Apoptosis in sepsis: Mechanisms, clinical impact and potential therapeutic targets

Current Pharmaceutical Design

Volumn 14, Issue 19, 2008, Pages 1853-1859

  Ayala, Alfred ^a   Perl, Mario ^a   Venet, Fabienne ^a   Lomas Neira, Joanne ^a   Swan, Ryan ^a   Chung, Chun Shiang ^a  

^a BROWN UNIVERSITY   (United States)

Author keywords

Death receptor pathway; Human; Immune and organ dysfunction; Mice; Mitochondrial pathway; Sepsis

Indexed keywords

3 [2 [(2 TERT BUTYLPHENYLAMINOOXALYL)AMINO]PROPIONYLAMINO] 4 OXO 5 (2,3,5,6 TETRAFLUOROPHENOXY)PENTANOIC ACID; ADRENOMEDULLIN; ADRENOMEDULLIN BINDING PROTEIN 1; BINDING PROTEIN; CASPASE; CASPASE INHIBITOR; DEATH RECEPTOR; DROTRECOGIN; FAS ASSOCIATED DEATH DOMAIN PROTEIN; MITOCHONDRIAL PROTEIN; PROTEIN BCL 2; PROTEIN KINASE B; PROTEINASE; PROTEINASE INHIBITOR; SMALL INTERFERING RNA;

APOPTOSIS; BIOCHEMISTRY; CELL DEATH; CELL SPECIFICITY; CLINICAL TRIAL; CRITICALLY ILL PATIENT; GENE THERAPY; HEPATITIS C; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE RESPONSE; LIVER INJURY; MULTIPLE ORGAN FAILURE; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; SEPSIS; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; CRITICAL ILLNESS; DRUG DELIVERY SYSTEMS; HUMANS; MULTIPLE ORGAN FAILURE; NECROSIS; RODENTIA; SEPSIS; SIGNAL TRANSDUCTION;

EID: 48249107889     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161208784980617     Document Type: Review

References (103)

1. Angus DC, Wax RS. Epidemiology of sepsis: An update. Crit Care Med 2001, 29: S109-16.
2. Rice TW, Bernard GR. Therapeutic interventions and tarpts for sepsis. Ann Rev Med 2005; 56:225-48.
3. Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC. Novel therapies for sepsis: A review. J Trauma 2005; 58: 867-74.
4. Bernard GR, Vincent JL, Laterre PP, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl J Med 2001; 344: 699-709.
5. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.
6. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive Insulin Therapy in Critically Ill Patients. N. Engl J Med 2001; 345: 1359-67.
7. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, et al. Apoptotic cell death in patients with sepsis, shock and multiple organ dysfunction. Crit Care Med 1999; 27: 1230-51.
8. Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J Leukocyte Biol 2005; 25: 325-37.
9. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-57.
10. Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu. Rev Immunol 1992; 10: 267-93.
11. Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, et al. The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 1997; 15: 1573-81.
12. Leist M, Jaattela M. Four deaths and a funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2001; 2: 589-98.
13. Liles WC. Apoptosis-role in infection and inflammation. Curr Opin Infect Dis 1997; 10: 165-70.
14. Barinaga M. Is apoptosis key in alzhimer's disease? Science 1998; 281:1303-4.
15. Barr PJ, Tomei LD. Apoptosis and its role in human disease. Biotechnology (NY) 1994; 12: 487-93.
16. Hotchkiss RS, Tinsley KW, Karl IE. Role of apoptotic cell death in sepsis. Scand J Infect Dis 2003; 35: 585-92.
17. Borner C. The Bcl-2 protein family sensors and checkpoints for life-or-death decisions. Mol Immunol 2003; 39: 615-47.
18. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bc12 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 2007; 94: 481-90.
19. Acehan D, Jiang Y, Morgan DG, Hauser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002; 9: 423-32.
20. Susin SA, Zamzami N, Casado M, Hirsch T, Marchetti P, Macho A, et al. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 1996; 184: 1331-41.
21. Li LY, Luo Y, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001; 412: 95-9.
22. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102: 43-53.
23. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17: 1675-87.
24. Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999; 400: 886-91.
25. Guicciardi ME, Bronk SF, Werneburg NW, Yin XM, Gores GJ. Bid is upstream of lysosome-mediated caspase 2 activation in tumor necrosis factor alpha-induced hepatocyte apoptosis. Gastroenterology 2005; 129: 269-84.
26. Nakagawa T, Zhu H, Morishima N, Li E, Yanker BA, Yuan J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403: 99-103.
27. Lamkanfi M, Declercq W, Kalai M, Saelens X, Vandenabeele P. Alice in caspase land. A phylogenetic analysis of caspases from worm to man. Cell Death Differ 2002; 9: 358-61.
28. Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Droin N, et al. Ebhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 2006; 440: 1064-1068.
29. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans Cell Death Gene ced-3 Encodes a protein Similar to Mammalian Interleukin-1b-Coverting Enzyme. Cell 1993; 75: 641-52.
30. Hengartner MO, Horvitz HR C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 1994; 76: 665-76.
31. Thompson CB. Apoptosis. In Fundamental Immunology (Paul, W.E: Ed) 1999; pp. 813-29. Lippincott-Raven, Philadelphia.
32. Kumar S. ICE-like proteases in apoptosis. Trends Biochem Sci 1995; 20: 198-202.
33. Miura M, Zhu H, Rotello R, Hartwieg EA, Junying Y. Induction of apoptosis in fibroblasts by IL-1b -converting enzyme, a mammalian homolog of the C. elegans cell death gene ced3. Cell 1993; 75: 653-60
34. Creagh EM, Martin SJ. Caspases: Cellular demolition experts. Biochem. Soc. Trans 2001; 29: 696-702.
35. Zhu C, Qiu L, Wang Y, Hallin U, Cande C, Kroemer G, et al. Involvement of apoptosis-inducing in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 2003; 86: 306-17.
36. Hisatomi T, Sakamoto T, Murata T, Yamanaka I, Oshima Y, Hata Y, et al. Relocalization of apoptosis-inducing factor in photoreceptor apoptosis induced by retinal detachment in vivo. Am J Pathol 2001; 158: 1271-8.
37. Xu Y, Kim SO, Li Y, Han J. Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem 2006; 281: 19179-87.
38. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489-95.
39. Ayala A, Evans TA, Chaudry IH. Does hepatocellular injury in sepsis involve apoptosis? J Surg Res 1998; 76: 165-73.
40. Szabo C. Poly (ADP-ribose) polymerase actvation and circulatory shock. In Sepsis: New. Insights, New Therapies. (ChadwickE D.J. Goode, J: eds) 2007; pp. 92-107. John Wiley SOns, Ltd: Chichester, UK.
41. Cobb JP, Hotchkiss RS, Karl IE, Buchman TG. Mechanisms of cell injury and death. Hr J Anesth 1996; 77: 3-10.
42. Piantadosi CA, Carraway MS, Haden DW, Suliman HB. Protecting the permeability pore and mitochondrial biogensis. In Sepsis: New Insights, New Therapies. (Chadwick, D.J. Goode, J: Eds) 2007; pp. 266-80. John WIley Sons, Ltd: Chichester, UK.
43. Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 2003; 125: 1246-57.
44. Kim JS, He L, Qian T, Lemasters JJ. Role of the mitochondrial permeability transition in apoptotic and necrotic death after ischemia/ reperfusion injury to hepatocytes. Curr Mol Med 2003; 3: 527-35.
45. Vercammen D, Brouckaert G, Denecker G, Van de Craen M, Declereq W, Fiers W, et al. Dual signalling of Fas receptor: Initiation of both apoptotic and necrotic cell death pathways. J Exp Med 1998; 188: 919-30.
46. Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem 2003; 278: 51613-51621.
47. Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis a well-orchestrated form of cell demise: Signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757: 1371-87.
48. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochoindrial apoptosis-inducing factor. Nature 1999; 397: 441-6.
49. Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med 2005; 11: 725-30.
50. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, et al. Monocyte deactivation in septic patients: Restoration by IFN-gamma treatment. Nat Med 1997; 3: 678-81.
51. Ayala A, Herdon CD, Lehman DL, Ayala CA, Chaudry IH. Differential induction of apoptosis in lymphoid tissues during sepsis: Variation in onset, frequency, and the nature of the mediators. Blood 1996; 87: 4261-75.
52. Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL. Apoptosis in sepsis: A new target for therapeutic exploration. FASEB J 2001; 15: 879-92.
53. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006; 6: 813-22.
54. Hotchkiss RS, Swanson PE, Knudson CM, Chang KC, Cobb JP, Osborne DF, et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 1999; 162: 4148-56.
55. Chung CS, Watkins L, Funches A, Lomas-Neira JL, Cioffi WG, Ayala A. Deficiency of gamma-delta T-lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol 2006; 291: 5-1338.
56. Ayala A, Herdon CD, Lehman DL, DeMaso CM, Ayala CA, Chaudry IH. The induction of accelerated thymic programmed cell death dunng polymcrobial sepsis: Control by corticosteroids but not tumor necrosis factor. Shock 1995; 3: 259-67.
57. Guo RF, Huber-Lang M, Wang Y, Sarma V, Padgaonkar VA, Craig RA, et al. Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis. J Clin Invest 2000; 106: 1271-80.
58. Ayala A, Lomas JL, Grutkoski PS, Chung CS. Pathological aspects of apoptosis in severe sepsis and shock? Int J Biochem Cell Biol 2003; 35: 7-15.
59. Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG, Karl IE. Apoptosis in lymphoid and parenchymal cells during sepsis: Findings in normal and T and B cell deficient mice. Crit Care Med 1997; 25: 1298-307.
60. Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochodrial pathway. J Immunol 2005; 174: 5110-8.
61. Williams MA, Withington S, Newland AC, Kelsey SM. Monocyte anergy in septic shock is associated with a prediliction to apoptosis and is reversed by granulocyte-macrophage colony stimulating factor ex vivo. J Infect Dis 1998; 178: 1421-33.
62. Iwata A, Stevenson VM, Minard A, Tasch M, Tupper J, Lagasse E, el al. Over-expression of Bcl-2 provides protection in septic mice by a trans effect. J Immunol 2003; 171: 3136-41.
63. Swan R, Albina JE, Cioffi WG, Perl M. Ayala A. Polymicrobial sepsis enhances apoptotic immune cell clearance by splenic macrophages. Surgery 2007; 142: 253-61.
64. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002; 168: 2493-500.
65. Ding Y, Chung CS, Newton S, Chen Y, Carlton S, Albina JE, et al. Polymicrobial sepsis induces divergent effects on splenic and peritoneal dendritic cell function in mice. Shock 2004; 22: 137-44.
66. Huang X, Venet F, Lomas-Neira JL, Chung CS, Ayala A. Changes in Dendritic Cell Function in the Immune ResponsetoSepsis. Expert Opin Biol Ther 2007; 7: 929-38.
67. Scumpia PO, McAuliffe PF, O'Malley KA, Ungaro R, Uchida T, Matsumoto T, et al. CD11c+ dendritic cells are required for survival in murine polymicrobial sepsis. J Immunol 2005; 175: 3282-6.
68. Coopersmith CM, Stromberg PE, Dunne WM, Davis CG, Amiot IDM, Buchman TG, et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002; 287: 1716-21.
69. Perl M, Chung CS, Lomas-Neira J, Rachel TM, Biffl WL, Cioffi WG, et al. Silencing of Fas- but not caspase-8 in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis. Am. J Pathol 2005; 167: 1545-59
70. Perl M, Chung CS, Perl U, Lomas-Neira JL, De Paepe ME, Cioffi WG, et al. Fas induced pulmonary apoptosis and inflammation during extrapulmonary acute lung injury. Am J Respir Crit Care Med 2007; 176: 591-601.
71. Kim YM, Kim TH, Chung HT, Talanian RV, Yin XM, Billiar TR. Nitric oxide prevents tumor necrosis factor a-induced rat hepatocyte apoptosis by the interruption of mitoctiondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 2000; 32: 770-8.
72. Mutunga M, Fulton B, Bullock R, Batchelor A, Gascoigne A, Gillespie JI, et al. Circulating endothelial cells in patients with septic shock. Am J Respis Crit Care Med 2001; 163: 195-200.
73. Zhou M, Simms HH, Wang P. Adrenomedullin and adrenomedullin binding protein - 1 attenuate vascular endothelial cell apoptosis in sepsis. Ann Surg 2004; 240: 321-30.
74. Fadok V, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101: 890-8.
75. Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: Recognition, uptake and consequences. J Clin Invest 2001; 108: 957-62.
76. Rana MW, Ayala A, Dean RE, Chaudry IH. Decreased Fc receptor expression on macrophages following simple hemorrhage as observed by scanning immuno electron microscopy. J Leukocyte Biol 1990; 48: 512-8.
77. Huber-Lang MS, Riedemann NC, Sarma JV, Younkin EM, McGuire SR, Laudes IJ, et al. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J 2002; 16: 1567-74.
78. Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002; 109: 661-70.
79. Miksa M, Wu R, Dong W, Das P, Yang D, Wang P. Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. Shock 2006; 25: 586-93
80. Hotchkiss RS, Swanson PE, Knudson CM, Chang KC, Cobb JP, Osborne DF, et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 1999; 162: 4148-56.
81. Coopersmith CM, Chang KC, Swanson PE, Tinsley KW, Stromberg PE, Buchman TG, et al. Overexpression of Bcl-2 in the intestinal epithelium improves survival in septic mice. Crit Care Med 2002; 30: 195-201.
82. Chang KC, Unsinger J, Davis CG, Schwulst SJ, Muenzer JT, Strasser A, et al. Multiple triggers of cell death in sepsis: Death receptor and mitochondrial-mediated apoptosis. FASEB J 2007; 21: 708-19.
83. Hotchkiss RS, Tinsley KW, Swanson PE, Chang KC, Cobb JP, Buchman TG, et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA 1999; 96: 14541-6.
84. Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, et al. Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte. Nat Immun 2001; 1: 496-501.
85. Hotchkiss RS, McConnell KW, Bullock K, Davis CG, Chang KC, Schwulst SJ, et al. TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo. J Immunol 2006; 179: 5471-7
86. McConnell KW, Muenzer JT, Chang KC, Davis CG, McDunn JE, Coopersmith CM, et al. Anti-apoptotic peptides protect against radiation-induced cell death. Biochem. Biophys. Res Commun 2007; 355: 501-7.
87. Chung CS, Chaudry IH, Ayala A. (2000) The apoptotic response of the lymphoid immune system to trauma, shock and sepsis. In Year-book of Intensive CareEand Emergency Medicine: 2000. (Vincent, JL: ed), pp. 27-40. Spinger-Verlag, Berlin.
88. Chung CS, Song GY, Lomas J, Simms HH, Chaudry IH, Ayala A. Inhibition of Fas/Fas ligand signaling improves septic survival: Differential effects on macrophage apoptotic and functional capacity. J Leukoc Biol 2003; 74: 344-51.
89. Wesche DE, Chung CS, Lomas-Neira J, Doughty LA, Gregory SH, Ayala A. In vivo delivery of caspase 8 or Fas siRNA improves the survival of septic mice. Blood 2005; 106: 2295-301.
90. Weaver JGR, Rouse MR, Steckelburg JM, Badley AM. Improved survival in experimental sepsis with an orally administered mhibitor of apoptosis. FASEB J 2004; 18: 1185-91.
91. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905-27.
92. Bommhardt U, Chang KC, Swanson PE, Wagner TH, Tinsley KW, Karl IE, et al. Akt decreases lymphocyte apoptosis and improves survival in sepsis. J Immunol 2004; 172: 7583-91.
93. Yang S, Zhou M, Chaudry IH, Wang P. Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis; role of adrenomedulli and adrenomedullin binding protein-1. Ann Surg 2002; 236: 625-33.
94. Joyce DE, Nelson DR, Grinnell BW. Leukocyte and endothelial cell interactions in sepsis: Relevance of the protein C pathway. Crit Care Med 2004; 32: S280-6.
95. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression and profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-203.
96. Pockros PJ, Schiff ER, Shiffman ML, Mchutchison JG, Gish RG, Afdhal NH, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007; 46: 324-9.
97. Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am J Transplant 2007; 7: 218-25.
98. Barik S, Bitko V. Prospects of RNA interference therapy in respiratory viral diseases: Update 2006. Expert Opin Biol Ther 2006; 6: 1151-60
99. Chung CS, Yang SL, Song GY, Lomas J, Wang P, Simms HH, et al. Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis. Surgery 2001; 130: 339-45.
100. Wesche-Soldato DE, Chung CS, Lomas-Neira JL, Doughty LA, Gregory SH, Ayala A. In vivo delivery of caspase 8 or Fas siRNA improves the survival of septic mice. Blood 2005; 106: 2295-301.
101. dos Santos NM, do Vale A, Reis MI, Silva MT, Fish and apoptosis: molecules and pathways. Curr Pharm Des 2008; 14(2): 148-69.
102. Giovannetti A, Pierdominici M, Di Iorio A, Cianci R, Murdaca G, Puppo F, et al. Apoptosis in the homeostasis of the immune system and in human immune mediated diseases. Curr Pharm Des 2008; 14(3): 253-68.
103. Vannini N, Pfeffer U, Lorusso G, Noonan DM, Albini A. Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model. Curr Pharm Des 2008; 14(3): 221-5.