Rho-kinase signalling mediates endotoxin hypersensitivity after partial hepatectomy

Slotta, Jan E.; Laschke, Matthias W.; Menger, Michael D.; Thorlacius, Henrik

doi:10.1002/bjs.6082

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…[11][12][13] Fasudil (1-[5-isoquinolinesulphonyl]-homopiperazine), a ROCK inhibitor, has been widely used clinically since 1995 for the treatment of subarachnoid haemorrhage in Japan.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Liu

et al. 2014

Immunology

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SummaryViewing multiple sclerosis (MS) as both neuroinflammation and neurodegeneration has major implications for therapy, with neuroprotection and neurorepair needed in addition to controlling neuroinflammation in the central nervous system (CNS). While Fasudil, an inhibitor of Rho kinase (ROCK), is known to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, it relies on multiple, short-term injections, with a narrow safety window. In this study, we explored the therapeutic effect of a novel ROCK inhibitor FSD-C10, a Fasudil derivative, on EAE. An important advantage of this derivative is that it can be used via non-injection routes; intranasal delivery is the preferred route because of its efficient CNS delivery and the much lower dose compared with oral delivery. Our results showed that intranasal delivery of FSD-C10 effectively ameliorated the clinical severity of EAE and CNS inflammatory infiltration and promoted neuroprotection. FSD-C10 effectively induced CNS production of the immunoregulatory cytokine interleukin-10 and boosted expression of nerve growth factor and brain-derived neurotrophic factor proteins, while inhibiting activation of p-nuclear factor-jB/p65 on astrocytes and production of multiple pro-inflammatory cytokines. In addition, FSD-C10 treatment effectively induced CD4 + CD25 + , CD4 + FOXP3 + regulatory T cells. Together, our results demonstrate that intranasal delivery of the novel ROCK inhibitor FSD-C10 has therapeutic potential in EAE, through mechanisms that possibly involve both inhibiting CNS inflammation and promoting neuroprotection.

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“…[11][12][13] Fasudil (1-[5-isoquinolinesulphonyl]-homopiperazine), a ROCK inhibitor, has been widely used clinically since 1995 for the treatment of subarachnoid haemorrhage in Japan.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Liu

et al. 2014

Immunology

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“…Notably, Rho-kinase inhibitors have been demonstrated to ameliorate reperfusion and endotoxemic injury in the liver [20] as well as protecting against tissue fibrosis [21], obstructive cholestasis [22], intestinal ischemia [23] and pulmonary hypertension [24]. Previous studies have shown that CXC chemokine formation in acute pancreatitis [25], colonic ischemia-reperfusion [23] as well as cholestatic [22] and endotoxemic [20] liver injury is regulated by Rho-kinase. However, the role of Rho-kinase signaling in regulating CXC chemokine formation, neutrophil recruitment and tissue edema in M1 protein-induced acute lung injury is not known.…”

Section: Introductionmentioning

confidence: 99%

Streptococcal M1 Protein-Provoked CXC Chemokine Formation, Neutrophil Recruitment and Lung Damage Are Regulated by Rho-Kinase Signaling

Zhang

Rahman²,

Zhang³

et al. 2012

J Innate Immun

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Streptococcal toxic shock syndrome is frequently caused by Streptococcus pyogenes of the M1 serotype. The aim of this study was to determine the role of Ras-homologous (Rho)-kinase signaling in M1 protein-provoked lung damage. Male C57BL/6 mice received the Rho-kinase-specific inhibitor Y-27632 before administration of M1 protein. Edema, neutrophil accumulation and CXC chemokines were quantified in the lung 4 h after M1 protein challenge. Flow cytometry was used to determine Mac-1 expression. Quantitative RT-PCR was used to determine gene expression of CXC chemokine mRNA in alveolar macrophages. M1 protein increased neutrophil accumulation, edema and CXC chemokine formation in the lung as well as enhanced Mac-1 expression on neutrophils. Inhibition of Rho-kinase signaling significantly reduced M1 protein-provoked neutrophil accumulation and edema formation in the lung. M1 protein-triggered pulmonary production of CXC chemokine and gene expression of CXC chemokines in alveolar macrophages was decreased by Y-27632. Moreover, Rho-kinase inhibition attenuated M1 protein-induced Mac-1 expression on neutrophils. We conclude that Rho-kinase-dependent neutrophil infiltration controls pulmonary tissue damage in response to streptococcal M1 protein and that Rho-kinase signaling regulates M1 protein-induced lung recruitment of neutrophils via the formation of CXC chemokines and Mac-1 expression.

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“…By now, Y-27632 is a well established pharmacological agent to analyze the involvement of Rho-kinase in the pathogenesis of various diseases [25]. Our present findings now add cholestatic liver injury to the list of diseases in which Rho-kinase appears to regulate tissue damage, including ischemiareperfusion damage of the liver [17] and heart [26], septic liver injury [16,18], cerebral ischemia [27,28], and pulmonary hypertension [29].…”

Section: Discussionmentioning

confidence: 65%

“…Moreover, the Rho/Rhokinase pathway has been implicated in several inflammatory processes, such as chemokine expression and leukocyte-endothelial cell interactions [15,16]. Accordingly, inhibition of Rho-kinase has been shown to be effective against liver injury in models of ischemiareperfusion [17] and sepsis [16,18] as well as carbon tetrachloride-induced hepatic fibrosis [19] and cell death [20]. However, the potential role of Rho-kinase in cholestasis-induced inflammation in the liver remains elusive.…”

Section: Introductionmentioning

confidence: 98%

Rho-Kinase Inhibitor Attenuates Cholestasis-Induced CXC Chemokine Formation, Leukocyte Recruitment, and Hepatocellular Damage in the Liver

Laschke

Dold

Jeppsson

et al. 2010

Journal of Surgical Research

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Rho-kinase signalling mediates endotoxin hypersensitivity after partial hepatectomy

Abstract: Hepatectomy increased susceptibility to LPS by Rho-kinase-dependent mechanisms. Blocking Rho-kinase signalling decreased LPS-induced liver injury in hepatectomized mice.

Cited by 12 publications

References 43 publications

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Streptococcal M1 Protein-Provoked CXC Chemokine Formation, Neutrophil Recruitment and Lung Damage Are Regulated by Rho-Kinase Signaling

Rho-Kinase Inhibitor Attenuates Cholestasis-Induced CXC Chemokine Formation, Leukocyte Recruitment, and Hepatocellular Damage in the Liver

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