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TLR4与各种疾病的综述

Expert Review

Discovery and Development of Toll-Like Receptor 4(TLR4)Antagonists:A New Paradigm for Treating Sepsis and Other Diseases

Carlos G.Leon,1,3Rita Tory,1,2Jessica Jia,1Olena Sivak,1and Kishor M.Wasan 1

Received January 18,2008;accepted March 13,2008;published online May 21,2008

Abstract.Sepsis remains the most common cause of death in intensive care units in the USA,with a current estimate of at least 750,000cases per year,and 215,000deaths annually.Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury.Endotoxin (lipopolysaccharide from Gram-negative bacteria,or LPS)has been implicated as a major cause of this syndrome.Inflammatory shock as a consequence of LPS release remains a serious clinical concern.In humans,inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages,which can cause fever,shock,organ failure and death.A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria,including blockage of one or more of the cytokines induced by LPS.Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor,TLR4.This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling,in vitro pre-clinical and in vivo clinical evaluation of TLR4antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction.KEY WORDS:drug discovery;LPS;sepsis;toll-like receptor antagonists.

LPS AND TLR

Bacteria are classified into two groups based on a staining procedure (1).This staining response is a consequence of the composition of their membranes.Gram-positive bacteria present a multi-layered,cross-linked polymer of peptidogly-can surrounding their plasma membrane,whereas Gram-negative bacteria have essentially a monolayer (1).The Gram-negative outer membrane is an asymmetric lipid bilayer interspersed with proteins.The lipid of this outer leaflet is almost exclusively constituted by LPS molecules.

Bacterial infection can be life threatening,requiring the host organism to develop a system to respond to this insult.The innate immune response is the first line of defense against infectious agents and is devoted to recognize highly conserved pathogen motifs in lipopeptides,DNA,dsRNA,ssRNA,specific proteins and LPS.These motifs are known as pathogen-associated molecular patterns (PAMPs)(2).

Lipopolysaccharide is composed of three distinct domains,lipid A,a short core of oligosaccharide and the O-

antigen polysaccharide (Fig.1).The lipid A domain is the bioactive component and is recognized during human infec-tion.The composition of the O-antigen varies between different Gram-negative bacterial strains.The presence or absence of O chains determines whether LPS is considered rough or smooth (3).Full length O chains would render the LPS smooth while the absence or reduction of O-chains would make the LPS rough (3,4).

Lipopolysaccharide is a potential drug target since its presence is critical in membrane stability and also it plays a prominent role in raising an immune response (2).LPS triggers the release of many inflammatory cytokines,in particular TNF α,interleukin-1βand IL-6,and it has been implicated as the etiological agent of a variety of pathologies ranging from mild (fever)to lethal (septic shock,organ failure and death)(5).Thus the structure,function and biosynthesis of LPS have been areas of intense research in the last decade (6).

The receptors capable of recognizing the pathogen-associated molecular patterns are Toll-like receptors (TLR)and scavenger receptors.Ten members of the TLR family have been identified in humans (7).The Toll was originally described as a type I transmembrane receptor that controls the embryonic dorsal-ventral pattern of Drosophila (8).In fact this pioneering work identified a group of ten different genes which when deleted produced qualitatively similar phenotypes.Null mutations on any of these genes lead to a failure to differentiate patterns on the dorsoventral axis and resulted on embryonic lethality.The identification of the sequence of Toll led to the recognition that its carboxyl

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0724-8741/08/0800-1751/0#2008Springer Science +Business Media,LLC

Pharmaceutical Research,Vol.25,No.8,August 2008(#2008)DOI:10.1007/s11095-008-9571-x

Division of Pharmaceutics and Biopharmaceutics,Faculty of Phar-maceutical Sciences,The University of British Columbia,Vancou-ver,British Columbia,Canada.2

Department of Pathology,St.Paul ’s Hospital,University of British Columbia,Vancouver,British Columbia,Canada.3

To whom correspondence should be addressed.(e-mail:cleon@interchange.ubc.ca)

terminal domain was significantly related to that of the vertebrate interleukin-1receptor (IL-1R)(8).IL-1R activa-tion is part of a cascade of events linked to an acute phase response to infection.This suggested that TLRs could not only be involved in development but also in the initial responses to infection in vertebrates.This hypothesis received further support from the work of Lemaitre et al.,who found that Toll and other genes from the dorsal group played a role in innate immune responses to pathogenic fungi and bacteria (9).

The TLRs belong to a cluster of molecules called the IL-1R/TLR super-family characterized by the presence of cytoplasmic Toll/IL-1R (TIR)domains (10).The three subgroups are:the IL-1R (which present extracellular immu-noglobulin domains),the adapter subgroup (cytoplasmic proteins without extracellular region)and the TLRs (9).TLRs are type I transmembrane proteins with extracellular amino terminus and a carboxy terminal intracellular domain.The extracellular domain of the TLR4contains over 600amino acids and is highly polymorphic compared with the transmembrane and cytosolic domains (6).The TIR domain,composed of three highly conserved regions,contains 150amino acids and modulates protein-protein interactions between the TLRs and the adaptor proteins involved in the signal transduction cascade (10).Unlike other receptors,TLRs do not have an enzymatic activity (6).Researchers have identified at least fifteen different negative regulators of the TLRs,including MyD88s (a short form of MyD88),IRAKM,suppressor of cell signaling-1(SOCS1),nucleotide-binding oligomerization domain 2(NOD2),phosphatidylino-sitol-3-kinase (PI3K)and Toll-interacting protein (TOLLIP)(11).The TLR activation leads to responses that involve the induction of new genes via transduction pathways such as NF κB and AP-1(9).The discovery of TLR lead to the understanding that an adaptive response mediated by anti-body responses and T cell activation is tightly coupled to a second unknown process that requires the presence of microbial extracts (2,7).

Toll-like receptor 4(TLR4)is the central signaling receptor for LPS in mammals (12).The current knowledge on the structure and function of the TLR4has opened the possibility to develop new drug targets to fight sepsis and other diseases associated with this signaling molecule.TLR4was identified as the first human homologue of the Drosoph-ila Toll (13).TLR4not only engages LPS but it recognizes an envelope glycoprotein encoded by mouse mammary tumor virus (MMTV)(14).In addition,TLR4recognizes ligands such as heat shock proteins and EDA (extracellular domain A)in fibronectin (15,16).

TLR4SIGNALING

TLRs activate a potent immunostimulatory response which needs to be tightly controlled.TLRs homo o hetero-dimerize upon ligand binding whereas TLR4and TLR9homodimerize (6).TLR signaling involves a family of adaptor proteins which recruit downstream protein kinases which activate transcription factors such as nuclear factor-kB (NF-κB)and members of the interferon (IFN)-regulatory factor (IRF)family (10).LPS signaling involves the binding of the LPS-binding protein (LBP)to LPS;this interaction leads to a disruption of LPS aggregates (10)(Fig.2LPS signaling,modified from (10)with permission).Upon ligand binding there is the formation of a TLR4complex with CD14.CD14was the first molecule shown to enhance LPS signals (17).Interestingly TLR4does not require CD14to trigger epithelial signaling to uropathogenic E.coli since bladder cells do not express CD14(18).In addition a small molecule,myeloid differentiation 2receptor (MD-2),participates in this complex by associating with the TLR4extracellular domain (19).

MD-2binds to the LPS monomer and is sensitive to the acylation pattern of the lipid A moiety.Association of the MD-2:LPS complex to the ectodomain of the TLR4finally trans-duces the signal through the association of intracellular TIR domain,recruiting the adapter proteins triggering the signaling cascade (20).In a similar way to TLR2,TLR4uses the myeloid differentiation primary-response gene 88adapter like protein (MAL)as a bridging adaptor to recruit the myeloid differen-tiation primary-response gene 88(MyD88)to activate the NF-κB,p38and JNK/MAPK pathways via TRAF6(9).MAL is recruited to plasma membrane microdomains containing the phospholipid PtdIns (4,5)P 2(phosphatidylinositol-4,5-bisphos-phate).MAL subsequently recruits MyD88(20).Another pathway activated by TLR4involves TRIF-related

adaptor

Fig.1.The structure of

LPS.

Fig.2.LPS signaling [modified from O ’Neill and Bowie (10)with permission].TLR4requires four signaling adaptors to function upon activation by LPS.Similarly to TLR2it uses MAL to recruit MyD88and to activate the NF κB pathway and p38and JNK MAPK pathways.A second signaling cascade triggered by the LPS-TLR4interaction involves TRAM.TRAM recruits TRIF which activates pathways involving TBK1to IRF3,TRAF6to NF κB and RIP1to apoptosis.

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Leon et al .

molecule(TRAM).Similar to MAL,TRAM is also membrane proximal and requires myristoylation to lodge into the membrane.TRAM recruits the Toll/interleukin-1receptor (TIR)-domain-containing adaptor protein inducing interferon-β(TRIF)which activates the tumor-necrosis factor-receptor-associated factor3(TRAF3),TRAF6and receptor interacting protein1(RIP1).Recent work with CD14knockout mice suggested that TRL4can function in two ways:one where full signaling occurs in the presence of CD14and one limited to MyD88-dependent signaling(21).

In addition to blocking the intracellular LPS signaling there are other means to modulate the endotoxin response. Approaches to alleviate the morbidity and mortality of patients associated with severe sepsis and septic shock include:(a)neutralizing LPS or blocking initial LPS-signaling events by preventing the generation of cell-surface signals,(b) blocking the intracellular signals induced by endotoxin or the synthesis of cytokines and other cellular mediators,(c) inhibiting the release of cytokines(Il-1,IL-6and IL-8)and cellular mediators,(d)blocking the TNF-αand IL-1receptors to the cellular mediators on their responsive target cell and (e)inhibiting downstream pathophysiological events such as acute respiratory distress or aberrant blood clotting(22). POTENTIAL CLINICAL USES OF TLR4 ANTAGONISTS

TLR mediated innate and/or adaptive immune responses play an important role in a variety of diseases,including sepsis,infectious disease,atherosclerosis,kidney failure,liver disease,pulmonary disease and myocardial ischemia/reperfu-sion injury(5,23–28).TLRs are expressed in a variety of cell types including immune and non-immune cells.In addition, the capability of these receptors to recognize PAMPs is indicative of their distinct roles in infection,inflammation and tissue damage(29)(Fig.3).

TLR4and Sepsis

According to the definition made by ACCP/SCCM Consensus Conference in1992,sepsis is known to be an early syndrome that may progress to a pathologic state manifested by hypotension and hypoperfusion known as septic shock.LPS has been associated with sepsis and the high mortality rate seen in septic shock(5).However,it is the exaggerated host response to the systemic release of endo-toxin that accounts for septic shock from Gram-negative bacteria(23).

TLR4up-regulation in non-immune cells after initial TLR mediated immune response may trigger secondary responses such as activation of endothelial cells that promotes the production of adhesion molecules,followed by macro-phage infiltration and vascular permeability during infection (30).This cascade may result in a systemic septic syndrome including tissue perfusions,an imbalanced coagulation cas-cade and organ failure(31).

TLR4and Atherosclerosis

Atherosclerosis is an inflammatory disease where acti-vated cells are involved in its initiation and progression.Guha and Mackman(32)have shown that activated TLR4elicits the production of inflammatory cytokines and chemokines. Edfeldt et al.(33)have also found that TLR4is prominently expressed in endothelial cells of human atherosclerotic lesion, but poorly expressed in normal human arteries.In the early atherosclerotic lesion,LPS and other ligands can stimulate the TLR4expression on macrophages.The activated recep-tors can then initiate the signaling cascade that induces the expression of inflammatory cytokines,proteases,and cyto-toxic oxygen and nitrogen radicals.These entities further speed up the progression of the atherosclerotic lesion(34).In advanced atherosclerotic lesion,LPS can induce the prolifer-ation of vascular smooth muscle cells,as well as the expression of elastin-degrading enzyme via TLR4(35). Besides that,in response to chemokines,more smooth muscle cells will also migrate to the sites of the lesions(36).These predominant changes cause the accumulation of cells,extra-cellular matrix components,thickening of the intima,as well as the deformity of the arterial wall.

Furthermore,TLR4signaling might also be involved in atherosclerotic plaque destabilization.Grenier and Grignon have demonstrated that LPS induces the expression of matrix metalloproteinase-9(MMP-9)by TLR4in macrophages; MMP-9has been shown to degrade collagen fibrous cap, thus predisposing plaque to rupture(37).

TLR4and Liver Injury

In many forms of liver diseases such as alcoholic or non-alcoholic liver disease,liver failure and inflammation are the result of a cascade of insults which result in hyper-activation of inflammatory pathways and liver injury(26,27).Velayudham and colleagues(26)have shown that there is an up-regulation of TLR4receptors in liver granulomas and LPS induced liver injury.Pathogen-induced TLR4activation also activates

reac-Fig.3.TLRs are involved in protective immunity in many infectious diseases,cancer,allergies and in the pathogenesis of sepsis,autoim-mune diseases or atherosclerosis.An efficient TLR antagonist may be of benefit to block or reduce exaggerated TLR stimulation[modified with permission from Ishii et al.(78)].

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Discovery and Development of TLR4Antagonists

tive oxygen species(ROS),which is a major source of acute hepatocyte injury and death in the liver.Up-regulation of peripheral blood monocyte expression of TLR4also occurs in patients with chronic hepatitis C(38).In addition,endogenous gut-derived bacterial LPS have also been implicated as important cofactors in the pathogenesis of liver injury.

Within the liver,LPS binds to LPS-binding protein (LBP),which then facilitates its transfer to membrane CD14 on the surface of Kupffer cells in the liver(39).Moreover, TLR4can also interact with a protein ligand released from damaged hepatocytes to extend an existing injury in the liver (40).

In other studies,there is evidence that high-mobility group box1(HMGB1)can interact with both TLR2and TLR4to induce an inflammatory response during liver ischemia/reperfusion(IR)injury similar to that initiated by LPS(41,42).HMGB1is an intracellular protein present in many species that functions in regulation and modulation of gene transcription(42).HMGB1is released readily from necrotic or damaged cells,which may signal through TLR4 the presence of advancing tissue injury,initiating an inflam-matory response that further damages viable cells(42).

TLR4and Ischemia/Reperfusion Injury

The restoration of blood flow to the ischemic heart has often caused myocardial ischemic/reperfusion(MI/R)injury. An inflammatory response triggered by MI/R injury can irreversibly cause damage to the viable tissue surrounding the infarct,thereby further extending the injury.It is still unclear how innate immune signaling pathways are initiated during MI/R injury(43).However,TLR4,which is also present in cardiomyocytes,has been thought to play a role in mediating MI/R injury.Schuster and Nelson(28)have shown that TLR4 receptor is up-regulated in response to myocardial injury. Furthermore,Shimamoto and colleagues have shown that TLR4activates NF-κB-dependent transcription of inflamma-tory cytokine genes in MI/R injury.The TLR4-mediated injury appears to occur through activation of c-Jun NH2-terminal kinase(JNK)and translocation of NF-κB(41).It is also believed that TLR4recognizes endogenous molecules that are exposed during cellular injury and extracellular matrix remodeling,independent of pathogen invasion(44). Thus,inhibition of TLR4signaling pathway may be a potential therapeutic target to treat the myocardium damage in the ischemia/reperfusion setting.

TLR4and Kidney Disease

Acute renal failure(ARF)occurs in close to5%of hospital admissions,and is a leading cause of morbidity and mortality.A common cause of ARF is sepsis,which results from overwhelming infection(25).Cunningham and col-leagues(25)have shown that LPS insult leads to renal cell apoptosis and renal neutrophil infiltration.

Tubular epithelial cells of the kidney are among the non-immune cells that express TLR1,TLR1-2,TLR1-3,TLR1-4, and TLR1-6,suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (45).In addition,receptors such as TLR4,TLR2,CD91and the receptor for the advanced glycation end-products (RAGE),allow leukocytes and renal cells to recognize molecules released by injured cells.These receptors are sentinels for tissue necrosis(46).Upon stimulation with LPS in renal infection or other endogenous ligands from necrotic tubular cells,the activated TLR4has been shown to specifically stimulate the NF-κB pathway in response to oxidative stress(47).Furthermore,TLR4activation on tubular epithelial cells and circulating immune cells leads to secretion of cytokines and chemokines that either directly or indirectly contributes to renal injury.

TLR4in Inflammatory Bowel Disease

Inflammatory bowel disease(IBD)is a medical condition that predominantly affects the gastrointestinal tract(48).De Jager et al.showed that TLR4and its signaling molecule TIRAP affect susceptibility to IBD(49).Recent studies have shown that TLR4?/?and MyD88?/?knockout mice tend to be more prone to severe dextran sulfate sodium-induced colitis than their wild-type littermates(50).Interestingly,CRX-526a TLR4antagonist has been shown to prevent an inflammatory disease in the dextran sulfate sodium and mdr1a?/?/1b?/?deficient mice models(51).To explain these contradictory results we have to consider that constitutive signaling through TLR4may result in the production of tissue protective factors such as IL-6and TNF-α(49).This is the scenario in the MyD88?/?knockout mice,while in the case of the CRX-526 we may have selective downregulation of one of the TLR-4/ LPS signaling pathways.

TLR4and Pulmonary Disease

Simpson and colleagues observed an increased expres-sion of TLR2,TLR4and CD14,as well as the pro-inflammatory cytokines IL-8and IL-1βin neutrophilic asthma and bronchiectasis patients compared to controls. These groups also had higher airway endotoxin levels than the control group(23).In another study,there was also an increased pulmonary expression of inflammatory cytokines occurring in the lung during experimental endotoxemia.The cytokine production further contributes to acute lung injury (ALI)and acute respiratory distress syndrome(ARDS) (52,53).Baumgarten and colleagues showed that LPS induces pro-inflammatory cytokines in the lung via the TLR4/CD14 signaling cascade,suggesting a role of the innate immune response in the pathogenesis of ALI/ARDS(52). SYNTHESIS OF NOVEL ANALOGUES

LPS biosynthesis occurs by two distinct,yet convergent pathways:one for the lipid A core and another for the polysaccharide O antigen.After independent synthesis,the two parts are ligated together to complete the LPS molecule (4).Amongst the most important TLR4antagonists devel-oped so far we have CRX-526,E5531and E5564.

CRX-526

Aminoalkyl glucosaminide4-phosphates or AGPs are a class of lipid A mimetics in which the reducing sugar of lipid A has been replaced with an N-acylated aminoalkyl aglycon

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unit (54).The AGPs contain an L-serine-based aglycon unit as well as three (R )-3-n -alkanoyloxytetradecanoyl residues comprised of even-numbered normal fatty acyl chains be-tween 6and 14carbon atoms in length.All members of this family have 14carbon atoms in the “primary ”fatty acid,which is the -hydroxy fatty acid attached directly to the AGP backbone.-Hydroxymyristic acid is the most common of the primary fatty acids present in lipid A.These compounds were used in a variety of cell-based and an in vivo model to determine structure-activity relationships related to AGP acyl chain length and stimulation via TLR4(54).Figure 4shows the chemical structure of two AGPs:MPL and CRX-526.The structure of CRX-526differs significantly from monophos-phoryl lipid A (MPL)and other TLR4-agonist AGP in the length of its secondary fatty acyl chains (SAC):for instance CRX-526contains 3SAC of 6carbons in length,whereas MPL and other AGP,which signal through the TLR4complex,contain SAC of >10carbons in length (55).

The synthesis of AGPs has been described elsewhere (55).Briefly,the AGPs were prepared by a highly convergent method,which allowed chemical differentiation of the hydroxyl and amino groups and sequential introduction of the (R )-3-n -alkanoyloxytetrahexanoyl residues.The AGPs were purified by flash chromatography on silica gel (to >95%purity)and analyzed as a triethylammonium salt by standard analytical methods.For stimulation in vitro ,the AGPs were formulated in water containing 216μg/ml dipalmitoylphos-phatidyl choline [aqueous formulation (AF)],0.2%trietha-nolamine (pH 7.4),or in 2%glycerol (i.v.formulation).E5531and E5564

E5531(6-O -{2-deoxy-6-O -methyl-4-O -phosphono-3-O -[(R )-3-Z -dodec-5-endoyloxydecl]-2-[3-oxo-tetradecanoyla-mino]-O -phosphono-D -glucopyranose tetrasodium salt)and E5564(Eritoran ?)[-D -glucopyranose,3-O -decyl-2-deoxy-6-O -[2-deoxy-3-O -[(3R )-3-methoxydecyl]-6-O -methyl-2-[[(11Z )-1-oxo-11-octadecenyl]amino]-4-O -phosphono-D -glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-1-(dihydrogen phosphate),tetrasodium salt],formula weight 1401.60)(mo-lecular formula:C 66H 122N 2Na 4O 19P 2)were synthesized by Eisai Research Institute of Boston (Andover,MA,USA)(53).The structure of E5531,an analog of the lipid A of Rhodobacter capsulatus,is presented elsewhere (56).The structure of E5564is depicted in Fig.5.The crystal structure of the TLR4-MD2complex with bound E5564was recently

published (57)suggesting that the mechanism of action of E5564is binding through a large internal pocket in MD-2.PRE-CLINICAL EV ALUATION

An important consideration in the development of assays is to determine the efficacy and toxicity of the compounds and the potency required to obtain a biological effect.A high potency is a key factor that would limit the high cost of synthesis and purification of such a compound.To illustrate the challenges in developing a synthetic endotoxin receptor antagonist we present the case of E5564.

In vitro ,E5564dose-dependently inhibited LPS-mediated activation of primary cultures of human myeloid cells and mouse tissue culture macrophage cell lines as well as human or animal whole blood at nanomolar concentrations as measured by production of tumor TNF-and other cytokines.E5564also blocked the ability of Gram negative bacteria to stimulate human cytokine production in whole blood.In vivo ,E5564blocked induction of LPS-induced cytokines and LPS or bacterial-induced lethality in primed mice.E5564was devoid of agonistic activity when tested both in vitro and in vivo and had no antagonistic activity against Gram positive-mediated cellular activation at concentrations up to 1μM.E5564blocked LPS-mediated activation of nuclear factor-B in TLR4/MD-2-transfected cells.In a mouse macrophage cell line,activity of E5564was independent of serum,suggesting that E5564exerts its activity through the cell surface receptor(s)for LPS,without the need for serum LPS transfer proteins.Similar to E5531,another lipid A-like antagonist,E5564associates with plasma lipoproteins,causing low concentrations of E5564to be quantitatively inactivated in a dose-and time-dependent manner.However,compared with E5531,E5564is a more potent inhibitor of cytokine generation,and higher doses retain activity for a period of time likely sufficient to permit clinical application.These results indicate that E5564is a potent LPS antagonist and lacks agonistic activity in human and animal model systems,making it a potentially effective therapeutic agent for treatment of disease states caused by

LPS.

Fig.4.The chemical structures of MPL and CRX-526[modified from

(51)with

permission].

Fig.5.The chemical structure of E5564.

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Discovery and Development of TLR4Antagonists

Compared with E5531,E5564is structurally and syn-thetically less complex,yet seems to possess superior activity and pharmacological characteristics.Although E5531demon-strated potent inhibition of LPS when added to blood in vitro and in vivo,activity decreased as a function of time.This reaction has been shown to be due to interaction of E5531 with plasma lipoproteins(58–60).E5564is an inhibitor of LPS-mediated stimulation of responsive cells in vitro and in vivo as measured by production of cytokines,as well as morbidity and mortality associated with LPS poisoning in animal models.Because E5564is a structural analog of the lipid A portion of LPS,it is logical to hypothesize that the antagonist interacts with the same signaling components that bind to LPS such as the soluble serum proteins LBP and sCD14,as well as membrane-associated CD14and perhaps the TLR4/MD-2receptor complex.E5564blocked LPS/ sCD14-induced reporter activity in TLR4/MD-2-expressing HEK293(61),but not TLR2-mediated signaling by heat-killed S.aureus.These findings indicate that E5564selectively inhibits LPS signaling via TLR4/MD-2.However,a limitation to this model system is that LPS requires the presence of sCD14for cellular activation,making it difficult to determine whether E5564blocks LPS binding to sCD14or TLR4/MD-2. Results from experiments indicated that serum components did not affect the potency of E5564,indicating that they are not critical to E5564antagonistic activity(61).

Further support of the hypothesis that interaction of E5564at CD14does not play a key role in its activity comes from a previous study by Lien et al.describing the activity of novel synthetic acyclic lipid A-like agonists that activate TLR4/MD-2in the absence of CD14(62).E5564inhibited the actions of these agonists under serum-free conditions. Taken together,these lines of evidence make it tempting to speculate that E5564binds to TLR4/MD-2complex,thereby blocking LPS binding or transmembrane signaling.The downstream effect of inhibiting the initial signaling by LPS seems to be an inhibition of all LPS-induced cytokines measured,including TNF-,IL-1,IL-6,IL-8,IL-10,and nitric oxide,which was measured in cultured cells,whole blood,and in vivo.Recently the crystal structure of the TLR4/MD-2and E5564has been described confirming the physical interaction of these molecules(57).

Comparisons of antagonistic potency in cells cultured in 10%serum versus whole blood allow us to determine whether the high concentration of proteins/lipoproteins present in serum inhibit E5564activity.In all systems but the rat, antagonistic activity of E5564in cultured cells was within fourfold that measured in high serum(blood)compared with assays done in low-serum conditions(cultured cells or mono-cytes)(60,63).This indicates that serum has little or no inhibitory effect on antagonistic activity under these in vitro conditions.However,extended incubations in whole blood demonstrated that activity of E5564was measurably reduced. Other studies indicate that like E5531,E5564is not rapidly metabolized,but binds to lipoproteins,and time dependently loses antagonistic activity(64).The observation that lipopro-teins reduce drug activity may explain the poor activity of E5564in rat blood that has relatively high lipoprotein content.

During extended incubation in whole blood,E5564 retained activity better than similar concentrations of the first-generation antagonist E5531.Based on the proposed mechanism of action as a cell surface antagonist,it is likely that E5564can completely block cellular activation by LPS. This block is achieved by concentrations of E5564as low as 10nM(14ng/ml)in vitro,and at doses of1mg/kg or less in animal models challenged with lethal LPS doses.

Both LPS-challenge model and infection model use animals that have been sensitized or primed to LPS by previous infection with BCG,increasing cytokine response and lowering the threshold lethal dose of endotoxin(61).All animal models of sepsis and infection have been criticized for their inability to closely mimic human sepsis.The primed model is the most relevant to the study of endotoxin antagonists such as E5564.It is well known that compared with humans,unprimed rodents such as rats and mice and primates demonstrate a profound insensitivity to endotoxin,requiring endotoxin doses as high as milligrams per kilogram,whereas humans demonstrate repro-ducible response to endotoxin at doses as low as2ng/kg.This argues that either LPS contributes only weakly to the inflammatory process in animal models,or that response to infection occurs only after the level of infection is very high, representing a process different from that in more LPS-sensitive species such as humans(61).

Even in primed animal models,lethal doses of LPS are high,approximately100μg/kg,generating estimated plasma concentrations of～1μg/ml.These plasma levels are still >100-fold that found in even the most extreme cases of human sepsis(65).Because the dose of E5564required to protect against LPS is proportional to the LPS challenge dose,studying E5564in these animal models indicates that E5564can be a safe and effective antagonist even under these extraordinary conditions.E5564is approximately tenfold better in human blood than mouse blood(IC50=1.6nM in human whole blood;Table I versus～20nM in mouse whole blood;Table II).

Complete block of cytokine response by10nM E5564in blood extrapolates to a human dose of approximately100μg in a70-kg individual.Recent studies have supported this extrap-olation by finding that a dose of100μg of E5564given to normal volunteers over30min completely blocks response(signs, symptoms,and cytokines)to a dose of4ng/kg endotoxin administered at the midpoint of the E5564infusion(66).

In vitro and ex vivo assays have found that low concentrations of E5564time dependently lose ability to inhibit LPS response.In light of these observations,it is perhaps not surprising that low doses of E5564demonstrate a time-dependent loss of activity after administration into normal volunteers.This loss in activity is overcome when E5564doses are increased(67).Phase I clinical safety and tolerability assays indicate that E5564is safe and except for the occurrence of phlebitis,well tolerated at doses up to 252mg administered over72h.At this dose,in vivo antagonistic activity is retained for at least an additional 72h after discontinuing infusion.This leads us to believe that sufficient therapeutic activity can readily be administered to patients(67).The safety and efficacy of E5564are currently been analyzed in a phase III randomized controlled study. TAK-242

TAK-242has been demonstrated to suppress LPS-induced inflammation(68,69).Recently,TAK-242has been

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shown to almost completely suppress production of nitric oxide or TNF αinduced by LPS in mouse RAW264.7,human U937and P31/FUJ cells (70).In a HEK293cell model where TLR4,MD-2and CD14were co-expressed,this antagonist showed specificity to TLR4as other TLRs,TLR1/2,TLR2/6,TLR3,TLR5,TLR7and TLT9were not affected by this drug (70).CLINICAL EV ALUATION

Sepsis is a major cause of high mortality rate in intensive care units in the USA (71).Severe sepsis usually leads to organ

failure.Currently,over 30pharmaceutical products have been in the development stage to treat this condition,yet only few have reached the market (72).Many of these target specific

inflammatory mediators have been unsuccessful because of the complex nature of sepsis.For the treatment of sepsis,there are a few products that are being investigated in clinical studies via blocking different mechanisms of the body ’s innate immune system.Eli Lilly ’s Xigris ?was one of the few drugs currently available on the market to treat sepsis.Xigris ?is a recombi-nant human activated protein C that has anti-inflammatory,anti-thrombotic and pro-fibrinolytic properties to block the coagulation cascade which plays a critical role in the develop-ment of organ failure due to sepsis (73).In addition,

simvastatin and atorvastatin had also shown to have some non-specific anti-inflammatory effects contributing to their clinical benefits in treating sepsis (63).However,statins are currently not been considered as a treatment for sepsis.To find a more specific target,scientists have identified TLR4as one of

the candidates in blocking the innate immune system.Only

two TLR4antagonists,E5564and TAK-242,have made far

into the clinical phase (Table III ).

E5564

In Wong,et al.,determined the safety and tolerability of

E5564following a 30-min intravenous infusion in healthy male volunteers (74).This was a single-center,randomized,double-blind,placebo-controlled,sequential-group,single-dose study of E5564.The drug dose levels used were 350,1,000,2,000or 3,500μg.All doses of E5564presented a long pharmacokinetic half-life and short in vivo pharmacodynamic half life which generally less than several hours when it is co-administered with LPS in healthy volunteers (74).The C max and AUC (area under the curve)of E5564increased in a dose-dependent manner.E5564pharmacokinetics was char-acterized by a slow clearance (0.67–0.95ml h ?1kg ?1),a small volume of distribution (41–54ml/kg),and a relatively long elimination half life (42–51h)in healthy male volunteers.Thus,to overcome this low PD,the doses of E5564given to the volunteers needed to be adjusted.In summary,all doses were demonstrated to be safe and well tolerated.Safety and

Table II.E5564Inhibition of TNF-and/or IL-6Induced by LPS in Peritoneal Macrophages and Whole Blood from Mice,Rats,and Guinea

Pigs

Assay

Cytokine Assayed

TNF-IL-6

TNF-Induced (pg/ml)

E5564IC 50(nM)

IL-6-Induced (ng/ml)E5564IC 50(nM)Mouse peritoneal macrophages 3,315±31820.4±12.5 5.0±0.5316.6±6.7Mouse blood

13.0±0.1820.2±7.0Rat peritoneal macrophages 2,867±3267±5.693±99

16.2±17.5(range 23–163)

(range 3.9–28.6)Rat blood

2,241±335136±6155.8±12～2,400

Guinea pig macrophages

1,897±348

0.3±0.15

3.0±0.43

0.5±0.3

Cells or blood prepared as described under “Materials and Methods ”(61)were stimulated with 10ng/ml LPS plus a range of doses of E5564for 2or 3h.Supernatant or plasma samples were assayed for the indicated cytokines.Most values were determined from triplicate incubations done three times,except rat peritoneal macrophages (n =2).Basal induction of cytokine (cytokine values measured after incubation in the absence of LPS)was 4%or less of values from the LPS-stimulated samples in all cases NT Not tested

Table I.E5564Inhibition of TNF-Induced by LPS from Various

Strains of Bacteria,Dead Bacteria,and Lipid A (61)

Agonist

Amount of agonist (ng/ml)

TNF-released (mean±SE)a (pg/ml)Antagonism by E5564Average IC 50(nM)

Strain of LPS b K.pneumoniae 102,868±1048.5±5.0

P .aeruginosa 102,027±185 1.0±0.21S.Minnesota 102,793±9912.4±5.1S.enteritidis 12,279±184 2.6±0.47S.typhimurium 103,091±1829.4±6.7S.marcescens

103,128±9110.3±6.2

S.minnesota R595101,578±2847.6±2.9

E.coli

101,142±155 1.6±0.3

Whole bacteria c

E.aerogenes (ATCC)1002,165±299 1.5±0.7

E.aerogenes (clinical isolate)1002,558±389 1.2±0.5

Whole E.coli 1003,172±4130.65±0.32Lipid A E.coli

2,500±294

1.2±0.7a

Each value represents the mean and standard error of triplicate determinations obtained from three experiments.c

Nanograms per milliliter of whole bacteria from lyophilized powder.b

LPS from V .cholerae Inaba 569B and B.pertussis 165were also analyzed;however,they were only weakly active at stimulating release of TNF-from whole blood and stimulation was highly variable.E5564inhibited this weak stimulation with IC 50values of 1nM or less for both strains.

1757

Discovery and Development of TLR4Antagonists

tolerability assessments included monitoring and questioning of the subjects about adverse events,physical examinations, clinical laboratory tests(including hematology,blood chemistry,and urinalysis),and vital sign measurements (including supine and standing pulse rate and blood pressure),and12-lead electrocardiograms(ECGs)and cytokine concentration testing.In this study,E5564inhibited LPS-induced tumor necrosis factor-αin a dose-dependent manner,and at the higher doses(2and3.5mg),antagonistic activity was measurable up to8h post-infusion.E5564lacked LPS-like agonist activity at doses up to3.5mg(74).

In another study of healthy volunteers with experimental endotoxemia,Lynn et al.(66)found phlebitis was only associated with72h continuous intravenous infusion of E5564 but not with four hour infusion of E5564into a peripheral vein. In this study the authors explored the possibility of extended pharmacokinetic activity of E5564.The infusion period was changed from bulk dosing to a4-and72-h infusions of E5564 into normal volunteers.They observed that at4h infusion of E5564,3mg/h completely blocked endotoxin administered8h post-dosing.Additionally,they observed that administration of 3.4mg of E5564/hX72h completely blocked the effects of endotoxin challenge at the end of dosing(72h),and at48and 72h post dosing.A lower dose of E5564of2mg was also studied,and they found that0.5mg/h×4h,ameliorated but did not block most effects of endotoxin8h post-dosing.This work also studied the effect of varying plasma lipoprotein content on E5564activity in subjects who have high or low cholesterol levels(>180or<140mg/dl)after a72h infusion of252mg of E5564.The distribution of E5564into the lipoprotein fractions was not significantly different between the low-and high-cholesterol groups(66).

In another study by Rossignol et al.,a72h intravenous infusion and higher doses(500,2,000or3,500μg/h)of E5564 were administered into healthy volunteers(67).E5564has a slow plasma clearance(0.679to0.930ml h?1kg?1of body weight),a small volume of distribution(45.6to49.8ml/kg),and a relatively long half-life(50.4to62.7h).All these pharmacokinetic parameters obtained are comparable to the study done by Wong et al.(74).The association of E5564with plasma lipoproteins was also investigated and it was found that the majority(～55%)of the drug was bound specifically to high-density lipoprotein(HDL),but not low-density lipoproteins,very-low-density lipoproteins,or albumin(67).

A Phase II multi-site,double-blind,randomized,ascending-dose,placebo-controlled safety study on E5564was conducted in cardiac surgery patients(75).Patients undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass were enrolled.Patients received a four hour infusion of2,12or28mg of E5564before cardiopulmo-nary bypass.No significant safety concerns were identified.No significant difference was observed in most variables related to systemic inflammation or organ dysfunction/injury.This phase II safety study suggests that the administration of E5564is not associated with toxicity in cardiac surgical patients.However, the relatively small sample size used in this study limits the conclusion regarding rare adverse events or the potential clinical benefits of this drug(75).

The potential of E5564as a sepsis treatment was addressed by Kaneko et al.(76),Surface Plasmon resonance (SPR)analysis indicated that E5564binds to LPS binding protein(LBP),in a manner similar to LPS.Blood withdrawn from healthy volunteers was treated with heparin to prevent clotting.At doses of E5564relevant to its clinical use(i.e. 6μg/ml),antibodies against LBP did not influence either the distribution of E5564to non-HDL lipoprotein fractions or the transfer of E5564from non-HDLs to HDL.LBP binds E5564 in a manner similar to LPS,but does not play a role in E5564 redistribution/binding to lipoprotein and plasma clearance.

Czeslick et al.(77)carried out an ex vivo study on the effect of E5564on production of LPS-induced pro-inflamma-tory cytokines,particularly IL-6and TNF-α,in LPS-induced human monocytes.In this study,they recruited10healthy volunteers and obtained their whole blood samples and pre-incubated with0.001,0.003,0.01,0.03,0.1,1and10ng/ml E5564for45min and after stimulated with0.2ng/ml of LPS. They found that E5564(0.003up to10ng/ml)caused a dose-dependent inhibitory effect on IL-6and TNF-αproduction in LPS-stimulated human monocytes.They concluded that E5564has a significant LPS inhibitory effect via down regulation of the intracellular generation of pro-inflammatory cytokines IL-6and TNF-αin human monocytes(77).

The association of E5564with plasma protein and lipoprotein was studied in plasma obtained from fasted human subjects with various lipid concentrations(64).It was reported that the majority of E5564was recovered in the high-density lipoprotein(HDL)fraction.Additionally,they had shown increasing levels of TG-rich lipoprotein(TRL)lipid(TC and TG)concentrations resulted in a significant increase in the percentage of E5564recovered in the TRL fraction.Further-more,their findings had suggested that E5564does not influence CETP-mediated transfer activity(64).

TAK-242

Human peripheral blood mononuclear cells(PBMCs) were isolated from peripheral blood obtained from healthy human volunteers by density gradient centrifugation(68). TAK-242was effective in human cells and inhibited the production of TNF-α,IL-6,and IL-1b from PBMCs stimulat-ed with LPS and IFN-gamma,with IC50values of TAK-242 ranging from5.3to58nM.There were four donors used for

Table III.Clinical Development of Two TLR4Antagonists(59,68)

Compound Status Studied population Timeline Company Indication E5564III Global2006–Eisai Septic shock (Eritoran)II North America2002–2005Eisai Septic shock

I North America1999–2001Eisai Septic shock TAK-242III Japan,US Europe2005–2008Takeda Severe sepsis

I Japan,US Europe2005Takeda Severe sepsis 1758Leon et al.

this study.There was no marked difference in the IC50values of TAK-242amongst them.TAK-242showed suppressive effects on the production of various inflammatory mediators from human monocytes and macrophages stimulated with LPS.TAK-242also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells(PBMCs)at IC50values from11to33 nM.In addition,the inhibitory effects on the LPS-induced IL-6and IL-12production were similar in human PBMCs, monocytes,and macrophages.TAK-242suppressed the cytokine production induced by Toll-like receptor(TLR)4 ligands,but not by ligands for TLR2,TLR3,and TLR9.TAK-242suppresses the production of multiple cytokines by selectively inhibiting TLR4intracellular signaling(68). CONCLUSIONS

The manipulation or intervention of TLR-mediated immune responses is a potential approach to treat and prevent the septic shock and variety of associated diseases. However,blocking TLR may lead to‘inappropriate’immune responses such allergic Th2responses,or immunological tolerance(78).Thus,it seems clear that the risks and benefits of manipulation of TLR mediated immune responses need to be balanced and require further investigation. REFERENCES

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Discovery and Development of TLR4Antagonists

语料库话语分析综述

近十年国内基于语料库的话语研究综述 A Review of Ten - year Research on Corpus-Based Discourse Analysis in China 摘要：文章从基于语料库的话语研究领域出发，通过对2002年至2011年发表在国内八种核心期刊上的论文进行统计与分析，发现这些研究在研究领域取得了很大的进步，涉及到话语各个方向，对于实践有重大指导作用，但同时也出现一些问题值得我们关注。 Abstract: From corpus-based discourse analysis, this thesis finds this field has made great progress, relates to many directions of discourse and has a significant guiding role for the practice, but also brings many problems worthy our attention. All of these are derived from the research and analysis of thesises published in 8 kinds of core journals from 2002 to 2011 in China. 关键词: 语料库话语基于语料库的话语研究 0. 引言现代语料库语言学是20世纪中后期兴起的一门语言研究科学。语料库是指按一定的语言学原则，运用随即抽样的方法，收集自然出现的连续的语言运用文本或话语片段而建成的具有一定容量的大型电子文库。在20 世纪后半叶的西方语言学界, Chomsky的观点大行其道,秉承该学说的语言研究者唯直觉语料独尊。他们躲在书斋,满足于依靠自己的直觉语料从事语言研究。随着社会语言学、话语分析、语用学、语料库语言学的兴起,越来越多的语言学家认识到光靠直觉语料来研究语言是远远不够的,人们还必须借助语料库语料以及其他各种语料,只有这样我们才能更好地揭示语言的本质,克服直觉语料的局限与不足。这样基于语料库的话语研究越发引起大家的重视，并取得了丰硕的成果。国内基于语料库的话语研究虽然起步较晚，但是成果仍然颇丰。 1. 研究样本由于近几年运用语料库来做话语研究已经成为语言研究的热点，笔者通过检索主题与关键词，将文献定在2002年至2011年这十年期间，研究样本来源为发表在八种外语类核心期刊的22篇文章。这是因为这8种外语类期刊有一定的权

情绪调适与疾病的关系

情绪调适与疾病的关系徐薇!，戴瑞婷"，杨安阳"，徐志刚" （!#北京军区天津疗养院，$%%$&!；"#天津第四中心医院）关键词’情绪调适；疾病；关系中国图书资料分类号：($)*’’’’’文献标识码：+’’’’’文章编号：!%%,-!"*.（"%%/）""-"%%,-%" ’’早在!)$"年，国际学者坎农［!］分析了不同情绪状态时对机体生理功能的影响。情绪学说是心理学的重要的组成部分，近代心理学家研究证明，情绪的生理基础既包括大脑皮质活动，又包括皮质下中枢的活动，大脑皮质起调节、制约的作用。情绪既是一个复杂的心理现象，也是一个复杂的心理过程。当人体受到外界各种不同事件刺激时，大脑皮质对各种事件会发生不同反映，这种反映就是情绪的外在表现。随着客观世界的复杂化、多维化，人们的感觉也深化繁衍，由于人的个性差异，情绪也随之千变万化。因此，要有一个好的心态、稳定的情绪，才能使身体健康。 !’情绪与健康的关系现代社会的疾病与心理情绪状态有着密切的关系，而心理情绪的状态也影响疾病的进程、转归和预后。在当今的社会变迁中，我们每一个人都有着自身的感触，有不同的情绪变化。高度紧张的生活节奏、千丝万缕的人际关系，在竞争中求生存，人们心理适应的差异导致了情绪的不稳定。情绪是人体心理活动的一种表现，心理活动与社会稳定是相互制约、相互协调的。当人体情绪的外环境发生突如其来的事件，且超过了人体正常心理承受能力，肌体就会产生疾病。 ’’人们在社会生活事件的刺激下产（01(0、事故、失恋）产生的紧张、焦虑、愤怒、悲伤或过喜等情绪反应，都伴随神经内分泌系统的功能改变。当心血管调控系统受到敏感的刺激后，植物神经系统、内分泌系统产生变化，肾上腺素分泌增加，交感神经兴奋、心肌收缩、心率加快、心博量增加，继而诱发心血管疾病。有人做过试验，被试者看不同的电影时，其尿中的儿茶酚胺浓度变化如下：看风光片时，尿中的肾上腺素与去甲肾上腺素均降低；看攻击性影片或喜剧片时，尿中的肾上腺素、去甲肾上腺素不变；看恐怖片时，尿中的肾上腺素、去甲肾上腺素均上升。试验还发现，人愉快时肾上腺素排出量最高，安静时最低；不愉快时肾上腺素的变化与去甲肾上腺素相似；情绪激动时，儿茶酚安排除量均上升，情绪压抑时，血与尿中肾上腺皮质激素量均持续相当高，肾上腺素、去甲肾上腺素及醛固酮也类似变化［!］。 ’’23455在!),!年报道了对胃瘘患者的观察，发现情绪可以引起胃粘膜、胃壁运动血管充盈和粘膜分泌的不同变化，长期紧张的精神刺激和不良的情绪反应，作用于大脑皮质开始引起兴奋。长时间过度兴奋的大脑皮质转为超限抑制，导致了皮质下中枢功能失调，植物神经的控制中心视丘脑下部紧张性增高，进而发生机能的紊乱和异常［!］。通常为副交感神经系统兴奋、肾上腺素皮质激素升高、粘膜下血管痉挛、胃部内分泌增加、胃运动亢进、胃酸分泌增加、胃蛋白酶原分泌增加、67逆向弥散增加而诱发溃疡病。 ’’紧张的刺激作用于大脑后，可通过下丘脑和垂体，促使肾上腺释放皮质激素，可降低巨噬细胞对抗原的吞噬及消化能力，以致病原体有可能在体内增殖而感染［!］。紧张的刺激情绪可使大脑皮质功能失调，紧张的刺激影响下丘脑，胸腺功能失调，8细胞成熟受损，巨细胞吞噬的能力下降，而干扰了淋巴细胞的再循环，免疫器官退化，功能低而产生自身免疫性疾病。如红斑狼疮、重症肌无力症等许多疾病，都与情绪的失控密切相关。近代医学证明，人体具有生物性、心理性两大防御体系。前者是人体的生物免疫系统，后者指人的良性情绪功能等心理作用［"］。心理活动是人体组织器官对外事务反应的集合。在这些器官的调解下，人体进行正常的生理活动和心理活动，与自然环境与社会保持动态的平衡。当这种平衡受到破坏，人失去了良好的心境和情绪，就会产生各种疾病。因此，调试好自我心境才能有良好的、稳定的情绪。 "’情绪的自我调适情绪明显带有社会性，或喜或忧、或惊或怒，与人对客观事物的认知水平有关。评定每个人的情绪、矫治不良情绪，掌握好这一点对疾病的防治都非常重要。产生不良情绪原因有三：!社会改革的步伐加快，社会关系网的微妙变化；"各种突发事件的产生，外环境的改变；#承受心理压力顺应度的较弱与应激不良。在生理和心理两方面，对于最敏感的应激源类型，各人有不同的反应。每人对应激源的敏感性也是各不相同。事态骤变、失意及其他问题，某人可以处之泰然，而另!人则会感到束手无策［$］。躯体反应与情绪体验是一致的，情绪一旦改变，相应的躯体反应立即消失。因为，心里紧张或不良的情绪，可诱发疾病，不良的情绪可以使病情加重，不良的情绪可以降低药物治疗的效果。因此，必须学会调整自我心态，保持良好的情绪状态，顺应各种应激源，缓解紧张、焦虑的不良情绪。笔者认为首要一点是超越自我，正确认识自我价值，做到胸襟开阔，理智宽容的对待生活、工作，为自己营造一个良好的心态。其次是平衡心理，善交朋友，学会自我放松，在遇到不愉快事件，想不通问题时，与朋友聊聊天，听听音乐，散散步或到大千世界去郊游，以达到放松心情的目的。再者，学会宣泄，把所有的不快讲出来，使压抑的情绪得以释放。另外，运动疗法也可使自身从不良的情绪中走出来。现代精神卫生科学阐明，稳定和乐观的良性情绪是防治疾病不可缺少的心理因素。笔者认为，身心健康状况受个人生活、社会和心理因素平衡的影响，情绪的失控会影响到人对事物的认知。因此，我们必须学会自我情绪调适。在绝望中摆脱烦恼，在痛苦中抓住快乐，在压力下寻找解脱，在失败的时候找回希望［,］。在这个世界中会有许多事情是我们难以预料的，我们不能控制际遇，无法预知未来，但我们能掌握自己，调试自我情绪。只有稳定的良性情绪，才能有一个健康的躯体。$’参考文献 ,%%"《职业与健康》’"%%/年!!月第""卷第""期’9++:;18<9=1=>6?1@86A3B#""=3#!!=3CDEFDG，"%%/

黄帝内经关于情绪与疾病

《黄帝内经》关于情绪与疾病中医认为，人的情绪有七种：怒、喜、思、忧、悲、恐、惊，即所谓“七情”。《黄帝内经》认为：某种情绪过于强烈、持久或失调，会引起脏腑气血功能紊乱，从而产生疾病。《素问·举痛论》云：怒则气上，喜则气缓，悲则气消，恐则气下，惊则气乱，思则气结。《素问·阴阳应象大论》云：怒伤肝，喜伤心，思伤脾，忧伤肺，恐伤肾。喜怒伤气，暴怒伤阴，暴喜伤阳。《素问·刺法论》云：大悲伤也，悲伤即肺动，而其气复散也。《素问·疏五过》云：暴怒伤阴，暴喜伤阳。《灵枢·寿夭刚柔》云：忧恐忿怒伤气。《灵枢·百病始生》云：忧思伤心，忿怒伤肝。《灵枢·九针论》云：形数惊恐，筋脉不通，病生于不仁。《黄帝内经》认为：某种情绪可以通过另一种情绪来调节。《素问·阴阳应象大论》云：怒胜思，喜胜忧，思胜恐，悲胜怒，恐胜喜。《黄帝内经》这些关于情绪失常导致疾病以及调节情绪治疗疾病的观点对后世运用情绪疗法治疗疾病产生了深远影响。古代名医通过调节情绪治疗疾病，不乏其例。《三国志·魏书·方伎传》载有华佗以情绪治病的例子：“一郡守病，佗以为其人盛怒则瘥，乃多受其货而不加治，无何弃去，留书骂之。郡守果大怒，……瞋恚既甚，吐黑血数声而愈。” 金代名医张从正（字子和，号戴人）对于用调节情绪的方法治疗疾病颇有发挥。其所著《儒门事亲·卷三》云：“悲可以治怒，以怆恻苦楚之言感之；

喜可以治悲，以谑浪亵狎之言娱之；恐可以治喜，以恐惧死亡之言怖之；怒可以治思，以污辱欺罔之言触之；思可以治恐，以虑彼志此之言夺之。” 《儒门事亲·卷五》记载了几个张从正通过调节患者情绪治病的例子：息城司侯，闻父死于贼，乃大悲哭之，罢，便觉心痛，日增不已，月余成块，状若覆杯，大痛不住，药皆无功，乃求于戴人。戴人至，适巫者在其旁，乃学巫者，杂以狂言以谑病者。至是大笑，一、二日，心下结块皆散。戴人曰∶《内经》言∶忧则气结，喜则百脉舒和。又云∶喜胜悲，《内经》自有此法治之。项关令之妻，病食不欲食，常好叫呼怒骂，欲杀左右，恶言不辍。众医皆处药，几半载尚尔。其夫命戴人视之。戴人曰∶此难以药治。乃使二娼，各涂丹粉，作伶人状，其妇大笑；次日，又令作角抵，又大笑；其旁常以两个能食之妇，夸其食美，其妇亦索其食，而为一尝。不数日，怒减食增，不药而瘥，后得一子。一富家妇人，伤思虑过甚，二年不寐，无药可疗。其夫求戴人治之。戴人曰∶两手脉俱缓，此脾受之也。脾主思故也。乃与其夫，以怒而激之。多取其财，饮酒数日，不处一法而去。其人大怒汗出，是夜困眠，如此者，八、九日不寤，自是而食进，脉得其平。卫德新之妻，旅中宿于楼上，夜值盗劫人烧舍，惊坠床下，自后每闻有响，则惊倒不知人，岁余不痊。戴人见而断之曰∶惊者为阳，从外入也；恐者为阴，从内出也。惊者，为自不知故也；恐者，自知也。足少阳胆经属肝木。胆者，敢也。惊怕则胆伤矣。乃命二侍女执其两手，按高椅之上，当面前，下置一小几。戴人曰∶娘子当视此。一木猛击之，其妇人大惊。戴人曰∶我以木击几，何以惊乎？伺少定击之，惊也缓。又斯须，连击三、五次；又以杖击门；又暗

性格情绪与十二经络及与人体生病之间的关系

大家有没有发现：身边总是会有人与某一种健康问题纠缠不清。比如，经常性的感冒、皮肤过敏、喉咙不适、胃痛胃溃疡、失眠多梦、经常性头痛等症状。当事人常常会想：我是不是身体出现什么问题了，但是，有时候，你不知道，经常的负面情绪才是幕后黑手…… 疾病与性格特征的关系英国研究人员发现，从胃溃疡、支气管哮喘到老年痴呆症，各种疾病都与性格特征存在着千丝万缕的联系。急躁易怒——原发性高血压排除富贵病的不良生活因素外，高血压病人被发现更容易具有趋向好斗和急躁易怒、要求过高过急等性格特点。易犯人群表现为雄心勃勃，醉心于工作，但是缺乏耐心，容易产生敌意情绪，常有时间紧迫感。同时临床还发现，此类人群与冠心病、中风、脑血管疾病、消化道溃疡关系密切。争强好胜——消化道溃疡消化道疾病与心理、情绪、性格的关系相当密切。病人常常具有以下特点：如争强好胜，即使休息仍不能松弛;个性太过认真严谨，同时认死理太执着，不撞南墙绝不回头;情绪易波动，但惯于克制，

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现在人们最爱说的一个字就是“累”，不仅累身更累心。生存压力让很多人越来越情绪化，有些情绪连自己都没意识到，但身体却早早地发出了“报警信号”。当人情绪变化时，往往伴随着一系列生理变化。比如恐怖会让人瞳孔变大、口渴、出汗、脸色发白；而情绪低落或过度紧张时，人会越来越讨厌自己的长相，觉得怎么穿、怎么梳妆都不顺心，然后就会发现自己头发爱出油、鼻翼出油、心烦冒汗，甚至下体分泌物异常或有味。精神科专家表示，不管是正面情绪还是负面情绪，长时间处在某种情绪中不能自拔，就会对健康产生不利影响。不同情绪对应不同疾病不同的情绪对应着不同的身体疾病。比如恐惧、焦虑会导致腹部疼痛；批评、内疚引发关节炎；压抑导致哮喘；经常愤怒的人容易有口臭，还爱发生脓肿；恐惧会引发晕车和痛经。胃肠道被认为是最能表达情绪的器官，心理上的点滴波动它们都能未卜先知。在所有的心身疾病中，胃肠疾病是排名第一位的，比如胃溃疡和十二指肠溃疡，全球约有10%的人一生中患过该病。很多人都有这样的经验：一遇到紧张焦虑的状况就会胃疼或腹泻，压力大的时候根本吃不下饭。司机、警察、记者、急诊科医生等患胃溃疡的比例最大。其次是皮肤。对很多人来说，紧张时头皮发痒、烦躁时头皮屑增加、睡不好狂掉头发，还有反复无常的荨麻疹、湿疹、痤疮，都可能是长期不良情绪带来的后果。第三就是内分泌系统。女性的卵巢、乳腺，男性的前列腺最容易受到不良情绪的冲击。大量临床医学研究表明，小到感冒，大到冠心病和癌症，都与情绪有着密不可分的关系。充满心理矛盾、压抑，经常感到不安全和不愉快的人，免疫力低下，经常感冒、

消化系统疾病及护理试题答案教学内容

消化系统疾病及护理试题答案

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心里暗示与疾病的关系

心里暗示与身体疾病的关系健康无忧网作者Emily yang 以下是四个有关心理暗示与疾病的真实例子。案例一：一天，我的朋友往我家沙发上一躺说：“我心脏病发作了，可惜我的药吃完了。”我急忙找来听诊器仔细听了她的心肺，发现都很正常，就问她：“你怎么知道你有心脏病？”她回答说：“反正我有心脏病，因为我父亲有心脏病。”我问她有没有看过医生，她回答说看过，我又问她医生怎么说；她回答说：“医生没说什么”；于是我告诉她：“你没有心脏病，你父亲有心脏病也不代表你就一定会得心脏病。下次切忌暗示自己有心脏病，否则你真的会患上心脏病。”从那以后她的心脏病消失。案例二：一个聪明漂亮的高中女生，失恋后不愿上学，呆在家里，她的父母不进行适当的心理疏导，反而，强行给她吃药，还经常喊：“犯精神病了！”结果女孩真的患上精神病，从此远离正常的生活。案例三：一位老太太，他儿子告诉她：“你患食道癌了，要住院开刀。”，老太回答说：“我这么大年纪了怕什么，开刀？不去！”一年后，结果老太太食道癌消失了。案例四：医生告诉老人的儿子：“将你父亲拉回家吧，他很快就不行了。”老人回到家中，开始到后院挖地，种花。半年后，花开了，老人依旧健在。老人的儿子打电话给医生，医生很吃惊，叫老人的儿子将老人带到医院。老人说：“你让我回家，我就认为我的病已经好了。” 前两例是负面心理暗示，后两例是正面心理暗示。可见，心理暗示对于疾病的发生发展有着多么重要的影响力。著名的人格与行为医学家Ritberger博士提醒我们：不要忽视我们内在的抗病机制及我们的思想与情绪在疾病中所担当的重要角色；她进一步提出，治病（treat）的那个人是医生，而使我们治愈（heal）的那个人是谁？是我们自己！你们看明白了吧：我们甚至可以治愈自己的疾病！病患的意义不是告诉患者：“自己快要死了。”而是告诉我们因为我们不良的生活习惯、思想情绪或行为方式等已经影响到我们的身体健康，我们需要认真反思与总结我们自己身上所有的不良习惯（包括负面的思想情绪），并加以改正。

心身疾病

医学心理学与医患沟通技巧相关知识讲座第六讲心身疾病一、心身疾病概述（一）心身疾病的概念心身疾病（psychosomatic disease），又称为心理生理疾病，包括狭义和广义的概念。所谓狭义心身疾病，是指心理社会因素造成的一类有病理形态学或生化改变的躯体疾病，例如，原发性高血压、支气管哮喘等，强调病理学和生化的临床改变。广义心身疾病是指心理社会因素在其发病过程中起了重要作用的一些躯体疾病或障碍，这些躯体疾病或障碍可以有也可以没有病理形态学的改变，没有病理形态学的改变的情况，例如，心因性阳痿、心因性厌食、书写痉挛、口吃等。（二）心身疾病的特点 1.以躯体症状为主，有明确的病理生理过程； 2.某种个性特征是疾病发生的易患素质； 3.疾病的发生和发展与心理社会应激（如生活事件）和情绪反应有关； 4.生物和躯体因素是某些心身疾病的发病基础，心理社会因素往往起“扳机”作用； 5.心身疾病通常发生在自主神经支配的系统和器官； 6.心身综合治疗比单用生物学治疗效果好。（三）心身疾病的范畴 1.内科心身疾病

⑴心血管系统：原发性高血压，原发性低血压，冠心病（心绞痛、心肌梗死），阵发性心动过速，心动过缓，期外收缩，雷诺氏病，神经性循环衰弱症等。 ⑵消化系统：胃十二指肠溃疡，神经性呕吐，神经性厌食，溃疡性结肠炎，过敏性结肠炎，贲门痉挛，幽门痉挛，习惯性便秘，直肠刺激综合征。 ⑶呼吸系统：支气管哮喘，过度换气综合征，心因性呼吸困难，神经性咳嗽。 ⑷神经系统：偏头痛，肌紧张性头痛，自主神经失调症，心因性知觉异常，心因性运动异常，慢性疲劳等。 ⑸内分泌系统：甲状腺机能亢进，阿迪森氏病，副甲状腺机能亢进，副甲状腺机能低下，垂体机能低下，糖尿病，低血糖。 2.外科：全身性肌肉痛，脊椎过敏，书写痉挛，过敏性膀胱炎，类风湿性关节炎。 3.妇科：痛经，月经不调，经前期紧张综合征，功能性子宫出血，功能性不孕症，性欲减退，更年期综合征，心因性闭经。 4.儿科：心因性发烧，遗尿症，遗粪症，周期性呕吐，胃肠功能紊乱症，脐周痛和心因性呼吸困难。 5.眼科：原发性青光眼，低眼压综合征，中心性视网膜炎，眼肌疲劳，眼肌痉挛等。 6.口腔科：心因性齿痛，下颌关节炎症，原发性慢性口腔溃疡，特发性舌痛症，口臭，唾液分泌异常，咀嚼肌痉挛等。

慢性病自我管理重点内容

慢性病自我管理重点内容慢性病自我管理1：慢性病的定义、急性病与慢性病的区别（表格）、慢性病发生的一般原因。慢性病：是慢性非传染性疾病的简称，它不是特指某种疾病，而是对一类起病隐匿，病程长且病情迁延不愈，缺乏确切的传染性生物病因证据，病因复杂，且有些病因尚未完全被确认的疾病的概括性总称。绝大多数慢性病都无法治愈，将与患者长期共存，甚至伴随终生。包括心脏病、高血压病、关节炎、支气管炎等。一、急性病与慢性病的区别急性的健康问题往往突然发生，病因单一，易诊断，病程短，经特定的治疗（如用药或手术）能有效的控制。一、急性病与慢性病的区别慢性病往往起病慢、进展也慢。多包含一个或多个随时间变化的因素。如遗传类因素，生活方式类因素（吸烟、饮酒、不合理膳食，过度紧张），环境中有害因素的接触。缺乏规律和不可预测性是急性病和慢性病的一个重要区别。一、急性病与慢性病的区别急性病能如人所愿的完全康复，慢性病却通常导致持续性的身体功能丧失。因为慢性病人易疲劳，她们不能完成以前能做的事务和活动。她们被迫放弃许多娱乐活动如散步、跳舞或日常事务如购物、做家务等。

发病迅速缓慢病因通常一个多个病程短长短不定诊断通常可诊断常无法确诊（疾病早期）诊断性检验起决定性作用检验的价值有限治疗通常能治愈很少治愈专业人员作用选择实施各种方案作为教师和伙伴病人作用服从医生安排负责慢性病日常管理二、慢性病发生的原因及后果一般原因包括：遗传因素、环境因素、行为生活方式因素。以环境因素和行为生活方式因素为主。不良的生活方式因素包括吸烟、饮酒、饮食不合理、缺乏体育锻炼、睡眠无规律、生活过于紧张等。二、慢性病发生的原因及后果各种原因引起的慢性病，一般先造成细胞水平的损害。要维持细胞的正常功能，有3件事必不可少：不断的获得营养、氧气、排除代谢产物。各种细胞水平的损害，最终造成的结果是功能的丧失。虽受累部位不同，但最终造成的结果相似。多数慢性病患者都有疲劳和精力不足。慢性病的发病原因和后果有许多相似之处，不同慢性病患者在日常生活中所必须面对的主要的管理任务和必须学习的管理技能是一致的。二、慢性病发生的原因及后果目前威胁人类健康的主要因素是心脑血管疾病、恶性肿瘤。共性因素是缺乏必要的卫生保健知识。采取健康的生活方式不吸烟、少饮酒、合理饮食、多运动、及保持正常体重、生活规律可以帮助预防慢性病的发生。要维持细胞的正常功能，有哪3件事必不可少健康的生活方式包括哪些内容、慢性病症状的变化轨迹（图）、疾病症状的定义、慢性病的常见症状。

消化系统疾病病人的护理试题及答案(四)

消化系统疾病病人的护理试题及答案一、选择题 1．十二指肠的好发部位是 B 169 A 十二指肠降部 B 十二指肠球部 C 十二指肠水平部 D 十二指肠升部 2．急性糜烂性胃炎的主要就诊的临床表现是A84 A 突发消化道出血 B 上腹部疼痛、烧灼感 C 恶心、呕吐 D 上腹饱胀、食欲不振、嗳气等 3.慢性胃炎的最可靠的确诊依据是 C186 A 活组织检查 B 胃肠钡餐检查 C胃镜检查D 胃液分析 4..上消化道出血的特征性表现是D A 氮质血症 B 发热 C 失血性周围循环衰竭 D 呕血与黑便 5.出现黑便一次出血量至少B A 5ml以上 B 50ml以上 C 150ml以上 D 200ml以上 E 250ml 以上 6.上消化道出血伴休克时首要的护理措施为C A 准备急救用品和药物 B 迅速配血备用 C 去枕平卧，头偏向一侧 D 遵医嘱应用止血药 E 开放静脉 7..呕血提示胃内出血量为：D A 出血量大于500ml B 出血量大于150ml C 出血量大于1000ml D 出血量大于250ml ? 8、上消化道出血量大于多少时，可导致失血性休克C A2500ml B2000ml C1000ml D 500ml ? 9、出现大便潜血阳性，出血量至少应是A A 5ml B 30ml C 60ml D 100ml 1. 放置三腔管后，应每日放气多少分钟？B A．6-12分钟B．15-30分钟C．24-36分钟D．36-48分钟 10.下列哪项提示上消化道出血患者出血在减少：B A．呕出的血液转为暗红色B．大便隐血试验转阴性 C．血尿素氮持续升高D．血压不稳定E．血红蛋白量下降 11.三腔气囊管压迫止血适应于A A 胃底静脉曲张破裂出血 B 急性出血糜烂性胃炎 C 胃癌引起的上消化道出血 D 消化性溃疡并发出血所致出血 12.用三腔气囊管压迫止血拔管指征一般不出血多久可试行拔管？D

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启示：为了发泄情绪，我们不必在大街上尖叫，也不一定要向激惹我们的上司大吼，但是在条件允许的情况下，我们一定要为自己找到一条表达情感的途径。我们可以向朋友倾诉心中的愤怒和焦虑，或在日记中叙述自己的害怕或嫉妒。偶尔，在独处时或在一个我们信任的人面前也要允许自己哭一场，无论那是悲伤的泪是幸福的眼泪。所以，我们要强调积极地生活，保持良好的情绪，不仅可以为我们创造一个更甜美的生活，还有可能为我们的未来奠定坚实得基础，使我们的生活得更健康、更长寿。、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、你的情绪影响着你的健康越来越多的研究表明，假如被迫顶着压力发言，身体的过敏症状会在接下来的两天中加重一倍；而这时如果能大哭一场，压力造成的荷尔蒙则会随着眼泪立刻被排出体外。那么，人的喜怒哀乐究竟是如何影响身体健康的呢？ 1、假如你对着另一半直抒爱意……

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