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A composite material with ordered pores in both the micro- and mesopore ranges was prepared by a dry gel conversion technique known as vapor-phase transport (VPT). Mesoporous silica SBA-15 was used as the SiO2 source, and sodium aluminate was used as the Al2O3 source on the silica. VPT was then carried out under an atmosphere of hexamethyleneimine and water vapors. The unique microporous structure of MCM-22, a micropocket on the external surface of the zeolite, was generated at a late stage of crystallization. A zeolitic acid site, as strong as that of MCM-22 with mesopores originated from SBA-15, was achieved to create before the long-range ordering of the zeolite. A building unit of the zeolite was also formed at an early stage of crystallization. A drastic change in the morphology of SBA-15, promoted with the help of water vapor, took place during the course of crystallization. Slow crystallization and a structural support (e.g., carbon) inside the mesopores are necessary to prevent collapse of the mesostructure derived from the original SBA-15, and to obtain an ordered micro- and mesoporous composite material.

The aim of this study was to determine the role of calcitonin gene-related peptide (CGRP) in the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Ethanol was administered to wild-type C57BL/6 mice on day 1 as a bolus by gavage at a dose that produces a peak plasma ethanol of 45 mg/dl 30 min after administration. Twenty-four hours later ( day 2), the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion (I/R). Intravital fluorescence microscopy was used to quantify the numbers of rolling (LR) and adherent (LA) leukocytes labeled with carboxyfluorescein diacetate succinimidyl ester in postcapillary venules of the small intestine. I/R increased LR and LA, effects that were prevented by antecedent ethanol. The postischemic anti-inflammatory effects of ethanol consumption were abolished by administration of a specific CGRP receptor antagonist [CGRP-(8–37)] or after sensory nerve neurotransmitter depletion using capsaicin administered 4 days before ethanol ingestion, which initially induces rapid release of CGRP from sensory nerves, thereby depleting stored neuropeptide. Administration of exogenous CGRP or induction of endogenous CGRP release by treatment with capsaicin 24 h before I/R mimicked the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Preconditioning with capsaicin 24 h before I/R was prevented by coincident treatment with CGRP-(8–37), while exogenous CGRP induced an anti-inflammatory phenotype in mice depleted of CGRP by capsaicin administration 4 days earlier. Our results indicate that the effect of antecedent ethanol ingestion to prevent postischemic LR and LA is initiated by a CGRP-dependent mechanism.

In order to control the surface wettability of hyperbranched hydrophilic poly(amidoamine) (PAMAM)-grafted nano-sized silica, hydrophilic alkyl chain (C n H2n+1) with different chain lengths (n = 4, 8, 15) were postgrafted onto PAMAM-grafted silica by the reaction of terminal amino groups of PAMAM grafted on the silica surface with alkyl acid chlorides (C n H2n+1-COCl). The postgrafting of C n H2n+1-COCl increased with increasing PAMAM grafting and alkyl chain length of C n H2n+1-COCl. However, the terminal amino groups of PAMAM-grafted silica used for the postgrafting of C n H2n+1-COCl decreased with increasing chain length. This may be due to the steric hindrance between terminal amino groups of PAMAM-grafted silica and C n H2n+1-COCl: the steric hindrance is considered to increase with increasing chain length of C n H2n+1-COCl. The surface wettability was estimated by contact angle measurement for water and methanol wettability. As a result, it was found that contact angle and methanol wettability incre...

Long-term ethanol consumption at low to moderate levels exerts cardioprotective effects in the setting of ischemia and reperfusion (I/R). The aims of this study were to determine whether 1) a single orally administered dose of ethanol [ethanol preconditioning (EtOH-PC)] would induce a biphasic temporal pattern of protection (early and late phases) against the inflammatory responses to I/R and 2) adenosine and nitric oxide (NO) act as initiators of the late phase of protection. Ethanol was administered as a bolus to C57BL/6 mice at a dose that achieved a peak plasma concentration of ∼45 mg/dl 30 min after gavage and returned to control levels within 60 min of alcohol ingestion. The superior mesenteric artery was occluded for 45 min followed by 60 min of reperfusion beginning 10 min or 1, 2, 3, 4, or 24 h after ethanol ingestion, and the numbers of fluorescently labeled rolling and firmly adherent (stationary) leukocytes in single postcapillary venules of the small intestine were quantified using intravital microscopic approaches. I/R induced marked increases in leukocyte rolling and adhesion, effects that were attenuated by EtOH-PC 2–3 h before I/R (early phase), absent when assessed after 10 min, 1 h, and 4 h of ethanol ingestion, with an even more powerful late phase of protection reemerging when I/R was induced 24 h later. The anti-inflammatory effects of late EtOH-PC were abolished by treatment with adenosine deaminase, an adenosine A2(but not A1) receptor antagonist, or a NO synthase (NOS) inhibitor during the period of EtOH-PC. Preconditioning with an adenosine A2(but not an A1) receptor agonist in lieu of ethanol 24 h before I/R mimicked the protective actions of late phase EtOH-PC. Like EtOH-PC, the effect of preconditioning with an adenosine A2receptor agonist was abrogated by coincident NOS inhibition. These findings suggest that EtOH-PC induces a biphasic temporal pattern of protection against the proinflammatory effects of I/R. In addition, our observations are consistent with the hypothesis that the late phase of EtOH-PC is triggered by NO formed secondary to adenosine A2receptor-dependent activation of NOS during the period of ethanol exposure.

Background: Tumour necrosis factor (TNF-α) is a candidate factor for involvement in inflammation-mediated gastric mucosal injury. However, the effect of this cytokine on gastric epithelial cells has been poorly investigated. In the present study, we examined whether gastric epithelial cells are resistant to TNF- α-induced apoptosis, and whether this resistance is related to ubiquitin-proteasome-associated nuclear factor-κB (NF-κB) activation. Methods: The rat gastric mucosal cell line RGM-1 was grown in DMEM/F12 medium supplemented with 10% FCS. Confluent monolayers of cells were pretreated or not for 60 min with PSI, a peptide aldehyde known to specifically inhibit the chymotrypsin-like activity of 26S proteasome. Cells were subsequently stimulated with recombinant rat TNF-α and their viability was determined by WST-1 assay. Apoptosis was confirmed by fluorescence microscopy after staining with Hoechst 33342 and propidium iodide, and DNA fragmentation was determined by flow cytometry using an APO-BRDU kit. IκB-α and the p65 binding subunit of NF-κB were detected by Western blots. Results: Twenty-four-hour incubation with TNF-α alone or PSI alone did not affect the cell viability of RGM-1 cells. Pretreatment with PSI significantly enhanced the level of apoptosis induced by TNF-α. In RGM-1 cells treated with TNF-α, cytoplasmic IκB-α decreased and p65 in nuclear extracts increased markedly 30 min after cytokine stimulation. Pretreatment with PSI at 12.5 μmol/L blocked these TNF-α-induced changes. Conclusion: PSI enhances TNF-α-induced apoptosis through inhibition of NF-κB activation in RGM-1 cells.

Prolonged ischemia followed by reperfusion (I/R) results in impaired endothelial cell function in all segments of the microvasculature. Moreover, endothelial dysfunction plays a major role in the genesis of the reperfusion component of total tissue injury in I/R. Thus, preservation of endothelial function is an important therapeutic goal for ameliorating injury in tissues subjected to I/R. An accumulating body of evidence indicates that both microvascular endothelium and parenchymal cells can be rendered resistant to the pathological effects of I/R by antecedent exposure to brief periods of ischemia, a phenomenon referred to as ischemic preconditioning (IPC). Although the mechanisms underlying the microvascular effects of preconditioning have been far less extensively studied, work conducted to date indicates that there are fundamental differences in the signaling pathways that underlie the adaptive transformation to a protected or defensive phenotype in the endothelium compared to those that contribute to the development of a preconditioned state in parenchymal cells. Thus, the purposes of this review are to summarize our current understanding of the mechanisms whereby IPC induces the adaptive transformation to a protected or defensive phenotype in parenchymal cells and to compare and contrast this with the signaling pathways that invoke a preconditioned state in arteriolar, capillary, and venular endothelium. In addition, we highlight understudied areas with regard to microvascular protection afforded by antecedent ischemia in the hopes that this will stimulate investigation of the underlying mechanisms. Understanding these signaling pathways may provide a mechanistic rationale for the development of novel treatment interventions that target both the microcirculatory and parenchymal sequelae to I/R, thereby maximizing the therapeutic potential of the protected phenotypes produced by pharmacological preconditioning.

It has been proposed that neutrophil-endothelial cell interactions mediated by adhesion molecules are involved in the pathogenesis of inflammatory bowel disease. The objective of the present study was to determine the effects of monoclonal antibodies (MAbs) directed against endothelial adhesion molecules, P-selectin and intercellular adhesion molecule-1 (ICAM-1), in rats with colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNB). Colonic inflammation was induced by administering an enema of TNB dissolved in 50% ethanol (120 mg/ml) to male Wistar rats (at a total volume of 0.25 ml per rat) after a 48-hour fast. Anti-P-selectin MAb or anti-ICAM-1 MAb was injected via the tail vein at a dose of 1 mg/kg after the induction of colitis. Rats in the control group received nonbinding mouse immunoglobulin G1. The plasma level of soluble P-selectin showed an increase within 48 h after the TNB enema. Colonic inflammation was assessed at 1 week after TNB administration. The colonic damage score and the wet weight of the colon were significantly decreased by treatment with either MAb. The increase of myeloperoxidase (MPO) activity, an index of neutrophil accumulation, and the increase of thiobarbituric acid-reactive substances (TBA-RS), an index of lipid peroxidation, in the colonic mucosa were inhibited by both MAbs. These results suggest that neutrophil-endothelial cell interactions via P-selectin and ICAM-1 play an important role in the development of TNB-induced colitis in rats.

This study was designed to investigate the effects of water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), on experimental colitis in rats. Colitis was induced in male Wistar rats weighing 200 grams using an enema of trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol; 1 ml of TMG dissolved in physiological saline (0.2 mg/ml, 2 mg/ml, 20 mg/ml) was injected intraperitoneally every day for 1 week after the enema. The damage score, wet weight of the colon, and increase in body weight were estimated 1 week after the enema of TNBS. Thiobarbituric acid-reactive substances (TBA-RS), an index of lipid peroxidation, and the level of alpha-tocopherol or TMG in the colonic mucosa were measured 1 week after the induction of colitis. As a result, increase in body weight was inhibited by the induction of colitis, although the inhibition was reduced in the group treated with TMG. The damage score, wet weight and TBA-RS were increased significantly in the colitis group; however, they were inhibited by the administration of TMG. The alpha-tocopherol level in the colonic mucosa was reduced by the induction of colitis, wheres TMG could not be detected in the colonic mucosa of rats treated with TMG. These results suggest that TMG is effective for the treatment of colitis in rats induced by TNBS.

A 68-year-old woman was admitted to the authors' hospital for hepatic encephalopathy. Her laboratory data and computed tomography findings were not suggestive of liver cirrhosis. Superior mesenteric angiography revealed an extrahepatic portal-systemic shunt with a main cause of hepatic encephalopathy. Despite treatment with branched-chain amino acid, lactulose, and kanamycin, hyperammonemia was prolonged, and the portal-systemic shunt was therefore treated with balloon-occluded retrograde transvenous obliteration. After the procedure, hyperammonemia was improved, and there were no signs of recurrent portal-systemic encephalopathy.

Ingestion of low levels of ethanol 24 h before [ethanol preconditioning (EPC)] ischemia and reperfusion (I/R) prevents postischemic leukocyte rolling (LR) and adhesion (LA), effects that were abolished by adenosine A2receptor (ADO-A2R) antagonists or nitric oxide (NO) synthase (NOS) inhibitors. The aims of this study were to determine whether NO derived from endothelial NOS (eNOS) during the period of ethanol exposure triggered entrance into this preconditioned state and whether these events were initiated by an ADO-A2R-dependent mechanism. Ethanol or distilled water vehicle was administered to C57BL/6J [wild type (WT)] or eNOS-deficient (eNOS−/−) mice by gavage. Twenty-four hours later, the superior mesenteric artery was occluded for 45 min. LR and LA were quantified by intravital microscopy after 30 and 60 min of reperfusion. I/R increased LR and LA in WT mice, effects that were abolished by EPC or NO donor preconditioning (NO-PC). NO-PC was not attenuated by coincident administration of an ADO-A2R antagonist. I/R increased LR and LA in eNOS−/− mice to levels comparable with those noted in WT animals. However, EPC only slightly attenuated postischemic LR and LA, whereas NO-PC remained effective as a preconditioning stimulus in eNOS−/− mice. Preconditioning with an ADO-A2R agonist (which we previously demonstrated prevents I/R-induced LR and LA in WT animals) failed to attenuate these postischemic adhesive responses in eNOS−/− mice. Our results indicate that EPC is triggered by NO formed secondary to ADO-A2R-dependent eNOS activation during the period of ethanol exposure 24 h before I/R.

Although recent reports indicate an increasing incidence of patients with reflux esophagitis, its pathomechanism remains unclear. Cytokines and neutrophils, the latter of which produce reactive oxygen species (ROS), have been implicated in the formation of gastrointestinal diseases. This study investigated the roles of neutrophils, ROS, and cytokines in the pathogenesis of experimental reflux esophagitis. Esophagitis was induced in male Wistar rats by ligation at both the limiting ridge of the stomach and lower portion of the duodenum. The esophagus was then removed, and the lesion index, wet weight, thiobarbituric acid-reactive substances (an index of lipid peroxidation), myeloperoxidase activity (an index of neutrophil accumulation), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were estimated, and a histological study (hematoxylin-and-eosin staining) was performed. The mRNA expression of TNF-alpha and CINC-1 was analyzed. Anti-neutrophil serum (ANS) was injected intraperitoneally prior to the induction of esophagitis, and inflammatory markers were estimated as described above. The values of all markers increased, and the histological study revealed neutrophil infiltration and edema in mucosa and submucosa at both 12 and 18 h after induction. However, the mRNA expression of both cytokines was observed earlier at 3 and 6 h after induction. ANS inhibited the increases in all inflammatory markers. These results indicate that ROS and lipid peroxidation mainly derived from neutrophils, which are stimulated and mobilized by TNF-alpha and CINC-1, are implicated in the pathogenesis of esophageal inflammation induced by the reflux of gastroduodenal contents.

The aim of this study was to determine whether protein kinase C (PKC) contributed to the effects of ethanol ingestion to prevent P-selectin expression, leukocyte rolling (LR), and stationary leukocyte adhesion (LA) induced by subjecting the small bowel to ischemia and reperfusion (I/R) 24 hr later. I/R increased P-selectin expression, LR, and LA, effects that were largely abolished by antecedent ethanol consumption. Exposing the bowel to a specific but nonisoform-selective PKC inhibitor (chelerythrine or bisindolylmaleimide I) during the period of ethanol exposure did not alter the anti-inflammatory effects induced by ethanol ingestion 24 hr prior to I/R. Go-6976, a PKC inhibitor that exhibits a high degree of selectivity for the calcium-dependent PKC isoforms, markedly reduced the effectiveness of antecedent ethanol exposure to abrogate these postischemic inflammatory responses. Our data indicate that antecedent ethanol exposure prevents postischemic P-selectin expression, LR, and LA by a mechanism that involves activation of calcium-dependent PKC isotypes.

Ethanol ingestion 24 h prior to ischemia and reperfusion (I/R) prevents postischemic leukocyte rolling and adhesion in postcapillary venules of the small bowel. Since I/R-induced leukocyte rolling is critically dependent on the expression of P-selectin by endothelial cells lining postcapillary venules, the authors hypothesized that antecedent ethanol consumption would attenuate postischemic expression of this adhesive ligand.To address this postulate, P-selectin expression was evaluated using a dual radiolabeled monoclonal antibody technique in the jejunum of mice that received either distilled water vehicle or ethanol by gavage (dose) on day 1 and then were subjected to sham I/R (nonischemic controls) or I/R (20 min ischemia/60 min reperfusion) 24 h later.I/R was associated with a 2-fold increase in P-selectin expression relative to nonischemic controls, an effect that was largely abolished by antecedent ethanol ingestion. Exposing the bowel to adenosine deaminase or adenosine A2 receptor antagonists (DMPX or ZM241385), an NO synthase inhibitor (L-NIO) or an NO scavenger (PTIO), or an antioxidant (mercaptoproprionyl glycine) during the period of ethanol exposure on day 1 prevented the beneficial effect of ethanol to limit I/R-induced P-selectin expression, on day 2.The data indicate that antecedent ethanol exposure prevents postischemic P-selectin expression on day 2 by a mechanism that is triggered by adenosine A2 receptor activation and the formation of nitric oxide (NO) and reactive oxygen species (ROS) during the period of ethanol exposure on day 1.

Prolonged ischemia followed by reperfusion (I/R) results in impaired endothelial cell function in all segments of the microvasculature. Moreover, microcirculatory dysfunction plays a major role in the genesis of the reperfusion component of total tissue injury in I/R. Thus, preservation of endothelial function is an important therapeutic goal for ameliorating injury in tissues subjected to I/R. An accumulating body of evidence indicates that low to moderate ethanol consumption produces an adaptive transformation to a protected phenotype in both microvascular endothelium and parenchymal cells such that they are rendered resistant to the pathologic effects of I/R. The purpose of this review is to summarize our current understanding of the signaling pathways underlying the development of the preconditioned state induced by antecedent ethanol in arteriolar, capillary, and venular endothelium. In addition, we will highlight understudied areas with regard to microvascular protection afforded by antecedent ethanol in the hopes that this will stimulate investigation of its underlying mechanisms. Understanding these signaling pathways may provide a mechanistic rationale for the development of novel treatment interventions that target both the microcirculatory and parenchymal sequelae to I/R, thereby maximizing the therapeutic potential of the protected phenotypes produced by pharmacologic preconditioning.

Background and aims Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of inflammatory bowel disease. To further define the role of TNF-alpha in intestinal inflammation, we studied the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of TNF-alpha gene. Methods Acute colitis was induced in female TNF-alpha-/- and TNF-alpha+/+ mice by administering 4.5% DSS orally in drinking water for seven days. The colonic mucosal injury and inflammation was evaluated based on body weight changes, total colon length, luminal hemoglobin, and histological findings. Colonic mRNA expression for inducible nitric oxide synthase (iNOS), TNF-alpha, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by reverse transcription polymerase chain reaction (RT-PCR), and nuclear factor kappaB (NF-kappaB) activation was evaluated by electrophoretic mobility shift assay. Results In each assessment, colonic injury was significantly aggravated in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. The survival rate of TNF-alpha-/- mice on day seven was 40%; in contrast, all TNF-alpha+/+ mice were alive. Histological study also showed an enhanced infiltration of inflammatory cells, especially neutrophils, and mucosal cell disruption in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. On day seven, mRNA levels of IFN-gamma and IL-4 in the colons of TNF-alpha-/- mice were faint or not detected; in contrast, those of TNF-alpha+/+ mice were detected. Although the expression of iNOS mRNA and luminal nitrite levels were similarly increased in both mice on day seven, this induction was delayed in TNF-alpha-/- mice during the early phase. The degree of NF-kappaB binding activity seemed to be similar between the two types of mice on day seven. Conclusion DSS-induced inflammation is significantly enhanced in TNF-alpha-/- mice compared to TNF-alpha+/+ mice. These data suggest that persistent and marked blockage of TNF-alpha bioactivity may provide a detrimental effect on acute intestinal inflammation.

Ingestion of alcoholic beverages at low to moderate levels 24 h prior to ischemia and reperfusion (I/R) prevents postischemic leukocyte/endothelial cell adhesive interactions, a phenomenon referred to as late ethanol preconditioning (EtOH-PC). The aim of this study was to determine whether oxidants act as initiators of late EtOH-PC. Ethanol was instilled into the stomachs of C57BL/6 mice as a bolus by gavage at a dose that produced a peak plasma concentration of 45 mg/dl 30 min after administration and returned to control levels 60 min after ingestion. Twenty four hours later, the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion. The numbers of rolling and firmly adherent leukocytes were quantified in postcapillary venules of the small intestine in sham animals (no EtOH-PC, no I/R), in mice subjected to I/R alone or EtOH-PC + I/R, and in animals treated with Mn-TBAP (a cell-permeant superoxide dismutase mimetic), oxypurinol (a XO inhibitor), the NAD(P)H oxidase inhibitors PR-39 or apocynin, or oxypurinol plus PR39 during the period of EtOH-PC on Day 1 followed by I/R on Day 2. In separate groups of mice, oxypurinol or apocynin were also administered 1 h after ethanol ingestion on Day 1, with induction of I/R 24 h later. I/R induced marked increases in leukocyte rolling and adherence, effects that were completely prevented by EtOH-PC. Coincident treatment with Mn-TBAP, oxypurinol, PR-39, apocynin, or oxypurinol plus PR-39 with ethanol attenuated these anti-inflammatory actions of EtOH-PC. However, administration of oxypurinol or apocynin 1 h after ethanol ingestion failed to prevent these protective effects of EtOH-PC. Our results indicate that reactive oxygen species formed during the period of ethanol exposure on Day 1 trigger the development of an anti-inflammatory phenotype that renders the small bowel resistant to the proadhesive effects of I/R 24 h later.

Preconditioning refers to a phenomenon whereby tissues are rendered resistant to the deleterious effects of prolonged ischemia and reperfusion (I/R) by prior exposure to oxidants, brief periods of vascular occlusion, endotoxin derivatives, heat shock, a variety of pharmacologic agents (chemical or pharmacologic preconditioning) or chronic ethanol consumption (6, 11, 16, 26, 29, 35, 40, 42, 48, 55, 71). Of these perturbations, our best understanding of the mechanisms involved in conferring protection is related to ischemic preconditioning (IPC). The beneficial effects of IPC are not related to improved collateral flow but instead represent an enhanced intrinsic ability of tissues to tolerate ischemia. However, recent work indicates that in addition to its anti-ischemic effects, IPC also completely prevents the reperfusion component of tissue injury by abrogating the inflammatory changes that are initiated in the microcirculation upon restitution of blood flow (1, 7, 14, 29, 36, 40, 41, 75). Additional support for this concept is provided by the demonstration that endothelium-dependent vasoregulatory mechanisms remain intact in preconditioned tissues (42, 71). Taken together, these observations indicate that adaptive changes in the microvasculature play a key role in the development of the preconditioned state. Thus, understanding the mechanisms whereby both arterial and venular endothelium enter a protective or defensive phenotype as a result of preconditioning may lead to the development of novel therapeutic strategies to manage I/R injury.

The importance of pancreatic enzymes, particularly phospholipase A2 (PLA2), for bacterial translocation, which is considered to be one of the aggravating causes of acute pancreatitis, was investigated. Male rats were administered an intraperitoneal or intravenous injection of normal saline, PLA2, or amylase. Four days later, the mesenteric lymph nodes (MLNs) and portal blood of the animals were cultured. None of the animals had a positive portal blood culture. The MLNs contained enteric bacteria in 78% of the animals given 50 mg/kg of PLA2 intraperitoneally. 5 mg/kg of PLA2 intraperitoneally, 50 mg/kg of amylase intraperitoneally, or 50 mg/kg of PLA2 intravenously showed positive cultures in 25%, 20%, and 11%, respectively. None of the animals given intraperitoneal or intravenous normal saline had positive cultures of their MLNs. Intraperitoneal injection of 25 mg/kg of nafamostat mesilate just before intraperitoneal PLA2 (50 mg/kg) resulted in a reduction of positive MLNs from 70% to 30%. The cecal myeroperoxidase (MPO) activity of animals administered 50 mg/kg of PLA2 intraperitoneally was significantly higher compared with animals administered saline intraperitoneally. These results indicate that intraperitoneal leakage of PLA2 plays an important role in bacterial translocation during acute pancreatitis and that administration of a protease inhibitor may be effective against the bacterial translocation.

OBJECTIVE To investigate the role of superoxide and nitric oxide in platelet-activating factor-induced acute lung injury, hypotension, and mortality. DESIGN Prospective, randomized, controlled, experimental study. SETTING University research laboratory. SUBJECTS Anesthetized male Wistar rats (180 to 220 g) were studied. INTERVENTIONS In the first set of experiments, animals were divided into three groups. Group 1 received platelet-activating factor (2 microg/kg i.v.). Group 2 received recombinant human superoxide dismutase (50,000 U/kg i.v.) 30 mins before platelet-activating factor injection. Group 3 received vehicle agents. In the second set of experiments, animals were divided into six groups that received N(G)-nitro-L-arginine (L-NNA), a selective inhibitor of nitric oxide synthesis, or L-arginine, the physiologic precursor of nitric oxide synthesis: a) vehicles (i.v.); b) vehicle plus L-arginine (100 mg/kg i.v.); c) vehicle plus L-NNA (10 mg/kg i.v.); d) vehicle plus platelet-activating factor (2 microg/kg i.v.); e) L-arginine plus platelet-activating factor; and f) L-NNA plus platelet-activating factor. The first intravenous administration was given 5 mins before the second intravenous injection for each group. MEASUREMENTS AND MAIN RESULTS In the first set of experiments, vascular labeling with Monastral blue B demonstrated diffuse microvascular injury in the alveolar capillary beds 2 hrs after platelet-activating factor challenge. Thiobarbituric acid-reactive substances in the lung significantly increased at 2 hrs after platelet-activating factor injection. Platelet-activating factor treatment also resulted in an increased concentration of total protein, albumin, and Evans blue dye in bronchoalveolar lavage fluid at 2 hrs after administration, suggesting platelet-activating factor induction of increased alveolar permeability. The platelet-activating factor-induced alveolar microvascular injury, lipid peroxidation, and increased alveolar permeability were inhibited by pretreatment with recombinant human superoxide dismutase. Although L-NNA alone did not affect alveolar permeability in the second set of experiments, L-NNA treatment before platelet-activating factor challenge significantly aggravated platelet-activating factor-induced increased alveolar permeability 2 hrs after platelet-activating factor challenge. Platelet-activating factor also produced a rapid decrease in blood pressure that was not ameliorated by treatment with L-NNA. However, L-NNA pretreatment was associated with a significant increase in platelet-activating factor-caused mortality within 6 hrs. All rats survived with L-arginine treatment before platelet-activating factor challenge. L-NNA treatment decreased nitrate/nitrite concentration, an index of total nitric oxide production, in plasma. CONCLUSIONS These results indicate that superoxide, the derived active oxygen species, and lipid peroxidation are implicated in the pathogenesis of platelet-activating factor-induced acute lung injury. Nitric oxide does not play a major role in platelet-activating factor-induced hypotension. Nitric oxide appears to play a protective role in the acute lung injury and mortality induced by platelet-activating factor.

Z-103 is a chelate compound consisting of zinc ion and L-carnosine. In this study, we investigated the protective effect of Z-103 against colonic damage induced by 2,4,6-trinitrobenzene sulfonic acid (TNB) in rats. Colonic inflammation was induced by administering TNB dissolved in 50% ethanol (120 mg/ml) in male Wistar rats (total volume of 0.25 ml per rat) following a 48-hour fast. After the administration of TNB, Z-103 was given at a dose of 30 mg/kg per rat for 1 week. A second group of rats received sulfasalazine (SASP) at 300 mg/kg and a third group of rats received 30 mg/kg of ZnSO4 for 1 week. Colonic inflammation was assessed 1 week following TNB administration. Both macro- and microscopic evaluation showed that the inflammatory responses induced by TNB were reduced by treatment with Z-103, SASP and ZnSO4. The score (graded from 0 to 5 according to the macroscopic lesions) and colonic wet weight (distal 8 cm of the colon) were significantly decreased by treatment with Z-103, SASP and ZnSO4. The increase in thiobarbituric acid-reactive substances in the colonic mucosa following TNB administration were inhibited in the Z-103 and SASP groups. These results suggest that Z-103 is as effective against TNB-induced colitis as SASP.