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LA PROTEOMICA

Nel documento diagnosi post-mortem di sepsi (pagine 102-108)

4. INDAGINI DI LABORATORIO NELLA DIAGNOSI DI SEPSI

4.5 LA PROTEOMICA

Lo sviluppo della proteomica e, cioè lo studio delle proteine espresse in un tessuto, in una cellula o in un organismo in un dato momento, può fornire al patologo forense ulteriori possibilità di affinamento e di perfezionamento della diagnosi di morte sepsi-correlata in quanto consente una valutazione dell’espressione funzionale delle proteine presenti in un determinato momento. La proteomica coinvolge tecniche di diversa natura, il cui scopo principale, molto schematicamente è quello di separare ed identificare le proteine oggetto dell’indagine73

.

Negli ultimi anni, la proteomica è stata sempre più utilizzata per la ricerca dei biomarkers in vari settori clinici; numerose sono le applicazioni operative dell’indagine proteomica nella sepsi, sia nell’uomo74

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diversamente espresse nel siero di ratti settici. Nello stesso modello animale, è stato dimostrato che 12/13 proteine, rispettivamente nel tessuto cardiaco ed epatico, erano espresse in maniera diversa nei ratti settici rispetto ai controlli74; nel tessuto cerebrale, la espressione di ben 35 proteine, principalmente coinvolte nella risposta infiammatoria, è risultata diversa fra ratti settici e controlli. Ulteriori sviluppi, cui i clinici confidano grandi speranze per l’affinamento della diagnosi di sepsi, sono rappresentati dallo studio metabolomico della sepsi. In modelli animali (ratti settici) sono state, infatti, dimostrate caratteristiche alterazioni di molti metaboliti (ad esempio, alanina, creatina, etc.) rispetto a ratti di controllo.

In conclusione dalla letteratura clinica emerge una sempre maggiore valorizzazione delle potenzialità diagnoatiche (ed anche prognostiche) offerte da tecnologie quali la proteomica e la matabolomica. Questi spunti devono trovare ampia applicazione nella ricerca forense che può, da un lato, offrire un utile contributo alla esatta comprensione dei meccanismi fisiopatologici della sepsi e, dall’altro, consentire di affinare la diagnosi post-mortem di sepsi attraverso lo studio, mediante tecniche di analisi proteomica applicabili anche al materiale autoptico, della espressione di markers e proteine della sepsi76.

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BIBLIOGRAFIA

1. van Ooij C, Apodaca G, Engel J. Characterization of the Chlamydia trachomatis vacuole and its interaction with the host endocytic pathway in HeLa cells. Infection and immunity. 1997; 65(2): 758-66.

2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29(7): 1303-10.

3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical care medicine. 2001; 29(7): 1303-10. 4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. The New England journal of medicine. 2003; 348(16): 1546-54. 5. Silva E, Pedro Mde A, Sogayar AC, Mohovic T, Silva CL, Janiszewski M, et al. Brazilian Sepsis Epidemiological Study (BASES study). Crit Care. 2004; 8(4): R251-60.

6. Elhag KM, Mustafa AK, Sethi SK. Septicaemia in a teaching hospital in Kuwait--I: Incidence and aetiology. J Infect. 1985; 10(1): 17- 24.

7. Flaatten H. Epidemiology of sepsis in Norway in 1999. Crit Care. 2004; 8(4): R180-4. 8. Hoa NT, Diep TS, Wain J, Parry CM, Hien TT, Smith MD, et al. Community-acquired septicaemia in southern Viet Nam: the importance of multidrug-resistant Salmonella typhi. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1998; 92(5): 503- 8.

9. Harrison DA, Welch CA, Eddleston JM. The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004:

secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care. 2006; 10(2): R42.

10. Angus DC, Pereira CA, Silva E. Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets. 2006; 6(2): 207-12.

11. Cooper H, Leigh MA, Lucas S, Martin I. The coroner's autopsy. The final say in establishing cause of death? Med Leg J. 2007;

75(Pt 3): 114-9.

12. Arismendi-Morillo GJ, Briceno-Garcia AE, Romero-Amaro ZR, Fernandez-Abreu MC, Giron- Pina HE. [Acute non-specific splenitis as indicator of systemic infection. Assessment of 71 autopsy cases]. Investigacion clinica. 2004; 45(2): 131-5. 13. Morris A, Masur H, Huang L. Current issues in critical care of the human immunodeficiency virus-infected patient. Critical care medicine. 2006; 34(1): 42-9.

14. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 36(1): 296-327. 15. Tissari P, Zumla A, Tarkka E, Mero S, Savolainen L, Vaara M, et al. Accurate and rapid identification of bacterial species from positive blood cultures with a DNA-based microarray platform: an observational study. Lancet. 2010;

375(9710): 224-30.

16. Tsokos M. Immunohistochemical detection of sepsis-induced lung injury in human autopsy material. Leg Med (Tokyo). 2003; 5(2): 73-86.

17. Alpers CE. Il rene. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins e Cotran - Le basi patologiche delle malattie: Vol 2 Malattie degli organi e degli apparati. 8.a ed. Milano: Elsevier Health Sciences Italy; 2011. p. 893-955. 18. Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992; 9(1): 63-74.

105 19. Henter JI, Arico M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Medical and pediatric oncology. 1997; 28(5): 342-7.

20. Takahashi H, Okada M, Thalib L, Toyokawa S, Kano K. A necessary and sufficient condition of comparability for using standardized mortality ratio (SMR). J Epidemiol. 2001; 11(1): 24-8.

21. Ningsanond V. Infection associated hemophagocytic syndrome: a report of 50 children. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2000; 83(10): 1141-9.

22. Ha T, Hua F, Grant D, Xia Y, Ma J, Gao X, et al. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice. American journal of physiology Heart and circulatory physiology. 2006; 291(4): H1910-8.

23. Frosch MP, Anthony DC, DE Girolami U. Il sistema nervoso centrale. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins e Cotran - Le basi patologiche delle malattie: Vol 2 Malattie degli organi e degli apparati. 8.a ed. Milano: Elsevier Health Sciences Italy; 2011. p. 1265-330. 24. Langenberg C, Bagshaw SM, May CN, Bellomo R. The histopathology of septic acute kidney injury: a systematic review. Crit Care. 2008; 12(2): R38.

25. Paladino JD, Hotchkiss JR, Rabb H. Acute kidney injury and lung dysfunction: a paradigm for remote organ effects of kidney disease? Microvascular research. 2009; 77(1): 8-12.

26. Leone V, Corazzola B, Milocco C, Facchini S, Ciambra R, Cerasoli G, et al. [Retrospective analysis of Henoch-Schonlein purpura in children: diagnostic difficulties and renal outcome]. La Pediatria medica e chirurgica : Medical and surgical pediatrics. 2002; 24(4): 284-8.

27. Mustonen J, Wirta O. [Ischemic kidney disease]. Duodecim; laaketieteellinen aikakauskirja. 2006; 122(2): 208-14.

28. Christmas AB, Wilson AK, Franklin GA, Miller FB, Richardson JD, Rodriguez JL. Cirrhosis and trauma: a deadly duo. The American surgeon. 2005; 71(12): 996-1000.

29. Turillazzi E, Bello S, Cantatore S, De Carlo D, Neri M, Pomara C, et al. Il patologo forense e

la diagnosi di morte da shock settico: un impegno diagnostico laboratoristico sensibile agli attuali avanzamenti tecnologici = The forensic pathologist and the diagnosis of sepsis - related death: a diagnostic challenge using technological innovations. Riv Ital Med Leg. 2012; 34(3): 1079- 101.

30. Tsokos M. Postmortem diagnosis of sepsis. Forensic Sci Int. 2007; 165(2-3): 155-64. 31. Tsokos M, Fehlauer F, Puschel K. Immunohistochemical expression of E-selectin in sepsis-induced lung injury. Int J Legal Med. 2000;

113(6): 338-42.

32. Lasky LA. Selectins: interpreters of cell- specific carbohydrate information during inflammation. Science. 1992; 258(5084): 964-9. 33. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991; 67(6): 1033-6.

34. Tsokos M, Fehlauer F. Post-mortem markers of sepsis: an immunohistochemical study using VLA-4 (CD49d/CD29) and ICAM-1 (CD54) for the detection of sepsis-induced lung injury. International journal of legal medicine. 2001;

114(4-5): 291-4.

35. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. Journal of molecular medicine. 1999; 77(7): 527- 43.

36. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res. 2000; 55: 15-35; discussion -6. 37. Tsokos M, Pufe T, Paulsen F, Anders S, Mentlein R. Pulmonary expression of vascular endothelial growth factor in sepsis. Arch Pathol Lab Med. 2003; 127(3): 331-5.

38. Ishikawa K, May CN, Gobe G, Langenberg C, Bellomo R. Pathophysiology of septic acute kidney injury: a different view of tubular injury. Contributions to nephrology. 2010; 165: 18-27. 39. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury. Neuroimmunomodulation. 2012; 19(1): 10-9. 40. Pytel P, Alexander JJ. Pathogenesis of septic encephalopathy. Curr Opin Neurol. 2009;

22(3): 283-7.

41. Tsokos M, Puschel K. Postmortem bacteriology in forensic pathology: diagnostic

106 value and interpretation. Leg Med (Tokyo). 2001;

3(1): 15-22.

42. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Critical care. 2010; 14(1): R15.

43. Hubl W, Krassler J, Zingler C, Pertschy A, Hentschel J, Gerhards-Reich C, et al. Evaluation of a fully automated procalcitonin chemiluminescence immunoassay. Clinical laboratory. 2003; 49(7-8): 319-27.

44. Carrigan SD, Scott G, Tabrizian M. Toward resolving the challenges of sepsis diagnosis. Clin Chem. 2004; 50(8): 1301-14.

45. Balc IC, Sungurtekin H, Gurses E, Sungurtekin U, Kaptanoglu B. Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care. 2003; 7(1): 85-90. 46. Dollner H, Vatten L, Austgulen R. Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. Journal of clinical epidemiology. 2001; 54(12): 1251-7.

47. Arnalich F, Garcia-Palomero E, Lopez J, Jimenez M, Madero R, Renart J, et al. Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infection and immunity. 2000; 68(4): 1942-5. 48. Astiz M, Saha D, Lustbader D, Lin R, Rackow E. Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. The Journal of laboratory and clinical medicine. 1996;

128(6): 594-600.

49. Kuster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I, Zbojan J, et al. Interleukin-1 receptor antagonist and interleukin- 6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet. 1998;

352(9136): 1271-7.

50. Pruitt JH, Welborn MB, Edwards PD, Harward TR, Seeger JW, Martin TD, et al. Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome. Blood. 1996;

87(8): 3282-8.

51. Oberholzer A, Steckholzer U, Kurimoto M, Trentz O, Ertel W. Interleukin-18 plasma levels are increased in patients with sepsis compared to severely injured patients. Shock. 2001; 16(6): 411-4.

52. Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, et al. Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infection and immunity. 2003; 71(10): 5803-13.

53. Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, et al. A novel IL- 18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine. 2001; 14(6): 334-42.

54. Emmanuilidis K, Weighardt H, Matevossian E, Heidecke CD, Ulm K, Bartels H, et al. Differential regulation of systemic IL-18 and IL- 12 release during postoperative sepsis: high serum IL-18 as an early predictive indicator of lethal outcome. Shock. 2002; 18(4): 301-5. 55. Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab. 1994; 79(6): 1605-8.

56. Katja B, Hartmut K, Pawel M, Stefan B, Kox WJ, Spies CD. The value of immune modulating parameters in predicting the progression from peritonitis to septic shock. Shock. 2001; 15(2): 95-100.

57. Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis. Intensive care medicine. 2000; 26(8): 1076-81. 58. Grobmyer SR, Barie PS, Nathan CF, Fuortes M, Lin E, Lowry SF, et al. Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia. Critical care medicine. 2000; 28(5): 1276-82. 59. Sungurtekin H, Sungurtekin U, Balci C. Circulating complement (C3 and C4) for differentiation of SIRS from sepsis. Adv Ther. 2006; 23(6): 893-901.

60. Tsokos M, Reichelt U, Nierhaus A, Puschel K. Serum procalcitonin (PCT): a valuable biochemical parameter for the post-mortem diagnosis of sepsis. Int J Legal Med. 2001; 114(4- 5): 237-43.

61. Al-Nawas B, Krammer I, Shah PM. Procalcitonin in diagnosis of severe infections. Eur J Med Res. 1996; 1(7): 331-3.

107 62. Russwurm S, Oberhoffer M, Zipfel PF, Reinhart K. Procalcitonin--a novel biochemical marker for the mediator-directed therapy of sepsis. Mol Med Today. 1999; 5(7): 286-7.

63. Kuse ER, Langefeld I, Jaeger K, Kulpmann WR. Procalcitonin-a new diagnostic tool in complications following liver transplantation. Intensive Care Med. 2000; 26 Suppl 2: S187-92. 64. Reith HB, Mittelkotter U, Wagner R, Thiede A. Procalcitonin (PCT) in patients with abdominal sepsis. Intensive Care Med. 2000; 26

Suppl 2: S165-9.

65. Axer H, Wohlfarth M, Meisner M, Finn S, Ragoschke-Schumm A, Mentzel HJ, et al. [Procalcitonin as a marker for severe sepsis in an immunosuppressed patient]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2005;

40(2): 97-102.

66. Schrag B, Iglesias K, Mangin P, Palmiere C. Procalcitonin and C-reactive protein in pericardial fluid for postmortem diagnosis of sepsis. Int J Legal Med. 2012; 126(4): 567-72.

67. McCann FJ, Chapman SJ, Yu WC, Maskell NA, Davies RJ, Lee YC. Ability of procalcitonin to discriminate infection from non-infective inflammation using two pleural disease settings. PLoS One. 2012; 7(12): e49894.

68. Suprin E, Camus C, Gacouin A, Le Tulzo Y, Lavoue S, Feuillu A, et al. Procalcitonin: a valuable indicator of infection in a medical ICU? Intensive care medicine. 2000; 26(9): 1232-8.

69. Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8

in critically ill patients admitted with suspected sepsis. American journal of respiratory and critical care medicine. 2001; 164(3): 396-402. 70. Tugrul S, Esen F, Celebi S, Ozcan PE, Akinci O, Cakar N, et al. Reliability of procalcitonin as a severity marker in critically ill patients with inflammatory response. Anaesth Intensive Care. 2002; 30(6): 747-54.

71. Hatherill M, Tibby SM, Sykes K, Turner C, Murdoch IA. Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count. Archives of disease in childhood. 1999; 81(5): 417-21.

72. Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med. 1999; 27(3): 498-504.

73. Tyers M, Mann M. From genomics to proteomics. Nature. 2003; 422(6928): 193-7. 74. Hinkelbein J, Feldmann RE, Jr., Peterka A, Schubert C, Schelshorn D, Maurer MH, et al. Alterations in cerebral metabolomics and proteomic expression during sepsis. Curr Neurovasc Res. 2007; 4(4): 280-8.

75. Hinkelbein J, Kalenka A, Feldmann RE, Jr. [Early alterations in rat brain protein expression during sepsis]. Der Anaesthesist. 2009; 58(2): 134-43.

76. Xu PB, Lin ZY, Meng HB, Yan SK, Yang Y, Liu XR, et al. A metabonomic approach to early prognostic evaluation of experimental sepsis. The Journal of infection. 2008; 56(6): 474-81.

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Nel documento diagnosi post-mortem di sepsi (pagine 102-108)