Pretreatment of Rho Kinase Inhibitor Inhibits Systemic Inflammation and Prevents Endotoxin-Induced Acute Lung Injury in Mice

Ding, Ren Yu; Zhao, Dong; Zhang, Zhi Dan; Guo, Ren Xuan; Chun, Xiao

doi:10.1016/j.jss.2011.08.009

Cited by 26 publications

(23 citation statements)

References 26 publications

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“…The RhoA-Rho kinase (ROCK) pathway is an important mediator of the cytoskeletal changes associated with HLMVEC exposure to LPS (13,25). ROCK inhibitors block LPS-induced MLC phosphorylation and protect against LPSinduced EBD (23,37). Recently, we reported that Hsp90 inhibition attenuates LPS-induced RhoA activation and MLC phosphorylation in HLMVEC (31).…”

Section: Hdac Inhibition Protects Against the Lps-mediated Decrease Imentioning

confidence: 99%

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Joshi

Barabutis

Birmpas

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.

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Section: Hdac Inhibition Protects Against the Lps-mediated Decrease Imentioning

confidence: 99%

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Joshi

Barabutis

Birmpas

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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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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“…The remaining mice were subjected to SCI (as described above) and treated with an intraperitoneal bolus of vehicle (saline) or fasudil 1 and 6 h after SCI. The dose was chosen on the basis of recent studies (Ding et al, 2011;Ma et al, 2011).…”

Section: Animalsmentioning

confidence: 99%

Effect of Fasudil, a Selective Inhibitor of Rho Kinase Activity, in the Secondary Injury Associated with the Experimental Model of Spinal Cord Trauma

Impellizzeri

Mazzon

Paterniti

et al. 2012

J Pharmacol Exp Ther

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Rho kinase (ROK) may play an important role in regulating the biological events of cells, including proliferation, differentiation, and survival/death. Blockade of ROK promotes axonal regeneration and neuron survival in vivo and in vitro, thereby exhibiting potential clinical applications in spinal cord damage and stroke. The aim of this experimental study was to determine the role of ROK signaling pathways in the inflammatory response, in particular in the secondary injury associated with the experimental model of spinal cord trauma. The injury was induced by application of vascular clips to the dura via a four-level T5 to T8 laminectomy in mice. Fasudil was administered in mice (10 mg/kg i.p.) 1 and 6 h after the trauma. The treatment with fasudil significantly decreased 1) histological damage; 2) motor recovery; 3) nuclear factor-B (NF-B) expression; 4) ROK activity; 5) inflammasome activation (caspase-1 and NOD-like receptor family, pyrin domain-containing 3 expression); 6) production of proinflammatory cytokine such as tumor necrosis factor and interleukin-1␤ (IL-1␤); 7) neutrophil infiltration; 8) nitrotyrosine and poly-ADPribose formation; 9) glial fibrillary acidic protein expression; 10) apoptosis (terminal deoxynucleotidyl transferase dUTP nickend labeling staining, FAS ligand expression, and Bax and Bcl-2 expression); and 11) mitogen-activated protein kinase activation (phospho-extracellular signal-regulated kinase and phospho-c-Jun NH 2 -terminal kinase expression). Our results indicate that inhibition of ROK by fasudil may represent a useful therapeutic perspective in the treatment of inflammation associated with spinal cord trauma.

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Pretreatment of Rho Kinase Inhibitor Inhibits Systemic Inflammation and Prevents Endotoxin-Induced Acute Lung Injury in Mice

Cited by 26 publications

References 26 publications

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

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

Effect of Fasudil, a Selective Inhibitor of Rho Kinase Activity, in the Secondary Injury Associated with the Experimental Model of Spinal Cord Trauma

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