Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombomodulin (TM), a widely expressing glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. TM appears to exhibit anti-inflammatory ability through both protein C-dependent and -independent pathways. We presently have demonstrated that recombinant N-terminal lectinlike domain of TM (rTMD1) functions as a protective agent against sepsis caused by Gram-negative bacterial infections. rTMD1 caused agglutination of Escherichia coli and Klebsiella pneumoniae and enhanced the macrophage phagocytosis of these Gram-negative bacteria. Moreover, rTMD1 bound to the Klebsiella pneumoniae and lipopolysaccharide (LPS) by specifically interacting with Lewis Y antigen. rTMD1 inhibited LPS-induced inflammatory mediator production via interference with CD14 and LPS binding. Furthermore, rTMD1 modulated LPS-induced mitogen-activated protein kinase and nuclear factor-kappaB signaling pathway activations and inducible nitric oxide synthase expression in macrophages. Administration of rTMD1 protected the host by suppressing inflammatory responses induced by LPS and Gram-negative bacteria, and enhanced LPS and bacterial clearance in sepsis. Thus, rTMD1 can be used to defend against bacterial infection and inhibit LPS-induced inflammatory responses, suggesting that rTMD1 may be valuable in the treatment of severe inflammation in sepsis, especially in Gram-negative bacterial infections.
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PMID:Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. 1871 Oct 2

Healthy vascular endothelium is luminally coated by an endothelial glycocalyx, which interacts with the bloodstream and assumes a filter function on the vascular wall. Although this structure was discovered nearly 70 years ago, its physiological importance has been underestimated for a long time. Recent findings indicate that the glycocalyx is, in addition to the endothelial cells themselves, a main constituent part of the vascular barrier. The existence of different colloid osmotic gradients within and beneath this structure has now led to a modification of the Starling equation. In many vascular beds the interstitial space features a protein concentration similar to that of the plasma. The inwardly directed gradient, which retains water and proteins in the vascular system, is generated beneath the glycocalyx by selective protein filtration over this structure. The endothelial glycocalyx, as an additional competent vascular permeability barrier has, therefore, not only a key role for perioperative fluid and protein shifts into the interstitial space, but it seems to be intimately involved in the pathophysiology of diabetes, arteriosclerosis, sepsis and ischemia/reperfusion, especially with respect to associated vascular dysfunctions. The fragile glycocalyx can be destroyed in the course of surgery, trauma, ischemia/reperfusion and sepsis and by inflammatory mediators such as TNF-alpha, causing leukocyte adhesion, platelet aggregation and edema formation. Recent studies have shown that protecting this structure not only maintains the vascular barrier, but constitutes an important component of a rational perioperative fluid therapy.
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PMID:[Expedition glycocalyx. A newly discovered "Great Barrier Reef"]. 1881 Mar 67

Francisella tularensis, the causative agent of tularemia, is a highly virulent organism, especially when exposure occurs by inhalation. Recent data suggest that Francisella interacts directly with alveolar epithelial cells. Although F. tularensis causes septicemia and can live extracellularly in a murine infection model, there is little information about the role of the vascular endothelium in the host response. We hypothesized that F. tularensis would interact with pulmonary endothelial cells as a prerequisite to the clinically observed recruitment of neutrophils to the lung. Using an in vitro Transwell model system, we studied interactions between F. tularensis live vaccine strain (Ft LVS) and a pulmonary microvascular endothelial cell (PMVEC) monolayer. Organisms invaded the endothelium and were visualized within individual endothelial cells by confocal microscopy. Although these bacteria-endothelial cell interactions did not elicit production of the proinflammatory chemokines, polymorphonuclear leukocytes (PMN) were stimulated to transmigrate across the endothelium in response to Ft LVS. Moreover, transendothelial migration altered the phenotype of recruited PMN; i.e., the capacity of these PMN to activate NADPH oxidase and release elastase in response to subsequent stimulation was reduced compared with PMN that traversed PMVEC in response to Streptococcus pneumoniae. The blunting of PMN responsiveness required PMN transendothelial migration but did not require PMN uptake of Ft LVS, was not dependent on the presence of serum-derived factors, and was not reproduced by Ft LVS-conditioned medium. We speculate that the capacity of Ft LVS-stimulated PMVEC to support transendothelial migration of PMN without triggering release of IL-8 and monocyte chemotactic protein-1 and to suppress the responsiveness of transmigrated PMN to subsequent stimulation could contribute to the dramatic virulence during inhalational challenge with Francisella.
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PMID:Francisella tularensis directly interacts with the endothelium and recruits neutrophils with a blunted inflammatory phenotype. 1934 32

Sepsis and septic shock are the major causes of death in intensive care units. The prevalent hypothesis regarding the mechanisms of sepsis and septic shock indicates that this syndrome is caused by an excessive defensive and inflammatory response characterised by massive increases in reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. The consequences of these syndromes are systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, glutathione depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O(2) consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves in a range of conditions, including sepsis. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria currently under development. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in antioxidants that target the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for sepsis.
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PMID:Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondria-targeted antioxidants. 1968 80

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.
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PMID:Activated protein C and acute kidney injury: Selective targeting of PAR-1. 1971 37

Up to date, the nature of the sepsis-induced vascular leakage is understood only partially, which limits pharmacological approaches for its management. Here we studied the protective effect of cAMP using endotoxin-induced hyperpermeability as a model for barrier dysfunction observed in gram-negative sepsis. We demonstrated that the alleviation of lipopolysaccharide (LPS)-induced barrier compromise could be achieved by the specific activation of either protein kinase A (PKA) or Epac with cAMP analogs Bnz-cAMP or O-Me-cAMP, respectively. We next studied the involvement of PKA substrates VASP and filamin1 in barrier maintenance and LPS-induced barrier compromise. Depletion of both VASP and filamin1 with the specific siRNAs significantly exacerbated both the quiescent cells barrier and LPS-induced barrier dysfunction, suggesting barrier-protective role of these proteins. VASP depletion was associated with the more severe loss of ZO-1 peripheral staining in response to LPS, whereas filamin1-depleted cells reacted to LPS with more robust stress fiber induction and more profound changes in ZO-1 and VE-cadherin peripheral organization. Both VASP and filamin1 phosphorylation was significantly increased as a result of PKA activation. We next analyzed the effect of VASP and filamin1 depletion on the PKA-dependent alleviation of LPS-induced barrier compromise. We observed that Bnz-cAMP ability to counteract LPS-induced hyperpermeability was attenuated only by VASP, but not filamin1 depletion. Our data indicate that while PKA-dependent VASP phosphorylation contributes to the protective effect of cAMP elicited on LPS-compromised monolayers, filamin1 phosphorylation is unlikely to play a significant role in this process.
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PMID:Molecular mechanisms mediating protective effect of cAMP on lipopolysaccharide (LPS)-induced human lung microvascular endothelial cells (HLMVEC) hyperpermeability. 1972 51

Sepsis is exceedingly burdensome for hospital intensive care unit caregivers, and its incidence, as well as sepsis-related deaths, is increasing steadily. Sepsis is characterized by a robust increase in NO production throughout the organism that is driven by iNOS. Moreover, NO is an important factor in the development of septic shock and is synthesized by NOS, an enzyme expressed by a variety of cells, including vascular endothelium, macrophages, and neutrophils. However, the effects of NO on leukocyte functions, and the underlying mechanisms, are relatively unknown. Thus, the present review focuses on the effects of NO and its derivatives on cells of the immune system. Experimental evidences discussed herein show that NO induces posttranslational modifications of key proteins in targeted processes with the potential of deterring cellular physiology. Consequently, the manipulation of NO distribution in septic patients, used in conjunction with conventional treatments aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.
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PMID:Sepsis, leukocytes, and nitric oxide (NO): an intricate affair. 1978 65

Hemorrhagic shock (HS) due to major trauma predisposes the host to the development of acute lung inflammation and injury. The lung vascular endothelium is an active organ that plays a central role in the development of acute lung injury through generating reactive oxygen species and synthesizing and releasing of a number of inflammatory mediators, including leukocyte adhesion molecules that regulate neutrophils emigration. Previous study from our laboratory has demonstrated that in a setting of sepsis, toll-like receptor-4 (TLR4) signaling can induce TLR2 expression in endothelial cells (ECs), thereby increasing the cells' response to TLR2 ligands. The present study tested the hypothesis that TLR4 activation by HS and the resultant increased TLR2 surface expression in ECs might contribute to the mechanism underlying HS-augmented activation of lung ECs. The results show that high-mobility group box 1 (HMGB1) through TLR4 signaling mediates HS-induced surface expression of TLR2 in the lung and mouse lung vascular endothelial cells (MLVECs). Furthermore, the results demonstrate that HMGB1 induces activation of NAD(P)H oxidase and expression of ICAM-1 in the lung, and MLVECs sequentially depend on TLR4 in the early phase and on TLR2 in the late phase following HS. Finally, the data indicate an important role of the increased TLR2 surface expression in enhancing the activation of MLVECs and augmenting pulmonary neutrophil infiltration in response to TLR2 agonist peptidoglycan. Thus, induction of TLR2 surface expression in lung ECs, induced by HS and mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for endothelial cell-mediated inflammation and organ injury following trauma and hemorrhage.
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PMID:Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. 1982 41

We have previously reported protective effects of atrial natriuretic peptide (ANP) against endothelial cell (EC) permeability induced by thrombin via suppression of Rho GTPase pathway of barrier dysfunction by protein kinase A and Epac-Rap1-Tiam1-Rac signaling cascades. This study tested effects of ANP on EC barrier dysfunction induced by inflammatory mediators lipopolysaccharide (LPS) and TNFalpha and linked them with activation of mitogen-activated protein kinase (MAPK) and NFkappaB signaling cascades known to promote EC hyperpermeability in the models of lung inflammation and sepsis. LPS and TNFalpha increased permeability in human pulmonary EC monitored by measurements of transendothelial electrical resistance, and caused disruption of EC monolayer integrity monitored by immunofluorescence staining for adherens junction marker protein VE-cadherin. Both disruptive effects were markedly attenuated by ANP. Both LPS and TNFalpha caused sustained activation of p38 and ERK1/2 MAP kinases, increased phosphorylation and degradation of negative regulator of NFkappaB signaling IkBalpha, and increased Rho-kinase mediated phosphorylation of myosin phosphatase MYPT1 leading to accumulation of phosphorylated myosin light chains. Consistent with protective effects on EC permeability and monolayer integrity, ANP dramatically attenuated activation of inflammatory signaling by LPS and TNFalpha in pulmonary EC. These results strongly suggest inhibitory effects of ANP on the LPS and TNFalpha induced inflammatory signaling as additional mechanism of EC barrier preservation in the models of acute lung injury and sepsis.
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PMID:ANP attenuates inflammatory signaling and Rho pathway of lung endothelial permeability induced by LPS and TNFalpha. 1993 45

Hemostasis is a sensitive and tightly regulated process, involving vascular endothelium and blood cells, as well as factors of the coagulation and fibrinolytic cascades. In severe and invasive infectious diseases, the equilibrium between the procoagulant and anticoagulant status of the host may change dramatically and can induce life-threatening complications. A growing body of evidence suggests that the contact system, also known as the intrinsic pathway of coagulation or kallikrein/kinin system, participate in these processes. Contact activation leads to the release of the highly potent proinflammatory peptide bradykinin and initiates the intrinsic pathway of coagulation. Several studies have shown a systemic activation of the contact system in animal models of severe bacterial infections, and similar findings were also reported when monitoring patients suffering from sepsis, severe sepsis, or septic shock. Complications resulting from a systemic activation of the contact system are pathologically high levels of bradykinin, consumption of contact factors, and a subsequent induction of inflammatory reactions. These conditions may contribute to serious complications such as hypotension and vascular leakage. Here, we summarize the state of the art in this field of research with a focus on the contact system, and we also discuss a potential role for the contact system as a target for the development of novel antimicrobial strategies.
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PMID:Contact system activation in severe infectious diseases. 2023 12


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