, Volume 13, Issue 4, pp 463–482 | Cite as

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

  • Manuel T. SilvaEmail author
  • Ana do Vale
  • Nuno M. N. dos Santos
Original Paper


In metazoans apoptosis is a major physiological process of cell elimination during development and in tissue homeostasis and can be involved in pathological situations. In vitro, apoptosis proceeds through an execution phase during which cell dismantling is initiated, with or without fragmentation into apoptotic bodies, but with maintenance of a near-to-intact cytoplasmic membrane, followed by a transition to a necrotic cell elimination traditionally called “secondary necrosis”. Secondary necrosis involves activation of self-hydrolytic enzymes, and swelling of the cell or of the apoptotic bodies, generalized and irreparable damage to the cytoplasmic membrane, and culminates with cell disruption. In vivo, under normal conditions, the elimination of apoptosing cells or apoptotic bodies is by removal through engulfment by scavengers prompted by the exposure of engulfment signals during the execution phase of apoptosis; if this removal fails progression to secondary necrosis ensues as in the in vitro situation. In vivo secondary necrosis occurs when massive apoptosis overwhelms the available scavenging capacity, or when the scavenger mechanism is directly impaired, and may result in leakage of the cell contents with induction of tissue injury and inflammatory and autoimmune responses. Several disorders where secondary necrosis has been implicated as a pathogenic mechanism will be reviewed.


Apoptotic secondary necrosis Apoptosis Necrosis Clearance Autoimmunity Infection 



We are grateful to Drs. Andrew H. Wyllie, Richard A. Lockshin, Luisa Minghetti, Ágnes Enyedi, David S. Pisetsky, Yasunobu Okada and in particular L. Felipe Barros for helpful discussions, to Drs. Frank Madeo, Paula Ludovico and Manuela Côrte-Real for helpful discussions and for reviewing the text and to Anabela Costa for editorial assistance. This work was supported by FCT project POCI/MAR/56111/2004 funded by POCI 2010 and co-funded by FEDER, and grant SFRH/BPD/26816/2006.


  1. 1.
    Lockshin RA, Williams CM (1965) Programmed cell death. I. Cytology of degeneration in the intersegmental muscles of the Pernyi Silkmoth. J Insect Physiol 11:123–133PubMedCrossRefGoogle Scholar
  2. 2.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  3. 3.
    Kerr JF, Searle J (1973) Deletion of cells by apoptosis during castration-induced involution of the rat prostate. Virchows Arch 13:87–102Google Scholar
  4. 4.
    Searle J, Lawson TA, Abbott PJ, Harmon B, Kerr JFR (1975) An electron-microscopic study of the mode of cell death induced by cancer-chemotherapeutic agents in populations of proliferating and neoplastic cells. J Pathol 116:129–138PubMedCrossRefGoogle Scholar
  5. 5.
    Don MM, Ablett G, Bishop CJ et al (1977) Death of cells by apoptosis following attachment of specifically allergized lymphocytes in vitro. Aust J Exp Biol Med Sci 55:407–417PubMedCrossRefGoogle Scholar
  6. 6.
    Robertson AM, Bird CC, Waddell AW, Currie AR (1978) Morphological aspects of glucocorticoid-induced cell death in human lymphoblastoid cells. J Pathol 126:181–187PubMedCrossRefGoogle Scholar
  7. 7.
    Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306PubMedGoogle Scholar
  8. 8.
    Silva RD, Sotoca R, Johansson B et al (2005) Hyperosmotic stress induces metacaspase- and mitochondria-dependent apoptosis in Saccharomyces cerevisiae. Mol Microbiol 58:824–834PubMedCrossRefGoogle Scholar
  9. 9.
    Ludovico P, Madeo F, Silva M (2005) Yeast programmed cell death: an intricate puzzle. IUBMB Life 57:129–135PubMedGoogle Scholar
  10. 10.
    Bursch W (2001) The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 8:569–581PubMedCrossRefGoogle Scholar
  11. 11.
    Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 1757:1371–1387PubMedCrossRefGoogle Scholar
  12. 12.
    Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598PubMedCrossRefGoogle Scholar
  13. 13.
    Kroemer G, El-Deiry WS, Golstein P et al (2005) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12(Suppl):1463–1467PubMedCrossRefGoogle Scholar
  14. 14.
    Galluzzi L, Maiuri MC, Vitale I et al (2007) Cell death modalities: classification and pathophysiological implications. Cell Death Differ 14:1237–1243PubMedCrossRefGoogle Scholar
  15. 15.
    Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245PubMedGoogle Scholar
  16. 16.
    Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283:1–16PubMedCrossRefGoogle Scholar
  17. 17.
    Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15PubMedCrossRefGoogle Scholar
  18. 18.
    Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32:37–43PubMedCrossRefGoogle Scholar
  19. 19.
    Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825–2837PubMedCrossRefGoogle Scholar
  20. 20.
    Fink SL, Cookson BT (2007) Pyroptosis and host cell death responses during Salmonella infection. Cell Microbiol 9:2562–2570PubMedCrossRefGoogle Scholar
  21. 21.
    Lemasters JJV (1999) Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am J Physiol 276:G1–G6PubMedGoogle Scholar
  22. 22.
    Degterev A, Huang Z, Boyce M et al (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119PubMedCrossRefGoogle Scholar
  23. 23.
    Henson PM, Hume DA (2006) Apoptotic cell removal in development and tissue homeostasis. Trends Immunol 27:244–250PubMedCrossRefGoogle Scholar
  24. 24.
    Domingos PM, Steller H (2007) Pathways regulating apoptosis during patterning and development. Curr Opin Genet Devel 17:294–299CrossRefGoogle Scholar
  25. 25.
    Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B (1995) The biochemistry of programmed cell death. FASEB J 9:1277–1287PubMedGoogle Scholar
  26. 26.
    Payne CM, Glasser L, Tischler ME et al (1994) Programmed cell death of the normal human neutrophil: an in vitro model of senescence. Microsc Res Tech 28:327–344PubMedCrossRefGoogle Scholar
  27. 27.
    Hebert MJ, Takano T, Holthofer H, Brady HR (1996) Sequential morphologic events during apoptosis of human neutrophils. Modulation by lipoxygenase-derived eicosanoids. J Immunol 157:3105–3115PubMedGoogle Scholar
  28. 28.
    Hacker G (2000) The morphology of apoptosis. Cell Tissue Res 301:5–17PubMedCrossRefGoogle Scholar
  29. 29.
    Skulachev VP, Bakeeva LE, Chernyak BV et al (2004) Thread-grain transition of mitochondrial reticulum as a step of mitoptosis and apoptosis. Mol Cell Biochem 256–257:341–358PubMedCrossRefGoogle Scholar
  30. 30.
    do Vale A, Silva MT, dos Santos NM et al (2005) AIP56, a novel plasmid-encoded virulence factor of Photobacterium damselae subsp. piscicida with apoptogenic activity against sea bass macrophages and neutrophils. Mol Microbiol 58:1025–1038PubMedCrossRefGoogle Scholar
  31. 31.
    do Vale A, Costa-Ramos C, Silva A et al (2007) Systemic macrophage and neutrophil destruction by secondary necrosis induced by a bacterial exotoxin in a Gram-negative septicaemia. Cell Microbiol 9:988–1003PubMedCrossRefGoogle Scholar
  32. 32.
    do Vale A, Marques F, Silva MT (2003) Apoptosis of sea bass (Dicentrarchus labrax L.) neutrophils and macrophages induced by experimental infection with Photobacterium damselae subsp. piscicida. Fish Shellfish Immunol 15:129–144PubMedCrossRefGoogle Scholar
  33. 33.
    Darzynkiewicz Z, Bruno S, Del Bino G et al (1992) Features of apoptotic cells measured by flow cytometry. Cytometry 13:795–808PubMedCrossRefGoogle Scholar
  34. 34.
    Zamai L, Canonico B, Luchetti F et al (2001) Supravital exposure to propidium iodide identifies apoptosis on adherent cells. Cytometry 44:57–64PubMedCrossRefGoogle Scholar
  35. 35.
    Raff MC (1992) Social controls on cell survival and cell death. Nature 356:397–400PubMedCrossRefGoogle Scholar
  36. 36.
    Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776PubMedCrossRefGoogle Scholar
  37. 37.
    Skulachev VP (2006) Bioenergetic aspects of apoptosis, necrosis, mitoptosis. Apoptosis 11:473–485PubMedCrossRefGoogle Scholar
  38. 38.
    Hail N Jr, Carter BZ, Konopleva M, Andreeff M (2006) Apoptosis effector mechanisms: a requiem performed in different keys. Apoptosis 11:889–904PubMedCrossRefGoogle Scholar
  39. 39.
    Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752PubMedCrossRefGoogle Scholar
  40. 40.
    Atlante A, Giannattasio S, Bobba A et al (2005) An increase in the ATP levels occurs in cerebellar granule cells en route to apoptosis in which ATP derives from both oxidative phosphorylation and anaerobic glycolysis. Biochim Biophys Acta 1708:50–62PubMedCrossRefGoogle Scholar
  41. 41.
    Zamaraeva MV, Sabirov RZ, Manabe K, Okada Y (2007) Ca(2+)-dependent glycolysis activation mediates apoptotic ATP elevation in HeLa cells. Biochem Biophys Res Commun 363:687–693PubMedCrossRefGoogle Scholar
  42. 42.
    Nicotera P, Melino G (2004) Regulation of the apoptosis–necrosis switch. Oncogene 23:2757–2765PubMedCrossRefGoogle Scholar
  43. 43.
    Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146:3–15PubMedGoogle Scholar
  44. 44.
    Sladek Z, Rysanek D (2005) Tissue pool neutrophils of the bovine mammary gland: ultrastructural features during in vitro senescence. Anat Histol Embryol 34:159–166PubMedCrossRefGoogle Scholar
  45. 45.
    Orlando KA, Stone NL, Pittman RN (2006) Rho kinase regulates fragmentation and phagocytosis of apoptotic cells. Exp Cell Res 312:5–15PubMedCrossRefGoogle Scholar
  46. 46.
    Sheehan JM, Young AR (2002) The sunburn cell revisited: an update on mechanistic aspects. Photochem Photobiol Sci 1:365–377PubMedCrossRefGoogle Scholar
  47. 47.
    Sheridan JW, Bishop CJ, Simmons RJ (1981) Biophysical and morphological correlates of kinetic change and death in a starved human melanoma cell line. J Cell Sci 49:119–137PubMedGoogle Scholar
  48. 48.
    Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407:784–788PubMedCrossRefGoogle Scholar
  49. 49.
    Fadok VA (1999) Clearance: the last and often forgotten stage of apoptosis. J Mammary Gland Biol Neoplasia 4:203–211PubMedCrossRefGoogle Scholar
  50. 50.
    Rabinovitch M (1995) Professional and non-professional phagocytes: an introduction. Trends Cell Biol 5:85–87PubMedCrossRefGoogle Scholar
  51. 51.
    Parnaik R, Raff MC, Scholes J (2000) Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Curr Biol 10:857–860PubMedCrossRefGoogle Scholar
  52. 52.
    Gregory CD, Devitt A (2004) The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? Immunology 113:1–14PubMedCrossRefGoogle Scholar
  53. 53.
    van Furth R (1981) Current view of the mononuclear phagocyte system. Haematol Blood Transfus 27:3–10PubMedGoogle Scholar
  54. 54.
    Rydell-Tormanen K, Uller L, Erjefalt JS (2006) Neutrophil cannibalism–a back up when the macrophage clearance system is insufficient. Respir Res 7:143PubMedCrossRefGoogle Scholar
  55. 55.
    Wiegand UK, Corbach S, Prescott AR, Savill J, Spruce BA (2001) The trigger to cell death determines the efficiency with which dying cells are cleared by neighbours. Cell Death Differ 8:734–746PubMedCrossRefGoogle Scholar
  56. 56.
    Mangahas PM, Zhou Z (2005) Clearance of apoptotic cells in Caenorhabditis elegans. Semin Cell Dev Biol 16:295–306PubMedCrossRefGoogle Scholar
  57. 57.
    Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86–89PubMedCrossRefGoogle Scholar
  58. 58.
    Rovere P, Sabbadini MG, Fazzini F et al (2000) Remnants of suicidal cells fostering systemic autoaggression. Apoptosis in the origin and maintenance of autoimmunity. Arthritis Rheum 43:1663–1672PubMedCrossRefGoogle Scholar
  59. 59.
    Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N (2000) Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 191:423–434PubMedCrossRefGoogle Scholar
  60. 60.
    Rovere P, Vallinoto C, Bondanza A et al (1998) Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol 161:4467–4471PubMedGoogle Scholar
  61. 61.
    Taylor PR, Carugati A, Fadok VA et al (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359–366PubMedCrossRefGoogle Scholar
  62. 62.
    Ip WK, Lau YL (2004) Distinct maturation of, but not migration between, human monocyte-derived dendritic cells upon ingestion of apoptotic cells of early or late phases. J Immunol 173:189–196PubMedGoogle Scholar
  63. 63.
    Albert ML (2004) Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev 4:223–231CrossRefGoogle Scholar
  64. 64.
    Franc NC (2002) Phagocytosis of apoptotic cells in mammals, Caenorhabditis elegans and Drosophila melanogaster: molecular mechanisms and physiological consequences. Front Biosci 7:d1298–d1313PubMedCrossRefGoogle Scholar
  65. 65.
    Lauber K, Bohn E, Krober SM et al (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–730PubMedCrossRefGoogle Scholar
  66. 66.
    Mueller RB, Sheriff A, Gaipl US, Wesselborg S, Lauber K (2007) Attraction of phagocytes by apoptotic cells is mediated by lysophosphatidylcholine. Autoimmunity 40:342–344PubMedCrossRefGoogle Scholar
  67. 67.
    Lauber K, Blumenthal SG, Waibel M, Wesselborg S (2004) Clearance of apoptotic cells: getting rid of the corpses. Mol Cell 14:277–287PubMedCrossRefGoogle Scholar
  68. 68.
    Krysko DV, D’Herde K, Vandenabeele P (2006) Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11:1709–1726PubMedCrossRefGoogle Scholar
  69. 69.
    Erwig LP, Henson PM (2008) Clearance of apoptotic cells by phagocytes. Cell Death Differ 15:243–250PubMedCrossRefGoogle Scholar
  70. 70.
    Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev 7:964–974Google Scholar
  71. 71.
    Aliprantis AO, Diez-Roux G, Mulder LC, Zychlinsky A, Lang RA (1996) Do macrophages kill through apoptosis? Immunol Today 17:573–576PubMedCrossRefGoogle Scholar
  72. 72.
    Diez-Roux G, Lang RA (1997) Macrophages induce apoptosis in normal cells in vivo. Development (Cambridge, England) 124:3633–3638Google Scholar
  73. 73.
    Durrieu F, Belloc F, Lacoste L et al (1998) Caspase activation is an early event in anthracycline-induced apoptosis and allows detection of apoptotic cells before they are ingested by phagocytes. Exp Cell Res 240:165–175PubMedCrossRefGoogle Scholar
  74. 74.
    McIlroy D, Tanaka M, Sakahira H et al (2000) An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev 14:549–558PubMedGoogle Scholar
  75. 75.
    Kurosaka K, Takahashi M, Watanabe N, Kobayashi Y (2003) Silent cleanup of very early apoptotic cells by macrophages. J Immunol 171:4672–4679PubMedGoogle Scholar
  76. 76.
    Haslett C (1999) Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med 160:S5–S11PubMedGoogle Scholar
  77. 77.
    Brouckaert G, Kalai M, Krysko DV et al (2004) Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol Biol Cell 15:1089–1100PubMedCrossRefGoogle Scholar
  78. 78.
    Krysko DV, Denecker G, Festjens N et al (2006) Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ 13:2011–2022PubMedCrossRefGoogle Scholar
  79. 79.
    Chung S, Gumienny TL, Hengartner MO, Driscoll M (2000) A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans. Nat Cell Biol 2:931–937PubMedCrossRefGoogle Scholar
  80. 80.
    Hirt UA, Gantner F, Leist M (2000) Phagocytosis of nonapoptotic cells dying by caspase-independent mechanisms. J Immunol 164:6520–6529PubMedGoogle Scholar
  81. 81.
    Meagher LC, Savill JS, Baker A, Fuller RW, Haslett C (1992) Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2. J Leukoc Biol 52:269–273PubMedGoogle Scholar
  82. 82.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351PubMedCrossRefGoogle Scholar
  83. 83.
    Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) 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 101:890–898PubMedCrossRefGoogle Scholar
  84. 84.
    Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, Henson PM (2006) Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem 281:38376–38384PubMedCrossRefGoogle Scholar
  85. 85.
    Hirt UA, Leist M (2003) Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells. Cell Death Differ 10:1156–1164PubMedCrossRefGoogle Scholar
  86. 86.
    Fadok VA, Bratton DL, Guthrie L, Henson PM (2001) Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J Immunol 166:6847–6854PubMedGoogle Scholar
  87. 87.
    Patel VA, Longacre A, Hsiao K et al (2006) Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells: Implications for the delayed clearance model of autoimmunity. J Biol Chem 281:4663–4670PubMedCrossRefGoogle Scholar
  88. 88.
    Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P (1999) Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr Biol 9:967–970PubMedCrossRefGoogle Scholar
  89. 89.
    Polzer K, Schett G, Zwerina J (2007) The lonely death: chondrocyte apoptosis in TNF-induced arthritis. Autoimmunity 40:333–336PubMedCrossRefGoogle Scholar
  90. 90.
    Redman SN, Khan IM, Tew SR, Archer CW (2007) In situ detection of cell death in articular cartilage. Methods Mol Med 135:183–200PubMedGoogle Scholar
  91. 91.
    Xu Y, Huang S, Liu ZG, Han J (2006) Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 281:8788–8795PubMedCrossRefGoogle Scholar
  92. 92.
    Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P (2007) RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ 14:400–410PubMedCrossRefGoogle Scholar
  93. 93.
    Artal-Sanz M, Samara C, Syntichaki P, Tavernarakis N (2006) Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans. J Cell Biol 173:231–239PubMedCrossRefGoogle Scholar
  94. 94.
    Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833PubMedCrossRefGoogle Scholar
  95. 95.
    Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–565PubMedCrossRefGoogle Scholar
  96. 96.
    Castro J, Bittner CX, Humeres A, Montecinos VP, Vera JC, Barros LF (2004) A cytosolic source of calcium unveiled by hydrogen peroxide with relevance for epithelial cell death. Cell Death Differ 11:468–478PubMedCrossRefGoogle Scholar
  97. 97.
    Castro J, Ruminot I, Porras OH et al (2006) ATP steal between cation pumps: a mechanism linking Na+ influx to the onset of necrotic Ca2+ overload. Cell Death Differ 13:1675–1685PubMedCrossRefGoogle Scholar
  98. 98.
    Syntichaki P, Tavernarakis N (2002) Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos? EMBO Rep 3:604–609PubMedCrossRefGoogle Scholar
  99. 99.
    Nicotera P, Orrenius S (1998) The role of calcium in apoptosis. Cell Calcium 23:173–180PubMedCrossRefGoogle Scholar
  100. 100.
    Yamashima T, Kohda Y, Tsuchiya K et al (1998) Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on ‘calpain-cathepsin hypothesis’. Eur J Neurosci 10:1723–1733PubMedCrossRefGoogle Scholar
  101. 101.
    Ono K, Kim SO, Han J (2003) Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death. Mol Cell Biol 23:665–676PubMedCrossRefGoogle Scholar
  102. 102.
    Zahrebelski G, Nieminen AL, al-Ghoul K, Qian T, Herman B, Lemasters JJ (1995) Progression of subcellular changes during chemical hypoxia to cultured rat hepatocytes: a laser scanning confocal microscopic study. Hepatology (Baltimore, MD) 21:1361–1372Google Scholar
  103. 103.
    Brunk UT, Dalen H, Roberg K, Hellquist HB (1997) Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts. Free Radic Biol Med 23:616–626PubMedCrossRefGoogle Scholar
  104. 104.
    Barros LF, Hermosilla T, Castro J (2001) Necrotic volume increase and the early physiology of necrosis. Comp Biochem Physiol 130:401–409Google Scholar
  105. 105.
    Buja LM, Eigenbrodt ML, Eigenbrodt EH (1993) Apoptosis and necrosis. Basic types and mechanisms of cell death. Arch Pathol Lab Med 117:1208–1214PubMedGoogle Scholar
  106. 106.
    Chen J, Liu X, Mandel LJ, Schnellmann RG (2001) Progressive disruption of the plasma membrane during renal proximal tubule cellular injury. Toxicol Appl Pharmacol 171:1–11PubMedCrossRefGoogle Scholar
  107. 107.
    Nishimura Y, Lemasters JJ (2001) Glycine blocks opening of a death channel in cultured hepatic sinusoidal endothelial cells during chemical hypoxia. Cell Death Differ 8:850–858PubMedCrossRefGoogle Scholar
  108. 108.
    Liu X, Schnellmann RG (2003) Calpain mediates progressive plasma membrane permeability and proteolysis of cytoskeleton-associated paxillin, talin, and vinculin during renal cell death. J Pharmacol Exp Ther 304:63–70PubMedCrossRefGoogle Scholar
  109. 109.
    Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49PubMedCrossRefGoogle Scholar
  110. 110.
    Gleiss B, Gogvadze V, Orrenius S, Fadeel B (2002) Fas-triggered phosphatidylserine exposure is modulated by intracellular ATP. FEBS Lett 519:153–158PubMedCrossRefGoogle Scholar
  111. 111.
    Zamaraeva MV, Sabirov RZ, Maeno E, Ando-Akatsuka Y, Bessonova SV, Okada Y (2005) Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracellular luciferase. Cell Death Differ 12:1390–1397PubMedCrossRefGoogle Scholar
  112. 112.
    Jaeschke H, Lemasters JJ (2003) Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 125:1246–1257PubMedCrossRefGoogle Scholar
  113. 113.
    Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470PubMedCrossRefGoogle Scholar
  114. 114.
    Honda H, Kondo T, Zhao QL, Feril LB Jr, Kitagawa H (2004) Role of intracellular calcium ions and reactive oxygen species in apoptosis induced by ultrasound. Ultrasound Med Biol 30:683–692PubMedCrossRefGoogle Scholar
  115. 115.
    Assefa Z, Bultynck G, Szlufcik K et al (2004) Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis. J Biol Chem 279:43227–43236PubMedCrossRefGoogle Scholar
  116. 116.
    Schwab BL, Guerini D, Didszun C et al (2002) Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ 9:818–831PubMedCrossRefGoogle Scholar
  117. 117.
    Paszty K, Verma AK, Padanyi R, Filoteo AG, Penniston JT, Enyedi A (2002) Plasma membrane Ca2+ATPase isoform 4b is cleaved and activated by caspase-3 during the early phase of apoptosis. J Biol Chem 277:6822–6829PubMedCrossRefGoogle Scholar
  118. 118.
    Paszty K, Antalffy G, Penheiter AR et al (2005) The caspase-3 cleavage product of the plasma membrane Ca2+-ATPase 4b is activated and appropriately targeted. Biochem J 391:687–692PubMedCrossRefGoogle Scholar
  119. 119.
    Paszty K, Antalffy G, Hegedus L et al (2007) Cleavage of the plasma membrane Ca+ATPase during apoptosis. Ann NY Acad Sci 1099:440–450PubMedCrossRefGoogle Scholar
  120. 120.
    Tombal B, Denmeade SR, Gillis JM, Isaacs JT (2002) A supramicromolar elevation of intracellular free calcium ([Ca(2+)](i)) is consistently required to induce the execution phase of apoptosis. Cell Death Differ 9:561–573PubMedCrossRefGoogle Scholar
  121. 121.
    Oshimi Y, Miyazaki S (1995) Fas antigen-mediated DNA fragmentation and apoptotic morphologic changes are regulated by elevated cytosolic Ca2+ level. J Immunol 154:599–609PubMedGoogle Scholar
  122. 122.
    Neumar RW, Xu YA, Gada H, Guttmann RP, Siman R (2003) Cross-talk between calpain and caspase proteolytic systems during neuronal apoptosis. J Biol Chem 278:14162–14167PubMedCrossRefGoogle Scholar
  123. 123.
    Zhan Y, van de Water B, Wang Y, Stevens JL (1999) The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells. Oncogene 18:6505–6512PubMedCrossRefGoogle Scholar
  124. 124.
    Wattiaux R, Wattiaux-de Coninck S, Thirion J, Gasingirwa MC, Jadot M (2007) Lysosomes and Fas-mediated liver cell death. Biochem J 403:89–95PubMedCrossRefGoogle Scholar
  125. 125.
    Vermes I, Haanen C, Reutelingsperger C (2000) Flow cytometry of apoptotic cell death. J Immunol Methods 243:167–190PubMedCrossRefGoogle Scholar
  126. 126.
    Denecker G, Vercammen D, Steemans M et al (2001) Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria. Cell Death Differ 8:829–840PubMedCrossRefGoogle Scholar
  127. 127.
    Wu X, Molinaro C, Johnson N, Casiano CA (2001) Secondary necrosis is a source of proteolytically modified forms of specific intracellular autoantigens: implications for systemic autoimmunity. Arthritis Rheum 44:2642–2652PubMedCrossRefGoogle Scholar
  128. 128.
    Mahoney JA, Rosen A (2005) Apoptosis and autoimmunity. Curr Opin Immunol 17:583–588PubMedCrossRefGoogle Scholar
  129. 129.
    Gaipl US, Munoz LE, Grossmayer G et al (2007) Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun 28:114–121PubMedCrossRefGoogle Scholar
  130. 130.
    Berg CP, Stein GM, Keppeler H et al (2008) Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis. Apoptosis 13:63–75PubMedCrossRefGoogle Scholar
  131. 131.
    Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57:1835–1840PubMedGoogle Scholar
  132. 132.
    Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486PubMedCrossRefGoogle Scholar
  133. 133.
    van der Toorn M, Slebos DJ, de Bruin HG et al (2007) Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis. Am J Physiol 292:L1211–L1218Google Scholar
  134. 134.
    do Vale A, Costa-Ramos C, Silva DS et al (2007) Cytochemical and ultrastructural study of anoikis and secondary necrosis in enterocytes detached in vivo. Apoptosis 12:1069–1083PubMedCrossRefGoogle Scholar
  135. 135.
    Vitale M, Zamai L, Mazzotti G, Cataldi A, Falcieri E (1993) Differential kinetics of propidium iodide uptake in apoptotic and necrotic thymocytes. Histochemistry 100:223–229PubMedCrossRefGoogle Scholar
  136. 136.
    Belloc F, Dumain P, Boisseau MR et al (1994) A flow cytometric method using Hoechst 33342 and propidium iodide for simultaneous cell cycle analysis and apoptosis determination in unfixed cells. Cytometry 17:59–65PubMedCrossRefGoogle Scholar
  137. 137.
    Sun F, Hamagawa E, Tsutsui C, Ono Y, Ogiri Y, Kojo S (2001) Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver. Biochim Biophys Acta 1535:186–191PubMedGoogle Scholar
  138. 138.
    Hentze H, Schwoebel F, Lund S et al (2001) In vivo and in vitro evidence for extracellular caspase activity released from apoptotic cells. Biochem Biophys Res Commun 283:1111–1117PubMedCrossRefGoogle Scholar
  139. 139.
    Holdenrieder S, Eichhorn P, Beuers U et al (2006) Nucleosomal DNA fragments in autoimmune diseases. Ann NY Acad Sci 1075:318–327PubMedCrossRefGoogle Scholar
  140. 140.
    Walker NI, Bennett RE, Kerr JF (1989) Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat 185:19–32PubMedCrossRefGoogle Scholar
  141. 141.
    Baxter FO, Neoh K, Tevendale MC (2007) The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia 12:3–13PubMedCrossRefGoogle Scholar
  142. 142.
    Erjefalt J (2005) Transepithelial migration, necrosis and apoptosis as silent and pro-inflammatory fates of airway granulocytes. Curr Drug Targets 4:425–431CrossRefGoogle Scholar
  143. 143.
    Uller L, Persson CG, Erjefalt JS (2006) Resolution of airway disease: removal of inflammatory cells through apoptosis, egression or both? Trends Pharmacol Sci 27:461–466PubMedCrossRefGoogle Scholar
  144. 144.
    Huettenbrenner S, Maier S, Leisser C et al (2003) The evolution of cell death programs as prerequisites of multicellularity. Mut Res 543:235–249Google Scholar
  145. 145.
    Golstein P, Kroemer G (2005) Redundant cell death mechanisms as relics and backups. Cell Death Differ 12(Suppl 2):1490–1496PubMedCrossRefGoogle Scholar
  146. 146.
    Albert ML, Pearce SF, Francisco LM et al (1998) Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188:1359–1368PubMedCrossRefGoogle Scholar
  147. 147.
    Erwig LP, McPhilips KA, Wynes MW, Ivetic A, Ridley AJ, Henson PM (2006) Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by Rho GTPases and ezrin-radixin-moesin (ERM) proteins. Proc Natl Acad Sci USA 103:12825–12830PubMedCrossRefGoogle Scholar
  148. 148.
    Misawa R, Kawagishi C, Watanabe N, Kobayashi Y (2001) Infiltration of neutrophils following injection of apoptotic cells into the peritoneal cavity. Apoptosis 6:411–417PubMedCrossRefGoogle Scholar
  149. 149.
    Liu CY, Liu YH, Lin SM et al (2003) Apoptotic neutrophils undergoing secondary necrosis induce human lung epithelial cell detachment. J Biomed Sci 10:746–756PubMedCrossRefGoogle Scholar
  150. 150.
    Naylor EJ, Bakstad D, Biffen M et al (2007) Haemophilus influenzae induces neutrophil necrosis: a role in chronic obstructive pulmonary disease? Am J Respir Cell Mol Biol 37:135–143PubMedCrossRefGoogle Scholar
  151. 151.
    Bell CW, Jiang W, Reich CF III, Pisetsky DS (2006) The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol 291:C1318–C1325PubMedCrossRefGoogle Scholar
  152. 152.
    Jiang W, Bell CW, Pisetsky DS (2007) The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. J Immunol 178:6495–6503PubMedGoogle Scholar
  153. 153.
    Apetoh L, Ghiringhelli F, Tesniere A et al (2007) The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 220:47–59PubMedCrossRefGoogle Scholar
  154. 154.
    Ito N, DeMarco RA, Mailliard RB et al (2007) Cytolytic cells induce HMGB1 release from melanoma cell lines. J Leukoc Biol 81:75–83PubMedCrossRefGoogle Scholar
  155. 155.
    Ren Y, Stuart L, Lindberg FP et al (2001) Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins. J Immunol 166:4743–4750PubMedGoogle Scholar
  156. 156.
    Stern M, Savill J, Haslett C (1996) Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta 3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am J Pathol 149:911–921PubMedGoogle Scholar
  157. 157.
    Rovere P, Sabbadini MG, Vallinoto C et al (1999) Delayed clearance of apoptotic lymphoma cells allows cross-presentation of intracellular antigens by mature dendritic cells. J Leukoc Biol 66:345–349PubMedGoogle Scholar
  158. 158.
    Gough MJ, Melcher AA, Ahmed A et al (2001) Macrophages orchestrate the immune response to tumor cell death. Cancer Res 61:7240–7247PubMedGoogle Scholar
  159. 159.
    Viorritto IC, Nikolov NP, Siegel RM (2007) Autoimmunity versus tolerance: can dying cells tip the balance? Clin Immunol (Orlando, FL) 122:125–134CrossRefGoogle Scholar
  160. 160.
    Kim HS, Han MS, Chung KW et al (2007) Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27:321–333PubMedCrossRefGoogle Scholar
  161. 161.
    Scott RS, McMahon EJ, Pop SM et al (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411:207–211PubMedCrossRefGoogle Scholar
  162. 162.
    Tuder RM, Petrache I, Elias JA, Voelkel NF, Henson PM (2003) Apoptosis and emphysema: the missing link. Am J Respir Cell Mol Biol 28:551–554PubMedCrossRefGoogle Scholar
  163. 163.
    Maher JJ, Gores GJ (1998) Apoptosis: silent killer or neutron bomb? Hepatology (Baltimore, MD) 28:865–867CrossRefGoogle Scholar
  164. 164.
    Farghali H, Canova N, Kucera T, Martinek J, Masek K (2003) Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects. Int Immunopharmacol 3:1627–1638PubMedCrossRefGoogle Scholar
  165. 165.
    Ogasawara J, Watanabe-Fukunaga R, Adachi M et al (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364:806–809PubMedCrossRefGoogle Scholar
  166. 166.
    Gujral JS, Farhood A, Jaeschke H (2003) Oncotic necrosis and caspase-dependent apoptosis during galactosamine-induced liver injury in rats. Toxicol Appl Pharmacol 190:37–46PubMedCrossRefGoogle Scholar
  167. 167.
    Unal-Cevik I, Kilinc M, Can A, Gursoy-Ozdemir Y, Dalkara T (2004) Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke 35:2189–2194PubMedCrossRefGoogle Scholar
  168. 168.
    Daemen MA, van’t Veer C, Denecker G et al (1999) Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. J Clin Invest 104:541–549PubMedCrossRefGoogle Scholar
  169. 169.
    James TN (1999) Apoptosis in cardiac disease. Am J Med 107:606–620PubMedCrossRefGoogle Scholar
  170. 170.
    Scarabelli TM, Gottlieb RA (2004) Functional and clinical repercussions of myocyte apoptosis in the multifaceted damage by ischemia/reperfusion injury: old and new concepts after 10 years of contributions. Cell Death Differ 11(Suppl 2):S144–S152PubMedCrossRefGoogle Scholar
  171. 171.
    Goldspink DF, Burniston JG, Tan LB (2003) Cardiomyocyte death and the ageing and failing heart. Exp Physiol 88:447–458PubMedCrossRefGoogle Scholar
  172. 172.
    Leist M, Single B, Naumann H et al (1999) Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp Cell Res 249:396–403PubMedCrossRefGoogle Scholar
  173. 173.
    Nicotera P, Leist M, Fava E, Berliocchi L, Volbracht C (2000) Energy requirement for caspase activation, neuronal cell death. Brain Pathol (Zurich, Switzerland) 10:276–282Google Scholar
  174. 174.
    Nicotera P (2003) Molecular switches deciding the death of injured neurons. Toxicol Sci 74:4–9PubMedCrossRefGoogle Scholar
  175. 175.
    Benchoua A, Guegan C, Couriaud C et al (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21:7127–7134PubMedGoogle Scholar
  176. 176.
    Veinot JP, Gattinger DA, Fliss H (1997) Early apoptosis in human myocardial infarcts. Hum Pathol 28:485–492PubMedCrossRefGoogle Scholar
  177. 177.
    Ankarcrona M, Dypbukt JM, Bonfoco E et al (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973PubMedCrossRefGoogle Scholar
  178. 178.
    Denecker G, Vercammen D, Declercq W, Vandenabeele P (2001) Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 58:356–370PubMedCrossRefGoogle Scholar
  179. 179.
    Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796–802PubMedCrossRefGoogle Scholar
  180. 180.
    Lehrer RI, Ganz T, Selsted ME, Babior BM, Curnutte JT (1988) Neutrophils and host defense. Ann Intern Med 109:127–142PubMedGoogle Scholar
  181. 181.
    Lee WL, Downey GP (2001) Leukocyte elastase: physiological functions and role in acute lung injury. Am J Respir Crit Care Med 164:896–904PubMedGoogle Scholar
  182. 182.
    Henson PM, Johnston RB Jr (1987) Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest 79:669–674PubMedCrossRefGoogle Scholar
  183. 183.
    Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–376PubMedCrossRefGoogle Scholar
  184. 184.
    Smith JA (1994) Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 56:672–686PubMedGoogle Scholar
  185. 185.
    Kawabata K, Hagio T, Matsuoka S (2002) The role of neutrophil elastase in acute lung injury. Eur J Pharmacol 451:1–10PubMedCrossRefGoogle Scholar
  186. 186.
    Stockley RA (2006) Neutrophilic inflammation: “don’t you go to pieces on me! Eur Respir J 28:257–258PubMedCrossRefGoogle Scholar
  187. 187.
    Faurschou M, Borregaard N (2003) Neutrophil granules and secretory vesicles in inflammation. Microbes Infect 5:1317–1327PubMedCrossRefGoogle Scholar
  188. 188.
    Owen CA, Campbell EJ (1999) The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol 65:137–150PubMedGoogle Scholar
  189. 189.
    Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C (1989) Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 83:865–875PubMedCrossRefGoogle Scholar
  190. 190.
    Brazil TJ, Dagleish MP, McGorum BC, Dixon PM, Haslett C, Chilvers ER (2005) Kinetics of pulmonary neutrophil recruitment and clearance in a natural and spontaneously resolving model of airway inflammation. Clin Exp Allergy 35:854–865PubMedCrossRefGoogle Scholar
  191. 191.
    Knapp S, Leemans JC, Florquin S et al (2003) Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. Am J Respir Crit Care Med 167:171–179PubMedCrossRefGoogle Scholar
  192. 192.
    Simon HU (2003) Neutrophil apoptosis pathways and their modifications in inflammation. Immunol Rev 193:101–110PubMedCrossRefGoogle Scholar
  193. 193.
    Bianchi SM, Dockrell DH, Renshaw SA, Sabroe I, Whyte MK (2006) Granulocyte apoptosis in the pathogenesis and resolution of lung disease. Clin Sci (Lond) 110:293–304CrossRefGoogle Scholar
  194. 194.
    Stockley RA (1999) Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 160:S49–S52PubMedGoogle Scholar
  195. 195.
    Konstan MW, Berger M (1997) Current understanding of the inflammatory process in cystic fibrosis: onset and etiology. Pediatr Pulmonol 24:137–142; discussion 159–161PubMedCrossRefGoogle Scholar
  196. 196.
    Fujie K, Shinguh Y, Inamura N, Yasumitsu R, Okamoto M, Okuhara M (1999) Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043. Eur J Pharmacol 374:117–125PubMedCrossRefGoogle Scholar
  197. 197.
    Bank U, Ansorge S (2001) More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control. J Leukoc Biol 69:197–206PubMedGoogle Scholar
  198. 198.
    Usher LR, Lawson RA, Geary I et al (2002) Induction of neutrophil apoptosis by the Pseudomonas aeruginosa exotoxin pyocyanin: a potential mechanism of persistent infection. J Immunol 168:1861–1868PubMedGoogle Scholar
  199. 199.
    Watt AP, Courtney J, Moore J, Ennis M, Elborn JS (2005) Neutrophil cell death, activation and bacterial infection in cystic fibrosis. Thorax 60:659–664PubMedCrossRefGoogle Scholar
  200. 200.
    Jaeschke H, Smith CW (1997) Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol 61:647–653PubMedGoogle Scholar
  201. 201.
    Jaeschke H (2006) Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol 290:G1083–G1088PubMedCrossRefGoogle Scholar
  202. 202.
    Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819–834PubMedCrossRefGoogle Scholar
  203. 203.
    Feuerstein G (2006) Inflammation and stroke: therapeutic effects of adenoviral expression of secretory Leukocyte Protease Inhibitor. Front Biosci 11:1750–1757PubMedCrossRefGoogle Scholar
  204. 204.
    Bone RC, Balk RA, Cerra FB et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655PubMedCrossRefGoogle Scholar
  205. 205.
    Vincent JL, Zambon M (2006) Why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? Implications for management. Clin Chest Med 27:725–731; abstract x–xiPubMedCrossRefGoogle Scholar
  206. 206.
    Wheeler AP, Bernard GR (2007) Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet 369:1553–1564PubMedCrossRefGoogle Scholar
  207. 207.
    Jochum M, Gippner-Steppert C, Machleidt W, Fritz H (1994) The role of phagocyte proteinases and proteinase inhibitors in multiple organ failure. Am J Respir Crit Care Med 150:S123–S130PubMedGoogle Scholar
  208. 208.
    Tumpey TM, Garcia-Sastre A, Taubenberger JK et al (2005) Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 79:14933–14944PubMedCrossRefGoogle Scholar
  209. 209.
    Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y (2004) PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320:258–266PubMedCrossRefGoogle Scholar
  210. 210.
    Rimmelzwaan GF, van Riel D, Baars M et al (2006) Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts. Am J Pathol 168:176–183; quiz 364PubMedCrossRefGoogle Scholar
  211. 211.
    Stockley RA (2002) Neutrophils and the pathogenesis of COPD. Chest 121:151S–155SPubMedCrossRefGoogle Scholar
  212. 212.
    Barnes PJ (2003) New concepts in chronic obstructive pulmonary disease. Annu Rev Med 54:113–129PubMedCrossRefGoogle Scholar
  213. 213.
    Shapiro SD, Ingenito EP (2005) The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. Am J Respir Cell Mol Biol 32:367–372PubMedCrossRefGoogle Scholar
  214. 214.
    Stockley RA (1994) The role of proteinases in the pathogenesis of chronic bronchitis. Am J Respir Crit Care Med 150:S109–S113PubMedGoogle Scholar
  215. 215.
    Ordonez CL, Shaughnessy TE, Matthay MA, Fahy JV (2000) Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am J Respir Crit Care Med 161:1185–1190PubMedGoogle Scholar
  216. 216.
    Palmqvist C, Wardlaw AJ, Bradding P (2007) Chemokines and their receptors as potential targets for the treatment of asthma. Brit J Pharmacol 151:725–736CrossRefGoogle Scholar
  217. 217.
    Doring G (1994) The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med 150:S114–S117PubMedGoogle Scholar
  218. 218.
    Birrer P, McElvaney NG, Rudeberg A et al (1994) Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 150:207–213PubMedGoogle Scholar
  219. 219.
    Taggart CC, Greene CM, Carroll TP, O’Neill SJ, McElvaney NG (2005) Elastolytic proteases: inflammation resolution and dysregulation in chronic infective lung disease. Am J Respir Crit Care Med 171:1070–1076PubMedCrossRefGoogle Scholar
  220. 220.
    Hartl D, Latzin P, Hordijk P et al (2007) Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 13:1423–1430PubMedCrossRefGoogle Scholar
  221. 221.
    Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 81:289–296PubMedCrossRefGoogle Scholar
  222. 222.
    Hodge S, Hodge G, Ahern J et al (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Amer J Resp Cell Mol Biol 37:748–755CrossRefGoogle Scholar
  223. 223.
    Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129:1673–1682PubMedCrossRefGoogle Scholar
  224. 224.
    Bianchi SM, Prince LR, McPhillips K et al (2008) Impairment of apoptotic cell engulfment by pyocyanin, a toxic metabolite of Pseudomonas aeruginosa. Amer J Resp Crit Care Med 177:35–43CrossRefGoogle Scholar
  225. 225.
    Medan D, Wang L, Yang X, Dokka S, Castranova V, Rojanasakul Y (2002) Induction of neutrophil apoptosis and secondary necrosis during endotoxin-induced pulmonary inflammation in mice. J Cell Physiol 191:320–326PubMedCrossRefGoogle Scholar
  226. 226.
    Rydell-Tormanen K, Uller L, Erjefalt JS (2006) Direct evidence of secondary necrosis of neutrophils during intense lung inflammation. Eur Respir J 28:268–274PubMedCrossRefGoogle Scholar
  227. 227.
    Kodama T, Yukioka H, Kato T, Kato N, Hato F, Kitagawa S (2007) Neutrophil elastase as a predicting factor for development of acute lung injury. Intern Med (Tokyo, Japan) 46:699–704Google Scholar
  228. 228.
    Fujishima S, Morisaki H, Ishizaka A et al (2007) Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients. Biomed Pharmacother. Available online July 31 2007Google Scholar
  229. 229.
    Vandivier RW, Fadok VA, Hoffmann PR et al (2002) Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 109:661–670PubMedGoogle Scholar
  230. 230.
    Zeiher BG, Matsuoka S, Kawabata K, Repine JE (2002) Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med 30:S281–S287PubMedCrossRefGoogle Scholar
  231. 231.
    Sakashita A, Nishimura Y, Nishiuma T et al (2007) Neutrophil elastase inhibitor (sivelestat) attenuates subsequent ventilator-induced lung injury in mice. Eur J Pharmacol 571:62–71PubMedCrossRefGoogle Scholar
  232. 232.
    Uchida Y, Kaibori M, Hijikawa T et al (2008) Protective effect of neutrophil elastase inhibitor (FR136706) in lethal acute liver failure induced by d-galactosamine and lipopolysaccharide in rats. J Surg Res 145:57–65PubMedCrossRefGoogle Scholar
  233. 233.
    Uller L, Rydell-Tormanen K, Persson CG, Erjefalt JS (2005) Anti-Fas mAb-induced apoptosis and cytolysis of airway tissue eosinophils aggravates rather than resolves established inflammation. Respir Res 6:90PubMedCrossRefGoogle Scholar
  234. 234.
    Walsh GM (2001) Eosinophil granule proteins and their role in disease. Curr Opin Hematol 8:28–33PubMedCrossRefGoogle Scholar
  235. 235.
    Campbell EJ, Cury JD, Shapiro SD, Goldberg GI, Welgus HG (1991) Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases. J Immunol 146:1286–1293PubMedGoogle Scholar
  236. 236.
    Reis MI, do Vale A, Pinto C et al (2007) First molecular cloning and characterisation of caspase-9 gene in fish and its involvement in a gram negative septicaemia. Mol Immunol 44:1754–1764PubMedCrossRefGoogle Scholar
  237. 237.
    Oliveira MS, Fraga AG, Torrado E et al (2005) Infection with Mycobacterium ulcerans induces persistent inflammatory responses in mice. Infect Immun 73:6299–6310PubMedCrossRefGoogle Scholar
  238. 238.
    George KM, Chatterjee D, Gunawardana G et al (1999) Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283:854–857PubMedCrossRefGoogle Scholar
  239. 239.
    Sebbane F, Gardner D, Long D, Gowen BB, Hinnebusch BJ (2005) Kinetics of disease progression and host response in a rat model of bubonic plague. Am J Pathol 166:1427–1439PubMedGoogle Scholar
  240. 240.
    Marketon MM, DePaolo RW, DeBord KL, Jabri B, Schneewind O (2005) Plague bacteria target immune cells during infection. Science (New York, NY) 309:1739–1741Google Scholar
  241. 241.
    Narayanan SK, Nagaraja TG, Chengappa MM, Stewart GC (2002) Leukotoxins of gram-negative bacteria. Vet Microbiol 84:337–356PubMedCrossRefGoogle Scholar
  242. 242.
    DeLeo FR (2004) Modulation of phagocyte apoptosis by bacterial pathogens. Apoptosis 9:399–413PubMedCrossRefGoogle Scholar
  243. 243.
    Kaplan MJ (2004) Apoptosis in systemic lupus erythematosus. Clin Immunol (Orlando, FL) 112:210–218CrossRefGoogle Scholar
  244. 244.
    Decker P (2006) Nucleosome autoantibodies. Clin Chim Acta 366:48–60PubMedCrossRefGoogle Scholar
  245. 245.
    Mackay IR, Leskovsek NV, Rose NR (2008) Cell damage and autoimmunity: a critical appraisal. J Autoimmun 30:5–11PubMedCrossRefGoogle Scholar
  246. 246.
    Devitt A, Parker KG, Ogden CA et al (2004) Persistence of apoptotic cells without autoimmune disease or inflammation in CD14−/− mice. J Cell Biol 167:1161–1170PubMedCrossRefGoogle Scholar
  247. 247.
    Stuart LM, Takahashi K, Shi L, Savill J, Ezekowitz RA (2005) Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol 174:3220–3226PubMedGoogle Scholar
  248. 248.
    Asano K, Miwa M, Miwa K et al (2004) Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med 200:459–467PubMedCrossRefGoogle Scholar
  249. 249.
    Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250PubMedCrossRefGoogle Scholar
  250. 250.
    Baumann I, Kolowos W, Voll RE et al (2002) Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum 46:191–201PubMedCrossRefGoogle Scholar
  251. 251.
    Ren Y, Tang J, Mok MY, Chan AW, Wu A, Lau CS (2003) Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 48:2888–2897PubMedCrossRefGoogle Scholar
  252. 252.
    Hanayama R, Tanaka M, Miyasaka K et al (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science (New York, NY) 304:1147–1150Google Scholar
  253. 253.
    Gaipl US, Voll RE, Sheriff A, Franz S, Kalden JR, Herrmann M (2005) Impaired clearance of dying cells in systemic lupus erythematosus. Autoimmun Rev 4:189–194PubMedCrossRefGoogle Scholar
  254. 254.
    Mitchell DA, Pickering MC, Warren J et al (2002) C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol 168:2538–2543PubMedGoogle Scholar
  255. 255.
    Cohen PL, Caricchio R, Abraham V et al (2002) Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 196:135–140PubMedCrossRefGoogle Scholar
  256. 256.
    Nagata S (2007) Autoimmune diseases caused by defects in clearing dead cells and nuclei expelled from erythroid precursors. Immunol Rev 220:237–250PubMedCrossRefGoogle Scholar
  257. 257.
    Munoz LE, Gaipl US, Franz S et al (2005) SLE—a disease of clearance deficiency? Rheumatology (Oxford, England) 44:1101–1107CrossRefGoogle Scholar
  258. 258.
    Gaipl US, Kuhn A, Sheriff A et al (2006) Clearance of apoptotic cells in human SLE. Curr Dir Autoimmun 9:173–187PubMedGoogle Scholar
  259. 259.
    Gaipl US, Sheriff A, Franz S et al (2006) Inefficient clearance of dying cells and autoreactivity. Curr Top Microbiol Immunol 305:161–176PubMedCrossRefGoogle Scholar
  260. 260.
    Oppenheim JJ, Yang D (2005) Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 17:359–365PubMedCrossRefGoogle Scholar
  261. 261.
    Yang H, Wang H, Czura CJ, Tracey KJ (2005) The cytokine activity of HMGB1. J Leukoc Biol 78:1–8PubMedCrossRefGoogle Scholar
  262. 262.
    Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedCrossRefGoogle Scholar
  263. 263.
    Hall JC, Casciola-Rosen L, Rosen A (2004) Altered structure of autoantigens during apoptosis. Rheum Dis Clin North Am 30:455–471, viiPubMedCrossRefGoogle Scholar
  264. 264.
    Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nature Rev 6:823–835CrossRefGoogle Scholar
  265. 265.
    Krieg AM, Vollmer J (2007) Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev 220:251–269PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Manuel T. Silva
    • 1
    Email author
  • Ana do Vale
    • 1
  • Nuno M. N. dos Santos
    • 1
  1. 1.Fish Immunology and Vaccinology, IBMC-Instituto de Biologia Molecular e CelularUniversidade do PortoPortoPortugal

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