• 四川大學(xué)華西醫(yī)院呼吸內(nèi)科（四川成都 610041）;

急性肺損傷/急性呼吸窘迫綜合征（ALI/ARDS）是指心源性以外的各種肺內(nèi)外致病因素導(dǎo)致的原發(fā)或繼發(fā)的急性、進(jìn)行性呼吸衰竭，其病理改變主要表現(xiàn)為肺上皮及內(nèi)皮細(xì)胞的損傷、炎性浸潤(rùn)和透明膜形成，并伴有肺間質(zhì)纖維化。臨床表現(xiàn)為以呼吸窘迫、頑固性低氧血癥和非心源性肺水腫為特征的一種急性進(jìn)行性呼吸困難。采用常規(guī)的治療難以糾正其低氧血癥，死亡率高達(dá)60%，嚴(yán)重威脅人們的生命健康[1]。自1967年Ashbaugh及其同事首次描述ALI/ARDS以來(lái)，醫(yī)學(xué)研究者進(jìn)行了大量關(guān)于ALI/ARDS發(fā)病機(jī)制及病理生理學(xué)的基礎(chǔ)及臨床研究，但是迄今ALI/ARDS的發(fā)病機(jī)理仍未完全闡明。近年來(lái)越來(lái)越多的研究提示凋亡因子（Fas/Fas配體，即Fas/FasL）介導(dǎo)的細(xì)胞凋亡在ALI/ARDS的發(fā)生發(fā)展過程中有著十分重要的作用[2，3]。本文就Fas/FasL的生物學(xué)特性及其在ALI/ARDS發(fā)病機(jī)制中的作用作一綜述。

引用本文： 蔣飛,范紅. Fas/FasL系統(tǒng)在急性肺損傷致病機(jī)制中的研究進(jìn)展. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2007, 6(2): 145-147. doi: 復(fù)制

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1. Ware LB，Matthay MA.The acute respiratory distress syndrome.N Engl J Med，2000，342：1334-1349.
2. Matute-Bello G，Winn RK，Jonas M，et al.Fas (CD95) induces alveolar epithelial cell apoptosis in vivo：implications for acute pulmonary inflammation.Am J Pathol，2001，158：153-161.
3. Kitamura Y，Hashimoto S，Mizuta N，et al.Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice.Am J Respir Crit Care Med，2001，163：762-769.
4. Perl M，Chung CS，Ayala A.Apoptosis.Crit Care Med，2005，33：S526-S529.
5. French LE，Tschopp J.Protein-based therapeutic approaches targeting death receptors.Cell Death Differ，2003，10：117-123.
6. Wajant H.Death receptors.Essays Biochem，2003，39：53-71.
7. Suda T，Takahashi T，Golstein P，et al.Molecular cloning and expression of the Fas ligand，a novel member of the tumor necrosis factor family.Cell，1993，75：1169-1178.
8. Itoh N，Yonehara S，Ishii A，et al.The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis，Cell，1991，66：233-243.
9. Peter ME，Krammer PH.The CD95 (APO-1/Fas) DISC and beyond.Cell Death Differ，2003，10：26-35.
10. Scaffidi C，F(xiàn)ulda S，Srinivasan A，et al.Two CD95 (APO-1/Fas) signaling pathways.EMBO J，1998，17：1675-1687.
11. Korsmeyer SJ，Wei MC，Saito M，et al.Pro-apoptotic cascade activates BID，which oligomerizes BAK or BAX into pores that result in the release of cytochrome c.Cell Death Differ，2000，7：1166-1173.
12. Jimenez MF，Watson RW，Parodo J，et al.Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.Arch Surg，1997，132：1263-1269.
13. Matute-Bello G，Liles WC，Radella F 2nd，et al.Neutrophil apoptosis in the acute respiratory distress syndrome.Am J Respir Crit Care Med，1997，156：1969-1977.
14. Kotecha S，Mildner RJ，Prince LR，et al.The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants.Thorax，2003，58：961-967.
15. Nwakoby JE，Reddy K，Patel P，et al.Fas-mediated apoptosis of neutrophils in sera of patients with infection.Infect Immunol，2001，69：3343-3349.
16. Dunican AL，Lenemoth SJ，Grutkoski P，et al.TNF alpha-induced suppression of PMN apoptosis is mediated through interleukin-8 production.Shock，2000，14：284-88.
17. Park WY，Goodman RB，Steinberg KP，et al.Cytokine balance in the lungs of patients with acute respiratory distress syndrome.Am J Respir Crit Care Med，2001，164：1896-1903.
18. Hu M，Lin X，Du Q，et al.Regulation of polymorphonuclear leukocyte apoptosis：role of lung endothelium-epithelium bilayer transmigration.Am J Physiol Lung Cell Mol Physiol，2005，288：L266-L274.
19. Nakamura M，Matute-Bello G，Liles WC，et al.Differential response of human lung epithelial cells to Fas-induced apoptosis.Am J Pathol，2004，164：1949-1958.
20. Albertine KH，Soulier MF，Wang Z，et al.Fas and Fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome.Am J Pathol，2002，161：1783-1796.
21. Matute-Bello G，Liles WC，F(xiàn)revert CW，et al.Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits.Am J Physiol Lung Cell Mol Physiol，2001，281：L328-L335.
22. Neff TA，Guo RF，Neff SB，et al.Relationship of acute lung inflammatory injury to Fas/FasL system.Am J Pathol，2005，166：685-694.
23. Kinoshita M，Ono S，Mochizuki H.Neutrophils mediate acute lung injury in rabbits：role of neutrophil elastase.Eur Surg Res，2000，32：337-346.
24. Wortinger MA，F(xiàn)oley JW，Larocque P，et al.Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue.Immunology，2003，110：225-233.
25. Wang R，Zagariya A，Ang E，et al.Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction.Am J Physiol，1999，277：L1245-L1250.
26. Hagimoto N，Kuwano K，Inoshima I，et al.TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.J Immunol，2002，168：6470-6478.
27. Vazquez de Lara L，Becerril C，Montano M，et al.Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression.Am J Physiol Lung Cell Mol Physiol，2000，279：L950-L957.
28. White MK，Baireddy V，Strayer DS.Natural protection from apoptosis by surfactant protein A in type II pneumocytes.Exp Cell Res，2001，263：183-192.
29. Scaffidi C，Schmitz I，Krammer PH，et al.The role of c-FLIP in modulation of CD95-induced apoptosis.J Biol Chem，1999，274：1541-1548.
30. Puneet P，Moochhala S，Bhatia M.Chemokines in acute respiratory distress syndrome Am J Physiol Lung Cell Mol Physiol，2005，288：L3-L15.
31. Chen JJ，Sun Y，Nabel GJ.Regulation of the proinflammatory effects of Fas ligand (CD95L).Science，1998，282：1714-1717.
32. Faouzi S，Burckhardt BE，Hanson JC，et al.Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent，caspase-3-dependent pathway.J Biol Chem，2001，276：49077-49082.
33. Yamaoka-Tojo M，Yamaguchi S，Nitobe J，et al.Dual response to Fas ligation in human endothelial cells：apoptosis and induction of chemokines，interleukin-8 and monocyte chemoattractant protein-1.Coron Artery Dis，2003，14：89-94.
  1. 1. Ware LB，Matthay MA.The acute respiratory distress syndrome.N Engl J Med，2000，342：1334-1349.
  2. 2. Matute-Bello G，Winn RK，Jonas M，et al.Fas (CD95) induces alveolar epithelial cell apoptosis in vivo：implications for acute pulmonary inflammation.Am J Pathol，2001，158：153-161.
  3. 3. Kitamura Y，Hashimoto S，Mizuta N，et al.Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice.Am J Respir Crit Care Med，2001，163：762-769.
  4. 4. Perl M，Chung CS，Ayala A.Apoptosis.Crit Care Med，2005，33：S526-S529.
  5. 5. French LE，Tschopp J.Protein-based therapeutic approaches targeting death receptors.Cell Death Differ，2003，10：117-123.
  6. 6. Wajant H.Death receptors.Essays Biochem，2003，39：53-71.
  7. 7. Suda T，Takahashi T，Golstein P，et al.Molecular cloning and expression of the Fas ligand，a novel member of the tumor necrosis factor family.Cell，1993，75：1169-1178.
  8. 8. Itoh N，Yonehara S，Ishii A，et al.The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis，Cell，1991，66：233-243.
  9. 9. Peter ME，Krammer PH.The CD95 (APO-1/Fas) DISC and beyond.Cell Death Differ，2003，10：26-35.
  10. 10. Scaffidi C，F(xiàn)ulda S，Srinivasan A，et al.Two CD95 (APO-1/Fas) signaling pathways.EMBO J，1998，17：1675-1687.
  11. 11. Korsmeyer SJ，Wei MC，Saito M，et al.Pro-apoptotic cascade activates BID，which oligomerizes BAK or BAX into pores that result in the release of cytochrome c.Cell Death Differ，2000，7：1166-1173.
  12. 12. Jimenez MF，Watson RW，Parodo J，et al.Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.Arch Surg，1997，132：1263-1269.
  13. 13. Matute-Bello G，Liles WC，Radella F 2nd，et al.Neutrophil apoptosis in the acute respiratory distress syndrome.Am J Respir Crit Care Med，1997，156：1969-1977.
  14. 14. Kotecha S，Mildner RJ，Prince LR，et al.The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants.Thorax，2003，58：961-967.
  15. 15. Nwakoby JE，Reddy K，Patel P，et al.Fas-mediated apoptosis of neutrophils in sera of patients with infection.Infect Immunol，2001，69：3343-3349.
  16. 16. Dunican AL，Lenemoth SJ，Grutkoski P，et al.TNF alpha-induced suppression of PMN apoptosis is mediated through interleukin-8 production.Shock，2000，14：284-88.
  17. 17. Park WY，Goodman RB，Steinberg KP，et al.Cytokine balance in the lungs of patients with acute respiratory distress syndrome.Am J Respir Crit Care Med，2001，164：1896-1903.
  18. 18. Hu M，Lin X，Du Q，et al.Regulation of polymorphonuclear leukocyte apoptosis：role of lung endothelium-epithelium bilayer transmigration.Am J Physiol Lung Cell Mol Physiol，2005，288：L266-L274.
  19. 19. Nakamura M，Matute-Bello G，Liles WC，et al.Differential response of human lung epithelial cells to Fas-induced apoptosis.Am J Pathol，2004，164：1949-1958.
  20. 20. Albertine KH，Soulier MF，Wang Z，et al.Fas and Fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome.Am J Pathol，2002，161：1783-1796.
  21. 21. Matute-Bello G，Liles WC，F(xiàn)revert CW，et al.Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits.Am J Physiol Lung Cell Mol Physiol，2001，281：L328-L335.
  22. 22. Neff TA，Guo RF，Neff SB，et al.Relationship of acute lung inflammatory injury to Fas/FasL system.Am J Pathol，2005，166：685-694.
  23. 23. Kinoshita M，Ono S，Mochizuki H.Neutrophils mediate acute lung injury in rabbits：role of neutrophil elastase.Eur Surg Res，2000，32：337-346.
  24. 24. Wortinger MA，F(xiàn)oley JW，Larocque P，et al.Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue.Immunology，2003，110：225-233.
  25. 25. Wang R，Zagariya A，Ang E，et al.Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction.Am J Physiol，1999，277：L1245-L1250.
  26. 26. Hagimoto N，Kuwano K，Inoshima I，et al.TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.J Immunol，2002，168：6470-6478.
  27. 27. Vazquez de Lara L，Becerril C，Montano M，et al.Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression.Am J Physiol Lung Cell Mol Physiol，2000，279：L950-L957.
  28. 28. White MK，Baireddy V，Strayer DS.Natural protection from apoptosis by surfactant protein A in type II pneumocytes.Exp Cell Res，2001，263：183-192.
  29. 29. Scaffidi C，Schmitz I，Krammer PH，et al.The role of c-FLIP in modulation of CD95-induced apoptosis.J Biol Chem，1999，274：1541-1548.
  30. 30. Puneet P，Moochhala S，Bhatia M.Chemokines in acute respiratory distress syndrome Am J Physiol Lung Cell Mol Physiol，2005，288：L3-L15.
  31. 31. Chen JJ，Sun Y，Nabel GJ.Regulation of the proinflammatory effects of Fas ligand (CD95L).Science，1998，282：1714-1717.
  32. 32. Faouzi S，Burckhardt BE，Hanson JC，et al.Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent，caspase-3-dependent pathway.J Biol Chem，2001，276：49077-49082.
  33. 33. Yamaoka-Tojo M，Yamaguchi S，Nitobe J，et al.Dual response to Fas ligation in human endothelial cells：apoptosis and induction of chemokines，interleukin-8 and monocyte chemoattractant protein-1.Coron Artery Dis，2003，14：89-94.