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Circulating endothelial progenitor cells inversely associate with organ dysfunction in sepsis

Sushma K. Cribbs| Diane J. Sutcliffe| William R. Taylor| Mauricio Rojas| Kirk A. Easley| Li Tang| Kenneth L. Brigham| Greg S. Martin
Original
Volume 38, Issue 3 / March , 2012

Pages 429 - 436

Abstract

Purpose

Endothelial dysfunction is a primary contributor to sepsis-related organ dysfunction and death. In sepsis animal models, endothelial progenitor cells (EPC) have contributed to vascular repair. The role of endothelial progenitor cells as a biomarker for organ dysfunction is still unknown. We hypothesized that circulating numbers of endothelial progenitor cells would be associated with improved outcomes in sepsis.

Methods

Prospective, observational single-center cohort study in adult intensive care units at Grady Memorial Hospital, an affiliate of Emory University, from July 2007 through April 2009. Peripheral blood was obtained from 95 patients with sepsis, 37 intensive care unit controls, and 51 healthy controls, of whom only 86 patients with sepsis were used in the analysis because we were not able to obtain enough blood in 9 sepsis patients. Clinical data were obtained, and organ dysfunction was measured by Sepsis-Related Organ Failure Assessment (SOFA) score. Endothelial progenitor cells were assessed by a colony-forming unit (CFU) assay in which peripheral blood mononuclear cells were isolated using Ficoll density-gradient centrifugation and cultured in growth media.

Results

The patients with sepsis had significantly lower mean endothelial progenitor cell colony counts compared with intensive care unit controls (p = 0.035) and healthy controls (p = 0.0005). There was no difference in colony counts between ICU controls and healthy controls (p = 0.81). In the sepsis patients, EPC CFU numbers inversely associated with SOFA score, adjusting for mortality (r2 = 0.05, p = 0.04).

Conclusion

Increased circulating endothelial progenitor cells inversely correlate with organ dysfunction in sepsis patients.

Keywords

References

  1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (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 101:1644–1655
    • View reference on PubMed
    • View reference on publisher's website
  2. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554
    • View reference on PubMed
    • View reference on publisher's website
  3. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353
    • View reference on PubMed
    • View reference on publisher's website
  4. Gilbert RP (1960) Mechanisms of the hemodynamic effects of endotoxin. Physiol Rev 40:245–279
    • View reference on PubMed
  5. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 32:1825–1831
    • View reference on PubMed
    • View reference on publisher's website
  6. Trzeciak S, McCoy JV, Phillip DR, Arnold RC, Rizzuto M, Abate NL, Shapiro NI, Parrillo JE, Hollenberg SM (2008) Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 34:2210–2217
  7. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967
    • View reference on PubMed
    • View reference on publisher's website
  8. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109:337–346
    • View reference on PubMed
  9. Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Eguchi H, Onitsuka I, Matsui K, Imaizumi T (2000) Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 105:1527–1536
    • View reference on PubMed
    • View reference on publisher's website
  10. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228
    • View reference on PubMed
  11. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438
    • View reference on PubMed
    • View reference on publisher's website
  12. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM (2006) Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 355:1222–1232
    • View reference on PubMed
    • View reference on publisher's website
  13. Assmus B, Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Tonn T, Seifried E, Schachinger V, Dimmeler S, Zeiher AM (2007) Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ Res 100:1234–1241
    • View reference on PubMed
    • View reference on publisher's website
  14. Burnham EL, Taylor WR, Quyyumi AA, Rojas M, Brigham KL, Moss M (2005) Increased circulating endothelial progenitor cells are associated with survival in acute lung injury. Am J Respir Crit Care Med 172:854–860
    • View reference on PubMed
    • View reference on publisher's website
  15. Rafat N, Hanusch C, Brinkkoetter PT, Schulte J, Brade J, Zijlstra JG, van der Woude FJ, van Ackern K, Yard BA, Beck GC (2007) Increased circulating endothelial progenitor cells in septic patients: correlation with survival. Crit Care Med 35:1677–1684
    • View reference on PubMed
    • View reference on publisher's website
  16. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R (1994) The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818–824
    • View reference on PubMed
  17. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600
    • View reference on PubMed
    • View reference on publisher's website
  18. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA (2007) Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 179:1855–1863
    • View reference on PubMed
  19. Mutunga M, Fulton B, Bullock R, Batchelor A, Gascoigne A, Gillespie JI, Baudouin SV (2001) Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 163:195–200
    • View reference on PubMed
  20. Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, Rojas M (2007) Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 293:L131–L141
    • View reference on PubMed
    • View reference on publisher's website
  21. Lee JW, Fang X, Gupta N, Serikov V, Matthay MA (2009) Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci USA 106:16357–16362
    • View reference on PubMed
    • View reference on publisher's website
  22. Becchi C, Pillozzi S, Fabbri LP, Al Malyan M, Cacciapuoti C, Della BC, Nucera M, Masselli M, Boncinelli S, Arcangeli A, Amedei A (2008) The increase of endothelial progenitor cells in the peripheral blood: a new parameter for detecting onset and severity of sepsis. Int J Immunopathol Pharmacol 21:697–705
    • View reference on PubMed
  23. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP (2000) Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 105:71–77
    • View reference on PubMed
    • View reference on publisher's website
  24. Zampetaki A, Kirton JP, Xu Q (2008) Vascular repair by endothelial progenitor cells. Cardiovasc Res 78:413–421
    • View reference on PubMed
    • View reference on publisher's website
  25. Timmermans F, Van Hauwermeiren F, De Smedt M, Raedt R, Plasschaert F, De Buyzere ML, Gillebert TC, Plum J, Vandekerckhove B (2007) Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol 27:1572–1579
    • View reference on PubMed
    • View reference on publisher's website
  26. Povsic TJ, Zavodni KL, Vainorius E, Kherani JF, Goldschmidt-Clermont PJ, Peterson ED (2009) Common endothelial progenitor cell assays identify discrete endothelial progenitor cell populations. Am Heart J 157:335–344
    • View reference on PubMed
    • View reference on publisher's website
  27. Burnham EL, Mealer M, Gaydos J, Majka S, Moss M (2010) Acute lung injury but not sepsis is associated with increased colony formation by peripheral blood mononuclear cells. Am J Respir Cell Mol Biol 43:326–333
    • View reference on PubMed
    • View reference on publisher's website
  28. Dimmeler S, Zeiher AM (2000) Endothelial cell apoptosis in angiogenesis and vessel regression. Circ Res 87:434–439
    • View reference on PubMed
  29. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC (2004) Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104:2752–2760
    • View reference on PubMed
    • View reference on publisher's website
  30. Prater DN, Case J, Ingram DA, Yoder MC (2007) Working hypothesis to redefine endothelial progenitor cells. Leukemia 21:1141–1149
    • View reference on PubMed
    • View reference on publisher's website
  31. Thijssen DH, Vos JB, Verseyden C, van Zonneveld AJ, Smits P, Sweep FC, Hopman MT, de Boer HC (2006) Haematopoietic stem cells and endothelial progenitor cells in healthy men: effect of aging and training. Aging Cell 5:495–503
    • View reference on PubMed
    • View reference on publisher's website
  32. Grisar J, Aletaha D, Steiner CW, Kapral T, Steiner S, Saemann M, Schwarzinger I, Buranyi B, Steiner G, Smolen JS (2007) Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy. Ann Rheum Dis 66:1284–1288
    • View reference on PubMed
    • View reference on publisher's website
  33. Soler MJ, Martinez-Estrada OM, Puig-Mari JM, Marco-Feliu D, Oliveras A, Vila J, Mir M, Orfila A, Vilaro S, Lloveras J (2005) Circulating endothelial progenitor cells after kidney transplantation. Am J Transplant 5:2154–2159
    • View reference on PubMed
    • View reference on publisher's website
  34. Liu L, Wei H, Chen F, Wang J, Dong JF, Zhang J (2011) Endothelial progenitor cells correlate with clinical outcome of traumatic brain injury. Crit Care Med 39:1760–1765
    • View reference on PubMed
    • View reference on publisher's website
  35. Lee ST, Chu K, Jung KH, Park HK, Kim DH, Bahn JJ, Kim JH, Oh MJ, Lee SK, Kim M, Roh JK (2009) Reduced circulating angiogenic cells in Alzheimer disease. Neurology 72:1858–1863
    • View reference on PubMed
    • View reference on publisher's website
  36. Sobrino T, Hurtado O, Moro MA, Rodriguez-Yanez M, Castellanos M, Brea D, Moldes O, Blanco M, Arenillas JF, Leira R, Davalos A, Lizasoain I, Castillo J (2007) The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke 38:2759–2764
    • View reference on PubMed
    • View reference on publisher's website
  37. Huertas A, Testa U, Riccioni R, Petrucci E, Riti V, Savi D, Serra P, Bonsignore MR, Palange P (2010) Bone marrow-derived progenitors are greatly reduced in patients with severe COPD and low-BMI. Respir Physiol Neurobiol 170:23–31
    • View reference on PubMed
    • View reference on publisher's website
  38. Caramori G, Rigolin GM, Mazzoni F, Leprotti S, Campioni P, Papi A (2010) Circulating endothelial stem cells are not decreased in pulmonary emphysema or COPD. Thorax 65:554–555
    • View reference on PubMed
    • View reference on publisher's website
  39. Sala E, Villena C, Balaguer C, Rios A, Fernandez-Palomeque C, Cosio BG, Garcia J, Noguera A, Agusti A (2010) Abnormal levels of circulating endothelial progenitor cells during exacerbations of COPD. Lung 188:331–338
    • View reference on PubMed
    • View reference on publisher's website

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