http://www.journal-inflammation.com The latest research articles published by Journal of Inflammation 2009-06-23T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Background: There are several reports suggesting that hyperosmolarity induces inflammation. We recently showed that Dextran Sodium Sulfate causes inflammatory bowel disease due to hyperosmolarity. The aim of this study was to confirm the link between hyperosmolarity and inflammation by assessing osmolarity values in vivo during inflammation, compare the inflammatory potential of different osmotic agents and finally study the long-term consequences of hyperosmolarity on cell fate. Methods: Osmotic pressures were measured in inflammatory liquids withdrawn from mice subjected to inflammation caused either by subcutaneous injection of Bacille Calmette-Guerin (BCG) or Freund adjuvant. Three epithelial cell lines (HT29, T24 and A549) were exposed up to 48 hours to increasing osmolarities (300, 600, 900 mOsm) of chemically inert molecules such as Mannitol, Propylene Glycol, and Glycerol and inflammatory response was assessed by Enzyme Linked ImmunoSorbent Assay (ELISA) and RNA Protection Assay (RPA). Finally, normal mouse macrophages were exposed to hyperosmotic conditions for long-term culture. Results: The inflammation caused either by BCG or Freund adjuvant is correlated to hyperosmolarity in inflammatory liquids. The exposure of cells to the different compounds, whatever their molecular weight, has no effect on the secretion of cytokines as long as the osmolarity is below a threshold of 300 mOsm. Higher osmolarities result in the secretion of proinflammatory cytokines (Interleukin-8, Interleukin-6, Interleukin-1beta and Tumor Necrosis factor-alpha). Long-term hyperosmotic culture extends normal macrophage half-life, from 44 days to 102 days, and alters the expression of p53, Bcl-2 and Bax. Conclusion: The present study further suggests inflammation and hyperosmolarity are closely related phenomena if not synonymous. http://www.journal-inflammation.com/content/6/1/21 Laurent Schwartz Adeline Guais Mohammad Pooya Mohammad Abolhassani Journal of Inflammation 2009, 6:21 2009-06-23T00:00:00Z doi:10.1186/1476-9255-6-21 Journal of Inflammation 1476-9255 6 21 2009-06-23T00:00:00Z PDF Background: The peptidyl-proline isomerase, Protein Never in Mitosis Gene A Interacting-1 (PIN1), regulates turnover of inducible nitric oxide synthase (iNOS) in murine aortic endothelial cells (MAEC) stimulated with E. coli endotoxin (LPS) and interferon-gamma (IFN). Degradation of iNOS was reduced by a calpain inhibitor, suggesting that PIN1 may affect induction of other calpain-sensitive inflammatory proteins, such as cyclooxygenase (COX)-2, in MAEC. Methods: MAEC, transduced with lentivirus encoding an inactive control short hairpin (sh) RNA or one targeting PIN1 that reduced PIN1 by 85%, were used. Cells were treated with LPS/IFN, calpain inhibitors (carbobenzoxy-valinyl-phenylalaninal (zVF), PD150606), cycloheximide and COX inhibitors to determine the effect of PIN1 depletion on COX-2 and calpain. Results: LPS or IFN alone did not induce COX-2. However, treatment with 10 micro g LPS plus 20 ng IFN per ml induced COX-2 protein 10-fold in Control shRNA MAEC. Induction was significantly greater (47-fold) in PIN1 shRNA cells. COX-2-dependent prostaglandin E2 production increased 3-fold in KD MAEC, but did not increase in Control cells. The additional increase in COX-2 protein due to PIN1 depletion was post-transcriptional, as induction of COX-2 mRNA by LPS/IFN was the same in cells containing or lacking PIN1. Instead, the loss of COX-2 protein, after treatment with cycloheximide to block protein synthesis, was reduced in cells lacking PIN1 in comparison with control cells, indicating that degradation of the enzyme was reduced. zVF and PD150606 each enhanced the induction of COX-2 by LPS/IFN. zVF also slowed the loss of COX-2 after treatment with cycloheximide, and COX-2 was degraded by exogenous mu-calpain in vitro. In contrast to iNOS, physical interaction between COX-2 and PIN1 was not detected, suggesting that effects of PIN1 on calpain, rather than COX-2 itself, affect COX-2 degradation. While cathepsin activity was unaltered, depletion of PIN1 reduced calpain activity by 55% in comparison with Control shRNA cells. Conclusions: PIN1 reduced calpain activity and slowed the degradation of COX-2 in MAEC, an effect recapitulated by an inhibitor of calpain. Given the sensitivity of COX-2 and iNOS to calpain, PIN1 may normally limit induction of these and other calpain substrates by maintaining calpain activity in endothelial cells. http://www.journal-inflammation.com/content/6/1/20 Tongzheng Liu Ryan Schneider Vaibhav Shah Yongcheng Huang Rostislav Likhotvorik Lakhu Keshvara Dale Hoyt Journal of Inflammation 2009, 6:20 2009-06-22T00:00:00Z doi:10.1186/1476-9255-6-20 Journal of Inflammation 1476-9255 6 20 2009-06-22T00:00:00Z PDF Background: Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. The relationship between inflammation and cell proliferation due to chronic infection has been studied, but the mechanism is not fully clear. Though the mode of cadmium toxicity is well characterized in animal cells, still it requires some further investigations. Previously we reported that cadmium induces immune cell death in Swiss albino mice. In the present study we showed that instead of inducing cell death mechanism, cadmium in low concentration triggers proliferation in mice lung cell and our results reveals that prior to the induction of proliferation it causes severe inflammation. Methods: Swiss albino mice were treated with different concentrations of cadmium to determine the LD50. Mice were subdivided (5 mice each) according to the exposure period (15, 30, 45, 60 days) and were given sub lethal dose (5 mg/Kg body weight) of cadmium chloride and ibuprofen (50 mg/Kg body weight, recommended dose) once in a week. SEM and histology were performed as evidence of changes in cellular morphology. Inflammation was measured by the expression of Cox-2 and MMPs. Expression of proinflammatory cytokines (Cox-2, IL-6), signaling and cell cycle regulatory molecules (STAT3, Akt, CyclinD1) were measured by western blot, ELISA and immunoprecipitation. Mutagenecity was evidenced by comet assay. Cell proliferation was determined by cell count, cell cycle and DNA analysis. Results: Prolonged exposure of low concentration of cadmium resulted in up regulation of proinflammatory cytokines and cell cycle regulatory molecules. Though NSAIDs like Ibuprofen reduces the expression of inflammatory cytokines, but it did not show any inhibitory effect on cadmium adopted lung cell proliferation. Conclusion: Our results prove that cadmium causes both inflammation and cell proliferation when applied in a low dose but proliferative changes occur independent of inflammation. http://www.journal-inflammation.com/content/6/1/19 Subhadip Kundu Suman Sengupta Soumya Chatterjee Soham Mitra Arindam Bhattacharyya Journal of Inflammation 2009, 6:19 2009-06-12T00:00:00Z doi:10.1186/1476-9255-6-19 Journal of Inflammation 1476-9255 6 19 2009-06-12T00:00:00Z XML Background: Neuromyelitis optica is a central nervous system demyelinating and inflammatory syndrome. The objective of this study is to identify cytokines related to the cellular immune response as well as blood brain barrier integrity and oxidative stress. Methods: We performed a molecular characterization of cellular immune response and oxidative stress in serum from relapsing-NMO (R-NMO) patients and established the correlations between the clinical measurements and molecular parameters using the Bayesian approach.Serum samples from 11 patients with R-NMO diagnosed according to Wingerchuk criteria and matched in terms of age, gender and ethnicity with the healthy controls were analyzed. The levels of TNF-α, IFN-γ, IL-10, MMP-9, TIMP-1 and oxidative stress markers: malondialdehyde, advanced oxidation protein products, peroxidation potential, superoxide dismutase, catalase, and total hydroperoxides were measured. Results: We found almost undetectable levels of TNF-α, a decreased production of IL-10 and a significant up-regulation of every oxidative stress biomarker studied. The insufficient production of TNF-α and IL-10 in R-NMO patients, which are two important players of T cell mediated immunoregulation, suggest an effector – regulator imbalance. The overproduction of oxygen reactive species as a consequence of the chronic inflammatory milieu is reflected on the excess of oxidative damage mediators detected. Furthermore, Multidimensional Scaling and a Bayesian linear regression model revealed a significant linear dependence between Expanded Disability Status Scale Kurtzke and TIMP-1; pointing to a possible predictive or prognostic value of this clinical-molecular relationship. Conclusion: These results suggest that there is a breakdown in immunoregulatory mechanisms and noteworthy pro-oxidant environment contributing to NMO pathogenesis. http://www.journal-inflammation.com/content/6/1/18 Giselle Penton-Rol Majel Cervantes-Llanos Gregorio Martinez-Sanchez Jose A. Cabrera-Gomez Carmen M. Valenzuela-Silva Omar Ramirez-Nunez Mayte Casanova-Orta Maria A. Robinson-Agramonte Ileana Lopategui-Cabezas Pedro A. Lopez-Saura Journal of Inflammation 2009, 6:18 2009-06-02T00:00:00Z doi:10.1186/1476-9255-6-18 Journal of Inflammation 1476-9255 6 18 2009-06-02T00:00:00Z XML Background: Recently, it has been reported that the Gly573Ser substitution of transient receptor potential V3 (TRPV3) leads to increased ion-channel activity in keratinocytes. Our previous studies have indicated that the spontaneous hairless and dermatitis phenotypes of DS-Nh mice, which were newly established as an animal model of atopic dermatitis (AD), are caused by TRPV3Gly573Ser. Although this substitution causes hairlessness in several kinds of rodents, in our investigations, dermatitis developed in only a few animals. Here, we generated NC/Nga-Nh mice to elucidate the role of TRPV3Gly573Ser in NC/Nga mice, which is one of the most studied animal models of AD. Methods: To establish and validate the new AD animal model, NC/Nga-Nh mice were generated using NC/Nga and DS-Nh mice, and their clinical features were compared. Next, T-cell receptor (TCR) Vβ usage in splenocytes, evaluation of bacterial colonization, and serological and histological analyses were carried out. Finally, repeated-hapten-application dermatitis was induced in these mice. Results: NC/Nga-Nh mice did not develop spontaneous dermatitis, whereas DS-Nh mice displayed this phenotype when maintained under the same conditions. Serological analysis indicated that there really was a phenotypic difference between these mice, and TCR repertoire analysis indicated that TCRVβ haplotypes played an important role in the development of dermatitis. Artificial dermatitis developed in DS and NC/Nga-Nh mice, but not in DS-Nh and NC/Nga mice. Histological and serological analyses indicated that mouse strains were listed in descending order of number of skin mast cells: DS-Nh > DS ≈ NC/Nga-Nh > NC/Nga, and serum IgE levels were increased after 2,4,6 trinitrochlorobenzene application in these mice. Serum IgE level in DS-Nh mice was lower than that mesured in other strains. Conclusion: Our results confirm the contribution of the TRPV3Gly573Ser gene to the development of repeated hapten dermatitis, but not spontaneous dermatitis in NC/Nga mice. http://www.journal-inflammation.com/content/6/1/17 Kinichi Imura Takeshi Yoshioka Tsutomu Hirasawa Tsuneaki Sakata Journal of Inflammation 2009, 6:17 2009-05-25T00:00:00Z doi:10.1186/1476-9255-6-17 Journal of Inflammation 1476-9255 6 17 2009-05-25T00:00:00Z XML Vascular aging is an independent risk factor for cardiovascular disease that can occur in the absence of other traditional risk factors. Inflammation is a hallmark of vascular aging that ultimately leads to structural changes in the vessel wall including an increase in medial thickness and perivascular fibrosis. Several classes of transcription factors have been identified that participate in the regulation of cellular responses associated with vascular aging. Nuclear factor (NF)-κB is the prototypic example of a transcriptional activator in the setting of inflammation, being activated in response to multiple inflammatory mediators including pro-inflammatory cytokines and bacterial endotoxin. In contrast, the activation of the nuclear hormone receptor and transcription factor peroxisome proliferator-activated receptor-alpha (PPAR-α) results in its translocation from the cell surface to the nucleus where it exerts anti-inflammatory effects. Vascular aging is also associated with endothelial dysfunction. One important repair mechanism for improving endothelial function is the recruitment of endothelial progenitor cells (EPCs). In the setting of aging the number of EPCs diminishes which has been linked to a decrease in the activity and/or expression of the transcription factor hypoxia inducible factor (HIF)-1 alpha. A change in the balance of the activity of pro-inflammatory transcription factors versus those that inhibit inflammation likely contributes to the process of vascular aging. The purpose of this review is to summarize our current knowledge of these age-related changes in transcriptional responses, and to discuss the therapeutic potential of targeting some of these factors. http://www.journal-inflammation.com/content/6/1/16 Yumei Zhan Lei Yuan Peter Oettgen Journal of Inflammation 2009, 6:16 2009-05-21T00:00:00Z doi:10.1186/1476-9255-6-16 Journal of Inflammation 1476-9255 6 16 2009-05-21T00:00:00Z XML Cystic Fibrosis (CF) is one of the most common autosomal genetic disorders in humans. This disease is caused by mutations within a single gene, coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The phenotypic hallmark of CF is chronic lung infection and associated inflammation from opportunistic microbes such as Pseudomonas aeruginosa (PA), Haemophilus influenzae, and Staphylococcus aureus. This eventually leads to deterioration of lung function and death in most CF patients. Unfortunately, there is no approved therapy for correcting the genetic defect causal to the disease. Hence, controlling inflammation and infection in CF patients are critical to disease management. Accordingly, anti-inflammatory agents and antibiotics are used to manage chronic inflammation and infection in CF patients. However, most of the anti-inflammatory agents in CF have severe limitations due to adverse side effects, and resistance to antibiotics is becoming an even more prominent problem. Thus, new agents that can be used to control chronic inflammation in CF are needed in the absence of a cure for the disease. Activation of the transcription factor NFκB through Toll-like receptors (TLR) following bacterial infection is principally involved in regulating lung inflammation in CF. NFκB regulates the transcription of several genes that are involved in inflammation, anti-apoptosis and anti-microbial activity, and hyper-activation of this transcription factor leads to a potent inflammatory response. Thus, NFκB is a potential anti-inflammatory drug target in CF. Screening of several compounds from natural sources in an in vitro model of CF-related inflammation wherein NFκB is activated by filtrates of a clinically isolated strain of PA (PAF) led us to Withaferin A (WFA), a steroidal lactone from the plant Withania Somnifera L. Dunal. Our data demonstrate that WFA blocks PAF-induced activation of NFκB as determined using reporter assays, IL-8 measurements and high-content fluorescent imaging of NFκB subunit p65 translocation. Since the airways of CF patients can be specifically targeted for delivery of therapeutics, we propose that WFA should be further studied as an anti-inflammatory agent in models of CF related inflammation mediated by NFκB. http://www.journal-inflammation.com/content/6/1/15 Rangan Maitra Melissa Porter Shan Huang Brian Gilmour Journal of Inflammation 2009, 6:15 2009-05-13T00:00:00Z doi:10.1186/1476-9255-6-15 Journal of Inflammation 1476-9255 6 15 2009-05-13T00:00:00Z XML Background: Nitric oxide (NO) can be both pro- and anti-apoptotic in various cell types, including macrophages. This apparent paradox may result from the actions of NO-related species generated in the microenvironment of the cell, for example the formation of peroxynitrite (ONOO-). In this study we have examined the ability of NO and ONOO- to evoke apoptosis in human monocyte-derived macrophages (MDMϕ), and investigated whether preconditioning by cyclic guanosine monophosphate (cGMP) is able to limit apoptosis in this cell type. Methods: Characterisation of the NO-related species generated by (Z)-1- [2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) and 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-, chloride (GEA-3162) was performed by electrochemistry using an isolated NO electrode and electron paramagnetic resonance (EPR) spectrometry. Mononuclear cells were isolated from peripheral blood of healthy volunteers and cultured to allow differentiation into MDMϕ. Resultant MDMϕ were treated for 24 h with DETA/NO (100 – 1000 μM) or GEA-3162 (10 – 300 μM) in the presence or absence of BAY 41–2272 (1 μM), isobutylmethylxanthine (IBMX; 1 μM), 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 20 μM) or 8-bromo-cGMP (1 mM). Apoptosis in MDMϕ was assessed by flow cytometric analysis of annexin V binding in combination with propidium iodide staining. Results: Electrochemistry and EPR revealed that DETA/NO liberated free NO radical, whilst GEA-3162 concomitantly released NO and O2-, and is therefore a ONOO- generator. NO (DETA/NO) had no effect on cell viability, but ONOO- (GEA-3162) caused a concentration-dependent induction of apoptosis in MDMϕ. Preconditioning of MDMϕ with NO in combination with the phosphodiesterase inhibitor, 3-Isobutyl-1-methylxanthine (IBMX), or the NO-independent stimulator of soluble guanylate cyclase, BAY 41–2272, significantly attenuated ONOO--induced apoptosis in a cGMP-dependent manner. Conclusion: These results demonstrate disparities between the ability of NO and ONOO- to induce apoptosis in human MDMϕ. Furthermore, this study provides evidence for a novel cGMP-dependent pre-conditioning mechanism to limit ONOO--induced apoptosis in human MDMϕ. http://www.journal-inflammation.com/content/6/1/14 Catherine Shaw David Webb Adriano Rossi Ian Megson Journal of Inflammation 2009, 6:14 2009-05-07T00:00:00Z doi:10.1186/1476-9255-6-14 Journal of Inflammation 1476-9255 6 14 2009-05-07T00:00:00Z XML Background: Zymosan-induced shock has been associated with an increased production of pro-inflammatory cytokines and mediators, causing a generalized dysfunction of liver, lung and kidneys. Herein, we investigate the effects of tyrphostin AG-490 on the early inflammation and on the late renal injury provoked by zymosan injection. Methods: Shock was induced by intraperitoneal injection of zymosan in a dose of 0.8–1.0 mg/g body weight in BALB/c mice and 0.8 mg/g body weight in SCID mice. Tyrphostin AG-490 was administered intraperitoneally in a dose of 5 mg/kg immediately after shock induction. Blood, peritoneal lavage and kidneys were collected at certain time points after zymosan injection. The levels of MIP-1α, RANTES, IL-6, IL-10, α1-antitrypsin and C5a in plasma were determined by ELISA. The number of IL-10-secreting cells in peritoneum was assayed by ELISPOT. Kidney function was monitored by measurement of urine/plasma creatinine levels and proteinuria. Histological assessment of renal injury was performed in a blinded fashion after hematoxylin/eosin staining. Immunohistochemistry analyses were used to evaluate the expression of C5aR, STAT1, STAT3 and the binding ability of IgGs in kidneys. Results: Tyrphostin AG-490 attenuated the early phase of zymosan-induced shock via inhibition of MIP-1α, RANTES and C5a plasma levels and via elevation of IL-10 in plasma. The drug increased IL-10 production in peritoneum and the number of IL-10-secreting peritoneal cells. AG-490 was able to retain the time of coagulation and the level of α1-antitrypsin to normal values. At the late stage of shock, AG-490 decreased scores of tubular injury, cell infiltration and glomerular lesions in parallel with diminished creatinine plasma level and protein excretion. These beneficial effects of AG-490 were related to lowered levels of circulating IL-6, MIP-1α and C5a, and to inhibited expression of STAT1, STAT3 and C5aR in kidneys. The drug diminished the production of zymosan-specific IgG antibodies and hindered the glomeruli from IgGs recognition. Conclusion: Tyrphostin AG-490 reduced the magnitude of the initial inflammatory response in zymosan-induced shock and prevented the development of severe kidney dysfunction. Our data suggest that the drug might be used as a therapeutic approach in cases where shock is combined with acute renal injury. http://www.journal-inflammation.com/content/6/1/13 Petya Dimitrova Valeriya Gyurkovska Irina Shalova Luciano Saso Nina Ivanovska Journal of Inflammation 2009, 6:13 2009-05-05T00:00:00Z doi:10.1186/1476-9255-6-13 Journal of Inflammation 1476-9255 6 13 2009-05-05T00:00:00Z XML Background: Toll-like receptors (TLRs) are present on monocytes and alveolar macrophages that form the first line of defense against inhaled particles. The importance of those cells in the pathophysiology of chronic obstructive pulmonary disease (COPD) has well been documented. Cigarette smoke contains high concentration of oxidants which can stimulate immune cells to produce reactive oxygen species, cytokines and chemokines. Methods: In this study, we evaluated the effects of cigarette smoke medium (CSM) on TLR4 expression and interleukin (IL)-8 production by human macrophages investigating the involvement of ROS.Results and DiscussionTLR4 surface expression was downregulated on short term exposure (1 h) of CSM. The downregulation could be explained by internalization of the TLR4 and the upregulation by an increase in TLR4 mRNA. IL-8 mRNA and protein were also increased by CSM. CSM stimulation increased intracellular ROS-production and decreased glutathione (GSH) levels. The modulation of TLR4 mRNA and surface receptors expression, IRAK activation, IκB-α degradation, IL-8 mRNA and protein, GSH depletion and ROS production were all prevented by antioxidants such as N-acetyl-L-cysteine (NAC). Conclusion: TLR4 may be involved in the pathogenesis of lung emphysema and oxidative stress and seems to be a crucial contributor in lung inflammation. http://www.journal-inflammation.com/content/6/1/12 Hadi Sarir Esmaeil Mortaz Khalil Karimi Aletta Kraneveld Irfan Rahman Eric Caldenhoven Frans Nijkamp Gert Folkerts Journal of Inflammation 2009, 6:12 2009-05-01T00:00:00Z doi:10.1186/1476-9255-6-12 Journal of Inflammation 1476-9255 6 12 2009-05-01T00:00:00Z XML