[Significance of Inflammatory/Nutritional Index in Pathological Stage â ¡-â ¢ Colorectal Cancer].

The aim of this study was to evaluate the inflammatory/nutritional index in patients with colorectal cancer. A total of 600 patients with pStage Ⅱ-Ⅲ colorectal cancer who underwent radical resection at our hospital between January 2008 and September 2022 were retrospectively reviewed. Onodera's prognostic nutritional index(OPNI), CRP-to-albumin ratio, modified Glasgow prognostic score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio were measured preoperatively. Clinical and pathological data were assessed using univariate and multivariate analysis to determine prognostic factors for overall survival(OS), relapse-free survival(RFS)and post-relapse overall survival (PROS). Moreover, these patients were divided into high and low groups based on OPNI, these survival outcome for OS, RFS and PROS were assessed using Kaplan-Meier analysis with the logrank test. In multivariate analysis, the independent prognostic factors were gender, age, OPNI, histological type, pStage for OS, gender, OPNI, venous invasion and pStage for RFS, and OPNI, histological type and resection of recurrent site for PROS. In Kaplan-Meier analysis, patients in the low OPNI group had significant poor prognosis for OS, RFS and PROS. OPNI is a useful prognostic factor in colorectal cancer.

Gastric type III heterotopic pancreas presenting as adenomyoma in the antrum of the stomach: a case report.

Although heterotopic pancreas usually occurs in the stomach and rarely presents as a submucosal tumor, an accurate preoperative diagnosis is often difficult because of the variety of clinical symptoms and findings depending on the size and location of the lesion. We experienced a case of gastric type III heterotopic pancreas presenting as a gastric adenomyoma in the antrum of the stomach. A 62-year-old woman visited a local hospital for epigastric discomfort. An esophagogastroduodenoscopy study indicated a submucosal tumor in the greater curvature of the gastric antrum. The patient underwent surgical resection of the tumor because it was enlarged. The histological sections of the resected specimen showed that the tumor was composed of ductular structures lined by tall columnar epithelia and a prominent smooth muscle stroma with no atypical cells. The tumor was compatible with Heinrich's type III heterotopic pancreas, which presented as an adenomyoma of the stomach. These findings provide useful histological features and some insight into a better understanding of the embryonic origin and development of adenomyoma and heterotopic pancreas in the antrum of the stomach.

A case of early-stage type 3 gastric neuroendocrine tumor in the upper body of the stomach: is endoscopic resection feasible?

Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy.

Gastric collision tumor composed of early-stage gastric carcinoma and gastrointestinal stromal tumor: a case report.

Collision tumors composed of adenocarcinoma and gastrointestinal stromal tumor (GIST) of the stomach are extremely uncommon, and only a few cases have been reported in the English literature. In the present case, a 67-year-old woman visited a local hospital for vomiting and hematemesis. An esophagogastroduodenoscopy study indicated an elevated lesion with ulceration. Histology of the endoscopic biopsy specimen indicated gastric adenocarcinoma. The patient underwent laparoscopic distal gastrectomy with D2 lymph node dissection. The resected specimen showed that the primary tumor consisted of a GIST and that early-stage gastric carcinoma coexisted in the mucosa surrounding the central ulceration of the GIST. Although close contact of the adenocarcinoma and GIST was observed on the mucosal surface, no intermixing of tumor cells was observed in the primary tumor. This case is an extremely rare case of a collision tumor composed of early-stage gastric adenocarcinoma and GIST occurring in the stomach, which provides some insight into a better understanding of the pathogenesis of collision tumors.

[A case of advanced esophageal cancer with no recurrence treated biweekly with postoperative docetaxel/nedaplatin combined chemotherapy after non-curative surgery].

We report a case of non-curatively resected esophageal cancer with no recurrence biweekly treated with postoperative docetaxel/nedaplatin combined chemotherapy. A 59-year-old woman underwent non-curative resection with esophagectomy for advanced esophageal cancer with direct invasion to the descending aorta in August, 2007. Postoperatively, she was treated biweekly with docetaxel/nedaplatin combined chemotherapy 32 times. In this period, there was no finding in the enhanced CTs, and clinically she was free from recurrence. The quality of life of this patient was also good. Thus, postoperative biweekly docetaxel/nedaplatin combined chemotherapy could be effective for advanced esophageal cancer after non-curative surgery and might be promising for long-term survival. This combined chemotherapy could be carried out on an outpatient basis, and the quality of life could also be preserved. More experience must be accumulated using this chemotherapy.

A case of gastric ischemia caused by massive gastric dilatation due to superior mesenteric artery syndrome.

Gastric ischemia is extremely rare and its endoscopic findings appear similar to those of malignant tumors, which makes accurate diagnosis difficult. We present the case of a 41-year-old woman who was admitted to our hospital for severe abdominal pain and vomiting. Laboratory data at the time of admission indicated high serum levels of C-reactive protein, fibrin/fibrinogen degradation products and D-dimer. An abdominal computed tomography (CT) scan revealed a massive dilatation of the stomach and descending portion of the duodenum, which abruptly narrowed at the portion between the superior mesenteric artery and the aorta, indicating massive gastric and duodenal dilatation due to superior mesenteric artery syndrome. Decompression of the upper gastrointestinal tract using a nasogastric tube was started immediately. An esophagogastroduodenoscopy revealed a massive, irregular ulcerative lesion with ill-defined boundaries located in the posterior wall along the greater curvature of the stomach. Although this lesion mimicked a malignant lesion, the biopsy findings revealed a benign gastric ulcer, indicating that the lesion was gastric ischemia caused by the increased intragastric pressure resulting from the massive dilatation. The gastric ischemia healing process was successfully observed through repeated endoscopic examinations of the upper gastrointestinal tract. The patient's abdominal symptoms disappeared within 10 days and she was discharged from the hospital 23 days after the abdominal episode. This case highlights gastric ischemia associated with an acute massive gastric dilatation resulting in increased intragastric pressure caused by superior mesenteric artery syndrome.

Obstructive jaundice impedes hepatic microcirculation in mice.

BACKGROUND/AIMS: To explore the mechanisms by which postoperative complications frequently occur in patients with obstructive jaundice, we examined the effects of obstructive jaundice on hepatic microcirculation and Kupffer cell activity in mice. METHODOLOGY: Common bile duct ligation and division was performed on C57BL/6 mice to induce obstructive jaundice. One and 2 weeks after surgery, sinusoidal perfusion, leukocyte rolling and sticking in the postsinusoidal venules, and diameters of sinusoids containing blood flow were evaluated using intravital microscopy. Kupffer cell phagocytic activity was estimated by the ratio of Kupffer cells that phagocytosed fluorescent-labeled particles to sinusoids containing blood flow. RESULTS: The sinusoidal perfusion significantly decreased in the jaundiced mice associated with a significant increase in the number of rolling leukocytes and sticking leukocytes. Obstructive jaundice significantly reduced diameters of sinusoids due to Kupffer cell swelling. Kupffer cell phagocytic activity significantly increased in the jaundiced mice associated with enhanced expression of tumor necrosis factor-alpha mRNA in the liver. These data suggest that obstructive jaundice stimulates Kupffer cell to induce inflammatory mediators and leukocyte-endothelial cell interaction. CONCLUSIONS: Leukocyte adhesion and narrowing of sinusoids due to Kupffer cell activation might impede hepatic microcirculation resulting in hypoxic damage of the liver with obstructive jaundice.

Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy.

The liver exhibits an exquisitely controlled cell cycle, wherein hepatocytes are maintained in quiescence until stimulated to proliferate. The retinoblastoma tumor suppressor, pRB, plays a central role in proliferative control by inhibiting inappropriate cell cycle entry. In many cases, liver cancer arises due to aberrant cycles of proliferation, and correspondingly, pRB is functionally inactivated in the majority of hepatocellular carcinomas. Therefore, to determine how pRB loss may provide conditions permissive for deregulated hepatocyte proliferation, we investigated the consequence of somatic pRB inactivation in murine liver. We show that liver-specific pRB loss results in E2F target gene deregulation and elevated cell cycle progression during post-natal growth. However, in adult livers, E2F targets are repressed and hepatocytes become quiescent independent of pRB, suggesting that other factors may compensate for pRB loss. Therefore, to probe the consequences of acute pRB inactivation in livers of adult mice, we gave adenoviral-Cre by i.v. injection. We show that acute pRB loss is sufficient to elicit E2F target gene expression and cell cycle entry in adult liver, demonstrating a critical role for pRB in maintaining hepatocyte quiescence. Finally, we show that liver-specific pRB loss results in the development of nuclear pleomorphism associated with elevated ploidy that is evident in adult mice harboring both acute and chronic pRB loss. Together, these results show the crucial role played by pRB in maintaining hepatocyte quiescence and ploidy in adult liver in vivo and underscore the critical importance of delineating the consequences of acute pRB loss in adult animals.

Age-dependent responses to hepatic ischemia/reperfusion injury.

The current study explored the concept that adult and pediatric populations differ in their response to major injury. Male C57BL/6 mice of a "young adult" (8-12 weeks) or "mature adult" (12-13 months) age were subjected to partial hepatic ischemia and reperfusion. Mature adult mice displayed significantly more liver injury than young adult mice as assessed histologically and by serum levels of alanine aminotransferase. Interestingly, there was far less neutrophil accumulation in the livers of mature adult mice. However, liver-recruited neutrophils from mature adult mice had a higher activation state than those from young adult mice. Activation of the inflammatory transcription factor, NF-kappaB, was suppressed in whole livers from mature adult mice. In isolated liver cells, Kupffer cells showed no difference in NF-kappaB activation, but hepatocytes from mature adult mice had delayed NF-kappaB activation in response to TNF. Furthermore, isolated hepatocytes from young adult mice produced abundant amounts of the chemokine, macrophage inflammatory protein-2, whereas hepatocytes from mature adult mice produced little, if any macrophage inflammatory protein-2. Mature adult mice had much lower hepatic expression of the cytoprotective protein, heat shock protein 70, than did young adult mice. In contrast, serum heat shock protein 70 levels, which has been linked to subsequent tissue injury, were higher in mature adult mice than in young adult mice. These data suggest that there are multiple alterations at the cellular and molecular levels that contribute to enhanced postischemic liver injury in mature adult mice.

Cytokine cascades and the hepatic inflammatory response to ischemia and reperfusion.

Ischemia/reperfusion injury of the liver has two distinct phases that contribute to hepatocyte damage. The acute phase is characterized by Kupffer cell production of reactive oxygen species, which results in moderate hepatocyte injury. The later phase includes an intricate cascade of inflammatory events culminating in neutrophil infiltration of the postischemic liver. Accumulated neutrophils cause substantial injury to hepatocytes through their release of oxidants and proteases. This review discusses the mechanisms by which this inflammatory response is initiated, propagated, and regulated and the impact of these pathways on neutrophil-dependent injury to the liver.

The alterations in hepatic microcirculation and Kupffer cell activity after biliary drainage in jaundiced mice.

BACKGROUND/PURPOSE: The aim of this study is to examine the effects of biliary drainage on hepatic microcirculation and Kupffer cell activity in the liver with obstructive jaundice. METHODS: Common bile duct ligation and division was performed on C57BL/6 mice to induce obstructive jaundice. Seven or 14 days after surgery, some mice underwent biliary drainage. Three days after biliary drainage, sinusoidal perfusion, leukocyte rolling and sticking in the postsinusoidal venules, and the diameters of sinusoids containing blood flow were evaluated using intravital microscopy. Kupffer cell phagocytic activity was estimated as the ratio of Kupffer cells that phagocytosed fluorescent-labeled particles to sinusoids containing blood flow. RESULTS: Sinusoidal perfusion after biliary drainage was significantly increased compared with that in livers with obstructive jaundice, but remained decreased compared with controls. Although the number of rolling leukocytes and sticking leukocytes was significantly decreased, the diameters of sinusoids remained reduced, associated with an increase in Kupffer cell phagocytic activity compared with controls even after biliary drainage. CONCLUSIONS: Leukocyte-endothelial cell interaction is ameliorated but sinusoids remain narrowed due to swelling of activated Kupffer cells; this might cause deterioration of hepatic microcirculation during the early phase of biliary drainage.

Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice.

Expression of spermine/spermidine-N1-acetyltransferase (SSAT), the rate-limiting enzyme of polyamine backconversion cascade, increases after ischemia-reperfusion injuries (IRI). We hypothesized that SSAT plays an important role in the mediation of IRI. To test our hypothesis, wild-type (SSAT-wt) and SSAT-deficient (SSAT-ko) mice were subjected to liver or kidney IRI by ligation of hepatic or renal arteries. The liver and kidney content of putrescine (Put), a downstream by-product of SSAT activity, increased in SSAT-wt animals but not in SSAT-ko animals after IRI, indicating that polyamine backconversion is not functional in SSAT-deficient mice. When subjected to hepatic IRI, SSAT-ko mice were significantly protected against liver damage compared with SSAT-wt mice. Similarly, SSAT-ko animals subjected to renal IRI showed significantly greater protection against damage to kidney tubules than SSAT-wt mice. These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI.

Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia.

The present study examined the role of hepatocyte NF-kappaB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-kappaB activation and liver injury. C57BL/6 mice underwent 90 min of partial hepatic ischemia and up to 8 h of reperfusion. Body temperature was regulated during the ischemic period between 35 and 37 degrees C, 33 and 35 degrees C, 29 and 33 degrees C or unregulated, where temperature fell to <29 degrees C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29 degrees C) being highly protected and the normothermic group (35-37 degrees C) displaying the greatest injury. Inflammation, as measured by production of TNF-alpha and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-kappaB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IkappaB proteins, IkappaB-alpha and IkappaB-beta, was greatest in the normothermic group, suggesting an alternate NF-kappaB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-kappaB p65 protein was increasingly degraded in normothermic versus hypothermic groups, and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase Pin1. The data suggest that NF-kappaB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-kappaB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-kappaB, and enhanced hepatocellular injury.

Hepatic expression of S32A/S36A IkappaBalpha does not reduce postischemic liver injury.

BACKGROUND: Activation of the transcription factor, NF-kappaB, during hepatic ischemia/reperfusion injury is associated with proinflammatory mediator expression and is thought to be one of the initial triggers for the inflammatory response after reperfusion. In the current study, we sought to determine whether in vivo adenoviral transfection of a mutant inhibitor of kappaB-alpha (IkappaBalpha), which cannot be serine phosphorylated or degraded (IkappaBalphaSR), would inhibit NF-kappaB and ameliorate the hepatic inflammatory response to ischemia/reperfusion. MATERIALS AND METHODS: Male C57BL/6 mice were subjected to sham surgery or partial hepatic ischemia (90 min) and reperfusion (up to 8 h). Mice were infected with 1 x 10(9) PFU of adenovirus containing either beta-galactosidase (LacZ) or IkappaBalphaSR 3 days prior to induction of ischemia. Serum and tissues were obtained at various times for analysis. RESULTS: In unmanipulated mice, degradation of IkappaBalpha, as occurs after serine phosphorylation, was evident in liver by the end of ischemia and during early reperfusion. Mice transfected with IkappaBalphaSR displayed the same degree of inflammation and hepatocellular injury as LacZ-transfected mice. There was no difference between LacZ- and IkappaBalphaSR-transfected livers in terms of NF-kappaB activation or proinflammatory cytokine production. CONCLUSIONS: The data demonstrate that the pathway of NF-kappaB activation involving serine phosphorylation of IkappaBalpha is not the primary mechanism for induction of liver inflammation after ischemia/reperfusion and suggest that alternative pathways, such as tyrosine phosphorylation of IkappaBalpha, may be essential for the postischemic response in liver.

Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion.

Hepatic ischemia-reperfusion results in an acute inflammatory response culminating in the recruitment of activated neutrophils that directly injure hepatocytes. Recent evidence suggests that CD4+ lymphocytes may regulate this neutrophil-dependent injury, but the mechanisms by which this occurs remain to be elucidated. In the present study, we sought to determine the type of CD4+ lymphocytes recruited to the liver after ischemia-reperfusion and the manner in which these cells regulated neutrophil recruitment and tissue injury. Wild-type and CD4 knockout (CD4-/-) mice were subjected to hepatic ischemia-reperfusion. CD4+ lymphocytes were recruited in the liver within 1 h of reperfusion and remained for at least 4 h. These cells were comprised of conventional (alphabetaTCR-expressing), unconventional (gammadeltaTCR-expressing), and natural killer T cells. CD4-/- mice were then used to determine the functional role of CD4+ lymphocytes in hepatic ischemia-reperfusion injury. Compared with wild-type mice, CD4-/- mice had significantly greater liver injury, yet far less neutrophil accumulation. Adoptive transfer of CD4+ lymphocytes to CD4-/- mice recapitulated the wild-type response. In wild-type mice, neutralization of interleukin (IL)-17, a cytokine released by activated CD4+ lymphocytes, significantly reduced neutrophil recruitment in association with suppression of MIP-2 expression. Finally, oxidative burst activity of liver-recruited neutrophils was higher in CD4-/- mice compared with those from wild-type mice. These data suggest that CD4+ lymphocytes are rapidly recruited to the liver after ischemia-reperfusion and facilitate subsequent neutrophil recruitment via an IL-17-dependent mechanism. However, these cells also appear to attenuate neutrophil activation. Thus the data suggest that CD4+ lymphocytes have dual, opposing roles in the hepatic inflammatory response to ischemia-reperfusion.

Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) in liver and other organs is manifested as an injury phase followed by recovery and resolution. Control of cell growth and proliferation is essential for recovery from the injury. We examined the expression of three related regulators of cell cycle progression in liver IRI: spermidine/spermine N-acetyltransferase (SSAT), p21 (a cyclin-dependent kinase inhibitor), and stathmin. Mice were subjected to hepatic IRI, and liver tissues were harvested at timed intervals. The expression of SSAT, the rate-limiting enzyme in the polyamine catabolic pathway, had increased fivefold 6 h after IRI and correlated with increased putrescine levels in the liver, consistent with increased SSAT enzymatic activity in IRI. The expression of p21, which is transactivated by p53, was undetectable in sham-operated animals but was heavily induced at 12 and 24 h of reperfusion and declined to undetectable baseline levels at 72 h of reperfusion. The interaction of the polyamine pathway with the p53-p21 pathway was shown in vitro, where activation of SSAT with polyamine analog or the addition of putrescine to cultured hepatocytes induced the expression of p53 and p21 and decreased cell viability. The expression of stathmin, which is under negative transcriptional regulation by p21 and controls cell proliferation and progression through mitosis, remained undetectable at 6, 12, and 24 h of reperfusion and was progressively and heavily induced at 48 and 72 h of reperfusion. Double-immunofluorescence labeling with antibodies against stathmin and PCNA, a marker of cell proliferation, demonstrated colocalization of stathmin and PCNA at 48 and 72 h of reperfusion in hepatocytes, indicating the initiation of cell proliferation. The distinct and sequential upregulation of SSAT, p21, and stathmin, along with biochemical activation of the polyamine catabolic pathway in IRI in vivo and the demonstration of p53-p21 upregulation by SSAT and putrescine in vitro, points to the important role of regulators of cell growth and cell cycle progression in the pathophysiology and/or recovery in liver IRI. The data further suggest that SSAT may play a role in the initiation of injury, whereas p21 and stathmin may be involved in the resolution and recovery after liver IRI.

Peroxisome proliferator-activated receptor-alpha regulates postischemic liver injury.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a transcription factor that in some in vitro systems has been linked with downregulation of proinflammatory mediators, thus implicating a potential role for PPARalpha in the regulation of inflammatory processes. Hepatic ischemia-reperfusion injury is characterized by an intense acute inflammatory response that is dependent on a number of proinflammatory mediators. PPARalpha is abundantly expressed in hepatic parenchymal cells but not in Kupffer cells. This study examined whether PPARalpha is involved in regulation of the hepatic inflammatory response to ischemia-reperfusion. Mice nullizygous for PPARalpha had significantly greater liver injury than did their wild-type counterparts. Consistent with these findings, C57BL/6 mice treated with the PPARalpha agonist, WY-14643, had significantly less liver injury than mice receiving vehicle. PPARalpha-knockout mice also had greatly augmented liver neutrophil accumulation and modest increases in activation of the transcription factors NF-kappaB and activator protein-1. However, these effects were not associated with increased expression of proinflammatory cytokines or chemokines. In addition, PPARalpha-knockout mice expressed far less inducible nitric oxide synthase in liver than did wild-type mice after ischemia-reperfusion. Finally, treatment of cultured murine hepatocytes with WY-14643, a specific agonist of PPARalpha, protected cells against oxidant-induced injury. The data suggest that PPARalpha is an important regulator of the hepatic inflammatory response to ischemia-reperfusion in a manner that is independent of proinflammatory cytokines.

Specific role of interleukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion.

Hepatic ischemia/reperfusion injury is caused primarily by the products of neutrophils recruited into the liver after reperfusion. The mediators responsible for the development of this inflammatory response are thought to be tumor necrosis factor-alpha and interleukin (IL)-1. Although there is abundant evidence to support a role for tumor necrosis factor-alpha, much less is known about the function of IL-1 in this injury. In the present studies, we investigated whether IL-1 was a critical mediator for the induction of liver inflammation after ischemia/reperfusion. Wild-type and IL-1 receptor I-knockout (IL-1RI(-/-)) mice were exposed to 90 minutes of partial hepatic ischemia and up to 24 hours of reperfusion. In wild-type mice, IL-1beta expression was maximal after ischemia and 8 hours of reperfusion. At the same time, both wild-type and IL-1RI(-/-) mice had severe liver injury as assessed by serum alanine aminotransferase levels and hepatic histopathology. However, IL-1RI(-/-) mice had significantly less neutrophil accumulation in liver tissues as measured by liver myeloperoxidase content and histology. The reduction in hepatic neutrophil recruitment in IL-1RI(-/-) mice was associated with decreased activation of the transcription factor, nuclear factor-kappaB, and reduced expression of the CXC chemokine, macrophage inflammatory protein-2. These data suggest that IL-1 functions to augment neutrophil accumulation, but does not play an essential role in this response.

Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury.

Hepatic ischemia/reperfusion injury involves a complex inflammatory cascade resulting in neutrophil-mediated injury of hepatocytes. Previous studies from our laboratory have established that exogenous administration of the anti-inflammatory cytokines interleukin 10 (IL-10) and IL-13 can ameliorate the inflammatory response and significantly reduce hepatocellular injury. The purpose of the present study was to determine if IL-10 and IL-13 function as endogenous regulators of the hepatic inflammatory response to ischemia/reperfusion. Wild-type, IL-10-, and IL-13-deficient (IL-10(-/-), IL-13(-/-)) mice were exposed to 90 minutes of partial hepatic ischemia and up to 24 hours of reperfusion. In wild-type mice, expression of IL-10 and IL-13 shared similar expression profiles with maximal production after 8 hours of reperfusion. There were no significant differences between wild-type and IL-10(-/-) mice in response to hepatic ischemia and reperfusion. IL-13(-/-) mice had much greater liver injury, as assessed biochemically and histologically, than wild-type mice. There were no differences between wild-type and IL-13(-/-) mice in their production of inflammatory cytokines, but IL-13(-/-) mice displayed disrupted neutrophil accumulation, with less neutrophils present in the hepatic parenchyma and far more neutrophils adherent to the endothelium of large hepatic venules than wild-type mice. These observations were associated with increased liver endothelial cell injury in IL-13(-/-) mice, as measured by serum levels of hyaluronic acid. In vitro, IL-13 protected hepatocytes from H(2)O(2)-induced cytotoxicity. In conclusion, IL-10 is not an important endogenous regulator of the inflammatory response to hepatic ischemia/reperfusion. In contrast, endogenous IL-13 appears to be critical for the control of this response, with prominent protective effects on hepatocytes and hepatic endothelial cells.