Expression Of Cellular Adhesion Molecules Research Articles

Abstract 3735: An anti-tumor immune response is evoked by partial-volume single dose radiation

Abstract Purpose: To study tumor growth delay resulting from partial irradiation in preclinical mouse models. Methods and Materials: We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2x2 cm collimator on a micro-irradiator. Radiation response was modulated by treating with anti-CD8 and anti-ICAM antibodies. Similar experiments were performed using the less immunogenic Lewis Lung Carcinoma (LLC) mouse model. Tumor growth delay and γH2AX phosphorylation were measured and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days post-radiotherapy (RT). Tumor expression of cellular adhesion molecules was also measured at different times post-RT. Results: Partial irradiation led to tumor responses similar to fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10Gy, infiltration of CD8+ T cells was observed, along with increased expression of ICAM. The response to 10Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic LLC mouse model delivering 15Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the non-irradiated area of the tumor, indicating that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10Gy in the 67NR model. Conclusions: In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This raises the possibility that this effect could be induced in the clinic. Citation Format: Adriana Haimovitz-Friedman, Johnn Humm, Joseph O. Deasy, Jedd Wolchok, Taha Merghoub, James Russell, Hongyan Li, Robert Samstein, Sadna Budhu, Simon Powell, Chloe Bodden, Ela Markovsky, Qing Chen. An anti-tumor immune response is evoked by partial-volume single dose radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3735.

H1-Antihistamines for Allergic Diseases: Old Aged but Not Old-Fashioned Drugs

Histamine is a chemical messenger synthesized from the amino acid histidine by L-histidine decarboxylase. It plays an important role in the system of immunoregulation and in acute and chronic allergic inflammation binding to four subtypes of receptors H1, H2, H3 and H4, described as heptahelical transmembrane molecules that activate specific G-proteins. These receptors placed on the membranes of different cellular jambs (mast cells, endothelial cells, sensory nerve fibres, bronchial smooth muscle) cause different biological actions: Vasodilatation, increased vascular permeability, itching, smooth muscle contraction, coronary spasm, sleep-wake rhythm regulation. Histamine interaction with H1-receptors potentially leads to increasing antigen-presenting cell capacity, release of histamine and other mediators from mast cells and basophils inducing cellular adhesion molecule expression and chemotaxis of eosinophils and neutrophils.

Activation of GPR39 with the agonist TC-G 1008 ameliorates ox-LDL-induced attachment of monocytes to endothelial cells

Attachment of monocytes to endothelial cells is a major event in the pathogenesis of atherosclerosis and cardiovascular disease. As atherosclerosis is considered to be an inflammatory disease, increased expression of proinflammatory cytokines greatly contributes to endothelial dysfunction and atherogenesis. Additionally, attachment of monocytes to endothelial cells triggered by cellular adhesion molecules such as vascular cellular adhesion molecule 1 (VCAM-1) and E-selectin plays a vital role in the development of atherosclerotic plaques. Zinc therapy has been suggested as a potential strategy for countering atherosclerosis. In the present study, for the first time to our knowledge, we investigated the potential role of the GPR39 zinc-sensing receptor in mediating the adhesion of monocytes to endothelial cells, oxidative stress and inflammation in human aortic endothelial cells induced by oxidized low-density lipoprotein (ox-LDL). Our findings show that agonism of GPR39 by the selective agonist TC-G 1008 potently reversed the effects of ox-LDL including increased expression of proinflammatory cytokines and chemokines, markers of oxidative stress, and enhanced expression of cellular adhesion molecules. Importantly, we also show that this protective effect is mediated through the nuclear factor-κB (NF-κB) pathway. Taken together, our findings suggest a potential role of GPR39 as a novel therapeutic target for the treatment and prevention of atherosclerosis induced by ox-LDL.

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

This study examined tumor growth delay resulting from partial irradiation in preclinical mouse models. We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2×2cm collimator on a microirradiator. Radiation response was modulated by treatment with anti-CD8 and anti-intercellular adhesion molecule (anti-ICAM) antibodies. Similar experiments were performed using the less immunogenic Lewis lung carcinoma mouse model. Tumor growth delay and γ-H2AX phosphorylation were measured, and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7days after radiation therapy. Tumor expression of cellular adhesion molecules was also measured at different times after radiation therapy. Partial irradiation led to tumor responses similar to those of fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10Gy, infiltration of CD8+ T cells was observed along with increased expression of ICAM. The response to 10Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic Lewis lung carcinoma mouse model delivering 15Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T-cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the nonirradiated area of the tumor. This result indicated that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10Gy in the 67NR model. In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This outcome raises the possibility that this effect could be induced in the clinic.

Development and characterization of a polarized human endometrial cell epithelia in an air\u2013liquid interface state

Human endometrial epithelia undergo injury repair and regeneration with the menstrual cycle; however, mechanisms underpinning the roles of endometrial epithelial cells in endometrial lesions and regeneration remain incompletely understood, mainly owing to the difficulty in the isolation and expansion of primary endometrial epithelial cells and the lack of reliable models for in vitro and in vivo studies. In this report, we sought to improve methods for the isolation and expansion of human endometrial epithelial cells with a Rho-associated protein kinase (ROCK) inhibitor–modified medium and subsequently characterize endometrial epithelium generated with primary cells cultured in an air–liquid interface (ALI) state. Immunocytochemistry staining revealed the expression of epithelial cellular adhesion molecule (EpCam) and stage-specific embryonic antigen-1 (SSEA-1) but a lack of CD13 in endometrial epithelial cells. Meanwhile, a large number of proliferative Ki67+ cells were observed in isolated epithelial cells. Importantly, the EpCam+/CD13− cells were capable of forming spheroids, a characteristic of epithelial stem/progenitor cells. Interestingly, these cells also exhibited a capacity to reconstitute epithelial layers in an ALI state. Morphological analysis revealed mucosal secretion of differentiated epithelial cells with cilia and microvilli in ALI epithelial cells as determined by electronic microscopy. Immunoblotting assay further demonstrated the expression of endometrial epithelial cell markers keratin 17/19 and EpCam and stem cell marker OCT3/4 but not stromal cell marker Vimentin protein and CD13 in cell expansions. Furthermore, molecular analysis also showed that the exposure of cells to estrogen elevated the expression of estrogen receptor and progesterone receptors in ALI cultures. Our results shed light on the possibility of expanding sufficient numbers of endometrial epithelial cells for stem cell biology studies, and they provide a feasible and alternative model that can recapitulate the characteristics and physiology of endometrial epithelium in vivo.

Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1

AbstractRecent studies show that endothelial cell protein C receptor (EPCR) interacts with diverse ligands, in addition to its known ligands protein C and activated protein C (APC). We showed in earlier studies that procoagulant clotting factor VIIa (FVIIa) binds EPCR and downregulates EPCR-mediated anticoagulation and induces an endothelial barrier protective effect. Here, we investigated the effect of FVIIa's interaction with EPCR on endothelial cell inflammation and lipopolysaccharide (LPS)-induced inflammatory responses in vivo. Treatment of endothelial cells with FVIIa suppressed tumor necrosis factor α (TNF-α)- and LPS-induced expression of cellular adhesion molecules and adherence of monocytes to endothelial cells. Inhibition of EPCR or protease-activated receptor 1 (PAR1) by either specific antibodies or small interfering RNA abolished the FVIIa-induced suppression of TNF-α- and LPS-induced expression of cellular adhesion molecules and interleukin-6. β-Arrestin-1 silencing blocked the FVIIa-induced anti-inflammatory effect in endothelial cells. In vivo studies showed that FVIIa treatment markedly suppressed LPS-induced inflammatory cytokines and infiltration of innate immune cells into the lung in wild-type and EPCR-overexpressing mice, but not in EPCR-deficient mice. Mechanistic studies revealed that FVIIa treatment inhibited TNF-α-induced ERK1/2, p38 MAPK, JNK, NF-κB, and C-Jun activation indicating that FVIIa-mediated signaling blocks an upstream signaling event in TNFα-induced signaling cascade. FVIIa treatment impaired the recruitment of TNF-receptor-associated factor 2 into the TNF receptor 1 signaling complex. Overall, our present data provide convincing evidence that FVIIa binding to EPCR elicits anti-inflammatory signaling via a PAR1- and β-arrestin-1 dependent pathway. The present study suggests new therapeutic potentials for FVIIa, which is currently in clinical use for treating bleeding disorders.

High-density lipoprotein attenuates secretion and gene expression of cellular adhesion molecules and proinflammatory cytokines in lipopolysaccharide-stimulated endothelial cells

This study was conducted to investigate the effects of high-density lipoprotein (HDL) on secretion and gene expression of intercellular adhesion molecules-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by human vascular endothelial cells (HUVEC). Lipoploysacharides-stimulated HUVEC was incubated with different concentrations of HDL (20-120 mg/dL) for 16 hours. The levels of all biomarkers were measured by ELISA. Total RNA was extracted and all bioamarkers’ mRNA levels were measured by Taqman real-time polymerase chain reaction assay Different HDL concentrations reduced the secretion and expressonof all biomarkers except VCAM-1, which may contribute to the prevention and regression of atherosclerosis.

The Impact of Laminar and Oscillatory Shear Stress on Cellular Adhesion Molecule Expression in HUVEC

PURPOSE: To investigate the influence of acute laminar shear stress (LSS) on the expression of VCAM-1 and fractalkine on human umbilical vein endothelial cells (HUVEC) following prolonged exposure to oscillatory shear stress (OSS) in vitro. METHODS: Cultured EC were stimulated with TNF-α for 24 hr and immediately exposed to shear experiments using a parallel-plate flow chamber: (i) 24 hr of LSS or OSS, and (ii) 24 hr of OSS followed by 30 min of LSS. Cells were collected and incubated with primary antibodies for surface VCAM-1 and fractalkine. Samples were analyzed via standard fluorescence-activated cell sorting. RESULTS: Prolonged LSS and OSS significantly reduced the TNF-α-induced elevation in the % of gated cells expressing VCAM-1 (p<0.001) and fractalkine (p=0.001); however, the reduction in VCAM-1 caused by LSS was shown to be significantly greater than the reduction elicited by OSS (p=0.006). Interestingly, the mean fluorescent intensity (MFI) of TNF-α-induced VCAM-1 was significantly elevated by prolonged OSS (1.60±0.01 fold [p<0.001]). Whereas, prolonged LSS had no impact on the MFI of TNF-α induced VCAM-1 (p=0.931). Prolonged LSS and OSS elicited a significant elevation in the MFI of TNF-α induced fractalkine (p=0.017). Lastly, acute LSS following prolonged OSS had no effect on the % of gated or MFI of cells expressing VCAM-1 and fractalkine. CONCLUSIONS: Prolonged OSS may increase markers of vascular inflammation. However, an acute period of LSS, utilized as a model of physical activity, does not appear to alter the OSS-induced inflammatory state.

Sphingosine 1-phosphate receptor 1 (S1PR1) agonist CYM5442 inhibits expression of intracellular adhesion molecule 1 (ICAM1) in endothelial cells infected with influenza A viruses.

BackgroundInfluenza A virus infection and its complications effect a large population worldwide. Endothelial cells are an important component in lung inflammation caused by influenza A virus infection. The roles of endothelial sphingosine 1-phophate receptor 1 (S1PR1) in the regulation of molecules involved in leukocyte recruitment during influenza A virus infection still remain unknown. In this report, we tested our hypothesis that S1PR1 agonist CYM5442 inhibits expression of intracellular adhesion molecules 1 (ICAM1) in endothelial cells infected with influenza A virus.MethodsHuman pulmonary microvascular endothelial cells (HPMEC) were infected with influenza A virus H1N1. Expression of cytokines, chemokines, interferons, and cellular adhesion molecules was measured by q-PCR. Expression of ICAM1 was further tested by Western Blotting. A S1PR1 agonist CYM5442 was added to the culture media to assess CYM5442’s inhibitory effects during virus infection.ResultsHPMEC could be infected with H1N1 and responded to produce pro-inflammatory cytokines, chemokines, type I interferons, and cellular adhesion molecules. Addition of CYM5442 in culture media reduced the production of ICAM1 via a dosage- and time-dependent manner. CYM5442 inhibited the activation of nuclear factor (NF)-κB. The regulatory effects of CYM5442 were β-arrestin2-dependent.ConclusionActivated S1PR1 signaling regulates the production of cellular adhesion molecules by inhibiting NF- κB activation via a β-arrestin2-dependent manner.

Rosuvastatin Inhibits Interleukin (IL)-8 and IL-6 Production in Human Coronary Artery Endothelial Cells Stimulated With Aggregatibacter actinomycetemcomitans Serotype b.

Rosuvastatin exhibits anti-inflammatory effects and reduces periodontal diseases and atherosclerosis; however, its role in regulating periodontopathogen-induced endothelial proinflammatory responses remains unclear. The purpose of this study is to determine whether rosuvastatin can reduce the proinflammatory response induced by Aggregatibacter actinomycetemcomitans (Aa) in human coronary artery endothelial cells (HCAECs). HCAECs were stimulated with purified Aa serotype b lipopolysaccharide (LPS) (Aa-LPS), heat-killed (HK) bacteria (Aa-HK), or live bacteria. Expression of Toll-like receptors and cellular adhesion molecules were evaluated by fluorometric enzyme-linked immunosorbent assay. Endothelial cell activation was evaluated by quantifying nuclear factor (NF)-kappa B-p65 and cytokine expression levels by quantitative polymerase chain reaction and flow cytometry. Effect of rosuvastatin in expression of the atheroprotective factor Krüppel-like factor 2 (KLF2) and cytokines were also studied using similar approaches. HCAECs showed increased interleukin (IL)-6, IL-8, intercellular adhesion molecule 1, and platelet endothelial cell adhesion molecule 1 expression when stimulated with Aa-LPS or Aa-HK. NF-κB-p65 activation was induced by all antigens. Aa-induced IL-6 and IL-8 production was inhibited by rosuvastatin, particularly at higher doses. Interestingly, reduced IL-6 and IL-8 levels were observed in HCAECs stimulated with Aa in the presence of higher concentrations of rosuvastatin. This anti-inflammatory effect correlated with a significant increase of rosuvastatin-induced KLF2. These results suggest Aa-induced proinflammatory endothelial responses are regulated by rosuvastatin in a mechanism that appears to involve KLF2 activation. Use of rosuvastatin to prevent cardiovascular disease may reduce risk of endothelial activation by bacterial antigens.

Immunohistochemical Investigation of HER/AKT/mTOR Pathway and Cellular Adhesion Molecules in Urothelial Carcinomas.

Background. Several investigators have suggested the possibility that the expression of both EGFR and HER2 could be utilized for molecularly targeted therapy in urinary bladder cancer. We tried to evaluate the expression of HER2 and EGFR and activation of the AKT/PTEN/mTOR pathway in urothelial carcinomas and if there is any association between them and cellular adhesion molecules (CAMs). Materials and Methods. Forty-one paraffin-embedded urothelial cancer tissue blocks were collected. Immunostains for HER2, EGFR, MIB1, phospho-AKT, PTEN, phospho-mTOR, e-cadherin, p-cadherin, and b-catenin were performed on tissue microarrays sections. The immunohistochemical results were correlated with clinicopathological parameters. Results. The overexpression of HER2 was found in 19.6% of the cases and it was associated with high grade tumors with a high mitotic index and phosphorylation of AKT and mTOR. Muscle-invasive tumors presented both cytoplasmic and nuclear losses of PTEN expression. There was no association between HER/AKT/mTOR pathway activation and CAM expression. Although cadherins were often coexpressed, only p-cadherin immunoreactivity was associated with tumor grade and high proliferative index. Conclusions. HER2 overexpression is found in a respective proportion of urothelial carcinomas. P-cadherin expression is associated with high grade UCs but it is not affected by HER2 overexpression or by activation of HER/AKT/mTOR pathway.

Exosomes from iPSCs Delivering siRNA Attenuate Intracellular Adhesion Molecule-1 Expression and Neutrophils Adhesion in Pulmonary Microvascular Endothelial Cells.

The pro-inflammatory activation of pulmonary microvascular endothelial cells resulting in continuous expression of cellular adhesion molecules, and subsequently recruiting primed neutrophils to form a firm neutrophils-endothelium (PMN-EC) adhesion, has been examined and found to play a vital role in acute lung injury (ALI). RNA interference (RNAi) is a cellular process through harnessing a natural pathway silencing target gene based on recognition and subsequent degradation of specific mRNA sequences. It opens a promising approach for precision medicine. However, this application was hampered by many obstacles, such as immunogenicity, instability, toxicity problems, and difficulty in across the biological membrane. In this study, we reprogrammed urine exfoliated renal epithelial cells into human induced pluripotent stem cells (huiPSCs) and purified the exosomes (Exo) from huiPSCs as RNAi delivery system. Through choosing the episomal system to deliver transcription factors, we obtained a non-integrating huiPSCs. Experiments in both vitro and vivo demonstrated that these huiPSCs possess the pluripotent properties. The exosomes of huiPSCs isolated by differential centrifugation were visualized by transmission electron microscopy (TEM) showing a typical exosomal appearance with an average diameter of 122nm. Immunoblotting confirmed the presence of the typical exosomal markers, including CD63, TSG 101, and Alix. Co-cultured PKH26-labeled exosomes with human primary pulmonary microvascular endothelial cells (HMVECs) confirmed that they could be internalized by recipient cells at a time-dependent manner. Then, electroporation was used to introduce siRNA against intercellular adhesion molecule-1 (ICAM-1) into exosomes to form an Exo/siRNA compound. The Exo/siRNA compound efficiently delivered the target siRNA into HMVECs causing selective gene silencing, inhibiting the ICAM-1 protein expression, and PMN-EC adhesion induced by lipopolysaccharide (LPS). These data suggest that huiPSCs exosomes could be used as a natural gene delivery vector to transport therapeutic siRNAs for alleviating inflammatory responses in recipient cells.

Novel approach to study the cardiovascular effects and mechanism of action of urban particulate matter using lung epithelial-endothelial tetra-culture system

In vitro models have become increasingly sophisticated, and their usefulness in supporting toxicity testing is well established. The present study was designed to establish a novel in vitro model that mimics the cellular network surrounding airways and pulmonary blood vessels, to study the cardiovascular toxic effects of particulate matter (PM). Transwell culture method was used to develop a novel tetra-culture system consisting of tri-cultures (one lung epithelial and two immune cell lines) in the apical chamber and endothelial cells in the basolateral chamber. Tri-cultures were exposed to standard reference material (SRM) 1648a, an urban PM. SRM 1648a did not show cytotoxic effects; however, it increased IL-6 level in apical and basolateral chambers. The cells in the basolateral chamber showed increased monocyte adhesion. Furthermore, exposure of tri-cultured cells to SRM 1648a in the apical chamber induced ICAM-1 expression in endothelial cells in the basolateral chamber by activating the IL-6/STAT3 pathway. In conclusion, a tetra-culture system was established to facilitate the identification of cellular adhesion molecule expression induced by the interaction between pulmonary epithelial and endothelial cells. The tetra-culture system will contribute to elucidation of the relationships between inhalable PM and cardiovascular diseases.

143 - Modification of Low-Density Lipoprotein by Myeloperoxidase Oxidants – a Pathway to Endothelial Dysfunction in Atherosclerosis?

There is strong evidence that low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase is present in atherosclerotic lesions and can propagate inflammation. Less is known about the biological reactivity of LDL modified by hypothiocyanous acid (HOSCN), the other major oxidant produced by myeloperoxidase in vivo . We examined the role of HOCl- and HOSCN-modified LDL in the induction of endothelial dysfunction, which is characterised by decreased nitric oxide ( ● NO) formation and is a key pathway to atherosclerotic lesion development. Exposure of human coronary artery endothelial cells (HCAEC) to both HOCl- and HOSCN-LDL resulted in a greater extent of endothelial nitric oxide synthase (eNOS) uncoupling compared to control LDL, which correlated with a decrease in eNOS activity. A significant decrease in ● NO production was also seen on exposure of HCAEC to each modified LDL for 24 h, though no elevation in superoxide (O 2 ●– ) production from uncoupled eNOS was observed. We also performed studies to see if the reduced eNOS functionality is consistent with the caveolin-1-mediated down-regulation of eNOS activity. While eNOS and caveolin-1 remained colocalised in the cell, as shown by fluorescence microscopy, we did not observe any binding of eNOS and caveolin-1 in HCAEC exposed to each modified LDL. The changes in ● NO production were also independent of mRNA and protein expression of cellular adhesion molecules; ICAM-1, VCAM-1 and E-selectin, and cytokines; MCP-1 and IL-6, which remained unchanged. Together, these data provide new insights regarding the role of LDL modified by myeloperoxidase-derived oxidants, in altering endothelial function within the setting of atherosclerosis, and may have particular significance for smokers, who have elevated plasma thiocyanate, the precursor to HOSCN.

Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction

Atherosclerosis, the underlying cause of ischemic heart disease and stroke, is an inflammatory disease of arteries in a hyperlipidemic milieu. Endothelial expression of cellular adhesion molecules, such as endothelial-leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 (ICAM-1), plays a critical role in the initiation and progression of atherosclerosis. The dietary flavonoid, quercetin, has been reported to inhibit expression of cellular adhesion molecules, but the underlying mechanisms are incompletely understood. In this study, we found that quercetin dose-dependently (5–20µM) inhibits lipopolysaccharide (LPS)-induced mRNA and protein expression of E-selectin and ICAM-1 in human aortic endothelial cells (HAEC). Incubation of HAEC with quercetin also significantly reduced LPS-induced oxidant production, but did not inhibit activation of the nuclear factor-kappaB (NF-κB). Furthermore, quercetin induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent mRNA and protein expression of the antioxidant enzymes, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase, quinone 1, and glutamate-cysteine ligase. The induction of Nrf2 and antioxidant enzymes was partly inhibited by the p38 mitogen-activated protein kinase (p38) inhibitor, SB203580. Our results suggest that quercetin suppresses LPS-induced oxidant production and adhesion molecule expression by inducing Nrf2 activation and antioxidant enzyme expression, which is partially mediated by p38; and the inhibitory effect of quercetin on adhesion molecule expression is not due to inhibition of NF-κB activation, but instead due to antioxidant-independent effects of HO-1.

Onset of Inflammation With Ischemia: Implications for Donor Lung Preservation and Transplant Survival.

Lungs stored ahead of transplant surgery experience ischemia. Pulmonary ischemia differs from ischemia in the systemic organs in that stop of blood flow in the lung leads to loss of shear alone because the lung parenchyma does not rely on blood flow for its cellular oxygen requirements. Our earlier studies on the ischemia-induced mechanosignaling cascade showed that the pulmonary endothelium responds to stop of flow by production of reactive oxygen species (ROS). We hypothesized that ROS produced in this way led to induction of proinflammatory mediators. In this study, we used lungs or cells subjected to various periods of storage and evaluated the induction of several proinflammatory mediators. Isolated murine, porcine and human lungs in situ showed increased expression of cellular adhesion molecules; the damage-associated molecular pattern protein high-mobility group box 1 and the corresponding pattern recognition receptor, called the receptor for advanced glycation end products; and induction stabilization and translocation of hypoxia-inducible factor 1α and its downstream effector VEGFA, all of which are participants in inflammation. We concluded that signaling with lung preservation drives expression of inflammatory mediators that potentially predispose the donor lung to an inflammatory response after transplant.

Adhesion Molecules and Subpopulation of Mononuclear Cells in Pulmonary Arteries

to study endothelial expression of platelet endothelial cellular adhesion molecules (PECAM) (CD31), intercellular adhesion molecules (ICAM-1), vascular cell adhesion molecules (VCAM-1F) as well as T-cells and monocytes adhered to endothelium. Research materials were en face specimens.

15-Lipoxygenase-1 Is Involved in the Effects of Atorvastatin on Endothelial Dysfunction.

Statins exert pleiotropic effects on endothelial cells in addition to lowering cholesterol. 15-Lipoxygenase-1 (ALOX15) has been implicated in vascular inflammation and disease. The relationship between atorvastatin and ALOX15 was investigated using a rat carotid artery balloon-injury model. Hematoxylin and eosin (HE) staining showed that ALOX15 overexpression increased the thickness of the intima-media (IMT). Immunohistochemistry and western blotting showed that atorvastatin increased the expression of cellular adhesion molecules (CAMs) but decreased the expression of endothelial nitric oxide synthase (eNOS); these effects of atorvastatin were blocked by ALOX15 overexpression. In human umbilical venous endothelial cells (HUVECs), silencing of ALOX15 enhanced the effects of atorvastatin on endothelial function. Expression levels of CAMs and Akt/eNOS/NO under oxidized low-density lipoprotein (ox-LDL) stimulation were modulated by ALOX15 inhibitor and ALOX15 small interfering RNA (siRNA). Atorvastatin abolished the activation of nuclear factor-kappa B (NF-κB) induced by ox-LDL. Exposure to ox-LDL induced upregulation of ALOX15 in HUVECs, but this effect was partially abolished by atorvastatin or the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). These results demonstrate that regulation of ALOX15 expression might be involved in the effects of atorvastatin on endothelial dysfunction.

Expression of epithelial cellular adhesion molecule in gastric cancer: A meta-analysis

Expression of epithelial cellular adhesion molecule in gastric cancer: A meta-analysis

Atheroprotective effects of pure tocotrienol supplementation in the treatment of rabbits with experimentally induced early and established atherosclerosis

BackgroundAtherosclerosis is the main cause of coronary artery disease -related deaths worldwide. The atheroprotective properties of pure tocotrienols (T3) in the absence of alpha-tocopherol (α-TCP) in vitamin E has not been extensively examined.AimTo determine the atheroprotective properties of T3 in early and established atherosclerosis rabbits.MethodsThirty New Zealand white rabbits were divided into two groups, B1 and B2 which represent early [fed 1% high cholesterol diet (HCD) for 2 weeks] and established (fed 1% HCD for 8 weeks) atherosclerosis. Each group was subdivided into three intervention arms: 1) T3–4 mg/kg, 2) T3–15 mg/kg and 3) vehicle without T3 (T3 negative) for 8 weeks. Serial fasting blood samples were obtained for lipid profile, and whole lengths of aorta were used to determine tissue markers of endothelial activation, inflammation and plaque stability.ResultsIn B1, atherosclerotic lesion in T3–4 mg/kg group was significantly reduced (p=0.008), while aortic tissue expression of vascular cellular adhesion molecule 1 (VCAM-1), interleukin-6 (IL-6) and matrix metalloproteinase (MMP-12) was reduced in T3–4 mg/kg compared to T3-negative rabbits group (0.2±0.1 vs. 28.5±3.1%; 3.0±1.6 vs. 14.0±1.7%; and 5.2±2.2 vs. 27.7±0.8%, respectively, p<0.05). T3–15 mg/kg group showed reduction in VCAM-1, E-selectin, IL-6 and MMP-12 (3.9±1.9 vs. 28.5±3.1%; 10.3±0.5 vs. 59.8±8.5%; 2.6±1.7 vs. 14.0±1.7%; and 16.2±3.2 vs. 27.7 0.8%, respectively, p<0.05). In B2, T3–4 mg/kg group reduced aortic tissue expression of intercellular adhesion molecule 1 (ICAM-1), E-selectin, IL-6, MMP-12 and MMP-9 compared to T3-negative rabbits group (29.9±2.4 vs. 55.3±1.3%; 26.7±1.5 vs. 60.5±7.6%; 15.7±0.7 vs. 27.7±4.8%; 34.8±2.7 vs. 46.5±3.4%; and 25.89±3.9 vs. 45.9±1.7%, respectively, p<0.05). T3–15 mg/kg group showed reduced VCAM-1, ICAM-1, E-selectin, IL-6, MMP-12 and MMP-9 (20.5±3.3 vs. 35.6±2.5%; 24.9±1.3 vs. 55.3±1.3%; 29.9±6.7 vs. 60.5±7.6; 11.3±2.2 vs. 27.7±4.8%; 23.0±1.7 vs. 46.5±3.4%; and 17.6±1.9 vs. 45.9±1.7%, respectively, p<0.05.ConclusionThese findings suggest the possible atheroprotective role T3 plays as an adjunct supplementation to standard treatment in the prevention of CAD.