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Hiroyuki Seki,
Sadatomo Tasaka,
Koichi Fukunaga,
Yoshiki Shiraishi,
Kiyoshi Moriyama,
Keisuke Miyamoto,
Yasushi Nakano,
Naoko Matsunaga,
Katsunori Takashima,
Tatsumi Matsumoto,
Masayuki Ii,
Akitoshi Ishizaka,
Junzo Takeda
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ABSTRACT: Toll-like receptor 4 (TLR4) plays important roles in the recognition of lipopolysaccharide (LPS) and the activation of inflammatory cascade. In this study, we evaluated the effect of TAK-242, a selective TLR4 signal transduction inhibitor, on acute lung injury (ALI).
C57BL/6J mice were intravenously treated with TAK-242 15 min before the intratracheal administration of LPS or Pam3CSK4, a synthetic lipopeptide. Six hours after the challenge, bronchoalveolar lavage fluid was obtained for a differential cell count and the measurement of cytokine and myeloperoxidase levels. Lung permeability and nuclear factor-kappaB (NF-kappaB) DNA binding activity were also evaluated.
TAK-242 effectively attenuated the neutrophil accumulation and activation in the lungs, the increase in lung permeability, production of inflammatory mediators, and NF-kappaB DNA-binding activity induced by the LPS challenge. In contrast, TAK-242 did not suppress inflammatory changes induced by Pam3CSK4.
TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.
Agents and Actions 04/2010; 59(10):837-45. · 1.59 Impact Factor
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ABSTRACT: Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of รน-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions both in vitro and in vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.
TheScientificWorldJOURNAL 01/2010; 10:818-31. · 1.66 Impact Factor
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Hiroyuki Seki,
Koichi Fukunaga,
Makoto Arita,
Hiroyuki Arai,
Hiroki Nakanishi,
Ryo Taguchi,
Taku Miyasho,
Rina Takamiya,
Koichiro Asano,
Akitoshi Ishizaka,
Junzo Takeda,
Bruce D Levy
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ABSTRACT: Whereas pneumonia is the most common cause of death and disability worldwide, most cases of pneumonia spontaneously resolve. Mechanisms that promote pneumonia resolution remain to be determined. Resolvin E1 (RvE1) is an endogenous mediator that displays proresolving actions in sterile inflammation. In this study, we developed a new model of aspiration pneumonia to evaluate the effect of RvE1 on acute lung injury caused by acid aspiration and subsequent bacterial challenge. Mice received hydrochloric acid into the left lung followed by the enteric pathogen Escherichia coli. I.v. administration of RvE1 (approximately 0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several proinflammatory chemokines and cytokines, including IL-1beta, IL-6, HMGB-1, MIP-1alpha, MIP-1beta, keratinocyte-derived chemokine, and MCP-1, in a manner independent of the anti-inflammatory mediators IL-10 and lipoxin A4. In addition, animals treated with RvE1 had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents the first candidate for a novel therapeutic strategy for acute lung injury and pneumonia that harnesses natural resolution mechanisms.
The Journal of Immunology 12/2009; 184(2):836-43. · 5.79 Impact Factor
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ABSTRACT: Inflammation is a defensive response to injury and infection, but excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of omega-3 polyunsaturated fatty acids (PUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) indicate their beneficial impact on human diseases in which inflammation is suspected as a key component of the pathogenesis. Although the mechanism of EPA and DHA action is still not fully defined in molecular terms, recent studies have revealed that, during the course of acute inflammation, omega-3 PUFA-derived mediators including resolvins and protectins with potent anti-inflammatory and pro-resolving properties are produced. In this review, we provide an overview of the formation and actions of EPA-derived anti-inflammatory lipid mediator resolvin E1.
Prostaglandins & other lipid mediators 10/2009; 89(3-4):126-30. · 2.70 Impact Factor
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Haiying Zhang,
Sadatomo Tasaka,
Yoshiki Shiraishi,
Koichi Fukunaga,
Wakako Yamada, Hiroyuki Seki,
Yuko Ogawa,
Keisuke Miyamoto,
Yasushi Nakano,
Naoki Hasegawa,
Taku Miyasho,
Ikuro Maruyama,
Akitoshi Ishizaka
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ABSTRACT: The interaction of receptor for advanced glycation end products (RAGE) and its ligands often leads to inflammatory processes or tissue injury, although the effect of the blockade of RAGE signaling on lung injury remains to be investigated.
Using a murine model of lung injury induced by intratracheal lipopolysaccharide (LPS), we evaluated RAGE expression in the airspace and the effect of recombinant soluble RAGE (sRAGE) on LPS-induced lung injury. Methods: First, the expression of sRAGE in bronchoalveolar lavage (BAL) fluid was determined at 24 hours after intratracheal instillation of LPS or phosphate-buffered saline. Next, to evaluate the effect of sRAGE, BAL fluid was collected for cell counting and measurements of lung permeability and cytokine concentrations 24 hours after intratracheal LPS in the mice with or without intraperitoneal administration of sRAGE 1 hour after the instillation. In another series, lungs were sampled for histopathology and detection of apoptotic cells. The activation of nuclear factor (NF)-kappaB was analyzed 4 hours after LPS instillation.
In response to LPS challenge, a RAGE isoform of 48 kD was detected in the BAL fluid. Treatment with sRAGE significantly attenuated the increases in neutrophil infiltration, lung permeability, production of inflammatory cytokines, NF-kappaB activation, and apoptotic cells in the lung as well as development of pathologic changes after LPS instillation.
RAGE plays an important role in the pathogenesis of LPS-induced lung injury in mice. It was suggested that sRAGE should be tested as a treatment modality in other models of acute lung injury.
American Journal of Respiratory and Critical Care Medicine 07/2008; 178(4):356-62. · 11.08 Impact Factor
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ABSTRACT: Dexamethasone is known to reduce the incidence of postoperative nausea and vomiting, associated with perioperative intrathecal, epidural, or intravenous morphine. However, the effect of dexamethasone on subcutaneous morphine is unclear. Therefore, we evaluated the antiemetic effect of intravenous dexamethasone during continuous subcutaneous infusion of morphine for postoperative pain relief.
Twenty patients scheduled for spinal surgery under general anesthesia were enrolled in this randomized, double-blind, and placebo-controlled study. The dexamethasone group (n=10) received dexamethasone 8 mg and the saline group (n=10) received the same amount of saline before the induction of anesthesia. Anesthesia was maintained with propofol and fentanyl. Postoperative pain was treated with continuous subcutaneous morphine via a patient-controlled analgesia device. Postoperatively patients were assessed during 48 hours for nausea and vomiting.
Nausea or vomiting ascribable to the subcutaneous morphine developed in 40% of the patients in each group (P:NS).
Our results suggest that the single dose of dexamethasone (8 mg) does not reduce postoperative nausea and vomiting associated with continuous subcutaneous infusion of morphine after spinal surgery.
Masui. The Japanese journal of anesthesiology 05/2005; 54(4):381-6.
