Recent advances in the pathophysiology and molecular basis of sepsis-associated organ dysfunction: Novel therapeutic implications and challenges

Hattori, Yoshiyuki; Hattori, Kohshi; Suzuki, Tateo; Matsuda, Naoyuki

doi:10.1016/j.pharmthera.2017.02.040

Cited by 116 publications

(102 citation statements)

References 184 publications

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“…8,9 In the case of sepsis, patients often die of organ failure and therapies directed against endothelial cell dysfunction and tissue damage may be of great interest in treating the disease. 2,8,10 Key to inflammation-induced tissue damage is excessive neutrophil migration across the vascular endothelium, and neutrophil dysregulation has a critical role in the early course of organ damage through release of proteases and oxygen radicals. 9,[11][12][13][14][15] Potential therapeutic target sites include local control of the vascular endothelial response to systemic inflammation as well as direct modulation of neutrophil recruitment and activation.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

et al. 2019

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Abbreviations: bMFA, biomimetic microfluidic assay; BSA, bovine serum albumin; CFD, computational fluid dynamics; CFDA/SE, carboxyfluorescein diacetate succinimidyl ester; ELISA, enzyme-linked immunosorbent assay; fMLP, N-formylmethionyl-leucyl-phenylalanine; GIS, geographic information system; HBSS, Hank's Balanced Salt Solution; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule 1; ICAM-2, intercellular adhesion molecule 2; JAM-C, junctional adhesion molecule C; PKCδ, protein kinase C-delta; PKCδ-i, protein kinase C-delta TAT peptide inhibitor; TEER, trans endothelial electrical resistance; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell adhesion protein 1. AbstractAll drugs recently developed in rodent models to treat inflammatory disease have failed in clinical trials. We therefore used our novel biomimetic microfluidic assay (bMFA) to determine whether the response of murine cells to inflammatory activation or anti-inflammatory treatment is predictive of the response in human cells.Under physiologically relevant flow conditions, permeability and transendothelial electrical resistance (TEER) of human or mouse lung microvascular endothelial cells (HLMVEC or MLMVEC), and neutrophil-endothelial cell interaction was measured.The differential impact of a protein kinase C-delta TAT peptide inhibitor (PKCδ-i) was also quantified. Permeability of HLMVEC and MLMVEC was similar under control conditions but tumor necrosis factor α (TNF-α) and PKCδ-i had a significantly higher impact on permeability of HLMVEC. TEER across HLMVEC was significantly higher than MLMVEC, but PKCδ-i returned TEER to background levels only in human cells. The kinetics of N-formylmethionyl-leucyl-phenylalanine (fMLP)-mediated neutrophil migration was significantly different between the two species and PKCδ-i was significantly more effective in attenuating human neutrophil migration. However, human and mouse neutrophil adhesion patterns to microvascular endothelium were not significantly different. Surprisingly, while intercellular adhesion molecule 1 (ICAM-1) was significantly upregulated on activated HLMVEC, it was not significantly upregulated on activated MLMVEC. Responses to activation and anti-inflammatory treatment in mice may not always be predictive of their response in humans. K E Y W O R D Sbiomimetic, endothelial cells, inflammation, microfluidics, mouse model 2692 | SOROUSH et al.

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Section: Introductionmentioning

confidence: 99%

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

et al. 2019

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“…; Hattori et al . ). Sepsis‐associated encephalopathy (SAE) represents diffuse cerebral dysfunction during sepsis when the source of infection is located outside of the central nervous system (CNS) (Gofton and Young ).…”

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confidence: 97%

Role of G protein‐coupled receptor kinase 2 in oxidative and nitrosative stress‐related neurohistopathological changes in a mouse model of sepsis‐associated encephalopathy

Kawakami

Hattori

Ohashi

et al. 2018

Journal of Neurochemistry

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Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.

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“…epsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection (1,2). Despite the implementation of goal-directed care, poor prognosis and high mortality still remain when it is associated with organ dysfunction, hypoperfusion, or hypotension.…”

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confidence: 99%

Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice

Guo

Zhu

et al. 2018

The Journal of Immunology

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Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro-Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.

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Recent advances in the pathophysiology and molecular basis of sepsis-associated organ dysfunction: Novel therapeutic implications and challenges

Cited by 116 publications

References 184 publications

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

Role of G protein‐coupled receptor kinase 2 in oxidative and nitrosative stress‐related neurohistopathological changes in a mouse model of sepsis‐associated encephalopathy

Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice

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