How relevant are vascular endothelial growth factor and intercellular adhesion molecule in the systemic capillary leak syndrome of psoriasis?

Abstract: Psoriasis is a chronic disease, characterized by erythematous scaly lesions, presented in eight different forms: plaques, guttate, pustular, erythrodermic, inverse, nail and scalp psoriasis, and psoriatic arthritis. Its development depends on genetic factors, external stimulus and immune response alteration.1 Proinflammatory cytokines such as TNF-alpha, IL-12 and 23 may also be involved. In the worst cases, systemic complications linked to endothelial alterations may occur. A literature review was conducted for a better understanding of what roles VEGF (vascular endothelial growth factor) and ICAM-1 (intercellular adhesion molecule) have, among other cytokines, in systemic capillary leak syndrome, involved in erythrodermic and pustular psoriasis, the most unstable forms of the disease.

Dexmedetomidine preconditioning inhibits the long term inflammation induced by renal ischemia/reperfusion injury in rats

PURPOSE: To investigate the protective effects of dexmedetomidine (Dex) against renal ischemia/reperfusion injury (IRI). METHODS: Sprague-Dawley rats were randomly divided to sham group, IRI group and Dex group. The SD rats were subjected to 45 min of ischemia followed by eight weeks of reperfusion. Prior to ischemia, rats were either treated with Dex or not. Blood samples were collected for the detection of blood urea nitrogen (BUN) and creatinine (Cr) levels. Immunohistochemistry was performed for CD3 T-cell infiltrates. Real-time PCR and western blot were detected for the expression of TNF-α, IL-1β, ICAM-1, HMGB1 and TLR4. RESULTS: Compared with sham group, renal IRI significantly increased the serum levels of BUN and Cr. The H&E staining indicated that renal IRI resulted in obvious renal injury and immunohistochemistry found that there were more CD3 T-cell infiltrates in IRI group. Also, renal IRI upregulated the expression of TNF-α, IL-1β, ICAM-1, HMGB1 and TLR4. However, all these changes were alleviated by the treatment with Dex. CONCLUSIONS: Dexmedetomidine has beneficial effects on long term inflammation induced by renal ischemia/reperfusion injury. Its mechanisms may be achieved through inhibiting the HMGB1/TLR4 pathway to exert protective effects.

Ozone oxidative preconditioning protects the rat kidney from reperfusion injury via modulation of the TLR4-NF-κB pathway

PURPOSE: To investigate the protective effects of ozone oxidative preconditioning (OzoneOP) were associated with the modulation of TLR4-NF-κB pathway. METHODS: Thirty six rats were subjected to 45 min of renal ischemia, with or without treatment with OzoneOP (1 mg/kg). Blood samples were collected for the detection of blood urea nitrogen and creatinine levels. Histologic examinations were evaluated and immunohistochemistry was also performed for localization of TLR4 and NF-κB. The expression of TNF-α, IL-1β, IL-6, ICAM-1 and MCP-1 were studied by Real-time PCR. Western blot was performed to detect the expression of TLR4 and NF-κB. RESULTS: The results indicated that blood urea nitrogen and creatinine levels increased significantly in I/R group. Rats treated with OzoneOP showed obviously less renal damage. Immunohistochemistry showed that TLR4 were ameliorated by OzoneOP. Realtime PCR showed that OzoneOP could significantly inhibit the increased mRNA levels of TNF-α, IL-1β, IL-6, ICAM-1 and MCP-1 induced by I/R. Western blot indicated that the expression of TLR4 and NF-κB were upregulated in I/R group, but OzoneOP could inhibit this increase. CONCLUSION: These findings indicated that OzoneOP had potent anti-inflammatory properties by the modulation of the TLR4-NF-κB pathway in renal ischemia/reperfusion injury. .

Therapeutic effects of compound hypertonic saline on rats with sepsis

Sepsis is one of the major causes of death and is the biggest obstacle preventing improvement of the success rate in curing critical illnesses. Currently, isotonic solutions are used in fluid resuscitation technique. Several studies have shown that hypertonic saline applied in hemorrhagic shock can rapidly increase the plasma osmotic pressure, facilitate the rapid return of interstitial fluid into the blood vessels, and restore the effective circulating blood volume. Here, we established a rat model of sepsis by using the cecal ligation and puncture approach. We found that intravenous injection of hypertonic saline dextran (7.5% NaCl/6% dextran) after cecal ligation and puncture can improve circulatory failure at the onset of sepsis. We found that the levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and intracellular adhesion molecule 1 levels in the lung tissue of cecal ligation and puncture rats treated with hypertonic saline dextran were significantly lower than the corresponding levels in the control group. We inferred that hypertonic saline dextran has a positive immunoregulatory effect and inhibits the overexpression of the inflammatory response in the treatment of sepsis. The percentage of neutrophils, lung myeloperoxidase activity, wet to dry weight ratio of lung tissues, histopathological changes in lung tissues, and indicators of arterial blood gas analysis was significantly better in the hypertonic saline dextran-treated group than in the other groups in this study. Hypertonic saline dextran-treated rats had significantly improved survival rates at 9 and 18 h compared to the control group. Our results suggest that hypertonic saline dextran plays a protective role in acute lung injury caused after cecal ligation and puncture. In conclusion, hypertonic/hyperoncotic solutions have beneficial therapeutic effects in the treatment of an animal model of sepsis.

Effects of Human Umbilical Cord Mesenchymal Stem Cells on Renal Ischaemia-reperfusion Injury in Rats

Objective This study aims to observe the function of umbilical cord-mesenchymal stem cells (UC-MSCs) labelled with enhanced green fluorescent protein (eGFP) in the repair of renal ischaemia-reperfusion (I/R) injury, to determine the effects on inflammatory cascade in an established rat model and to explore possible pathogenesis. Materials and Methods Sixty rats were randomly divided into three groups: the sham-operated, I/R and UC-MSC treatment groups. All rats underwent right nephrectomy. Ischaemia was induced in the left kidney by occlusion of the renal artery and vein for 1hour, followed by reperfusion for 24 hours or 48 hours. Kidney samples were collected to observe morphological changes. Immunohistochemistry was performed to assess the expression of intercellular adhesion molecule 1 (ICAM-1) in the renal tissue sample, as well as the number of infiltrating polymorphonuclear neutrophils (PMNLs) and UC-MSCs with positive eGFP. Results Renal histopathological damages and the expression of ICAM-1 and PMNL increased significantly in the I/R group compared with those in the sham-operated group, whereas the damages were less conspicuous in the UC-MSC treatment group. Conclusions Renal ICAM-1, which mediated PMNL infiltration and contributed to renal damage, was significantly up-regulated in the I/R group. UC-MSCs were identified to inhibit these pathological processes and protect the kidney from I/R injury. .

Mesenteric lymph reperfusion after superior mesenteric artery occlusion shock exacerbates endotoxin translocation in brain

PURPOSE: To determine the role of mesenteric lymph reperfusion (MLR) on endotoxin translocation in brain to discuss the mechanism of brain injury subjected to superior mesenteric artery occlusion (SMAO) shock. METHODS: Twenty-four rats were randomly assigned to MLR, SMAO, MLR+SMAO and sham groups. MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h and then allowing reperfusion for 2 h in the MLR group; SMAO involved clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h in the SMAO group; occlusion of both the SMA and MLD for 1 h was followed by reperfusion for 2 h in the MLR+SMAO group rats. RESULTS: SMAO shock induced severe increased levels of the endotoxin, lipopolysaccharide receptor, lipopolysaccharide-binding protein, intercellular adhesion molecule-1 and tumor necrosis factor-α. Concurrently, MLR after SMAO shock further aggravates these deleterious effects. CONCLUSION: Mesenteric lymph reperfusion exacerbated the endotoxin translocation in brain; thereby increased inflammatory response occurred, suggesting that the intestinal lymph pathway plays an important role in the brain injury after superior mesenteric artery occlusion shock. .

Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock

The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-α, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses.

Alprostadil attenuates inflammatory aspects and leucocytes adhesion on renal ischemia and reperfusion injury in rats

PURPOSE: To evaluate the effects of alprostadil in an experimental model of ischemia and reperfusion injury (IRI) in rat renal tissue. METHODS: Adult male Wistar rats were randomized into three groups Vehicle-treated group(Veh), Alprostadil-treated(Al), and sham(Sh) group. Veh and Al groups had suprarenal aorta occluded for 30 minutes and reperfused for 60 minutes. Saline or 20 µg/kg of Alprostadil was intravenously infused immediately before declamping. Sh group animals underwent similar procedure without aortic occlusion. Left nephrectomy and blood sampling were performed after 60 minutes of reperfusion. Renal ICAM-1 expression and histological analysis were performed to estimate inflammatory response and tissue disarrangement. Serum biochemical markers for IRI were also measured. Kruskal-Wallis test was used to assess differences between the groups. RESULTS: There was lower expression of ICAM-1 in groups Veh and Sh. On histologically evaluation, inflammation and necrosis in the Veh group was significantly higher (grades III/IV) than Al group (Veh>Al=Sh; p = 0.025), as well as CPK levels (Veh>Al=Sh; p = 0.03). CONCLUSION: Alprostadil attenuates the immunohistochemical and histological repercussions in the renal tissue of rats submitted to a post-ischemic reperfusion with supra-renal aortic clamping. .

Correlação entre mediadores inflamatórios na secreção nasofaríngea e no soro de crianças com infecção do trato respiratório inferior por vírus sincicial respiratório e a gravidade da doença / Correlation between inflammatory mediators in the nasopharyngeal secretion and in the serum of children with lower respiratory tract infection caused by respiratory syncytial virus and disease severity

OBJETIVO: Avaliar se as concentrações dos mediadores inflamatórios (CCL5, soluble intercellular adhesion molecule type 1 [sICAM-1], TNF-α, IL-6 e IL-10) na secreção nasofaríngea e no soro de crianças com infecção do trato respiratório inferior (ITRI) por vírus sincicial respiratório (VSR) apresentam correlação com os marcadores clínicos de gravidade da doença. MÉTODOS: Entre julho de 2004 e dezembro de 2005, 30 crianças com idade inferior a três meses, diagnosticadas com ITRI por VSR e admitidas em uma UTI neonatal foram incluídas neste estudo. RESULTADOS: Houve uma correlação positiva significante entre a gravidade da doença na admissão hospitalar, determinada por um sistema de escore clínico modificado, e as concentrações de sICAM-1 e de IL-10 na secreção nasofaríngea e de IL-6 no soro dos pacientes. Houve também uma correlação positiva significante entre a concentração de IL-6 no soro e o tempo de oxigenoterapia e a duração da internação. CONCLUSÕES: As concentrações de sICAM-1 e IL-10 na secreção nasofaríngea e de IL-6 no soro determinadas na admissão poderiam ser usadas como marcadores de gravidade da ITRI por VSR. Os níveis de IL-6 determinados no soro na admissão também poderiam ser usados para predizer o prolongamento da oxigenoterapia e da duração da internação.

OBJECTIVE: To determine whether the concentrations of inflammatory mediators (CCL5, soluble intercellular adhesion molecule type 1 [sICAM-1], TNF-α, IL-6 and IL-10) in the nasopharyngeal secretion and in the serum of children with lower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) correlate with the clinical markers of disease severity. METHODS: Between July of 2004 and December of 2005, 30 children less than three months of age, diagnosed with LRTI caused by RSV and admitted to a neonatal ICU, were included in this study. RESULTS: The severity of disease at hospital admission, as determined with a modified clinical scoring system, presented a significant positive correlation with sICAM-1 and IL-10 concentrations in the nasopharyngeal secretion, as well as with IL-6 concentrations in the serum, of the patients. In addition, serum IL-6 concentrations presented a significant positive correlation with the duration of oxygen therapy and with the length of hospital stay. CONCLUSIONS: At hospital admission, the concentrations of sICAM-1 and IL-10 in the nasopharyngeal secretion, as well as the concentration of IL-6 in the serum, could be used as markers of severity in patients with LRTI caused by RSV. The serum levels of IL-6 determined at admission could also be used to predict prolonged oxygen supplementation and hospital stay.

Divergent effects of Nitric oxide on airway epithelial cell activation

Nitric oxide (NO*) is a gaseous mediator synthesized by Nitric oxide sinthases. NO* is involved in the modulation of inflammation, but its role in airway inflammation remains controversial. We investigated the role of NO* in the synthesis of the chemok Nes Interleukin-8 and Monocyte Chemotactic Protein-1, and of Intercellular Adhesion Molecule-1 by human airway epithelial cells. normal human bronchial epithelial cells and the bronchial epithelial cell line BEAS-2B were used. Neterleukin-8 (IL-8) and Monocyte Chemotactic Protein-1 (MCP-1) secretion and Intercellular Adhesion Molecule-1 (ICAM-1) expression were measured by ELISA. mRNA was assessed by semiquantitative RTI-PCR. Neterleukin-8 secretion was significantly reduced after 24h incubation with the NO* donor, sodium nitroprusside. The effect was dose-dependent. Similar results were obta Ned with S-Nitroso-N-D,L-penicillam Ne and S-Nitroso-L-glutathione. Inhibition of endogenous NO* with the Nitric oxide synthase inhibitor N-Nitro-L-arg N Ne-methyl-esther caused an increase in IL-8 secretion by lypopolisaccharide- and cytok Ne-stimulated BEAS-2B cells. Sodium nitroprusside also caused a reduction in Monocyte Chemotactic Protein-1 secretion by both cell types. In contrast, Intercellular Adhesion Molecule-1 expression was upregulated by sodium NItroprusside. RTI-PCR results indícate that the modulation of protein levels was paralleled by modification in mRNA levels. NO* has divergent effects on the synthesis of different inflammatory mediators in human bronchial epithelial cells.

Early effect of Mycobacterium tuberculosis infection on Mac-1 and ICAM-1 expression on mouse peritoneal macrophages

Effect of M. tuberculosis infection was studied on the expression of intercellular adhesion molocule-1 (ICAM-1) and Mac-1 markers on murine peritoneal macrophages. Intraperitoneal administration of M. tuberculosis resulted in a marked increase in the proportion of Mac-1+ cells whereas the proportion of ICAM-1+ cells declined sharply 4 h post infection. Absolute numbers of Mac-1+ and ICAM-1+ cells however increased at all time points after the infection. Comparison of kinetics of changes observed in Mac-1+ and ICAM-1+ cell populations with differential leukocyte counts in peritoneal cells indicated that these alterations could be due to cellular influx, especially that of neutrophils, or up regulation of these markers on macrophages and other peritoneal cells. In adherent peritoneal macrophages infected in vitro with M. tuberculosis, proportion of Mac-1+ and ICAM-1+ cells increased markedly within 24 h of infection. Mean expression of these markers on per cell basis also increased significantly. Similar results were obtained by using RAW 264.7 mouse macrophage cell line, suggesting that the enhanced expression of Mac-1 and ICAM-1 markers was a direct effect of M. tuberculosis infection and not mediated by contaminating cell types present in adherent macrophage preparations. Mac- 1 and ICAM-1 expression was further studied on macrophages that had actually engulfed M. tuberculosis and compared with bystander macrophages without intracellular M. tuberculosis. For this purpose M. tuberculosis pre-stained with DilC18 fluorescent dye were used for infecting adherent peritoneal macrophages. Mac-1 and ICAM-1 expression on gated DilC18 positive and negative cell populations was analyzed. Our results indicate that the expression of Mac-1 and ICAM- 1 markers was significantly enhanced on all macrophages incubated with M. tuberculosis but was more pronounced on macrophages with internalized mycobacteria. Taken together, our results suggest that the expression of Mac-1 and ICAM-1 markers is significantly up regulated

Avaliação dos efeitos da reanimação volêmica com solução salina hipertônica, Ringer lactato e pentoxifilina na microcirculação de ratos após choque hemorrágico / Resuscitation effects microcirculatory neutrophil behavior after hemorrhagic shock: role of hypertonic saline and pentoxifylline

O objetivo desse estudo foi avaliar a interação neutrófilo-endotélio e a expressão de ICAM-1 após choque hemorrágico em ratos. A pressão foi mantida em 35 mmHg por 1 h por retirada de sangue, e em seguida os animais foram randomizados em 3 grupos: solução hipertônica (SH, NaCl 7,5 por cento), Ringer lactato (RL), RL+pentoxifilina (RL+PTX). O grupo controle não sofreu hemorragia nem tratamento. Duas horas após tratamento, os grupos SH, RL+PTX e controle apresentaram redução significativa na adesão de leucócitos comparados ao grupo RL. O grupo RL apresentou aumento no número de células migradas comparados ao grupo controle, e aumento na expressão de ICAM-1 comparados aos grupos SH, RL+PTX e controle / The objective was to study neutrophil–endothelial cell interactions and ICAM-1 expression in a controlled hemorrhagic shock model. Rats were bled to a MAP of 35 mmHg for 1 h and then randomized into 3 groups: HS (hypertonic saline) (7.5 per cent NaCl, 4 ml/Kg); LR (Lactated ringer) (3x shed blood); LR+PTX (pentoxifylline) (25 mg/Kg). A sham group underwent no shock and no treatment. Two hours after treatment, HS, LR+PTX and sham groups presented significant reductions in leukocyte adherence compared with LR group (p<0.05). LR-treated animals also presented higher number of migrated cells compared to sham; and higher ICAM-1 expression compared with HS, PTX and sham groups (p<0.01)...

Melatonin ameliorates autoimmune encephalomyelitis through suppression of intercellular adhesion molecule-1

Melatonin (N-acetyl-5-methoxytryptamine), a pineal neurohormone, is a hydroxyl radical scavenger and antioxidant, and plays an important role in the immune system. We studied the effect of exogenous melatonin on the pathogenesis of experimental autoimmune encephalomyelitis (EAE). EAE was induced in Lewis rats by immunization with rat spinal cord homogenates. Subsequent oral administration of melatonin at 5 mg/kg significantly reduced the clinical severity of EAE paralysis compared with administration of the vehicle alone (p<0.01). Infiltration of ED1 macrophages and CD4 T cells into spinal cords occurred both in the absence and presence of melatonin treatment, but melatonin-treated rats had less spinal cord infiltration of inflammatory cells than did the control group. ICAM-1 immunoreactivity in the blood vessels of EAE lesions was decreased in melatonin-treated rats compared to vehicle-treated rats. These findings suggest that exogenous melatonin ameliorates EAE via a mechanism involving reduced expression of ICAM-1 and lymphocyte function associated antigen-1a in autoimmune target organs.

Clinicopathologic study of Castleman's disease in Korea

Castleman's disease represents an atypical lymphoproliferative disorder, infrequently associated with various immunologic abnormalities or subsequent development of malignancy such as Kaposi sarcoma, malignant lymphoma and plasmacytoma. Its clinicopathologic features depend on various etiologic factors such as Kaposi sarcoma herpesvirus (KSHV), oversecretion of IL-6, adhesion molecule and follicular dendritic cell dysplasia, etc. To investigate the relationship of Castleman's disease (CD) and the above factors, we reviewed 22 cases of CD. Four cases of KSHV positive CD were detected, all multicentric, plasma cell type, and these cases displayed prominent vascular proliferation, characteristic 'Kaposi-like lesion'. IL-6 and CD54 positive mononuclear cells were scattered in interfollicular areas of KSHV positive cases. Follicular dendritic cell hyperplasia, vascular proliferation, expression of IL-6 and CD54 did not show any significant difference between solitary vs multicentric type, and plasma cell type vs hyaline vascular type. Our study suggests that KSHV positive CD reveals unique pathologic features, and the probable relationship of KSHV and IL-6 and CD54 is discussed.

Proteoglycan's activation by adhesion molecules and L metalloproteases in rheumathoid arthritis and ostheoarthritis

Two groups of patients were studied, both in accordance with ACR criteria. First group (41 cases) suffering R.A.. Second group (36 cases) suffering O.A. In both pathologies MMPs, ICAM and VCAM from synovial fluid and plasma were studied. Measurements were made with ELISA-sandwich in a Metrolab spectrophotometer at 410 mm for MMPs, and 491 nm for ICAM and VCAM. As control, samples of patients with noninflammatory muscle skeletal disorders or traumatic arthritis and healthy witness were used. Synovial concentration of MMPs in R.A. was 1402+76 ng/ml, a higher significant value (p<0.0001) compared with ostheoarthritis: 353+23 ng/ml. In the witness plasma, MMPs were not detected. Plasmatic and synovial levels of the adhesion molecules present different values in both pathologies and between them. Synovial ICAM level in R.A. (280+9.8 ng/ml) is significantly higher than in O.A. (163+10 ng/ml) (p<0.001), but lower than plasmatic ones (370+35 ng/ml) (p,0.001). All these values are significantly higher than the normal plasma (121+6.5 ng/ml) (p<0.005, and p<0.0001, respectively) VCAM increase regarding basal values (140+5.6 ng/ml) (p<0.001) and in a similar proportion for both pathologies (R.A.: 186+9.3 ng/ml and O.A.: 207+14.3 ng/ml). Their plasmatic levels were higher (270+45 and 320+38 ng/ml) (p<0.001) but without significative difference between them. There is correlation among MMPs, ICAM and VCAM variations. The variability can be explained by concomitance several evolutive steps. Each pathology shows a different grade of cellularity, inverted predominance in the relation TIMPs/collagenase and different generator mechanisms of MMPs. Our findings reinforce the importance as diagnostic guide of adhesion molecules dosage, and possible therapeutic use of MMPs inhibitors and ICAM ou VCAM antagonists en R.A. and related pathologies.

Isolation and pure culture of microvascular endothelial cells from the fetal skin

Microvascular endothelial cells were purely isolated from human fetal skin using magnetic particles. The principle of this technique is based on the selective binding of the lectin Ulex europaeus I (UEA I) to the endothelial cell surface via fucose residues. Initially UEA I was covalently bound to tosyl-activated magnetic polydisperse polymer particles (Dynabeads) and then the UEA I-coated beads were collected using a magnetic particle concentrator (MPC). Endothelial cells were isolated by extracting microvascular segments from trypsin-treated fetal skin tissue and were purified by sieving with nylon mesh and by 35% Percoll gradient centrifugation. For further purification, the obtained cells were incubated with UEA I-coated Dynabeads. The endothelial cells bound to the Dynabeads were collected using MPC. This is a simple and reproducible technique for isolating a pure population of microvascular endothelium from the fetal skin.