Mesenteric Ischemia-reperfusion Research Articles

Effects of the TREM-1 pathway modulation during mesenteric ischemia-reperfusion in rats

The triggering receptor expressed on myeloid cells (TREM)-1, a receptor expressed on the surface of neutrophils and monocytes/macrophages, synergizes with the Toll-like receptors in amplifying the inflammatory response mediated by microbial components. Because the pathogenesis of ischemia-reperfusion-induced gastrointestinal tissue injury and multiple organ failure implies leukocyte activation and bacterial translocation, we hypothesized that the TREM-1 pathway modulation would prove beneficial in this setting. Animal study. Research laboratory. Adult male Wistar rats (250-300 g). Rats were subjected to intestinal ischemia-reperfusion induced by occlusion of the superior mesenteric artery during 60 mins and reperfused for 180 mins. At the time of reperfusion, animals were administered with LP17 (a synthetic TREM-1 inhibitor), a control peptide, or a vehicle (normal saline). Plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and soluble TREM-1 were measured by enzyme-linked immunosorbent assay. Hepatic activation of the transcriptional factor nuclear factor-kappaB was assessed by electrophoretic mobility shift assay. Hepatic oxidant-antioxidant balance was estimated by measurement of lipid peroxidation and catalase activity. Ileal mucosal permeability was estimated by fluorescein dextran-4 clearance and bacterial translocation by mesenteric lymph nodes culture. Ischemia-reperfusion was associated with cardiovascular collapse, lactic acidosis, and systemic and hepatic inflammatory response that were partly prevented by LP17 administration. Liver lipid peroxidation and catalase depletion were attenuated by LP17. Ischemia-reperfusion induced a marked increase in ileal mucosal permeability and an associated bacterial translocation that was also prevented by TREM-1 modulation. LP17 delayed mortality. The modulation of the TREM-1 pathway by the means of a synthetic peptide may be useful during acute mesenteric ischemia.

Evidence for the involvement of 5-HT 2A receptors in mild mesenteric ischemia/reperfusion dysfunctions in mice

In this study, the involvement of 5-HT 2A receptors on mesenteric ischemia–reperfusion injury was examined in mice. Intestinal ischemia produced by 45 min occlusion of superior mesenteric artery was followed by 24 h reperfusion (I/R). The 5-HT 2A selective antagonist, ketanserin (0.5 mg kg −1) or the 5-HT 2A agonist DOI (0.25 mg kg −1) was intravenously administered before ischemia and 8 h after the beginning of reperfusion. The effects were compared with those obtained in sham operated animals (S). Ketanserin prevented the upper gastrointestinal transit delay induced by I/R ( P < 0.01), protected intestine from leukocyte recruitment as indicated by jejunal myeloperoxidase activity ( P < 0.05) and reverted Evans Blue extravasation elicited by I/R in lung, colon and jejunum ( P < 0.05). On the other hand, 5-HT 2A activation by DOI mimicked the effects of I/R in S mice prolonging small intestine transit ( P < 0.05) and enhancing neutrophil accumulation in jejunal tissues ( P < 0.05). Furthermore, the reduction of ADP-induced platelet aggregation in plasma of I/R mice was prevented by ketanserin treatment. All together, these findings support the critical involvement of 5-HT 2A receptor subtype in mediating the damage induced by mesenteric I/R in mice.

Decay-accelerating factor attenuates remote ischemia–reperfusion-initiated organ damage

Complement activation contributes to the expression of local and remote organ injury in animal models of ischemia–reperfusion (IR). We demonstrate here that a soluble form of decay-accelerating factor (DAF) protects normal C57Bl/6 and autoimmunity-prone B6.MRL/ lpr mice subjected to hindlimb IR from remote intestinal and lung injury without affecting the degree of local skeletal muscle injury. In addition, DAF treatment attenuates remote organ injury in mice subjected to mesenteric IR. Soluble DAF allowed the deposition of complement 3 in local and remote injury sites while it limited the presence of terminal membrane attack complex and did not increase animal susceptibility to sepsis. These data provide evidence that soluble DAF might offer clinical benefit to patients suffering remote intestinal or lung damage in response to muscle or other organ injury.

Ergothioneine Modulates Proinflammatory Cytokines and Heat Shock Protein 70 in Mesenteric Ischemia and Reperfusion Injury

Ergothioneine (EGT) is a natural compound that is synthesized by soil bacteria in fungal substrates and exhibits antioxidant functions in many cell models. The purpose of this study was to investigate the effect of EGT on mesenteric ischemia and reperfusion injury. Rats were supplemented with or without l-ergothioneine (10 mg/kg/d) for 15 days prior to intestinal ischemia. Animals were subjected to ischemia induced by clamping the superior mesenteric artery for 60 min followed by reperfusion. Serum tumor necrosis factor (TNF)-alpha and interleukin-1beta (IL-1beta) levels, tissue malondialdehide (MDA), myleoperoxidase (MPO), and heat shock protein (HSP) 70 levels, as well as histological findings, were evaluated after 1, 2, and 4 h of reperfusion. Serum TNF-alpha and IL-1beta levels, and tissue MDA and MPO activities at 1, 2 and 4 h after reperfusion in the EGT group, were significantly lower than the control group (P < 0.05). Tissue HSP-70 levels of the study group were significantly greater than the control group at any time point of reperfusion. No significant differences in tissue damage including morphological changes ranging from villous denudation to focal necrosis, ulceration, hemorrhage, and architectural disintegration at 1 and 2 h after reperfusion exist between the two groups; however, after 4 h of reperfusion, the tissue damage based on histopathologic scores by Chiu was considerably lower in the study group (P < 0.05). After 4 h of reperfusion, focal epithelial lifting and occasional areas of denuded villi could be seen in the samples of the treated animals, thus preserving villous height and mucosal architecture. EGT attenuates mesenteric ischemia reperfusion injury in rat intestine by increasing tissue HSP-70 and decreasing TNF-alpha, IL-1beta, MDA, and MPO levels. EGT also improves morphological alterations, which occurred after IR injury after prolonged periods of reperfusion.

Loss of renal function and microvascular blood flow after suprarenal aortic clamping and reperfusion (SPACR) above the superior mesenteric artery is greatly augmented compared with SPACR above the renal arteries

Renal insufficiency continues to be a complication that can affect patients after treatment for suprarenal aneurysms and renal artery occlusive disease. To our knowledge, no data are available showing that suprarenal aortic clamping and reperfusion (SRACR) above the renal arteries (renal-SRACR) preserves renal function compared with SRACR above the superior mesenteric artery (SMA-SRACR). This study examined the hypothesis that SMA-SRACR-induced downregulation of renal blood flow and function is more severe than renal-SRACR owing to the addition of systemic oxygen-derived free radical (ODFR) release. Male Sprague-Dawley rats (about 350 g) were anesthetized and microdialysis probes or laser Doppler fibers were inserted into the renal cortex (depth of 2 mm) and into the renal medulla (depth of 4 mm). Laser Doppler blood flow was continuously monitored, and the microdialysis probes were connected to a syringe pump and perfused in vivo at 3 microL/min with lactated Ringer's solution. SMA-SRACR and Renal-SRACR decreased medullary and cortical blood flow and nitric oxide (NO) synthesis. SMA-SRACR downregulated cortical inducible NO synthase, whereas renal-SRACR did not. The cortex and medulla responded to the decreased blood flow and NO synthesis by increasing in prostaglandin E2 synthesis, which was due to increased cyclooxygenase-2 content. Superoxide dismutase restored SMA-SRACR (but not renal-SRACR) cortical and medullary NO synthesis, suggesting that ODFRs generated during mesenteric ischemia-reperfusion were one of the systemic mechanisms contributing to decreased renal NO synthesis in the SMA-SRACR model. The 90% decrease in creatinine clearance after SMA-SRACR was greater than the 60% decrease after renal-SRACR. These data show that NO is important in maintaining renal cortical and medullary blood flow and NO synthesis after renal and SMA-SRACR. These data also suggest that in addition to the renal ischemia-reperfusion caused by both models, SMA SRACR induces mesenteric ischemia-reperfusion, resulting in the generation of ODFRs, which contribute to decreased renal cortical and medullary NO synthesis. Maintaining splanchnic blood flow or attempting to keep SRACR below the SMA level may be helpful in developing strategies to minimize the renal injury after SRACR.

Tempol prevents harmful effects of remote ischemia reperfusion injury on healing of experimental colonic anastomoses

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a water-soluble analogue of the spin label TEMPO. As an antioxidative agent, it is a member of nitroxides, which detoxifies superoxide and possibly other toxic radicals in vivo. In this study, we aimed to investigate whether tempol prevents harmful systemic effects of superior mesenteric ischemia-reperfusion on left colonic anastomosis in rats. Anastomosis of the left colon was performed in 30 rats that were divided into three groups each having ten animals: sham-operated control (group I), 60 min of intestinal ischemia-reperfusion by superior mesenteric artery occlusion (group II), and tempol-treated group (30 mg/kg before and after the ischemia-reperfusion (group III). On postoperative day 5, all animals were killed and anastomotic bursting pressures were measured in vivo. Tissue samples were obtained for further investigation of anastomotic hydroxyproline content, perianastomotic malondialdehyde, and glutathione levels. There was a statistically significant increase in the quantity of myeloperoxidase activity and malondialdehyde levels in group II, along with a decrease in glutathione levels, anastomotic hydroxyproline content, and bursting pressure values when compared to controls. However, all of the investigated parameters were normalized in tempol-treated animals (group III). We conclude that tempol significantly prevents harmful systemic effects of reperfusion injury on colonic anastomoses in a rat model of superior mesenteric artery occlusion.

Avaliação inicial dos gradientes sistêmicos e regionais da pCO2 como marcadores de hipoperfusão mesentérica

Mesenteric ischemia is a life-threatening emergency with a mortality rates still ranging between 60% and 100%. To evaluate the systemic and regional pCO2 gradients changes induced by mesenteric ischemia-reperfusion injury. In addition, we sought to determine if other systemic marker of splanchnic hypoperfusion could detect the initial changes in intestinal mucosal microcirculation after superior mesenteric artery occlusion. Seven pentobarbital anesthetized mongrel dogs (20.6 +/- 1.1 kg) were subjected to superior mesenteric artery occlusion for 45 minutes, and followed for an additional 120 minutes. Systemic hemodynamic was evaluated through a Swan-Ganz and arterial catheters, while gastrointestinal tract perfusion by superior mesenteric vein and jejunal serosal blood flows (ultrasonic flowprobe). Intestinal oxygen delivery, extraction and consumption (DO2intest, ERO2intest and VO2intest, respectively), intramucosal pH (gas tonometry), and mesenteric-arterial and mucosal arterial pCO2 gradients (D(vm-a)pCO2 and D(t-a)pCO2, respectively) were calculated. Superior mesenteric artery occlusion was not associated with significant changes on systemic hemodynamics parameters. A significant increase of D(vm-a)pCO2 (1.7 +/- 0.5 to 5.7 +/- 1.8 mm Hg) and D(t-a)pCO2 (8.2 +/- 4.8 to 48.7 +/- 4.6 mm Hg) were detected. During the reperfusion period a significant decrease on DO2intest (67.7 +/- 9.9 to 38.8 +/- 5.3 mL/min) and a compensatory increase on ERO2intest from 5.0 +/- 1.1% to 12.4 +/- 2.7% was observed. We conclude that gas tonometry can detect the mesenteric blood flow disturbances sooner than other analyzed parameters. Additionally, we demonstrated that changes on systemic or regional pCO2 gradients are not able to detect the magnitude of intestinal mucosal blood flow reduction after mesenteric ischemia-reperfusion injury.

The mechanism of immune mediated ischemia-reperfusion injury is conserved between different animal species

Introduction: Reperfusion injury is initiated by binding of certain IgM natural antibodies to neo-antigens exposed in ischemic tissue with subsequent activation of complement and other cytolytic pathways. Peptides that mimic the site of IgM binding to these antigens prevent IgM binding and prevent reperfusion injury when given intravenously to ischemic mice before reperfusion occurs. We now wish to determine whether this pathogenic natural IgM antibody-ischemia neo-antigen biology is restricted to mice or whether it is more general. We have therefore tested the ability of the peptide mimics to prevent reperfusion injury in a dissimilar species, the rat. Methods: Sprague-Dawley rats were subjected to 40 minutes of mesenteric ischemia followed by 180 minutes of reperfusion. The 12-mer peptide mimic was administered i.v. shortly prior to reperfusion at 300 ug/mL, estimated from the effective dose in the mouse. Gut injury was quantified using a scoring system based on the H+E section. 125-I labeled albumin was used to assess local injury as gut permeability and remote injury as lung permeability. Results: All injured rats showed gross bowel hemorrhage and edema, but bowel from peptide treated animals appeared much less edematous and hemorrhagic. Microscopic analysis of microvilli showed a significantly reduced injury score in peptide treated animals, although injury had not been completely prevented. Permeability data indicated a significant reduction in local and remote injury in peptide treated animals. Conclusions: The data demonstrates attenuation of rat gut microvillus injury, of gut edema, and of remote injury following mesenteric ischemia-reperfusion due to administration of an i.v. peptide mimic of a murine ischemia neo-antigen prior to reperfusion, thus indicating that a second species utilizes the same ischemia neo-antigen and corresponding natural antibody specificity to amplify reperfusion injury to the point of necrosis. This implies that this mechanism of inflammation is potentially applicable to higher species.

Preventive strategy for Candida gut translocation during ischemia–reperfusion injury supervening on protein–calorie malnutrition

The aim of the present study was to test the hypothesis that protein-calorie malnutrition aggravates the gut translocation of Candida albicans triggered by mesenteric ischemia-reperfusion (IR) injury in an experimental model while testing a natural product containing the antifungal anethole/polygodial mixture (Kolorex). MFI strain white mice (n = 90) were randomly allocated to a 4-week dietary regimen: (1) standard pellet diet containing 25% casein; (2) low-protein (2.5%) casein diet; (3) as group 2 plus oral supplementation with 20 microL of a 5% solution of Kolorex during the last 4 days. Twenty rats from each of these groups (termed 1a, 2a and 3a) were orally inoculated with Candida suspension 6 h prior to mesenteric IR injury. Animals of each group but without Candida inoculation (termed 1b, 2b and 3b) served as control. A colon permeability study was carried out as well. Rats were killed prior to the IR injury and 3 h afterwards. Control rats were killed at the same time. Over 60% of the mesenteric lymph nodes and 30% of kidney samples were positive for C. albicans in the low-protein-fed rats after IR injury. Kolorex significantly decreased that rate of positivity and also significantly reduced the concentration of C. albicans per gram of each positive tissue sample examined. Protein-calorie malnourished animals showed a statistically significant increase in colon permeability and this phenomenon further increased after IR injury. The groups of rats treated with Kolorex compound showed a partial, although significant, improvement of this parameter. These results suggest that Kolorex might exert a competitive effect against with C. albicans colonization. The present study represents the first experimental in vivo investigation of the anethole/polygodial-containing compound under the specific conditions of calorie-protein malnutrition and the results have potential clinical interest.

Hypocapnia attenuates mesenteric ischemia-reperfusion injury in a rat model

Hypocapnia, a recognized complication of high frequency oscillation ventilation, has multiple adverse effects on lung and brain physiology in vivo, including potentiation of free radical injury. We hypothesized that hypocapnia would potentiate the effects of mesenteric ischemia-reperfusion on bowel, liver and lung injury. Anesthetized male Sprague-Dawley rats were ventilated with high frequency oscillation and were randomized to one of four groups, exposed to either mesenteric ischemia-reperfusion or sham surgery, and to either hypocapnia or normocapnia. All animals survived the protocol. Ischemia-reperfusion caused significant histologic bowel injury. Bowel 8-isoprostane generation was greater in ischemia-reperfusion vs sham, but was attenuated by hypocapnia. Laser-Doppler flow studies of bowel perfusion confirmed that hypocapnia attenuated reperfusion following ischemia. Plasma alanine transaminase, reflecting overall hepatocellular injury, was not increased by ischemia-reperfusion but was increased by hypocapnia; however, hepatic isoprostane generation was increased by ischemia-reperfusion, and not by hypocapnia. Oxygenation was comparable in all groups, and compliance was impaired by ischemia-reperfusion but not by hypocapnia. Hypocapnia, although directly injurious to the liver, attenuates ischemia-reperfusion induced lipid peroxidation in the bowel, possibly through attenuation of blood flow during reperfusion.

Permissive hypercapnia: role in protective lung ventilatory strategies

Hypercapnia is a central component of current protective ventilatory strategies. This review aims to present and interpret data from recent clinical and experimental studies relating to hypercapnia and its role in protective ventilatory strategies. Increasing clinical evidence supports the use of permissive hypercapnia, particularly in acute lung injury/acute respiratory distress syndrome, status asthmaticus, and neonatal respiratory failure. However, there are no clinical data examining the contribution of hypercapnia per se to protective ventilatory strategies. Recent experimental studies provide further support for the concept of therapeutic hypercapnia, whereby deliberately elevated PaCO2 may attenuate lung and systemic organ injury. CO2 administration attenuates experimental acute lung injury because of adverse ventilatory strategies, mesenteric ischemia reperfusion, and pulmonary endotoxin instillation. Hypercapnic acidosis attenuates key effectors of the inflammatory response and reduces lung neutrophil infiltration. At the genomic level, hypercapnic acidosis attenuates the activation of nuclear factor-kappaB, a key regulator of the expression of multiple genes involved in the inflammatory response. The physiologic effects of hypercapnia, both beneficial and potentially deleterious, are increasingly well understood. In addition, reports suggest that humans can tolerate extreme levels of hypercapnia for relatively prolonged periods without adverse effects. The potential for hypercapnia to contribute to the beneficial effects of protective lung ventilatory strategies is clear from experimental studies. However, the optimal ventilatory strategy and the precise contribution of hypercapnia to this strategy remain unclear. A clearer understanding of its effects and mechanisms of action is central to determining the safety and therapeutic utility of hypercapnia in protective lung ventilatory strategies.

Antithrombin III attenuates pulmonary tissue injury caused by mesenteric ischemia-reperfusion

Background Mesenteric ischemia-reperfusion (I/R) is a well-known event causing both local and remote organ injuries, including the lungs. Recently, several studies indicated that activated leukocyte-endothelial cell interactions play an important role in the mechanisms of these injuries. As a natural inhibitor of serine proteases, antithrombin was shown previously to attenuate the tissue damage after local I/R in several organ systems. Here, we examined the effects of antithrombin on pulmonary injury after mesenteric I/R. Methods Wistar albino rats underwent median laparotomy and were randomized into 3 groups: (1) sham-operated control (n = 12), (2) 60 minutes of mesenteric ischemia and 3 hours of reperfusion (n = 12), and (3) antithrombin-pretreated (250 U/kg) group before the I/R (n = 12). At the end of reperfusion, animals were killed and neutrophil sequestration, myeloperoxidase (MPO) activity, and Evans blue dye extravasation in the lung parenchyma were assessed and compared. Results There was a statistically significant increase in the quantity of Evans blue dye concentration, leukocyte sequestration, and MPO activity in the I/R group when compared with the control group. The pretreatment of animals with antithrombin significantly decreased the pulmonary injury characterized by increased Evans blue dye extravasation, leukocyte sequestration, and MPO activity. Conclusion The data of the present study suggest that mesenteric ischemia and reperfusion induces pulmonary injury characterized by activated neutrophil sequestration and increased microvascular leakage in the lungs. A significant attenuation of intestinal I/R-related lung injury with the use of antithrombin concentrate warrants further studies to elucidate the potential role of this natural serine protease inhibitor in clinical settings.

Interleukin-10 Gene Therapy Attenuates Pulmonary Tissue Injury Caused by Mesenteric Ischemia-Reperfusion in a Mouse Model

To investigate the role of interleukin (IL)-10 gene therapy on the reperfusion-induced lung injury, we utilised the technique of liposomal gene delivery before the induction of intestinal ischemia. Plasmid DNA encoding human IL10 (hIL-10) or empy vector was injected intraperitoneally 24 h before the study. Male Balb/c mice randomized into three groups: Sham operated control (n = 12), empty plasmid vector (n = 12), and hIL-10 gene therapy group (n = 12). The ischemia was generated by selective occlusion of superior mesenteric artery for 60 min and followed by reperfusion for 30 min. Lung tissue neutrophil infiltration was determined by myeloperoxidase assay and neutrophil counts. For the determination of lung tissue microvascular permeability, Evans blue dye injection was made and the lung edema was assessed by wet/dry ratio. hIL-10 protein expression was studied by immunostaining and ELISA. We found that pre-ischemic hIL-10 overexpression attenuated dye extravasation, leukocyte sequestration and reduced pulmonary tissue injury compared to the empty vector-injected control. Our study indicates that pre-ischemic hIL-10 overexpression attenuates lung injury caused by intestinal ischemia-reperfusion.

Melatonin reduces bacterial translocation after intestinal ischemia-reperfusion injury

Melatonin, the primary pineal hormone, has been reported to protect from oxidative injury after ischemia-reperfusion (IR). The aim of this study was to evaluate the effects of exogenous melatonin on intestinal integrity, ileal colonization, and bacterial translocation 45-minute after mesenteric IR. Sixteen male ACI rats randomly divided into two groups underwent 45-minutes intestinal ischemia by clamping the superior mesenteric artery. One hour prior to ischemia, study animals ( n = 8, group A) were treated with melatonin (10 mg/kg IP) while control animals ( n = 8, group B) received the same volume of saline solution. An additional six animals underwent laparotomy and served as a sham-operated group. Animals were sacrificed 24 hours after reperfusion; peritoneal swabs and biopsies of liver, spleen, lung, mesenteric lymph nodes, cecum, and terminal ileum were obtained for microbiology. The ileum samples were also processed for histopathological evaluation of IR-induced injury. Twenty-four hours after reperfusion bacterial translocation to the peritoneal cavity present in all group B animals was reduced to 37.5% among those that were melatonin-treated (group A; P < .05). Furthermore bacterial translocation to mesenteric lymph nodes, spleen, and liver was significantly lower in group A than group B ( P < .05). Although cecal and ileal counts did not differ between the two groups, ileal counts from control animals showed increased colonization. Accordingly, a single injection of exogenous melatonin significantly reduced the intestinal IR injury and prevented bacterial translocation.

Intravenous immunoglobulin attenuates mesenteric ischemia–reperfusion injury

Intravenous immunoglobulin (IVIG) has been found useful in the treatment of various clinical entities and its effect has been associated with inhibition of complement-mediated tissue damage. The aim of this study was to determine the ability of IVIG to protect against mesenteric ischemia–reperfusion (IR)-induced local and remote injury. Rats received vehicle or IVIG (150–600 mg/kg) 5 min prior to sham operation or 30 min of superior mesenteric artery occlusion, followed by 5, 120, or 240 min of reperfusion. IVIG reduced IR-induced mucosal injury without altering IR-induced increases in PMN infiltration or LTB 4 generation. At 5 min post IR, the deposition of IgG and C3 in the lamina propria and surface epithelial cells was attenuated by IVIG. The increased capillary leak, evident at 240 min, was inhibited by IVIG and coincided with a reduction in C3 deposition in lung tissue. The beneficial effects of IVIG may be related to the ability to scavenge deleterious products.

Ventilation strategy affects cytokine release after mesenteric ischemia-reperfusion in rats.

To evaluate the impact of different ventilation modalities on lung and plasma concentrations of cytokines in a model of secondary lung inflammation, mesenteric ischemia-reperfusion, in rats. Prospective, randomized, controlled animal study. Research laboratory of a university. Sixty-four male adult Wistar rats weighing 320-380 g. Eight groups were studied. Two groups underwent no surgical procedure: They were either not ventilated or ventilated with an injurious modality consisting of 30 mL/kg tidal volume (Vt) without positive-end expiratory pressure (PEEP). Animals of the other groups underwent laparotomy with or without 2-hr mesenteric ischemia followed by 4 hrs of reperfusion during which the rats were mechanically ventilated. Ventilation modalities were conventional (tidal volume 10 mL/kg, PEEP 3 cm H2O), protective (6 mL/kg, 6 cm H(2)O), or injurious (tidal volume 30 mL/kg and no PEEP). Rats were killed by exsanguination, and their lungs were excised and homogenized in buffer. Supernatants of lung homogenates and plasmas were stored at -80 degrees C for subsequent measurements. Tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, macrophage inhibitory protein 2, and interleukin-10 were determined in lung supernatants and plasmas with a rat-specific enzyme-linked immunosorbent assay. Lung and plasma cytokine concentrations were not significantly different between rats ventilated with the injurious modality only and nonventilated rats. Lung and plasma cytokine concentrations were higher in rats that had undergone mesenteric ischemia-reperfusion than in rats with laparotomy only, whatever ventilation modality. Lung and plasma cytokine concentrations were higher in these rats after the injurious ventilation modality than after the other modalities. This study shows that an injurious ventilation does not produce significant in vivo release of cytokines in intact animals but promotes the release of pro- and anti-inflammatory cytokines in an inflammatory context.

Genomic and proteomic determinants of outcome in patients undergoing thoracoabdominal aortic aneurysm repair.

Thoracoabdominal aortic aneurysm repair, with its requisite intraoperative mesenteric ischemia-reperfusion, often results in the development of systemic inflammatory response syndrome, multiorgan dysfunction syndrome (MODS), and death. In the present study, an adverse clinical outcome following thoracoabdominal aortic aneurysm repair was identified by blood leukocyte genomic and plasma proteomic responses. Time-dependent changes in the expression of 146 genes from blood leukocytes were observed (p < 0.001). Expression of 138 genes (p < 0.001) and the concentration of seven plasma proteins discriminated between patients who developed MODS and those who did not, and many of these differences were evident even before surgery. These findings suggest that changes in blood leukocyte gene expression and plasma protein concentrations can illuminate pathophysiological processes that are subsequently associated with the clinical sequelae of systemic inflammatory response syndrome and MODS. These changes in gene expression and plasma protein concentrations are often observed before surgery, consistent with either a genetic predisposition or pre-existing inflammatory state.

Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury.

Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing FICO2 resulted in a dose-dependent increase in PaO2. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.

C5a causes limited, polymorphonuclear cell-independent, mesenteric ischemia/reperfusion-induced injury☆,☆☆

C5 is critical in the development of local mucosal damage and inflammation as well as in the development of remote organ injury after mesenteric ischemia/reperfusion (IR). To define the role of C5a in tissue injury, we treated wild-type mice with a cyclic hexapeptide C5a receptor antagonist (C5aRa) and administered recombinant C5a to C5 deficient (C5 −/−) mice subjected to mesenteric IR. We demonstrate that at 2-h postreperfusion, C5a administered to C5−/− mice during IR induces limited intestinal mucosal injury but failed to cause remote lung injury despite the fact that it upregulated adhesion molecule expression. C5aRa treatment of C5+/+ mice undergoing IR limited local injury and prevented distant organ injury. We conclude that although C5a can trigger certain components of the IR induced injury, other mediators such as C5b-9 and local factors are needed for the complete expression of IR tissue damage.

Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury.

Mesenteric ischemia-reperfusion injury is a serious complication of shock. Because activation of nuclear factor-kappaB (NF-kappaB) has been implicated in this process, we treated rats with vehicle or the IkappaB-alpha inhibitor BAY 11-7085 (25 mg/kg ip) 1 h before mesenteric ischemia-reperfusion (45 min of ischemia followed by reperfusion at 30 min or 6 h) and examined the ileal injury response. Vehicle-treated rats subjected to ischemia-reperfusion exhibited severe mucosal injury, increased myeloperoxidase (MPO) activity, increased expression of interleukin-6 and intercellular adhesion molecule 1 protein, and a biphasic peak of NF-kappaB DNA-binding activity during the 30-min and 6-h reperfusion courses. In contrast, BAY 11-7085-pretreated rats subjected to ischemia-reperfusion exhibited less histological injury and less interleukin-6 and intercellular adhesion molecule 1 protein expression at 30 min of reperfusion but more histological injury at 6 h of reperfusion than vehicle-treated rats subjected to ischemia-reperfusion. Studies with phosphorylation site-specific antibodies demonstrated that IkappaB-alpha phosphorylation at Ser(32),Ser(36) was induced at 30 min of reperfusion, whereas tyrosine phosphorylation of IkappaB-alpha was induced at 6 h of reperfusion. BAY 11-7085 inhibited the former, but not the latter, phosphorylation pathway, whereas alpha-melanocyte-stimulating hormone, which is effective in limiting late ischemia-reperfusion injury to the intestine, inhibited tyrosine phosphorylation of IkappaB-alpha. Thus NF-kappaB appears to play an important role in the generation and resolution of intestinal ischemia-reperfusion injury through different activation pathways.