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

Joshi, Atul; Barabutis, Nektarios; Birmpas, Charalampos; Dimitropoulou, Christiana; Thangjam, Gagan; Cherian‐Shaw, Mary; Dennison, John; Catravas, John D.

doi:10.1152/ajplung.00180.2015

Cited by 39 publications

(55 citation statements)

References 59 publications

(83 reference statements)

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“…[42][43][44] These same pathways signal for de novo inflammatory gene expression in cells of the innate immune system, suggesting a potential role for Hsp90 inhibition in a variety of acute and chronic inflammatory disorders. Inhibition of Hsp90 attenuates the increased endothelial permeability associated with systemic endotoxemia in mice 19 and results in a reduction in LPS-induced acute lung injury 45 and ischemia-reperfusioninduced kidney injury. 46 Consistent with this, a polymorphism in the promoter region of the Hsp90 beta gene that results in reduced release of TNF-in whole blood in response to LPS is also associated with reduced severity of organ dysfunction following multiple trauma.…”

Section: Discussionmentioning

confidence: 99%

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Gupta

Lee

Wang

et al. 2018

Journal of Leukocyte Biology

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The brief lifespan of the polymorphonuclear neutrophil (PMN) is regulated through its capacity to undergo apoptosis, a constitutive process that is actively inhibited during sepsis. We sought to define the cellular mechanisms through which Heat Shock Protein 90 (Hsp90) prolongs the survival of inflammatory PMN. We evaluated Hsp90 expression and interaction with client proteins in PMNs from patients with sepsis and in healthy control PMNs treated with LPS (1 μg/mL). Hsp90 activity was inhibited pharmacologically using radicicol (Rad; 1 μM), and Hsp90 transcription was silenced in septic PMN using siRNA. PMN apoptosis was evaluated by flow cytometry and expression of cleaved caspase-8 and -3. Septic PMNs showed reduced rates of apoptosis compared with control PMNs 21 h after isolation, and Hsp90-α mRNA was significantly more abundant in septic PMN. Caspase-8 coimmunoprecipitated with Hsp90, c-Src, and the p85 inhibitory subunit of PI3K in both septic and LPS-treated PMN. Inhibition of Hsp90 activity with Rad or its translation using siRNA restored basal rates of apoptosis in both septic and LPS-treated PMN. Radicicol further reduced c-Src protein abundance, increased the ubiquitination of caspase-8 and c-Src, and enhanced the cleavage of caspase-8 and -3. We conclude that Hsp90 prolongs the survival of activated neutrophils by stabilizing a molecular complex of c-Src kinase and caspase-8, preventing their ubiquitination, and resulting in inhibition of the catalytic activity of caspase-8 and -3.

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Section: Discussionmentioning

confidence: 99%

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Gupta

Lee

Wang

et al. 2018

Journal of Leukocyte Biology

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“…We also cannot exclude other mechanisms of HDAC6-induced RhoA pathway activation. For example, inhibition of HDAC6 or HDAC3 has been shown to protect LPSinduced endothelial dysfunction and ALI by suppressing HSP90-mediated Rho activation (56).…”

Section: Figure 8 Hdac6 Inhibition Prevents Hksa-induced Vascular Lementioning

confidence: 99%

Staphylococcus aureus–induced endothelial permeability and inflammation are mediated by microtubule destabilization

Karki

Tian

et al. 2019

Journal of Biological Chemistry

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Edited by Velia M. FowlerStaphylococcus aureus is a major etiological agent of sepsis and induces endothelial cell (EC) barrier dysfunction and inflammation, two major hallmarks of acute lung injury. However, the molecular mechanisms of bacterial pathogen-induced EC barrier disruption are incompletely understood. Here, we investigated the role of microtubules (MT) in the mechanisms of EC barrier compromise caused by heat-killed S. aureus (HKSA). Using a customized monolayer permeability assay in human pulmonary EC and MT fractionation, we observed that HKSAinduced barrier disruption is accompanied by MT destabilization and increased histone deacetylase-6 (HDAC6) activity resulting from elevated reactive oxygen species (ROS) production. Molecular or pharmacological HDAC6 inhibition rescued barrier function in HKSA-challenged vascular endothelium. The HKSA-induced EC permeability was associated with impaired MT-mediated delivery of cytoplasmic linkerassociated protein 2 (CLASP2) to the cell periphery, limiting its interaction with adherens junction proteins. HKSA-induced EC barrier dysfunction was also associated with increased Rho GTPase activity via activation of MT-bound Rho-specific guanine nucleotide exchange factor-H1 (GEF-H1) and was abolished by HDAC6 down-regulation. HKSA activated the NF-B proinflammatory pathway and increased the expression of intercellular and vascular cell adhesion molecules in EC, an effect that was also HDAC6-dependent and mediated, at least in part, by a GEF-H1/Rho-dependent mechanism. Of note, HDAC6 knockout mice or HDAC6 inhibitor-treated WT mice were partially protected from vascular leakage and inflammation caused by both HKSA or methicillin-resistant S. aureus (MRSA). Our results indicate that S. aureus-induced, ROS-dependent up-regulation of HDAC6 activity destabilizes MT and thereby activates the GEF-H1/Rho pathway, increasing both EC permeability and inflammation.

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“…The lung endothelium is the first barrier preventing cells and proteins in the blood from infiltrating into the interstitial space and alveoli of the lungs. Therefore, damage to pulmonary endothelial cell can contribute to the development of ALI/ARDS and several treatments targeting pulmonary endothelial cell dysfunction have shown validity and efficacy for the prognosis of ALI/ARDS [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

Chen

Zhang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has therapeutic effects on endothelial damage during acute lung injury (ALI). Heme oxygenase-1 (HO-1) can restore homeostasis and implement cytoprotective defense functions in many pathologic states. Therefore, we explored whether transduction of HO-1 into BM-MSCs (MSCs-HO-1) would have an increased beneficial effect on lipopolysaccharide (LPS)-induced inflammatory and oxidative damage in human pulmonary microvascular endothelial cells (PVECs). Methods: MSCs were isolated from rat bone marrow and transfected with the HO-1 gene by a lentivirus vector. The phenotype and multilineage differentiation of MSCs were assessed. MSCs or MSCs-HO-1 were co-cultured with PVECs using a transwell system, and LPS was added to induce PVEC injury. The production of reactive oxygen species (ROS), and the activities of lipid peroxide (LPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in PVECs were determined by flow cytometry and colorimetric assays, respectively. The levels of human PVEC-derived tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the supernatants of the co-culture system, and the activity of nuclear transcription factor-κB and NF-E2-related factor 2 (Nrf2) in PVECs were examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of TNF-α, IL-1β and IL-6 in PVECs was detected by quantitative real-time polymerase chain reaction (qRT-PCR), HO-1 expression and enzymatic activity in PVECs and the influence of zinc protoporphyrin (ZnPP) or HO-1 small interfering RNA on the above inflammatory and oxidative stress markers were evaluated. In addition, the expression of rat MSC-derived hepatocyte growth factor (HGF) and IL-10 was determined by ELISA and qRT-PCR. Results: MSCs showed no significant changes in phenotype or multilineage differentiation after transduction. LPS strongly increased the production of inflammatory and oxidative stress indicators, as well as decreased the levels of antioxidant components and the activity of Nrf2 in PVECs. MSC co-cultivation ameliorated these detrimental effects in PVECs and MSCs-HO-1 further improved the damage to PVECs induced by LPS when compared with MSCs alone. The beneficial effects of MSCs-HO-1 were dependent on HO-1 overexpression and may be attributed to the enhanced paracrine production of HGF and IL-10. Conclusion: MSCs-HO-1 have an enhanced ability to improve LPS-induced inflammatory and oxidative damage in PVECs, and the mechanism may be partially associated with the enhanced paracrine function of the stem cells. These data encourage further testing of the beneficial effects of MSCs-HO-1 in ALI animal models.

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

Cited by 39 publications

References 59 publications

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Staphylococcus aureus–induced endothelial permeability and inflammation are mediated by microtubule destabilization

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

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