Occlusive vasculopathy in human immunodeficiency virus (HIV)-associated vasculitis: unusual clinical and imaging course.

Human immunodeficiency virus (HIV)-associated vasculitis is a rare secondary systemic vasculitis involving small and medium arteries. We report a 42-year-old man with uncontrolled HIV infection presenting with long-lasting abdominal pain. An abdominal CT angiography revealed multiple microaneurysms and stenoses in intrarenal arteries, with involvement of mesenteric and hepatic arteries. HIV-associated vasculitis was diagnosed and glucocorticoids and raltegravir-based antiretroviral therapy were administered with good initial clinical and virological response. Several episodes of acute intestinal ischaemia were later developed requiring bowel resections of which histological examination showed vascular occlusive fibrotic changes without active vasculitic lesions. Vasculitis persisted in remission and intrarenal microaneurysms disappeared.

Protective effects of osthole on intestinal ischemia-reperfusion injury in mice.

OBJECTIVES: The purpose of this study was to evaluate the effect of intravenous injection of osthole on intestinal ischemia-reperfusion injury and parameters of oxidative stress. MATERIALS AND METHODS: In 45 Kunming male mice, treatment included sham surgery (15 mice); intestinal ischemia-reperfusion injury (clamping of the superior mesenteric artery, 2 h; clamp release, 1 h; 15 mice); or osthole treatment before and after ischemia-reperfusion injury (15 mice). Evaluation included histopathology, determination of intestinal wet/dry weight ratio, and measurement of levels of diamine oxidase, superoxide dismutase, malondialdehyde, interleukin 1ß, tumor necrosis factor α, and interleukin 2. Intestinal barrier permeability was evaluated with Evans blue test. RESULTS: The mean wet-to-dry weight ratio, Evans blue content, and Chiu score were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than the ischemia-reperfusion group. The mean serum diamine oxidase, malondialdehyde, interleukin 1ß, and tumor necrosis factor α levels were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than in the ischemia-reperfusion group. The mean superoxide dismutase activity and interleukin 2 levels were lower in the ischemia-reperfusion than in the sham group and greater in the osthole-treated than in the ischemia-reperfusion group. CONCLUSIONS: Treatment with osthole may protect against oxidative stress and tissue damage from intestinal ischemia-reperfusion injury.

Beneficial effects of intra-arterial and intravenous prostaglandin E1 in intestinal ischaemia-reperfusion injury.

OBJECTIVES: Ischaemia-reperfusion (I/R) injury is encountered in conditions that diminish intestinal blood flow. There is no clinically feasible technique available for mucosal preservation. METHODS: One hundred Wistar rats were subjected to intestinal ischaemia for 15 and 60 min (I15', I60'), followed by 1 and 7 days of reperfusion (R1d, R7d). Rats were subjected to ischaemia by clamping the superior mesenteric artery. Prostaglandin E1 (PGE1) (2.500 ng/kg intra-arterial bolus or 20 ng/kg intravenous infusion) was administered immediately prior to the commencement of the experimental period. Animals were divided into 20 groups: sham (laparotomy alone), sacrificed at 1 or 7 days; saline administration, 15 or 60 min of ischaemia, 1 or 7 days of reperfusion; prostaglandin E1 administration, 15 or 60 min of ischaemia, 1 or 7 days of reperfusion, each one for intra-arterial or intravenous administration. Ileal segments were excised and assessed for histopathological score, polymorphonuclear (PMN) leucocytes encountered and myeloperoxidase (MPO) activity measurement. RESULTS: I/R caused deterioration of histological characteristics. Prophylactic administration of PGE1 resulted in a significant decrease in the histological score compared with the respective saline group (analysis of variance, P < 0.005). In groups treated with PGE1, PMN leucocyte infiltration was lower for the 60 min of ischaemia group (I60'/R1d *P = 0.026; I60'/R7d P = 0.015). I15'/R7d did not lead to a significant reduction in PMN infiltration (P = 0.061). Pretreatment with PGE1 attenuates MPO levels after intestinal I/R injury (P < 0.05). No differences were encountered between types of administration. CONCLUSIONS: Results of this study showed that administration of prostaglandin E1 prevents I/R injury by diminishing histological damage parameters, inhibiting PMN leucocyte infiltration and attenuating MPO activity.

Effects of exogenous vasoactive intestinal peptide on mesenteric lymph pathway during early intestinal ischemia-reperfusion injury in rats.

Mesenteric lymph pathway serves as the primary route by which gut injury leads to systemic inflammation and distant organ injury. The inflammation of the intestinal tract is partially mediated by vasoactive intestinal peptide (VIP). Therefore, the aim of this study was to test whether exogenous VIP affects mesenteric lymph pathway during early intestinal ischemia-reperfusion (IIR) injury. Rats were randomized into control, control+VIP, IIR and IIR+VIP groups. The observation of mesenteric lymph flow was carried out by cannulation of mesenteric lymphatics. The distribution of in vivo lymphocyte trafficking was performed by (51)Cr labeled lymphocytes and was measured by γ-counter. Endotoxin concentration was assayed using the limulus test kit and TNF-α level was detected by ELISA. When IIR injury treated with VIP, the volumes of lymph flow increased by 80%, which caused the number of lymphocytes exiting in mesenteric lymphatic increased by 50% while the proportion of (51)Cr-lymphocytes in Peyer's patches, intestinal effector tissues, mesenteric nodes, large intestine, stomach decreased by 58%, 51%, 58%, 63%, 64% respectively at the 6th h after reperfusion following intestinal ischemia. Meanwhile, endotoxin and TNF-α levels in intestinal lymph decreased by 51% and 83%. These results suggest that exogenous VIP ameliorates IIR induced splanchnic organ damage via inhibition of toxic mediators reaching systemic circulation and reinforcement of the effective immune responses in gut-associated lymphoid tissues (GALT).

Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-α-regulated mechanism.

AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-α blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay. RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-α levels. Administration of anti-TNF-α IgG or anti-TNF-α receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO-1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-α levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury.

Clinical analysis of patients with autoimmune disease complicated by mesenteric vein thrombosis: a retrospective study in a hospital.

BACKGROUND/AIMS: To analyze the clinical characteristics of patients with mesenteric venous thrombosis related to autoimmune disease (AID). METHODOLOGY: Retrospective study of 5 AID patients with mesenteric vein thrombosis in a single hospital. RESULTS: All 5 patients were female with an average age of 57.6 years. At the clinical visit all patients had clinical manifestations with signs of mesenteric blood vessel involvement and a significant increase of inflammatory markers. Surgical exploration identified peritonitis in all 5 cases - 2 cases of intestinal stenosis with mucosal ulcers and 3 cases of intestinal necrosis complicated by perforation. All 5 patients underwent partial bowel resection. Pathological examination confirmed chronic inflammation and vasculitis of intestinal connective tissue, combined with the formation of mesenteric vein thrombosis. CONCLUSIONS: Mesenteric vein thrombosis is a serious complication of AID. AID patients with digestive tract symptoms should be screened by abdominal imaging. In addition to early hormonal therapy and immunosuppressant treatment of the primary disease, surgical treatment should be performed as soon as possible if the disease progresses.

Semapimod a new pretreatment modality of acute intestinal ischemia-reperfusion syndrome: experimental study in rabbits.

AIM: Semapimod is an experimental drug that strongly inhibits macrophages and stimulates the cholinergic anti-inflammatory pathway. The aim of this study was to evaluate the effect of semapimod on experimentally-induced acute intestinal ischemia-reperfusion syndrome in rabbits. METHODS: The experimental protocol included 16 adult male White New Zealand rabbits divided into two equal groups, A and B. Animals were subjected to 150 min of intestinal ischemia, followed by 30 min of reperfusion. At 30, 90 and 150 min after the onset of ischemia the animals in group A received i.v. placebo (2 mg/kg; Cytokine PharmaSciences Inc, PA, USA) and those of group B received i.v. semapimod (2 mg/kg; Cytokine PharmaSciences Inc, PA, USA). Blood samples were taken for plasma measurements of tumor necrosis factor-a (TNF-a), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) at 0, 60, 120 and 180 min after the onset of ischemia. At the same time points, wedge intestinal biopsies were taken for histopathological evaluation of mucosal injury. All data were analyzed by the non-parametric Mann-Whitney test as appropriate. The power effect of Semapimod was evaluated by mixed between-within Anova statistical analysis. RESULTS: Measurements of TNF-a and IL-1ß levels showed significant differences between groups A and B at 120 min (P=0.004 and P=0.003 respectively) and at 180 min (P=0.001 and p<0.005 respectively). IL-6 values were lower in animals of group B but the differences were not significant. Intestinal mucosal injuries were significantly milder in animals of group B at 120 and 180 min CONCLUSION: Semapimod minimized intestinal mucosa injury and reduced the systemic inflammatory response during acute intestinal ischemia-reperfusion. Further studies are required to investigate the possible value of semapimod as a new pretreatment modality in acute vascular abdomen.

Antiallergic cromones inhibit neutrophil recruitment onto vascular endothelium via annexin-A1 mobilization.

OBJECTIVE: To determine whether the inhibitory action of the antiallergic cromone "mast cell stabilizing" drugs on polymorphonuclear leukocyte (PMN) trafficking is mediated through an annexin-A1 (Anx-A1) dependent mechanism. METHODS AND RESULTS: Intravital microscopy was used to monitor the actions of cromones in the inflamed microcirculation. Reperfusion injury provoked a dramatic increase in adherent and emigrated leukocytes in the mesenteric vascular bed, associated with augmented tissue levels of myeloperoxidase. Nedocromil, 2 to 20 mg/kg, significantly (P<0.05) inhibited cell adhesion and emigration, as well as myeloperoxidase release, in wild-type but not Anx-A1(-/-) mice. Short pretreatment of human PMNs with nedocromil, 10 nmol/L, inhibited cell adhesion (P<0.05) in the flow chamber assay, and this effect was reversed by specific anti-AnxA1 or a combination of antiformyl peptide receptors 1 and 2, but not irrelevant control, antibodies. Western blotting experiments revealed that cromones stimulate protein kinase C-dependent phosphorylation and release Anx-A1 in human PMNs. CONCLUSIONS: We propose a novel mechanism to explain the antiinflammatory actions of cromones on PMN trafficking, an effect that has long puzzled investigators.

Carbon monoxide liberated from CO-releasing molecule (CORM-2) attenuates ischemia/reperfusion (I/R)-induced inflammation in the small intestine.

CORM-released CO has been shown to be beneficial in resolution of acute inflammation. The acute phase of intestinal ischemia-reperfusion (I/R) injury is characterized by oxidative stress-related inflammation and leukocyte recruitment. In this study, we assessed the effects and potential mechanisms of CORM-2-released CO in modulation of inflammatory response in the small intestine following I/R-challenge. To this end mice (C57Bl/6) small intestine were challenged with ischemia by occluding superior mesenteric artery (SMA) for 45 min. CORM-2 (8 mg/kg; i.v.) was administered immediately before SMA occlusion. Sham operated mice were injected with vehicle (0.25% DMSO). Inflammatory response in the small intestine (jejunum) was assessed 4 h following reperfusion by measuring tissue levels of TNF-alpha protein (ELISA), adhesion molecules E-selectin and ICAM-1 (Western blot), NF-kappaB activation (EMSA), along with PMN tissue accumulation (MPO assay) and leukocyte rolling/adhesion in the microcirculation of jejunum (intravital microscopy). The obtained results indicate that tissue levels of TNF-alpha, E-selectin and ICAM-1 protein expression, activation of NF-kappaB, and subsequent accumulation of PMN were elevated in I/R-challenged jejunum. The above changes were significantly attenuated in CORM-2-treated mice. Taken together these findings indicate that CORM-2-released CO confers anti-inflammatory effects by interfering with NF-kappaB activation and subsequent up-regulation of vascular pro-adhesive phenotype in I/R-challenged small intestine.

Heterogeneity of atherosclerosis in mesenteric arteries and outgrowth remodeling.

BACKGROUND: In patients with acute mesenteric ischemia by occlusive thrombo-embolism, the superior mesenteric artery (SMA) is more affected than the inferior mesenteric artery (IMA). METHODS: This study investigated postmortem mesenteric arteries from aged subjects (n=21). Four atherosclerotic stages were defined by signs of degeneration and inflammation in sections stained with Elastica-van-Gieson and immunohistology, respectively. RESULTS: In females and males, Stages 3 and 4 were found in 62% of the SMA and 24% of the IMA. Lumenal areas based on diameter measurements remained essentially unchanged between Stages 1 and 4. Compared to a Stage 1 reference, remodeling was associated with thinning of the media below the plaque base and with pronounced thickening below the shoulder in the IMA. In Stages 3 and 4, the adventitia of the IMA had more vasa vasorum and a higher number of CD45-positive leukocytes than the adventitia of the SMA. During atherosclerotic progression, a stable fraction of leukocytes represented mast cells (6%) and CD117-positive cells as potential progenitor cells (1%). CONCLUSIONS: Outgrowth remodeling occurred in both the SMA and the IMA. Less severe atherosclerosis in the IMA than in the SMA was associated with stronger signs of inflammation.

Immune-enhancing enteral nutrients differentially modulate the early proinflammatory transcription factors mediating gut ischemia/reperfusion.

BACKGROUND: Recent reports suggest that enteral diets enriched with arginine may be harmful by enhancing inflammation. This is consistent with our gut ischemia/reperfusion (I/R) model in which arginine induced the proinflammatory mediator inducible nitric oxide synthase and resulted in injury and inflammation whereas glutamine was protective. We now hypothesize that arginine and glutamine differentially modulate the early proinflammatory transcription factors activated by gut I/R. METHODS: At laparotomy, jejunal sacs were filled with either 60 mmol/L glutamine, arginine, or an iso-osmotic control followed by 60 minutes of superior mesenteric artery occlusion and 6 hours of reperfusion and compared with shams. Jejunum was harvested for nuclear factor (NF)-kappaB and activator protein-1 (AP-1) measured by electrophoretic mobility shift assay and c-jun and c-fos (AP-1 family) by supershift. RESULTS: Both NF-kappaB and AP-1 were activated by gut I/R. Arginine and glutamine had no differential effect on NF-kappaB, whereas AP-1 expression (c-jun but not c-fos) was markedly enhanced by arginine and significantly lessened by glutamine. CONCLUSION: Arginine enhanced expression of the early proinflammatory transcription factor AP-1 but not NF-kappaB. This represents a novel mechanism by which arginine may be harmful when administered to critically ill patients.

Superior mesenteric vein thrombosis presented transient false positivity for lupus anticoagulant under heparin treatment.

A 24-year-old Japanese man was admitted because of massive haematemesis and melaena with persistent abdominal pain. Markedly bloody ascites and severely oedematous small intestine were recognized, and angiography then revealed superior mesenteric vein thrombosis. After resection of the necrotic small intestine, continuous intravenous infusion of heparin and urokinase was performed. This patient had no familial or personal history of thrombosis. On the 15th day after operation, an initial search for lupus anticoagulant revealed that the prothrombin time (PT) ratio and dilute activated partial thromboplastin time (aPTT) were positive under heparin treatment, without evidence of rheumatic or connective tissue disease. Thrombocytopenia was observed with a nearly normocellular bone marrow. A follow-up examination 1 year later still revealed an increased aPTT. However, all tests for antiphospholipid antibodies had been negative including dilute aPTT for about 2 years since the 15th day after operation. These findings suggest that, in this patient, superior mesenteric vein thrombosis has not been associated with primary antiphospholipid syndrome but is probably idiopathic. Positive tests for lupus anticoagulant in the initial period may be unreliable due to heparin treatment.

Portal and mesenteric vein and inferior vena cava thrombosis associated with antiphospholipid syndrome.

We report a 48-year-old man with thrombosis of the portal and superior mesenteric vein and inferior vena cava associated with primary antiphospholipid syndrome (APS). Primary APS was diagnosed by a positive reaction with anticardiolipin antibody (aCL) and the absence of any evidence suggesting the presence of other disease states known to be associated with aCL. A coeliac angiography showed obstruction of the portal and superior mesenteric vein with prominent collaterals and cavernous transformation. Femoral vein angiography showed total obstruction of the external iliac vein and inferior vena cava, and dilation of the pelvic veins, with contrast medium in the lumbar vein. This case is noteworthy as a report of primary APS accompanied by extensive abdominal and pelvic venous thrombosis.

[Acute mesenterial artery occlusion--an unusual symptom of primary antiphospholipid antibody syndrome]. / Akuter Mesenterialarterienverschluss als seltene Manifestation eines primären Antiphospholipid-Antikörpersyndroms.

BACKGROUND: The antiphospholipid-antibody syndrome (APS) is a thrombophilic disorder, in which venous and arterial thrombosis can occur. We report the rare case of a patient with mesenteric infarction due to primary APS. CASE REPORT: A 46-year-old male patient was admitted to the hospital because of severe abdominal pain. A laparotomy was performed and revealed infarction of a jejunal loop which was resected. At pathohistological examination mesenteric artery infarction was found. Preoperatively prolonged partial thromboplastin time led to coagulation analysis. Lupus anticoagulant and anticardiolipin antibodies were found. TREATMENT: The diagnosis of primary APS was made and the patient was treated with aspirin (100 mg/day) and low molecular weight heparin (2,500 IE/day) permanently. Eighteen months after mesenteric infarction the patient is free of further thromboembolic events.

Lipocortin 1 protects against splanchnic artery occlusion and reperfusion injury by affecting neutrophil migration.

Splanchnic artery occlusion and reperfusion (SAO/R) shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp (60-min reperfusion). Following this reperfusion period, rats developed a fall in mean arterial blood pressure, associated with a significant increase in tissue myeloperoxidase (MPO) activity in the intestine and a marked histologic injury to the distal ileum. Treatment of rats with a lipocortin-1 (LC1)-derived N-terminal peptide, peptide Ac(2-26), dose-dependently (0.125-0.5 mg/kg s.c.) reduced the progressive fall in blood pressure and prevented the infiltration of neutrophils into the reperfused intestine (reduced MPO activity). The LC1 peptide also reduced the degree of ischemia/reperfusion injury in the bowel as evaluated by histologic examination. The glucocorticoid dexamethasone (0.1 mg/kg s.c., -1 h) also produced a marked improvement in SAO/R shock (i.e., maintained mean arterial blood pressure and reduced tissue MPO activity), and this was reversed by pretreatment with two different antisera raised against the LC1 pharmacophore. Peptide Ac(2-26) (0.5 mg/kg s.c., -30 min) reduced (>60%) the extent of IL-1beta-induced cell emigration and significantly attenuated (approximately 45%) the number of adherent leukocytes in the rat mesenteric vascular bed, as assessed by video microscopy. These results suggest that LC1 inhibits neutrophil migration and accumulation into reperfused tissues, thereby ameliorating the outcome of SAO/R shock.

[Intestinal cytokine liberation after intestinal ischemia in the rat--studies in the Ussing chamber system]. / Intestinale Zytokinfreisetzung nach Darmischämie in der Ratte--Untersuchungen im Ussing-Kammersystem.

UNLABELLED: Intestinal ischemia, frequently found in clinical states such as aortic bypass operations or hemorrhagic shock, is associated with loss of gut barrier function. Subsequent translocation of indigenous bacteria and endotoxin have been implicated as a major contributor to a systemic immuno-inflammatory response, which finally leads to multiple organ failure. There is increasing evidence that intestinal injury can result in the gut becoming a cytokine generating organ. This study was designed to show direct evidence of the gut as a major source of proinflammatory cytokines after intestinal ischemia and to further relate this cytokine response to the extent of intestinal ischemia/reperfusion. Additionally the potential role of the altered intestinal barrier function after intestinal ischemia for this cytokine response was investigated. METHODS: Rats were subjected to occlusion of the superior mesenteric artery for 45 min. (SMAO45), 75 min. (SMAO75), SMAO for 45 min. and 30 min. reperfusion (SMAO45/30), or sham SMAO, and then killed. Mucosal membranes from the terminal ileum were mounted in a Ussing chamber. E. coli C25 was added to the mucosal side of the stripped gut epithelium in half of the chambers. TNF and IL-6 levels on mucosal and serosal side of the stripped gut epithelium were assessed serially over 3 hrs. Gut barrier function was assessed by in vitro bacterial translocation (BT) and the transepithelial resistance (TER) of the mucosal membrane. RESULTS: The TNF response was greatest in the SMAO75 group, the IL-6 response in the SMAO75 and SMAO45/30 groups. In the absence of E. coli C25. IL-6 was produced to a greater extent on the serosal side, while addition of bacteria led to a significantly increased TNF/IL-6 response at the mucosal side of the stripped gut epithelium. BT was increased in SMAO75 and SMAO45/30 rats. Baseline TER was decreased in all experimental compared to sham SMAO groups. Although gut barrier function was impaired after intestinal ischemia/reperfusion there was no correlation between intestinal cytokine response and gut permeability. CONCLUSIONS: The gut becomes a cytokine liberating organ alter intestinal ischemia/reperfusion. This cytokine response is affected by certain conditions, but is not directly related to an impaired intestinal barrier function.

Complement plays an essential role in shock following intestinal ischaemia in rats.

Intestinal ischaemia lasting more than 30 min in rats causes fatal systemic shock. Systemic shock was suppressed by preadministration of cobra venom factor (CVF), which reduced the serum complement to less than 5% of the normal level, indicating that complement is involved in the syndrome. After complement activation, anaphylatoxins such as C3a and C5a are generated, and their activity is restricted by carboxypeptidases which remove C-terminal arginine from such bioactive peptides. As expected, preadministration of a carboxypeptidase inhibitor enhanced the systemic shock induced by the intestinal ischaemia. However, when the complement level was suppressed by CVF treatment, no fatal systemic shock was induced by the intestinal ischaemia even with preadministration of the carboxypeptidase inhibitor. These results indicate that complement plays a crucial role in systemic shock induced by intestinal ischaemia, and that anaphylatoxins generated by the complement activation should be involved in induction of the shock syndrome.

Mesenteric thrombosis associated with anticardiolipin antibodies in a patient with systemic lupus erythematosus.

A 45-yr-old female with mild chronic systemic lupus erythematosus for 20 yr, and with a stroke, digital infarction, and transient vocal cord paralysis during those 20 yr, had severe abdominal pain for 2 wk due to omental infarction associated with the presence of anticardiolipin antibodies. This report suggests that patients with otherwise mild systemic lupus erythematosus may develop severe recurrent thromboembolic events associated with anticardiolipin antibodies, that anticardiolipin antibodies may be associated with mesenteric ischemia, and that mesenteric ischemia associated with anticardiolipin antibodies should be considered in the differential of significant, unexplained abdominal pain in patients with systemic lupus erythematosus.