Circulating miRNA 887 is differentially expressed in ARDS and modulates endothelial function.

Circulating microRNAs (miRNAs) can be taken up by recipient cells and have been recently associated with the acute respiratory distress syndrome (ARDS). Their role in host predisposition to the syndrome is unknown. The objective of the study was to identify circulating miRNAs associated with the development of sepsis-related ARDS and examine their impact on endothelial cell gene expression and function.

miR-145a Regulation of Pericyte Dysfunction in a Murine Model of Sepsis.

Background: Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored.

Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.

Background: The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. We previously found that endothelial progenitor cell (EPC) exosomes prevent endothelial dysfunction and lung injury in sepsis in part due to their encapsulation of miRNA-126. However, the effects of EPC exosomes in acute lung injury (ALI) remain unknown.

Fli-1 transcription factor regulates the expression of caspase-1 in lung pericytes.

Our previous data demonstrated that Friend leukemia virus integration 1 (Fli-1), an ETS transcription factor, governs pericyte loss and vascular dysfunction in cecal ligation and puncture-induced murine sepsis by regulating essential pyroptosis markers including caspase-1. However, whether Fli-1 regulates caspase-1 expression levels in vitro and how Fli-1 regulates caspase-1 remain unknown. Our present work further demonstrated that overexpressed Fli-1 significantly increased caspase-1 and IL-18 expression levels in cultured mouse lung pericytes.

Application of Deacetylated Poly-N-Acetyl Glucosamine Nanoparticles for the Delivery of miR-126 for the Treatment of Cecal Ligation and Puncture-Induced Sepsis.

Sepsis is an acute inflammatory syndrome in response to infection. In some cases, excessive inflammation from sepsis results in endothelial dysfunction and subsequent increased vascular permeability leading to organ failure. We previously showed that treatment with endothelial progenitor cells, which highly express microRNA-126 (miR-126), improved survival in mice subjected to cecal ligation and puncture (CLP) sepsis.

Fli-1 Governs Pericyte Dysfunction in a Murine Model of Sepsis.

Background: Pericytes are vascular mural cells and are embedded in the basement membrane of the microvasculature. Recent studies suggest a role for pericytes in lipopolysaccharide (LPS)-induced microvascular dysfunction and mortality, but the mechanisms of pericyte loss in sepsis are largely unknown.

Methods: By using a cecal ligation and puncture (CLP)-induced murine model of sepsis, we observed that CLP led to lung and renal pericyte loss and reduced lung pericyte density and pericyte/endothelial cell (EC) coverage.

Exosomes from Endothelial Progenitor Cells Improve the Outcome of a Murine Model of Sepsis.

Microvascular dysfunction leads to multi-organ failure and mortality in sepsis. Our previous studies demonstrated that administration of exogenous endothelial progenitor cells (EPCs) confers protection in sepsis as evidenced by reduced vascular leakage, improved organ function, and increased survival. We hypothesize that EPCs protect the microvasculature through the exosomes-mediated transfer of microRNAs (miRNAs).

The role of miRNAs in cardiovascular disease risk factors.

Coronary artery disease and atherosclerosis are complex pathologies that develop over time due to genetic and environmental factors. Differential expression of miRNAs has been identified in patients with coronary artery disease and atherosclerosis, however, their association with cardiovascular disease risk factors, including hyperlipidemia, hypertension, obesity, diabetes, lack of physical activity and smoking, remains unclear. This review examines the role of miRNAs as either biomarkers or potential contributors to the pathophysiology of these aforementioned risk factors.

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth.

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414.

Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study.

Background: Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; however, the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways.

Age-dependent therapeutic effects of liver X receptor-α activation in murine polymicrobial sepsis.

The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-α (LXRα) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXRα in age-dependent lung injury and outcome of sepsis.

Combined treatment with a CXCL12 analogue and antibiotics improves survival and neutrophil recruitment and function in murine sepsis.

Previous studies demonstrated that the CXCL12 peptide analogue CTCE-0214 (CTCE) has beneficial effects in experimental sepsis induced by cecal ligation and puncture (CLP). We examined the hypothesis that CTCE recruits neutrophils (PMN) to the site of infection, enhances PMN function and improves survival of mice in CLP-induced sepsis with antibiotic treatment. Septic mice (n=15) were administered imipenem (25mg/kg) and CTCE (10 mg/kg) subcutaneously vs.

Endothelial progenitor cells and a stromal cell-derived factor-1α analogue synergistically improve survival in sepsis.

Rationale: Endothelial progenitor cells (EPCs) have been associated with human sepsis but their role is incompletely understood. Stromal cell-derived factor (SDF)-1α facilitates EPC recruitment and is elevated in murine sepsis models. Previous studies have demonstrated that the SDF-1α analog CTCE-0214 (CTCE) is beneficial in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice.

Toll-like receptor-induced inflammatory cytokines are suppressed by gain of function or overexpression of Gα(i2) protein.

Previous studies have implicated a role of Gα(i) proteins as co-regulators of Toll-like receptor (TLR) activation. These studies largely derived from examining the effect of Gα(i) protein inhibitors or genetic deletion of Gα(i) proteins. However, the effect of increased Gα(i) protein function or Gα(i) protein expression on TLR activation has not been investigated.

Increased expression of beta-arrestin 1 and 2 in murine models of rheumatoid arthritis: isoform specific regulation of inflammation.

Pro-inflammatory cytokines and chemokines play critical roles in autoimmune diseases including rheumatoid arthritis (RA). Recently, it has been reported that β-arrestin 1 and 2 are involved in the regulation of inflammation. We hypothesized that β-arrestin 1 and 2 play critical roles in murine models of RA.

Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation.

The chemokine CXC receptor 4 (CXCR4) is activated by stromal cell-derived factor (SDF-1α). CXCR4 may be part of a lipopolysaccharide (LPS) sensing co-clustering complex that modulates TLR4 activation and evidence suggest that SDF-1α can activate anti-inflammatory signaling pathways and suppress inflammation. In the present study we examined the hypothesis that the SDF-1α peptide analog and CXCR4 agonist CTCE-0214 is anti-inflammatory in three distinct models of murine systemic inflammation.

Heterotrimeric Gα(i) proteins are regulated by lipopolysaccharide and are anti-inflammatory in endotoxemia and polymicrobial sepsis.

Previous studies have implicated a role of heterotrimeric Gα(i) proteins in lipopolysaccharide (LPS)-induced inflammatory responses. We hypothesized that Toll-like receptor (TLR) signaling regulates Gα(i) proteins, which are anti-inflammatory in endotoxemia and polymicrobial sepsis. RAW 264.

Peroxisome proliferator-activated receptor {delta} regulates inflammation via NF-{kappa}B signaling in polymicrobial sepsis.

The nuclear peroxisome proliferator-activated receptor δ (PPARδ) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPARδ in the modulation of the nuclear factor-κB (NF-κB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro.

Beta-arrestin 2 negatively regulates sepsis-induced inflammation.

Beta-arrestins 1 and 2 are ubiquitously expressed proteins that alter signalling by G-protein-coupled receptors. beta-arrestin 2 plays an important role as a signalling adaptor and scaffold in regulating cellular inflammatory responses. We hypothesized that beta-arrestin 2 is a critical modulator of inflammatory response in experimental sepsis.

beta-Arrestin 2: a Negative Regulator of Inflammatory Responses in Polymorphonuclear Leukocytes.

Heterotrimeric Gi proteins have been previously implicated in signaling leading to inflammatory mediator production induced by bacterial lipopolysaccharide (LPS). beta-arrestins are ubiquitously expressed proteins that alter G-protein-coupled receptors signaling. beta-arrestin 2 plays a multifaceted role as a scaffold protein in regulating cellular inflammatory responses.

Lysophosphatidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: potential anti-inflammatory signaling pathways.

Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression. Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation.

Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis.

The fundamental mechanisms that underlie endotoxin tolerance remain to be elucidated, and the clinical significance of endotoxin tolerance in the context of active systemic infection remains in question. We hypothesized that the endotoxin tolerance phenotype would result in decreased inflammation at the expense of altered bacterial clearance and, thus, higher mortality in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Endotoxin tolerance was induced in C57Bl/6 mice with 5 mg/kg LPS or vehicle 18 h before subsequent CLP.

Peroxisome proliferator activated receptor gamma is not necessary for the development of LPS-induced tolerance in macrophages.

Peroxisome proliferator activated receptor-gamma (PPARgamma) has been reported to exert anti-inflammatory properties in endotoxic shock and sepsis. One phenomenon that alters the inflammatory response to endotoxin [lipopolysaccharide (LPS)] is endotoxin tolerance, which is caused by previous exposure to endotoxin. Here, we investigate whether changes in endogenous PPARgamma function regulate this phenomenon using three different models of LPS-induced tolerance in macrophages.

Peroxisome proliferator-activated receptor gamma is required for the inhibitory effect of ciglitazone but not 15-deoxy-Delta 12,14-prostaglandin J2 on the NFkappaB pathway in human endothelial cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated nuclear receptor with effects on inflammation, atherosclerosis, and apoptosis. The endogenous PPARgamma ligand, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), and the synthetic ligand, ciglitazone, have anti-inflammatory properties in endothelial cells. In addition to PPARgamma-dependent effects on the anti-inflammatory process, it has been proposed that PPARgamma ligands may also inhibit the nuclear transcription factor kappaB (NFkappaB) pathway in a PPARgamma-independent manner.

Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by Galpha(i) proteins.

Heterotrimeric G(i) proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of G(i) proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice were investigated.