A novel leukotriene B4-receptor antagonist in endotoxin shock

Mp, Fink; Bp, O'Sullivan; Mj, Menconi; Ps, Wollert; Wang, H; Me, Youssef; Jh, Fleisch

doi:10.1097/00003246-199312000-00008

Cited by 45 publications

(8 citation statements)

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“…It is known that endotoxin activates C5 to generate C5a (43), and it seems reasonable to suggest that commercial endotoxin preparations such as we used would likely be contaminated with bacterial tripeptides (e.g., fMLP). Furthermore, given that LTB 4 antagonism is of significant benefit in airway endotoxemia (17,44), it is also reasonable to suggest that this agonist would also have been present in our endotoxemic animals, although we did not assess this. This suggests that the neutrophilic pathology we observed could well be related to the combined effects of multiple agonists, including ELR-CXC chemokines, C5a, LTB 4 , and perhaps fMLP.…”

Section: Discussionmentioning

confidence: 99%

ELR-CXC Chemokine Receptor Antagonism Targets Inflammatory Responses at Multiple Levels

Zhao

Town

et al. 2009

The Journal of Immunology

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The ELR-CXC chemokines play important roles in neutrophilic inflammation. We report in this study that a fully human ELR-CXC chemokine antagonist that we have generated, CXCL8(3–72)K11R/G31P (G31P), has potent anti-inflammatory effects that arise through its actions at multiple levels. G31P inhibited CXCL8-induced chemotactic responses and intracellular Ca2+ flux in CXCR1-transfected HEK cells and neutrophils, and responses of neutrophils to CXCR2-exclusive ligands. G31P desensitized heterologous G protein-coupled receptors on neutrophils, 52–86% reducing their Ca2+ flux and chemotactic responses to leukotriene B4, C5a, and the bacterial tripeptide fMLP. G31P also 60–90% blocked neutrophil chemotactic responses to mediators present in 10 of 12 sputum samples from cystic fibrosis or bronchiectasis subjects with bacterial pneumonia. Moreover, whereas A549 bronchial epithelial cells (which expressed CXCR1) secreted ≈29,000 pg/ml CXCL8 in response to in vitro endotoxin challenge, G31P reduced this response by up to 98%, presumably by interrupting an autocrine inflammatory loop. The anti-inflammatory effects of G31P extended also to reversing the antiapoptotic influence of ELR-CXC chemokines on neutrophils. That these effects were relevant in vivo was confirmed in a guinea pig model of airway endotoxemia, wherein the human form of G31P >95% blocked neutrophil infiltration into and activation within the airways, as determined by airway levels of the neutrophil primary, secondary, and tertiary granule markers myeloperoxidase, lactoferrin, and matrix metalloproteinase-9, respectively, and the epithelial cell marker matrix metalloproteinase-2. These data suggest that the beneficial effects of ELR-CXC chemokine antagonism arise through effects that occur at multiple levels, including epithelial cells, neutrophils, and alternate G protein-coupled receptors.

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Section: Discussionmentioning

confidence: 99%

ELR-CXC Chemokine Receptor Antagonism Targets Inflammatory Responses at Multiple Levels

Zhao

Town

et al. 2009

The Journal of Immunology

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“…It has a key role in pathological conditions, such as bronchial asthma, rheumatoid arthritis, adult respiratory distress syndrome, as well as endotoxin shock. [26][27][28][29][30][31] Leukotrienes trigger or potentiate the synthesis of specific inflammatory cytokines in distinct cell populations, and many cytokines affect cell responsiveness to leukotrienes by modulating the expression levels of their receptors. 32 Cytokines and bioactive local lipid metabolites such as LTB 4 are thus thought to contribute to the pathogenesis of acute and chronic pulmonary inflammation via autocrine or paracrine activation of macrophages.…”

Section: Nox1-ros Signaling Functions Downstream Of Blt2 In Lpsinducementioning

confidence: 99%

MyD88–BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage

2015

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Endotoxic responses to bacterial lipopolysaccharide (LPS) are triggered by Toll-like receptor 4 (TLR4) and involve the production of inflammatory mediators, including interleukin-6 (IL-6), by macrophages. The detailed mechanism of IL-6 production by macrophages in response to LPS has remained unclear, however. We now show that LPS induces IL-6 synthesis in mouse peritoneal macrophages via the leukotriene B 4 receptor BLT2. Our results suggest that TLR4-MyD88 signaling functions upstream of BLT2 and that the generation of reactive oxygen species (ROS) by NADPH oxidase 1 (Nox1) and consequent activation of the transcription factor nuclear factor (NF)-κB function downstream of BLT2 in this response. These results suggest that a TLR4-MyD88-BLT2-Nox1-ROS-NF-κB pathway contributes to the synthesis of IL-6 in LPS-stimulated mouse macrophages.

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“…Leukotriene antagonists, such as ONO-1078 [21], LY255283 [22] and ICI 198,615 [23], seemed to ameliorate the clinical outcome in models of LPS-induced acute lung injury. These antagonists reduced pulmonary extravascular water contents and bronchoalveolar lavage fluid protein concentrations.…”

Section: Discussionmentioning

confidence: 99%

Eicosanoids as Risk and Prognostic Factors for Acute Respiratory Distress Syndrome in Sepsis Patients

Takahashi¹,

Shibata²,

Endo³

2017

J Pulm Respir Med

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A novel leukotriene B4-receptor antagonist in endotoxin shock

Cited by 45 publications

References 0 publications

ELR-CXC Chemokine Receptor Antagonism Targets Inflammatory Responses at Multiple Levels

ELR-CXC Chemokine Receptor Antagonism Targets Inflammatory Responses at Multiple Levels

MyD88–BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage

Eicosanoids as Risk and Prognostic Factors for Acute Respiratory Distress Syndrome in Sepsis Patients

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