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PubMed2006

Insulin-like growth factor binding protein-2 stimulates proliferation and activates multiple cascades of the mitogen-activated protein kinase pathways in NIH-OVCAR3 human epithelial ovarian cancer cells.

Insulin-like growth factor binding protein-2 (IGFBP-2), the second most abundant IGFBP in the circulation, is dramatically increased in the serum and ovarian cyst fluid of women with epithelial ovarian cancer. The specific role of IGFBP-2 in ovarian carcinogenesis remains elusive. Using NIH-OVCAR3 human epithelial ovarian cancer cells, we have evaluated the effects of IGFBP-2 and its antibody on cell proliferation, activation of mitogen-activated protein kinase (MAP kinase) pathways and on cytokine expression. Treatment of the cells with IGFBP-2 stimulates cell growth significantly (p<.05) and potentiates the activation of (1) the extracellular signal regulated kinase (ERK1/2) signaling pathway, which transduces cell-specific growth and differentiation signals; (2) the stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) pathway, which is activated by environmental stresses, inflammatory cytokines, growth factors and G-protein coupled receptor (GPCR) agonists; and (3) the p38 MAP kinase pathway, which mediates inflammatory and stress responses. Suppression of IGFBP-2, with its neutralizing antibody, significantly (p<.05) retards cell growth, blocks the activation of all three cascades of the MAPK pathways and downregulates the expression of a number of potential cancer-promoting cytokines. These novel findings may have important clinical implications for developing innovative strategies for the treatment and management of ovarian cancer.

Adenocarcinoma↗
PubMed2003

[A study on the heterogeneous apoptosis of lymphocytes, eosinophils, and neutrophils from peripheral blood of asthmatic patients].

OBJECTIVES: To observe different responsiveness of lymphocytes, eosinophils, and neutrophils from peripheral blood of asthmatic patients to dexamethasone and montelukast-induced apoptosis and to explore the roles of Fas antigen and caspase-3 in the heterogeneity of cell apoptosis. METHODS: Lymphocytes, eosinophils, and neutrophils were isolated from peripheral blood of 18 asthmatic patients. Cells were incubated in vitro and treated with dexamethasone and leukotriene receptor antagonist montelukast respectively. Cell apoptosis rates and Fas expression rates were examined by flowcytometry whereas caspase-3 levels in these cells were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: (1) Apoptosis rates: in vitro lymphocytes, eosinophils and neutrophils were compromised of spontaneous apoptosis at lower rates [(6.9 +/- 0.7)%, (31 +/- 11)% and (32 +/- 30)%, respectively]. With induction of dexamethasone, the apoptosis rates were (17.1 +/- 10.8)%, (44 +/- 22)% and (35 +/- 24)%. Montelukast markedly elevated the apoptosis rates of these three cells [(22.5 +/- 17.6)%, (50 +/- 27)% and (55 +/- 22)%, respectively] (compared to control, P < 0.01, < 0.05, > 0.05, respectively). (2) Fas expression: lymphocytes, eosinophils and neutrophils expressed low levels of Fas antigen at baseline [(1.50 +/- 0.07)%, (2.20 +/- 0.10)% and (1.21 +/- 0.09)%, respectively]. Dexamethasone induced Fas antigen expression levels of these cells of (6.58 +/- 2.10)%, (7.52 +/- 3.20)% and (3.24 +/- 2.34)%, and montelukast induced the expression levels of (5.06 +/- 1.66, 7.45 +/- 2.63, 3.03 +/- 2.47, P < 0.01, < 0.01, > 0.05, respectively). (3) caspase-3 levels: lymphocytes, eosinophils and neutrophils expressed constitutive caspase-3 levels of [(3.3 +/- 2.9) ng/L, (5 +/- 4) ng/L and (4.3 +/- 2.6) ng/L, respectively]. The dexamethasone induced caspase-3 levels were (6.7 +/- 3.1) ng/L, (6 +/- 3) ng/L and (3.1 +/- 1.8) ng/L. The montelukast induced levels were (5.2 +/- 3.7) ng/L, (8 +/- 4) ng/L, and (3.1 +/- 2.0) ng/L (compared to control, P < 0.01, < 0.01, > 0.05, respectively). It was demonstrated that dexamethasone and montelukast significantly induced apoptosis of lymphocytes and eosinophils which were assocreased with increased expression of Fas antigen and caspase-3. Dexamethasone was incapable of inducing neutrophils to apoptosis and had no significant effects on Fas expression and caspase-3 activity. Neutrophils underwent significant apoptosis after montelukast treatment, however, the induction was unlikely to be regulated by Fas and caspase-3 pathway. CONCLUSIONS: In asthmatic inflammatory modulating and effective cells, neutrophils is distinct from lymphocytes and eosinophils in profile of apoptosis induced by glucocorticoids and leukotriene receptor antagonist. The signal pathway contributing neutrophil apoptosis heterogeneity may involve deficient caspase cascade or Fas/FasL.

Acetates↗
PubMed2002

Essential role of caspase-11 in activation-induced cell death of rat astrocytes.

We have previously shown that rat astrocytes undergo apoptosis upon inflammatory activation. Nitric oxide (NO) produced by activated astrocytes was the major cytotoxic mediator in this type of autoregulatory apoptosis. However, an inhibitor of nitric oxide synthase did not completely block the apoptosis of activated astrocytes, suggesting the presence of other apoptotic pathways. Here, we present evidence that caspase-11 is an essential molecule in NO-independent apoptotic pathway of activated astrocytes. Inflammatory activation (lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha treatment) of rat astrocyte cultures and C6 glioma cells led to the induction of caspase-11 followed by activation of caspases-11, -1, and -3. In contrast, NO donors induced activation of caspase-3 only. Inactivation of caspase-11 by the transfection of dominant negative mutant or treatment with the caspase inhibitors rendered the astrocytes partially resistant to the apoptosis following inflammatory activation, but not NO donor exposure. These results indicate that inflammatory stimuli not only induce the production of cytotoxic NO, but also initiate NO-independent apoptotic pathway through the induction of caspase-11 expression.

Animals↗
PubMed2006

Phosphoinositide 3-kinase signalling and FoxO transcription factors in rheumatoid arthritis.

Although the mechanisms leading to the induction of RA (rheumatoid arthritis) are poorly understood, improper activation, proliferation, survival and retention of neutrophils, macrophages, lymphocytes and other leucocytes contribute to perpetuation of inflammation and eventual joint destruction through activation of stromal fibroblast-like synoviocytes. Fundamental studies in developmental biology, cellular biology and immunology have established critical roles for PI3K (phosphoinositide 3-kinase) signal transduction pathways in cellular chemotactic responses, proliferation, apoptosis and survival. Despite profound alteration of these cellular processes in RA, involvement of PI3K signalling pathways in this chronic inflammatory disease, and their assessment as potential therapeutic targets, has until recently received scant attention. This review highlights recent advances in our understanding of PI3K signalling pathways, in particular regulation of FoxO (forkhead box O) transcription factors, and their relevance to RA.

Arthritis, Rheumatoid↗
PubMed2026

Temporal Transcriptomic Profiling of NMBA-Induced Rat Esophageal Squamous Carcinogenesis Identifies Early Inflammatory Activation and Late NRF2-Associated Oxidative-Stress Remodeling.

Temporal molecular events during early esophageal squamous carcinogenesis remain incompletely defined, in part because human precursor tissues are difficult to obtain sequentially. We used the N-nitrosomethylbenzylamine (NMBA)-induced rat model to characterize stage-associated transcriptional programs during esophageal squamous carcinogenesis. Vehicle-control reference esophageal tissues and NMBA-treated esophageal tissues, collected at weeks 6 and 29, were profiled using Affymetrix Rat Genome 230 2.0 arrays, followed by pathway analysis and qRT-PCR validation of selected genes. Relative to vehicle-control reference tissues, 173 genes were differentially expressed at week 6, whereas 1628 genes were differentially expressed at week 29, indicating marked expansion of transcriptional dysregulation during carcinogenic progression. Sixteen genes were differentially expressed only at week 6, while 157 genes were altered at both time points. Pathway analysis suggested that inflammatory and immunologic processes were prominent during the early response to NMBA exposure, whereas late-stage carcinogenesis was characterized by NRF2-associated oxidative-stress response and dysregulation of multiple glutathione S-transferase family members. A subset of progression-associated genes, including Defb4, Gsta2, Sbsn, Spink5, Plcd4, Hbb, and Hba-a2, showed increasing dysregulation from week 6 to week 29. These findings define temporally distinct molecular programs in NMBA-induced esophageal squamous carcinogenesis and provide a framework for prioritizing candidate pathways and genes relevant to esophageal cancer prevention, early detection, and progression biology.

Animals↗
PubMed2005

Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases.

OBJECTIVES: Cytokine signaling pathways involving transcription factors of the signal transducers and activators of transcription (STAT) family play a key role in the pathogenesis of inflammatory bowel diseases (IBD). STAT proteins are latent cytoplasmic transcription factors that induce transcription upon phosphorylation, dimerization, and nuclear translocation. However, their activation pattern in IBD is poorly understood. The aim of our study was to characterize STAT-expression in IBD. METHODS: Mononuclear cells were isolated from 36 colonic specimens of Crohn's disease, ulcerative colitis, or from control patients. Cells were stimulated overnight with antibodies against human CD2 and CD28 and mononuclear cells were analyzed by flow cytometry. Alternatively, CD4(+) T cells were immunomagnetically separated and then assessed by flow cytometry. Intracellular stainings of the following transcription factors were performed: STAT-1, STAT-2, STAT-3, STAT-4, and STAT-6. In addition, immunofluorescence staining on cryosections for phosphorylated STAT-1 and STAT-3 was performed. RESULTS: Average expression of the IFN-gamma inducible transcription factor STAT-1 was increased in Crohn's disease as compared to patients with ulcerative colitis and control patients. However, levels of phospho-STAT-1 were surprisingly not markedly upregulated in IBD as compared to controls. In contrast, STAT-3 and phospho-STAT-3 levels were significantly increased in IBD patients as compared to controls (p < 0.01). No differences could be detected in STAT-6 levels. Finally, average expression of STAT-2, which is involved in type I interferon signalling, was downregulated in IBD as compared to control patients. CONCLUSIONS: The analysis of STAT activation patterns could serve as a helpful tool to characterize intestinal inflammation. Furthermore, the IL-6/STAT-3 rather than the IFN-gamma/STAT-1 signaling pathway emerges as a key target for the development of future therapeutic concepts in IBD.

CD4-Positive T-Lymphocytes↗
PubMed1989

[Dynamics of inherent interactions between the classical and alternative pathways of complement activation in premature infants with suppurative-inflammatory diseases].

Altogether 57 premature infants were examined. Of these, 15 presented with neonatal sepsis, 36 with local purulent infection (LPI) of different etiology, and 6 children were conventionally normal serving as control. Early activation of the alternative pathway of the complement system was shown by the patients as compared with control. The development of neonatal sepsis was attended by the increased role played by the classical pathway of complement activation. At the same time the course of LPI was characterized by differences in the degree of participation of the classical and alternative pathways in the antiinfectious defence of the neonates. It has been established that high activation of the alternative pathway seen in the premature children may be considered as a prognostic sign enabling one to classify them with the risk group in terms of the possibility of the development in them of an infectious process.

Acute Disease↗
PubMed2006

Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities.

The anticoagulant protein C system is a dual function cofactor-dependent system. On one hand, it is designed to regulate coagulation, maintain the fluidity of the vasculature and prevent thrombosis. On the other hand, the protein C pathway provides anti-inflammatory and cytoprotective activities. Protein C, a vitamin K-dependent serine protease zymogen that circulates in plasma, is converted by limited proteolysis to activated protein C (APC) by the thrombin-thrombomodulin-endothelial protein C receptor complex on endothelial surfaces. APC and the cofactors of the protein C pathway exert two major distinct types of activities, namely a well-studied anticoagulant activity and a more recently revealed cytoprotective activity due to direct effects on cells. Because of these pleiotropic properties, APC and the protein C pathway components have important roles in the body's host-defense system and provide opportunities for therapeutic treatment of complex and challenging medical disorders, including thrombosis, severe sepsis and stroke.

Anticoagulants↗
PubMed2005

Thymoquinone: a promising anti-cancer drug from natural sources.

There has been growing interest in naturally occurring compounds with anti-cancer potential. Black seed is one of the most extensively studied plants. This annual herb grows in countries bordering the Mediterranean Sea and India. Thymoquinone (TQ) is the bioactive constituent of the volatile oil of black seed. It has been shown to exert anti-neoplastic and anti-inflammatory effects. The molecular pathways of TQ action are not clear. Nevertheless, TQ is known to induce apoptosis by p53-dependent and p53-independent pathways in cancer cell lines. Growth inhibition is associated with induction of cell cycle arrest. TQ also acts on the immune system by modulating the levels of inflammatory mediators. To date, the chemotherapeutic potential of TQ in the clinic has not been tested, but numerous studies have shown its promising anti-cancer effects in animal models. The combination of TQ with clinically used anti-cancer drugs has led to improvements in their therapeutic index and prevents non-tumor tissues from sustaining chemotherapy-induced damage.

Animals↗
PubMedDate not supplied

Mechanisms and prevention of secondary brain damage during intensive care.

The injured brain may be damaged by primary impact, secondary injury from secondary damage due to initiation of destructive inflammatory and biochemical cascades by the primary injury or secondary ischemic injury following secondary insults that initiate or augment these immunological and biochemical cascades. Cerebral ischemia will arise whenever delivery of oxygen and substrates to the brain fall below metabolic needs. Many factors lead to the development of secondary insults to the injured brain during initial resuscitation, transport, surgery, and subsequent intensive care. Continuous monitoring of cerebral oxygenation (jugular oximetry, brain tissue PO2) and cerebral blood flow velocity (transcranial Doppler ultrasonography) in patients with brain trauma reveals multiple episodes of transient hypoperfusion with an adverse relationship between incidence and outcome. Secondary brain insults arise through systemic or intracranial mechanisms that reduce cerebral blood flow from compromised CPP, vascular distortion or cerebrovascular narrowing or lower oxygen delivery from hypoxemia associated with airway obstruction, pulmonary pathology, or anemia. Secondary brain ischemia remains a common pathway to secondary brain damage in most critically ill neurosurgical patients. In the future prevention of secondary brain injury may well hinge on giving a cocktail of novel agents that modify destructive biochemical and inflammatory pathways, each having a potential therapeutic window possibly in a subgroup of patients. To date, phase 3 clinical trials of several agents including PEGSOD and tyrilizad mesylate have failed to show relevant efficacy after brain trauma or subarachnoid hemorrhage. The therapeutic role of calcium channel blockers in traumatic subarachnoid hemorrhage is currently under investigation following the results of subgroup metaanalysis. Several phase 3, NMDA receptor antagonist studies are underway in brain trauma with results expected soon. Although we know that secondary insults promote excitotoxic secondary brain damage there is currently no pharmacological intervention with proven efficacy and, therefore, detection and correction of secondary insults appear to offer the best therapeutic strategy. After brain trauma, systemic hypotension, compromised CPP, raised ICP, elevated temperature, hypoxemia, and jugular bulb venous desaturation are associated with poor prognosis. Clinical trials of moderate hypothermia following brain trauma are ongoing. Following adult brain trauma maintenance of CPP above at least 65 mmHg (probably > 40 mmHg in children below 8 years) seems important to improve outcome indicating the need for continuous ICP monitoring during intensive care of brain-injured patients.

Adult↗
PubMed2005

AP-1 mediates beta-amyloid-induced iNOS expression in PC12 cells via the ERK2 and p38 MAPK signaling pathways.

Nitrosative stress with subsequent inflammatory cell death has been implicated in some neurodegenerative disorders such as Alzheimer's disease (AD). Expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) have been frequently elevated in AD. In this study, we have investigated the molecular mechanisms underlying nitrosative stress induced by beta-amyloid (A beta), a neurotoxic peptide associated with senile plaques formed in the brains of patients with AD. Exposure of rat pheochromocytoma (PC12) cells to the A beta resulted in increased mRNA and protein expression of iNOS and generation of NO. NO can rapidly interact with superoxide anion, forming more reactive peroxynitrite. Treatment of PC12 cells with A beta led to increased peroxynitrite production and nitrotyrosine formation. A beta induced activation of redox sensitive transcription factor activator protein-1 (AP-1), and AP-1 antisense oligonucleotide abolished the A beta-induced iNOS expression. Moreover, A beta transiently activated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) via phosphorylation. Pharmacologic inhibition of both enzymes or dominant-negative mutation of ERK2 or p38 MAPK effectively down-regulated DNA binding as well as transcriptional activity of AP-1 and subsequent iNOS expression and NO production. The above findings suggest that A beta induces iNOS expression in PC12 cells through activation of AP-1 which is regulated by upstream kinases, such as ERK and p38 MAPK.

Amyloid beta-Peptides↗
PubMed2006

Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis.

INTRODUCTION: Disturbed protein C (PC) pathway homeostasis might contribute to the development of multiple organ failure (MOF) in acute pancreatitis (AP). We therefore evaluated circulating levels of PC and activated protein C (APC), evaluated monocyte deactivation in AP patients, and determined the relationship of these parameters to MOF. PATIENTS AND METHODS: Thirty-one patients in the intensive care unit were categorized as cases (n = 13, severe AP with MOF) or controls (n = 18, severe AP without MOF). Blood samples were drawn every second day to determine the platelet count, the levels of APC, PC, and D-dimer, and the monocyte HLA-DR expression using flow cytometry. The APC/PC ratio was used to evaluate turnover of PC to APC. RESULTS: During the initial two weeks of hospitalization, low PC levels (<70% of the adult mean) occurred in 92% of cases and 44% of controls (P = 0.008). The minimum APC level was lower in cases than in controls (median 85% versus 97%, P = 0.009). Using 87% as the cut-off value, 8/13 (62%) cases and 3/18 (17%) controls showed reduced APC levels (P = 0.021). A total of 92% of cases and 50% of controls had APC/PC ratios exceeding the upper normal limit (P = 0.013). Plasma samples drawn before MOF showed low PC levels and high APC/PC ratios. HLA-DR-positive monocytes correlated with PC levels (r = 0.38, P < 0.001) and APC levels (r = 0.27, P < 0.001), indicating that the PC pathway was associated with systemic inflammation-triggered immune suppression. CONCLUSION: PC deficiency and decreased APC generation in severe AP probably contributed to a compromised anticoagulant and anti-inflammatory defence. The PC pathway defects were associated with the development of MOF. The data support feasibility of testing the use of APC or PC to improve the clinical outcome in AP.

Acute Disease↗
PubMed2004

Sphingolipids in inflammation: roles and implications.

Sphingolipids, historically described as potential reservoirs for bioactive lipids, presently define a new family of cellular mediators, joining the well-established glycerolipid-derived mediators of signal transduction such as diacylglycerol, phosphatidylinositides, and eicosanoids. Sphingolipid metabolism is clearly involved in the regulation of cell growth, differentiation, and programmed cell death. Indeed, a majority of the greater than four thousand studies conducted on sphingolipids during the past five years were investigations of the role of sphingolipids as cellular bioregulators. Studies spanning more than a decade have shown multiple interactions and intersections of the sphingolipid-mediated pathways and the eicosanoid pathway. This review will discuss the emerging mechanisms by which sphingolipids induce inflammatory responses via the eicosanoid pathway in addition to linking previous literature on sphingolipids and inflammation with newer findings of distinct roles for sphingosine-1-phosphate in regulating cyclooygenase-2 and ceramide-1-phosphate in the regulation of cytosolic phospholipase A2alpha. Finally, the relationship between bioactive sphingolipids and inflammation is discussed.

Ceramides↗
PubMed1999

Gi-mediated activation of mitogen-activated protein kinase (MAPK) pathway by receptor mimetic basic secretagogues of connective tissue-type mast cells: bifurcation of arachidonic acid-induced release upstream of MAPK.

The family of basic secretagogues of connective tissue mast cells act as receptor mimetic agents, which trigger exocytosis by directly activating G proteins. We now demonstrate that pertussis toxin (Ptx)-sensitive Gi proteins, activated by compound 48/80 (c48/80), a potent member of this family, also activate the p42/p44 MAP kinases (MAPKs). This activation was potentiated by the protein tyrosine phosphatase inhibitor vanadate, whereas the tyrphostin AG-18, a competitive inhibitor of protein tyrosine kinases (PTKs); the protein kinase C inhibitors K252a and GF109203X; the phosphatidylinositol-3-kinase (PI-3K) inhibitors wortmannin and LY294002; and EGTA have abolished this activation. These results suggest that c48/80 activated the p42/p44 MAPKs via a mechanism that involves PTKs, protein kinase C, phosphatidylinositol-3-kinase and Ca2+ as mediators. Protein tyrosine phosphorylation and activation of the p42/p44 MAPKs were closely correlated with stimulation of arachidonic acid (AA) release by c48/80 but not with histamine secretion. However, whereas PD98059, the inhibitor of the MAPK kinase has abrogated MAPK activation, this inhibitor failed to effect release of AA. We therefore conclude that by activating Ptx-sensitive Gi protein(s), the basic secretagogues of mast cells stimulate multiple signaling pathways, which diverge to regulate the production and release of the different inflammatory mediators. Whereas the signaling pathway responsible for triggering histamine release is PTK independent, the pathway responsible for the stimulation of AA release bifurcates downstream to PTKs but upstream to the activation of MAPKs.

Androstadienes↗
PubMed2005

Adenosine kinase inhibitor attenuates the expression of inducible nitric oxide synthase in glial cells.

The present study demonstrates the anti-inflammatory effect of adenosine kinase inhibitor (ADKI) in glial cells. Treatment of glial cells with IC51, an ADKI, stimulated the extracellular adenosine release and reduced the LPS/IFNgamma-mediated production of NO, and induction of iNOS and TNF-alpha gene expression. The recovery of IC51-mediated inhibition of iNOS expression by adenosine transport inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI), and the inhibition of LPS/IFNgamma-induced iNOS gene expression by exogenous adenosine indicate a role for adenosine release in IC51-mediated iNOS expression. The rescue of IC51-mediated inhibition of iNOS expression by adenosine receptor antagonist for A2A, 8-(3-chlorostyryl)caffeine (CSC) and alloxazine for A2B, further supports a role for interaction of adenosine and its receptors in anti-inflammatory activity. The IC51-mediated induction of cAMP levels, downstream target of A2A and A2B, and inhibition of LPS/IFNgamma-induced expression of iNOS by forskolin, a cAMP activator, document a role for cAMP mediated pathway in anti-inflammatory activity of IC51. Taken together, these studies document that IC51-mediated inhibition of iNOS expression is through activation of adenosine receptors, which activates A2A and A2B resulting in increased cAMP levels following LPS/IFNgamma stimulation. Moreover, the lack of effect of IC51 or adenosine on NFkappaB DNA binding activity and its transactivity indicates that the inhibition of iNOS expression mediated by IC51 may be through an NFkappaB independent pathway.

Adenosine↗
PubMed2005

IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation.

Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases. Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The IkappaB kinase (IKK) complex contains two catalytic subunits, IKKalpha and IKKbeta, and controls the activation of NF-kappaB transcription factors, which play a pivotal role in inflammation. Ample evidence indicates that IKKbeta mediates NF-kappaB activation in response to pro-inflammatory cytokines and microbial products. IKKalpha regulates an alternative pathway important for lymphoid organogenesis, but the role of IKKalpha in inflammation is unknown. Here we describe a new role for IKKalpha in the negative regulation of macrophage activation and inflammation. IKKalpha contributes to suppression of NF-kappaB activity by accelerating both the turnover of the NF-kappaB subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKKalpha in mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity.

Animals↗
PubMed2006

[Effects of costimulatory pathway OX40/OX40L on the pathogenesis of allergic asthma in mice].

OBJECTIVE: Allergic asthma is thought to be mediated by CD4+ T lymphocytes producing the Th2-associated cytokines, which play a critical role in the development of the airway hyper-responsiveness and the eosinophilic inflammatory response. The costimulatory pathway CD28/B7 has been shown to play an important role in CD4+ T cell activation in allergic asthma. This study was conducted to evaluate the role of another costimulatory pathway OX40/OX40 ligand (L) in the pathogenesis of allergic asthma in BALB/c mice. METHODS: An allergic asthma model in BALB/c mice was established. Thirty-six BALB/c mice were randomly divided into three groups with 12 in each. Mice in treatment group (group B) were treated with neutralizing anti-OX40L monoclonal antibody (mAb, 300 microg per mouse) during the sensitization period. Mice in two control groups, asthma model group (group A) and IgG antibody group (group C) were treated with normal saline (NS) and control IgG respectively instead of anti-OX40L mAb. Bronchoalveolar lavage fluid (BALF) was collected from the mice of each group for counting the total number of white blood cells (including neutrophil granulocyte, lymphocyte, monocyte and eosinophil granulocyte) and the proportions of these cells. The levels of IL-4 and INF-gamma in BALF were measured by ELISA. Lungs were removed for morphological examination after HE and PAS staining, and expression of OX40 in lungs was evaluated by immunohistochemical method. RESULTS: (1) The count of total number of white blood cells in BALF (x10(6)/ml) was lower in group B than that of group A and group C (26.6 +/- 4.6 vs. 36.8 +/- 5.2 and 34.3 +/- 6.9, respectively), the difference between the treatment group (group B) and two control groups (groups A and C) was significant; The proportions of eosinophils and lymphocytes in the BALF (%) were lower in group B than those in group A and group C (eosinophils 15.1 +/- 2.6 vs. 20.0 +/- 4.1 and 19.9 +/- 3.9, respectively; lymphocytes 7.0 +/- 0.9 vs. 8.9 +/- 1.6 and 8.6 +/- 1.8, respectively), the difference between the treatment group and two control groups was significant. (2) The IL-4 level in BALF (pg/ml) was lower in group B than that in group A and group C (672 +/- 58 vs. 809.57 +/- 106.00 and 784 +/- 58, respectively), but the INF-gamma levels in BALF (pg/ml) were higher than those in group A and group C (0.86 +/- 0.09 vs. 0.69 +/- 0.15 and 0.67 +/- 0.13 respectively), and all the differences were statistically significant. (3) The expression of OX40 in the lungs of mice in group B were at a lower level than that of group A and group C, and the morphological changes of asthma were ameliorated in the mice of the treatment group. The signs of mice in treatment group were obviously ameliorated as compared to the two control groups. CONCLUSION: Blocking the costimulatory pathway by administering the neutralizing anti-OX40L mAb during the sensitization period of allergic asthma model could balance the Th1/Th2 responses, inhibit lung inflammation and ameliorate the signs of mice model of asthma.

Animals↗
PubMed1998

Septic shock.

1. Septic shock is still a major complication of patients in intensive care units (ICUs) and, therefore, a main goal of ICU-related research. 2. After the unsatisfying results of multicenter clinical trials in blocking proinflammatory mediators such as tumor necrosis factor and interleukin-1 or endotoxin itself, research has focused on other important members of the cytokine pathways--in particular, anti-inflammatory cytokines such as interleukin 10. Moreover, there is an increasing knowledge of intracellular activation and deactivation pathways, inaugurating the theoretical advantage to block, attenuate or manipulate the inflammatory response at an early stage of disease or in a more specific fashion. 3. This review points out new developments in our understanding of the pathophysiology of septic shock and gives an example of a more recent approach in septic shock research--the heat shock response.

Clinical Trials as Topic↗