PCSK9在脓毒症治疗的关键地位
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摘要
脓毒症时,病原菌脂质(pathogenic lipid,PL)如脂多糖是诱发严重炎症反应的主要成分。血浆中低密度脂蛋白(LDL)在PL清除过程中起到重要作用。通过调节前蛋白转化酶枯草溶菌素9(PCSK9)能加速LDL代谢,从而促进PL清除,因此PCSK9可能成为治疗脓毒症的有效靶点。了解PCSK9在清除PL中的详细机制和干预手段对防治脓毒症具有重要指导意义。
引文
1 Singer M,Deutschman CS,Seymour CW,et al.The third international consensus definitions for sepsis and septic shock(Sepsis-3).JAMA,2016,315775~787.
2 Gautier T,Lagrost L.Plasma PLTP(phospholipid-transfer protein):an emerging role in'reverse lipopolysaccharide transport'and innate immunity.Biochem Soc Trans,2011,39984~988.
3 Trinel PA,Plancke Y,Gerold P,et al.The candida albicans phospholipomannan is a family of glycolipids presenting phosphoinositolmannosides with long linear chains ofβ-1,2-linked mannose residues.J Biol Chem,1999,27430520~30526.
4 Cinel I,Opal SM.Molecular biology of inflammation and sepsis:a primer.Critical Care Medicine,2009,37291.
5 Yamashita S,Sakai N,K H,et al.Roles of plasma lipid transfer proteins in reverse cholesterol transport.Front Biosci,2001,6D366~D387.
6 Levels JH,Marquart JA,Abraham PR,et al.Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein.Front Biosci,2005,732321~2326.
7 Hailman E,Albers JJ,Wolfbauer G,et al.Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein.J Biol Chem,1996,27112172~12178.
8 Wittmann I,Sch9nefeld M,Aichele D,et al.Murine bactericidal/permeability-increasing protein inhibits the endotoxic activity of lipopolysaccharide and gram-negative bacteria.JImmunol,2008,1807546~7552.
9 Steinemann S,Ulevitch RJ,Mackman N.Role of the lipopolysaccharide(LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells.Arterioscler Thromb,1994,141202~1209.
10 de Haas CJ,van der Tol ME,Van Kessel KP,et al.Asynthetic lipopolysaccharide-binding peptide based on amino acids 27-39 of serum amyloid P component inhibits lipopolysaccharide-induced responses in human blood.J Immunol,1998,1613607~3615.
11 Vesy CJ,Kitchens RL,Wolfbauer G,et al.Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes.Infect Immun,2000,682410~2417.
12 Cazita PM,Barbeiro DF,Moretti AI,et al.Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model:a novel role for CETP.Shock,2008,30590~595.
13 Clark RW,Cunningham D,Cong Y,et al.Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection.J Lipid Res,2010,51967~974.
14 Dos SC,Marshall JC.Bridging lipid metabolism and innate host defense.Sci Transl Med,2014,6241~258.
15 Walley KR,Thain KR,Russell JA,et al.PCSK9 is a critical regulator of the innate immune response and septic shock outcome.Sci Transl Med,2014,6143~258.
16 Zhang DW,Lagace TA,Garuti R,et al.Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.J Biol Chem,2007,28218602~18612.
17 Stein EA,Mellis S,Yancopoulos GD,et al.Effect of a monoclonal antibody to pcsk9 on LDL cholesterol.N Engl JMed,2012,3661108~1118.
18 Tavori H,Giunzioni I,Linton MRF,et al.Loss of plasma proprotein convertase subtilisin/kexin 9(PCSK9)after lipoprotein apheresis.Circ Res,2013,1131290~1295.
19 Cameron J,Bogsrud MP,Tveten K,et al.Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways.Transl Res,2012,160125~130.
20 Jnis MT,Tarasov K,Ta HX,et al.Beyond LDL-C lowering:distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9(PCSK9)deficiency.Atherosclerosis,2013,228380~385.
21 Berger JM,Loza VA,Gromada J,et al.Inhibition of PC-SK9 does not improve lipopolysaccharide-induced mortality in mice.J Lipid Res,2017,581661~1669.
22 Kovanen PT,Bilheimer DW,Goldstein JL,et al.Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog.PNAS,1981,781194~1198.
23 Davignon J,Dubuc G.Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9(PCSK9)levels.Trans Am Clin Climatol Assoc,2009,120163~173.
24 Berthold HK,Seidah NG,Benjannet S,et al.Evidence from a randomized trial that simvastatin,but not ezetimibe,upregulates circulating PCSK9 levels.Plos One,2013,8e60095.
25 Papazian L,Roch A,Charles PE,et al.Effect of statin therapy on mortality in patients with ventilator-associated pneumonia:a randomized clinical trial.JAMA,2013,3101692~1700.
2 Gautier T,Lagrost L.Plasma PLTP(phospholipid-transfer protein):an emerging role in'reverse lipopolysaccharide transport'and innate immunity.Biochem Soc Trans,2011,39984~988.
3 Trinel PA,Plancke Y,Gerold P,et al.The candida albicans phospholipomannan is a family of glycolipids presenting phosphoinositolmannosides with long linear chains ofβ-1,2-linked mannose residues.J Biol Chem,1999,27430520~30526.
4 Cinel I,Opal SM.Molecular biology of inflammation and sepsis:a primer.Critical Care Medicine,2009,37291.
5 Yamashita S,Sakai N,K H,et al.Roles of plasma lipid transfer proteins in reverse cholesterol transport.Front Biosci,2001,6D366~D387.
6 Levels JH,Marquart JA,Abraham PR,et al.Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein.Front Biosci,2005,732321~2326.
7 Hailman E,Albers JJ,Wolfbauer G,et al.Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein.J Biol Chem,1996,27112172~12178.
8 Wittmann I,Sch9nefeld M,Aichele D,et al.Murine bactericidal/permeability-increasing protein inhibits the endotoxic activity of lipopolysaccharide and gram-negative bacteria.JImmunol,2008,1807546~7552.
9 Steinemann S,Ulevitch RJ,Mackman N.Role of the lipopolysaccharide(LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells.Arterioscler Thromb,1994,141202~1209.
10 de Haas CJ,van der Tol ME,Van Kessel KP,et al.Asynthetic lipopolysaccharide-binding peptide based on amino acids 27-39 of serum amyloid P component inhibits lipopolysaccharide-induced responses in human blood.J Immunol,1998,1613607~3615.
11 Vesy CJ,Kitchens RL,Wolfbauer G,et al.Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes.Infect Immun,2000,682410~2417.
12 Cazita PM,Barbeiro DF,Moretti AI,et al.Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model:a novel role for CETP.Shock,2008,30590~595.
13 Clark RW,Cunningham D,Cong Y,et al.Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection.J Lipid Res,2010,51967~974.
14 Dos SC,Marshall JC.Bridging lipid metabolism and innate host defense.Sci Transl Med,2014,6241~258.
15 Walley KR,Thain KR,Russell JA,et al.PCSK9 is a critical regulator of the innate immune response and septic shock outcome.Sci Transl Med,2014,6143~258.
16 Zhang DW,Lagace TA,Garuti R,et al.Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.J Biol Chem,2007,28218602~18612.
17 Stein EA,Mellis S,Yancopoulos GD,et al.Effect of a monoclonal antibody to pcsk9 on LDL cholesterol.N Engl JMed,2012,3661108~1118.
18 Tavori H,Giunzioni I,Linton MRF,et al.Loss of plasma proprotein convertase subtilisin/kexin 9(PCSK9)after lipoprotein apheresis.Circ Res,2013,1131290~1295.
19 Cameron J,Bogsrud MP,Tveten K,et al.Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways.Transl Res,2012,160125~130.
20 Jnis MT,Tarasov K,Ta HX,et al.Beyond LDL-C lowering:distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9(PCSK9)deficiency.Atherosclerosis,2013,228380~385.
21 Berger JM,Loza VA,Gromada J,et al.Inhibition of PC-SK9 does not improve lipopolysaccharide-induced mortality in mice.J Lipid Res,2017,581661~1669.
22 Kovanen PT,Bilheimer DW,Goldstein JL,et al.Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog.PNAS,1981,781194~1198.
23 Davignon J,Dubuc G.Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9(PCSK9)levels.Trans Am Clin Climatol Assoc,2009,120163~173.
24 Berthold HK,Seidah NG,Benjannet S,et al.Evidence from a randomized trial that simvastatin,but not ezetimibe,upregulates circulating PCSK9 levels.Plos One,2013,8e60095.
25 Papazian L,Roch A,Charles PE,et al.Effect of statin therapy on mortality in patients with ventilator-associated pneumonia:a randomized clinical trial.JAMA,2013,3101692~1700.