also abolished the increase in prostaglandin synthesis stimulated by FCS in both cells. A specific cyclooxygenase inhibitor piroxicam mimicked the effects of dexamethasone. No additive effect of dexamethasone and piroxicam was observed. Conclusions: Inhibition of FCS-accerelated restitution by dexamethasone and piroxicam suggests the important role of endogenous eicosanoids in restitution process of intestinal epithelial cells.
,testinal Disorde,
THE RELEASE OF ENTERIC NEUROPEPTIDES FOLLOWING SMALL BOWEL RESECTION, WITH AND WITHOUT BYPASS OF THE ILEOCECAL JUNCTION. T.E. Adrian, J.S. Thompson, E.M.M. Quigley, P. Staab. Department of Biomedical Sciences, Creighton University School of Medicine, and Surgery and Medicine, VAMC and University of Nebraska Medical Center, Omaha, NE. The mechanisms responsible for the slowing of transit and improved absorption which occurs over time after bowel resection are largely unknown, but retention of the ileocecal junction (ICJ) appears to promote a better nutritional outcome. Bacterial overgrowth, due to loss of this sphincteric region, may influence neuropeptide function through production of volatile fatty acids or by disrupting digestion: The influence of the ICJ on resection-induced changes in neuropeptide release were investigated in dogs. The portal release of neuropeptides and hormones by perfusion (40ml/10 min) with mixed volatile fatty acids (MVFA, 145mM), or fat (26 % corn oil, Lipomul) into a loop of intestine was investigated in 12 dogs with 50% distal bowel resection, 6 with and 6 without ileocolonic anastomosis,and in 5 controls (transection). MVFA caused a marked release of VIP in control dogs but not in either resection group (P < 0.05). In contrast, MVFA-stimulated substance P release was similar in all three groups. Fat substantially increased VIP and substance P release in control dogs but the VIP rise was virtually abolished by resection (P<0.05) and the substance P increase was obtunded. CGRP levels were unchanged by MVFA and fat and were similar between the groups. Basal PYY levels were increased in the resection groups, but a fat-indflced increase was only seen in the control group. Similarly, M V F ~ and fat induced release o f neurotensin was significant only in the cmttrol group. Control perfusions with lactic acid and saline had no effect in any group. Small boweL, resection is associated with marked changes in neuropeptide and hormone release in response to luminal volatile fatty acids and fat; and features a striking blunting of the responses of VIP~' substance P, PYY, and neurotensin to luminal fat and volatile fatty acids. While changes in release of these regulatory peptides may be involved in motor and secretory adaptation to resection, they are unlikely to account for the malabsorption seen after loss of the ileocecal junction.
• EFFECTS OF ACUTE AND CHRONIC NITRIC OXIDE SYNTHASE (NOS) I N H I B m O N ON SPLANCHNIC ORGAN BLOOD FLOW: IMPLICATIONS IN GUT AND LIVER PATHOPHYSIOLOGY. S. Aiko. J. Davis, J.N. Banoit, M.B. Grisham, Dept. of Physiology and Biophysics, LSU Medical Center, Shreveport, LA 71130. Recent studies from our laboratory as well as others have demonstrated that oral administration of certain NOS inhibitors attenuates tissue inju~ and inflammation in several different models of gut and liver pathdbiolngy. Although these data have been interpreted to suggest that NO-may directly or indirectly play an important role in promoting gut inflammation and dysfunction, it is possible that inhibition of vascular-NOS may pro.tect gut by promoting vasoconstriction wnich would decrease blood flow mereay limiting the defivery of inflammatory cells and media.to.rs to the tissue, Therefore, the objective of this study was to quanti~ blood flow t? the splaochnlc organs before and after acute or chronic administration of two different NOS inldbitors. A total of 46 male Sprague-Dawley ~ts (300= 325g) were randomized_ into 5 grou.ps,consisting ot one untreated control grpup (n=15), two N~-nitro-L-argmine methyIester (L-NAME) groups ~vhich were treated for 1 or 21 days with 15/~mnies/kg/day (p.o.; nffie rer each group) and two aminoguanidine (AG) groups w~ich were treated for 1 or 21 days with 15 ~xonles~g/day (p.o.; n=7 for 1 day and n=8 for 21 day group~. L-NAME and AG were chosen as the NOS.mhibitors be~.use of their relative selectivities for me constitutive ano inouciole Nu~, respf,ctively. The radiolabeled micrnspbere/reference organ metho¢[, was used to ~terrnine tissue blood flo.ws in the splanclmic organs and pmsma nitrate and nitrite levels were qcantined using the Grieas reaction following reduction of all nitrate to fiitrite. We found that acute and chronic administration of L-NAME but not AG enhanced mean arterlalpressure (134 vs 163 and 170 mmHg for 1 and 21 day, rnspoctivaly~ p~:0.005). Plasma levels of nitrate and nitrite were signi6cantly inldbit~ omy in the 21 .day L-NAME group (14+1 vs 20+I #M; p<~0.05). Acute (1 day) administration L-NAME produced a significant decrease m hepatic arterml blood flow (28+3 vs 54+5 ml/min/100g wet wt; p<0.05) Whereas acute administration of AG reduced blood flow in the stomach 0 9 + 5 vs 64+7 ml/mirdl00 g wet wt;.p<0.05), p~creas_ (66+8 vs 105~10^ml/min/100 g wet wt; p<0.05) one mesentery (43+~; vs 80+10 m!/mm/lw g. wet ~ ; p<0.05). Blood flow to all other splanchnic org.~ (including me smad intestine and colon) was unaffected by acute administration of either LNAME or AG. Interesfingly~chronic (21 day.) administration of L-NAME reauced hepatic arterial blood flow Dy approximately 70% (154-3 vs 544-5 ml/min/100 g wet wt; p<0.05) whereas chronic administration of AG Od not affect blood flow to any splaocbeic organ/We conclude that the protective effects of L-NAME or AG in models of intestinal or colonic injury and inflammation are not due to reductions in blood flow to these organs. However, L-NAME does reduce hepatic arterial BF and thus this ettact may be important in models of hepatic pathophysiology. (Supported by DK47663)