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IL-11 is upregulated in human NEC
reported a murine model of intestinal I/R, in which an increase in mucosal production of interleukin 6 (IL-6) messenger RNA (mRNA) and serum protein, but not tumor necrosis factor ␣ mRNA and serum protein, is detected within 4 hours of reperfusion. Interleukin 6 exhibits both pro- and anti-inflammatory activities in vitro. Therefore we further investigated the role of IL-6 synthesis. Methods: Interleukin 6 – deficient (IL-6⫺/⫺) mice on a Balb.b background and their normal litter mates (IL-6⫹/⫹) were subjected to 50 minutes of superior mesenteric artery occlusion with subsequent reperfusion. Segments of distal jejunum and proximal ileum were evaluated microscopically using a previously described histopathologic grading score, which assessed villus height, epithelial cell necrosis, erosion, and presence of neutrophils in lamina propria. The data were analyzed by the Student t test. Results: In IL-6⫹/⫹ mice, microscopic and macroscopic injuries to the small intestine are maximal by 4 hours after the start of reperfusion. Interleukin 6 – deficient mice had a significantly greater degree of mucosal damage (2.75 ⫾ 0.35) than their wild-type litter mates (1.67 ⫾ 0.29) at 4 hours (p ⬍ 0.02). By 16 hours, significant repair of the epithelium is observed in both immunocompetent and IL-6⫺/⫺ animals. Conclusions: The peak mucosal expression of IL-6 mRNA prevented maximal mucosal epithelial and ischemic injury. In contrast to the previously accepted viewpoint that IL-6 functions as a proinflammatory cytokine, these observations delineate a protective role for IL-6 during ischemic intestinal injury. 12 Concurrent reduction of glycogenolysis, glycolysis, and NAⴙ/Kⴙ pump activity after hemorrhagic shock McCarter FD, Evans JA, Luchette FA, Friend LA, James JH, Davis K Jr, Frame SB. From the Division of Trauma and Critical Care, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio. Purpose: Lactate has been has long been associated with anaerobic metabolism. Hemorrhagic shock (HSK) increases muscle glycogenolysis and muscle lactate production. We hypothesized hyperlactemia after HSK is a result of epistimulated Na⫹/K⫹ pump activity. Thus, ␣- and -adrenergic blockade should alter lactate production and glycogen loss after HSK. Methods: Sprague–Dawley rats (125 g) were bled to a mean arterial pressure of 40 mm Hg. Phenoxybenzamine and propranolol were given for complete adrenergic blockade during HSK. Extensor digitorum (EDL) and soleus muscles were harvested at 1 hour. Muscle lactate, glycogen, glucose 6-phosphate (G6P), and intracellular Na⫹:K⫹ ratio were measured. Results: Only EDL shown, similar results produced by soleus. Lactate Glycogen G6P Na⫹:K⫹
No HSK
HSK only
1.27 ⫾ 0.1 32.21 ⫾ 0.9 0.74 ⫾ 0.1 0.136 ⫾ 0.02
7.95 ⫾ 2.0 26.97 ⫾ 2.1 3.47 ⫾ 0.4 0.159 ⫾ 0.08
HSK and blockers 2.51 ⫾ 0.2* 40.34 ⫾ 0.9* 0.79 ⫾ 0.6* 0.101 ⫾ 0.01
Combined adrenergic blockade during HSK significantly (*) reduced lactate production, glycogen loss, and G6P production, as compared with HSK only.
hydrolase (GTP-CH). We sought to determine the role of GTP-CH and other inflammatory cytokines such as IL-8 and IL-12 in acute NEC. Methods: Intestinal GTP-CH, IL-8, and IL-12 messenger RNA expression was measured by Northern blot or semiquantitative reverse transcription polymerase chain reaction in 20 infants with acute NEC, 13 patients with other inflammatory conditions, and 7 patients undergoing bowel resection without inflammation. Guanosine triphosphate– cyclohydrolase enzyme activity was also measured. Cytokine band density
NEC (n ⴝ 20)
Inflammation (n ⴝ 13)
No disease (n ⴝ 7)
IL-8 IL-12 GTP-CH activity
60.4 ⫾ 35.0* 8/20† 23.9 ⫾ 12.9 (n ⫽ 13)‡
40.3 ⫾ 19.6 6/13 7.5 ⫾ 1.0 (n ⫽ 2)
40.4 ⫾ 21.5 6/7 18.9 ⫾ 0.7 (n ⫽ 4)
*p ⬍ 0.05 vs no disease or inflammation. †p ⬍ 0.08 vs no disease. ‡p ⬍ 0.05 vs inflammation.
Results: There was no difference in GTP-CH enzyme activity between patients with acute NEC and those without inflammation; however, GTP-CH enzyme activity was decreased in other inflammatory conditions. Interleukin-8 expression was upregulated, whereas IL-12 was detected in only a third of the NEC patients. Conclusions: De novo NO synthesis in acute NEC may not require coinduction of GTP-CH. Interleukin-8 upregulation may promote neutrophil recruitment, whereas decreased IL-12 production may impair bacterial clearance and thus may facilitate bacterial invasion in NEC. 14 IL-11 is upregulated in human NEC Nadler EP, Stanford A, Zhang XR, Upperman JS, Ford HR. From the Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Purpose: Interleukin 11 (IL-11) is a pleiotropic cytokine that promotes epithelial regeneration after chemo- and radiotherapy and enhances intestinal adaptation after massive small bowel resection. We previously demonstrated that IL-11 prevents mucosal atrophy in defunctionalized intestinal segments in rats. However, its role in human gastrointestinal diseases is unknown. We examined the pattern of IL-11 expression in resected intestinal segments from infants with acute necrotizing enterocolitis (NEC). Methods: We measured intestinal IL-11 messenger RNA (mRNA) expression by semiquantitative reverse transcription polymerase chain reaction in 29 infants undergoing bowel resection for acute NEC, 22 patients with other inflammatory conditions, and 10 patients undergoing bowel resection for intestinal stoma closure or other conditions without inflammation. Results: Interleukin-11 mRNA expression was upregulated in the intestine in all patients with inflammation. Infants with acute NEC showed the highest expression of IL-11. Interleukin-11 expression was diminished at the time of intestinal stoma closure in infants who had recovered from NEC.
Conclusions: Changes in glycogen metabolism and lactate production during HSK can be altered by adrenergic blockade. Increased lactate production and glycogen breakdown may reflect elevations in Na⫹,K⫹–adenosine triphosphatase activity in response to epirelease, rather than hypoxia.
BDV
13
Conclusions: Interleukin-11 is upregulated in acute NEC and is downregulated at the time of stoma closure. This phenomenon may represent an adaptive response designed to limit the extent of intestinal damage in NEC or other inflammatory conditions affecting the gastrointesinal tract.
GTP-cyclohydrolase and cytokine gene expression in NEC Stanford A, Nadler EP, Zhang XR, Ford HR. From the Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Purpose: Inducible nitric oxide (NO) synthase (iNOS) is upregulated in infants with acute necrotizing enterocolitis (NEC) and may contribute to bowel necrosis. Furthermore, interferon ␥ is consistently elevated in the intestine in acute NEC, but tumor necrosis factor ␣, interleukin 1 (IL-1), and IL-6 expression varies. Nitric oxide production by iNOS requires the cofactor tetrahydrobiopterin, whose synthesis is regulated by guanosine triphosphate– cyclo-
IL-11 mRNA
Acute NEC (n ⴝ 29) 70.1 ⫾ 37.6*
Inflammation (n ⴝ 22)
No disease (n ⴝ 10)
54.5 ⫾ 35.2
35.6 ⫾ 28.7
*p ⬍ 0.05 vs no disease (Fisher least significant difference).
15 Intracoronary E- and L-selectin blockade attenuates myocardial neutrophil infiltration in cardiac ischemia/reperfusion injury Carter YM, Thomas R, Bargatze R, Jutila M, Murry C, Allen MD. From the Division of Cardiothoracic Surgery, University of Washington, Seattle, Washington.
CURRENT SURGERY • Volume 57/Number 6 • November/December 2000
639
No HSK
HSK only
1.27 ⫾ 0.1 32.21 ⫾ 0.9 0.74 ⫾ 0.1 0.136 ⫾ 0.02
7.95 ⫾ 2.0 26.97 ⫾ 2.1 3.47 ⫾ 0.4 0.159 ⫾ 0.08
HSK and blockers 2.51 ⫾ 0.2* 40.34 ⫾ 0.9* 0.79 ⫾ 0.6* 0.101 ⫾ 0.01
Combined adrenergic blockade during HSK significantly (*) reduced lactate production, glycogen loss, and G6P production, as compared with HSK only.
hydrolase (GTP-CH). We sought to determine the role of GTP-CH and other inflammatory cytokines such as IL-8 and IL-12 in acute NEC. Methods: Intestinal GTP-CH, IL-8, and IL-12 messenger RNA expression was measured by Northern blot or semiquantitative reverse transcription polymerase chain reaction in 20 infants with acute NEC, 13 patients with other inflammatory conditions, and 7 patients undergoing bowel resection without inflammation. Guanosine triphosphate– cyclohydrolase enzyme activity was also measured. Cytokine band density
NEC (n ⴝ 20)
Inflammation (n ⴝ 13)
No disease (n ⴝ 7)
IL-8 IL-12 GTP-CH activity
60.4 ⫾ 35.0* 8/20† 23.9 ⫾ 12.9 (n ⫽ 13)‡
40.3 ⫾ 19.6 6/13 7.5 ⫾ 1.0 (n ⫽ 2)
40.4 ⫾ 21.5 6/7 18.9 ⫾ 0.7 (n ⫽ 4)
*p ⬍ 0.05 vs no disease or inflammation. †p ⬍ 0.08 vs no disease. ‡p ⬍ 0.05 vs inflammation.
Results: There was no difference in GTP-CH enzyme activity between patients with acute NEC and those without inflammation; however, GTP-CH enzyme activity was decreased in other inflammatory conditions. Interleukin-8 expression was upregulated, whereas IL-12 was detected in only a third of the NEC patients. Conclusions: De novo NO synthesis in acute NEC may not require coinduction of GTP-CH. Interleukin-8 upregulation may promote neutrophil recruitment, whereas decreased IL-12 production may impair bacterial clearance and thus may facilitate bacterial invasion in NEC. 14 IL-11 is upregulated in human NEC Nadler EP, Stanford A, Zhang XR, Upperman JS, Ford HR. From the Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Purpose: Interleukin 11 (IL-11) is a pleiotropic cytokine that promotes epithelial regeneration after chemo- and radiotherapy and enhances intestinal adaptation after massive small bowel resection. We previously demonstrated that IL-11 prevents mucosal atrophy in defunctionalized intestinal segments in rats. However, its role in human gastrointestinal diseases is unknown. We examined the pattern of IL-11 expression in resected intestinal segments from infants with acute necrotizing enterocolitis (NEC). Methods: We measured intestinal IL-11 messenger RNA (mRNA) expression by semiquantitative reverse transcription polymerase chain reaction in 29 infants undergoing bowel resection for acute NEC, 22 patients with other inflammatory conditions, and 10 patients undergoing bowel resection for intestinal stoma closure or other conditions without inflammation. Results: Interleukin-11 mRNA expression was upregulated in the intestine in all patients with inflammation. Infants with acute NEC showed the highest expression of IL-11. Interleukin-11 expression was diminished at the time of intestinal stoma closure in infants who had recovered from NEC.
Conclusions: Changes in glycogen metabolism and lactate production during HSK can be altered by adrenergic blockade. Increased lactate production and glycogen breakdown may reflect elevations in Na⫹,K⫹–adenosine triphosphatase activity in response to epirelease, rather than hypoxia.
BDV
13
Conclusions: Interleukin-11 is upregulated in acute NEC and is downregulated at the time of stoma closure. This phenomenon may represent an adaptive response designed to limit the extent of intestinal damage in NEC or other inflammatory conditions affecting the gastrointesinal tract.
GTP-cyclohydrolase and cytokine gene expression in NEC Stanford A, Nadler EP, Zhang XR, Ford HR. From the Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Purpose: Inducible nitric oxide (NO) synthase (iNOS) is upregulated in infants with acute necrotizing enterocolitis (NEC) and may contribute to bowel necrosis. Furthermore, interferon ␥ is consistently elevated in the intestine in acute NEC, but tumor necrosis factor ␣, interleukin 1 (IL-1), and IL-6 expression varies. Nitric oxide production by iNOS requires the cofactor tetrahydrobiopterin, whose synthesis is regulated by guanosine triphosphate– cyclo-
IL-11 mRNA
Acute NEC (n ⴝ 29) 70.1 ⫾ 37.6*
Inflammation (n ⴝ 22)
No disease (n ⴝ 10)
54.5 ⫾ 35.2
35.6 ⫾ 28.7
*p ⬍ 0.05 vs no disease (Fisher least significant difference).
15 Intracoronary E- and L-selectin blockade attenuates myocardial neutrophil infiltration in cardiac ischemia/reperfusion injury Carter YM, Thomas R, Bargatze R, Jutila M, Murry C, Allen MD. From the Division of Cardiothoracic Surgery, University of Washington, Seattle, Washington.
CURRENT SURGERY • Volume 57/Number 6 • November/December 2000
639