Advertisement

Molecular Medicine

, Volume 17, Issue 1–2, pp 126–133 | Cite as

Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury

  • Akihisa Matsuda
  • Asha Jacob
  • Rongqian Wu
  • Mian Zhou
  • Jeffrey M. Nicastro
  • Gene F. Coppa
  • Ping Wang
Review Article

Abstract

Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.

Notes

Acknowledgments

This work is supported by the National Institutes of Health (NIH) grants, R01 GM057468 and R01 GM053008 (PW).

References

  1. 1.
    Oberholzer A, Oberholzer C, Moldawer LL. (2001) Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 16:83–96.CrossRefGoogle Scholar
  2. 2.
    Angus DC, et al. (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care. Med. 29:1303–10.CrossRefGoogle Scholar
  3. 3.
    Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL. (2001) Apoptosis in sepsis: a new target for therapeutic exploration. FASEB J. 15:879–92.CrossRefGoogle Scholar
  4. 4.
    Riedemann NC, Guo RF, Ward PA. (2003) Novel strategies for the treatment of sepsis. Nat. Med. 9:517–24.CrossRefGoogle Scholar
  5. 5.
    van den Berghe G, et al. (2001) Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 345:1359–67.CrossRefGoogle Scholar
  6. 6.
    Arumugam TV, Shiels IA, Woodruff TM, Granger DN, Taylor SM. (2004) The role of the complement system in ischemia-reperfusion injury. Shock. 21:401–9.CrossRefGoogle Scholar
  7. 7.
    Carden DL, Granger DN. (2000) Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 190:255–66.CrossRefGoogle Scholar
  8. 8.
    Neary P, Redmond HP. (1999) Ischaemia-reperfu-sion injury and the systemic inflammatory response syndrome. In: Ischaemia-Reperfusion Injury. Grace PA, Mathie RT (ed.) Blackwell Science, London, pp. 123–6.Google Scholar
  9. 9.
    Stubbs JD, et al. (1990) cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc. Natl. Acad. Sci. U. S. A. 87:8417–21.CrossRefGoogle Scholar
  10. 10.
    Bu HF, et al. (2007) Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J. Clin. Invest. 117:3673–83.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ensslin MA, Shur BD. (2003) Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell. 114:405–17.CrossRefGoogle Scholar
  12. 12.
    Hanayama R, Nagata S. (2005) Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc. Natl. Acad. Sci. U. S. A. 102:16886–91.CrossRefGoogle Scholar
  13. 13.
    Hanayama R, et al. (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature. 417:182–7.CrossRefGoogle Scholar
  14. 14.
    Hanayama R, et al. (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 304:1147–50.CrossRefGoogle Scholar
  15. 15.
    Silvestre JS, et al. (2005) Lactadherin promotes VEGF-dependent neovascularization. Nat. Med. 11:499–506.CrossRefGoogle Scholar
  16. 16.
    Aoki N, et al. (1995) Molecular cloning of glycoprotein antigens MGP57/53 recognized by monoclonal antibodies raised against bovine milk fat globule membrane. Biochim. Biophys. Acta. 1245:385–91.CrossRefGoogle Scholar
  17. 17.
    Couto JR, Taylor MR, Godwin SG, Ceriani RL, Peterson JA. (1996) Cloning and sequence analysis of human breast epithelial antigen BA46 reveals an RGD cell adhesion sequence presented on an epidermal growth factor-like domain. DNA Cell. Biol. 15:281–6.CrossRefGoogle Scholar
  18. 18.
    Hvarregaard J, Andersen MH, Berglund L, Rasmussen JT, Petersen TE. (1996) Characterization of glycoprotein PAS-6/7 from membranes of bovine milk fat globules. Eur. J. Biochem. 240:628–36.CrossRefGoogle Scholar
  19. 19.
    Larocca D, et al. (1991) A Mr 46,000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res. 51:4994–8.PubMedGoogle Scholar
  20. 20.
    Aziz MM, et al. (2009) MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling. J. Immunol. 182:7222–32.CrossRefGoogle Scholar
  21. 21.
    Andersen MH, Graversen H, Fedosov SN, Petersen TE, Rasmussen JT. (2000) Functional analyses of two cellular binding domains of bovine lactadherin. Biochemistry. 39:6200–6.CrossRefGoogle Scholar
  22. 22.
    Raymond A, Ensslin MA, Shur BD. (2009) SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. J. Cell. Biochem. 106:957–66.CrossRefGoogle Scholar
  23. 23.
    Taylor MR, Couto JR, Scallan CD, Ceriani RL, Peterson JA. (1997) Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA Cell. Biol. 16:861–9.CrossRefGoogle Scholar
  24. 24.
    Oshima K, et al. (1999) Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochem. Biophys. Res. Commun. 254:522–8.CrossRefGoogle Scholar
  25. 25.
    Burgess BL, Abrams TA, Nagata S, Hall MO. (2006) MFG-E8 in the retina and retinal pigment epithelium of rat and mouse. Mol. Vis. 12:1437–47.PubMedGoogle Scholar
  26. 26.
    Asano K, et al. (2004) Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J. Exp. Med. 200:459–67.CrossRefGoogle Scholar
  27. 27.
    Miyasaka K, Hanayama R, Tanaka M, Nagata S. (2004) Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur. J. Immunol. 34:1414–22.CrossRefGoogle Scholar
  28. 28.
    Watanabe T, et al. (2005) Production of the long and short forms of MFG-E8 by epidermal keratinocytes. Cell Tissue Res. 321:185–93.CrossRefGoogle Scholar
  29. 29.
    Jinushi M, et al. (2007) MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J. Clin. Invest. 117:1902–13.CrossRefGoogle Scholar
  30. 30.
    Leonardi-Essmann F, Emig M, Kitamura Y, Spanagel R, Gebicke-Haerter PJ. (2005) Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia. J. Neuroimmunol. 160:92–101.CrossRefGoogle Scholar
  31. 31.
    Miksa M, Amin D, Wu R, Ravikumar TS, Wang P. (2007) Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol. Med. 13:553–60.CrossRefGoogle Scholar
  32. 32.
    Boddaert J, et al. (2007) Evidence of a role for lactadherin in Alzheimer’s disease. Am. J. Pathol. 170:921–9.Google Scholar
  33. 33.
    Ait-Oufella H, et al. (2007) Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation. 115:2168–77.CrossRefGoogle Scholar
  34. 34.
    Komura H, Miksa M, Wu R, Goyert SM, Wang P. (2009) Milk fat globule epidermal growth factor-factor VIII is downregulated in sepsis via the lipopolysaccharide-CD14 pathway. J. Immunol. 182:581–7.CrossRefGoogle Scholar
  35. 35.
    Miksa M, et al. (2006) Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. Shock. 25:586–93.CrossRefGoogle Scholar
  36. 36.
    Miksa M, et al. (2009) Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor-factor VIII. J. Immunol. 183:5983–90; erratum 2009;183:8295.CrossRefGoogle Scholar
  37. 37.
    Cui T, et al. (2010) Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. Am. J. Respir. Crit. Care. Med. 181:238–46.CrossRefGoogle Scholar
  38. 38.
    Matsuda A, et al. (2010) The renoprotective effect of Milk Fat Globule EGF-Factor VIII after ischemia and reperfusion injury in mice. Shock. 33(Suppl 1):53.Google Scholar
  39. 39.
    Yamaguchi H, et al. (2008) Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus. J. Leukoc. Biol. 83:1300–7.CrossRefGoogle Scholar
  40. 40.
    Atabai K, et al. (2009) Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Invest. 119:3713–22.CrossRefGoogle Scholar
  41. 41.
    Jinushi M, et al. (2008) Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment. Cancer Res. 68:8889–98.CrossRefGoogle Scholar
  42. 42.
    Henson PM, Hume DA. (2006) Apoptotic cell removal in development and tissue homeostasis. Trends Immunol. 27:244–50.CrossRefGoogle Scholar
  43. 43.
    Henson PM, Bratton DL, Fadok VA. (2001) Apoptotic cell removal. Curr. Biol. 11: R795–805.CrossRefGoogle Scholar
  44. 44.
    Savill J, Dransfield I, Gregory C, Haslett C. (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2:965–75.CrossRefGoogle Scholar
  45. 45.
    Wu Y, Tibrewal N, Birge RB. (2006) Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol. 16:189–97.CrossRefGoogle Scholar
  46. 46.
    Fadok VA, et al. (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature. 405:85–90.CrossRefGoogle Scholar
  47. 47.
    Oka K, et al. (1998) Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 95:9535–40.CrossRefGoogle Scholar
  48. 48.
    Kawasaki Y, Nakagawa A, Nagaosa K, Shiratsuchi A, Nakanishi Y. (2002) Phosphatidylserine binding of class B scavenger receptor type I, a phagocytosis receptor of testicular sertoli cells. J. Biol. Chem. 277:27559–66.CrossRefGoogle Scholar
  49. 49.
    Anderson HA, et al. (2003) Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat. Immunol. 4:87–91.CrossRefGoogle Scholar
  50. 50.
    Fink SL, Cookson BT. (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73:1907–16.CrossRefGoogle Scholar
  51. 51.
    Bell CW, Jiang W, Reich CF, 3rd, Pisetsky DS. (2006) The extracellular release of HMGB1 during apoptotic cell death. Am. J. Physiol. Cell Physiol. 291: C1318–25.CrossRefGoogle Scholar
  52. 52.
    Munoz LE, et al. (2005) SLE—a disease of clearance deficiency? Rheumatology (Oxford). 44:1101–7.CrossRefGoogle Scholar
  53. 53.
    Silva MT, do Vale A, dos Santos NM. (2008) Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis. 13:463–82.CrossRefGoogle Scholar
  54. 54.
    Zheng L, He M, Long M, Blomgran R, Stendahl O. (2004) Pathogen-induced apoptotic neutrophils express heat shock proteins and elicit activation of human macrophages. J. Immunol. 173:6319–26.CrossRefGoogle Scholar
  55. 55.
    Hotchkiss RS, et al. (2003) Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc. Natl. Acad. Sci. U. S. A. 100:6724–9.CrossRefGoogle Scholar
  56. 56.
    Henson PM. (2005) Dampening inflammation. Nat. Immunol. 6:1179–81.CrossRefGoogle Scholar
  57. 57.
    Fadok VA, et al. (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. 101:890–8.CrossRefGoogle Scholar
  58. 58.
    Voll RE, et al. (1997) Immunosuppressive effects of apoptotic cells. Nature. 390:350–1.CrossRefGoogle Scholar
  59. 59.
    Monks J, et al. (2005) Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ. 12:107–14.CrossRefGoogle Scholar
  60. 60.
    Miksa M, et al. (2008) Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. Int. J. Mol. Med. 22:743–8.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Chung CS, Xu YX, Chaudry IH, Ayala A. (1998) Sepsis induces increased apoptosis in lamina propria mononuclear cells which is associated with altered cytokine gene expression. J. Surg. Res. 77:63–70.CrossRefGoogle Scholar
  62. 62.
    Hotchkiss RS, Nicholson DW. (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat. Rev. Immunol. 6:813–22.CrossRefGoogle Scholar
  63. 63.
    Wang SD, Huang KJ, Lin YS, Lei HY. (1994) Sepsis-induced apoptosis of the thymocytes in mice. J. Immunol. 152:5014–21.PubMedGoogle Scholar
  64. 64.
    Miksa M, Komura H, Wu R, Shah KG, Wang P. (2009) A novel method to determine the engulfment of apoptotic cells by macrophages using pHrodo succinimidyl ester. J. Immunol. Methods. 342:71–7.CrossRefGoogle Scholar
  65. 65.
    Chaudry IH. (1999) Sepsis: lessons learned in the last century and future directions. Arch. Surg. 134:922–9.CrossRefGoogle Scholar
  66. 66.
    Deitch EA. (1998) Animal models of sepsis and shock: a review and lessons learned. Shock 9:1–11.CrossRefGoogle Scholar
  67. 67.
    Echtenacher B, Freudenberg MA, Jack RS, Mannel DN. (2001) Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis. Infect. Immun. 69:7271–6.CrossRefGoogle Scholar
  68. 68.
    Li P, et al. (1995) Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 80:401–11.CrossRefGoogle Scholar
  69. 69.
    Lotze MT, Tracey KJ. (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5:331–42.CrossRefGoogle Scholar
  70. 70.
    Meyer TA, et al. (1995) Sepsis and endotoxemia stimulate intestinal interleukin-6 production. Surgery. 118:336–42.CrossRefGoogle Scholar
  71. 71.
    Tracey KJ, et al. (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 330:662–4.CrossRefGoogle Scholar
  72. 72.
    Wang H, et al. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285:248–51.CrossRefGoogle Scholar
  73. 73.
    Qin S, et al. (2006) Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med. 203:1637–42.CrossRefGoogle Scholar
  74. 74.
    Levonen AL, Vahakangas E, Koponen JK, Yla-Herttuala S. (2008) Antioxidant gene therapy for cardiovascular disease: current status and future perspectives. Circulation. 117:2142–50.CrossRefGoogle Scholar
  75. 75.
    Thurman JM. (2007) Triggers of inflammation after renal ischemia/reperfusion. Clin. Immunol. 123:7–13.CrossRefGoogle Scholar
  76. 76.
    Arumugam TV, et al. (2006) Complement mediators in ischemia-reperfusion injury. Clin. Chim. Acta. 374:33–45.CrossRefGoogle Scholar
  77. 77.
    Huk I, et al. (2000) Prostaglandin E1 reduces ischemia/reperfusion injury by normalizing nitric oxide and superoxide release. Shock. 14:234–42.CrossRefGoogle Scholar
  78. 78.
    Zingarelli B, et al. (2007) Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone, in reperfusion injury: role of nuclear factor-kappaB, heat shock factor 1, and Akt. Shock. 28:554–63.PubMedGoogle Scholar
  79. 79.
    Vedder NB, et al. (1990) Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear. Proc. Natl. Acad. Sci. U. S. A. 87:2643–6.CrossRefGoogle Scholar
  80. 80.
    Winn RK, Ramamoorthy C, Vedder NB, Sharar SR, Harlan JM. (1997) Leukocyte-endothelial cell interactions in ischemia-reperfusion injury. Ann. N. Y. Acad. Sci. 832:311–21.CrossRefGoogle Scholar
  81. 81.
    Chen CH, Liu K, Chan JY. (2008) Anesthetic preconditioning confers acute cardioprotection via up-regulation of manganese superoxide dismutase and preservation of mitochondrial respiratory enzyme activity. Shock. 29:300–8.PubMedGoogle Scholar
  82. 82.
    Rivo J, et al. (2007) Attenuation of reperfusion lung injury and apoptosis by A2A adenosine receptor activation is associated with modulation of Bcl-2 and Bax expression and activation of extracellular signal-regulated kinases. Shock. 27:266–73.CrossRefGoogle Scholar
  83. 83.
    Wei Q, Yin XM, Wang MH, Dong Z. (2006) Bid deficiency ameliorates ischemic renal failure and delays animal death in C57BL/6 mice. Am. J. Physiol. Renal Physiol. 290: F35–42.CrossRefGoogle Scholar
  84. 84.
    Steffens S, Montecucco F, Mach F. (2009) The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb. Haemost. 102:240–7.CrossRefGoogle Scholar
  85. 85.
    Walsh KB, Toledo AH, Rivera-Chavez FA, Lopez-Neblina F, Toledo-Pereyra LH. (2009) Inflammatory mediators of liver ischemia-reperfusion injury. Exp. Clin. Transplant. 7:78–93.PubMedGoogle Scholar
  86. 86.
    Wanderer AA. (2008) Ischemic-reperfusion syndromes: biochemical and immunologic rationale for IL-1 targeted therapy. Clin. Immunol. 128:127–32.CrossRefGoogle Scholar
  87. 87.
    An S, Hishikawa Y, Liu J, Koji T. (2007) Lung injury after ischemia-reperfusion of small intestine in rats involves apoptosis of type II alveolar epithelial cells mediated by TNF-alpha and activation of Bid pathway. Apoptosis. 12:1989–2001.CrossRefGoogle Scholar
  88. 88.
    Collange O, et al. (2005) Pulmonary apoptosis after supraceliac aorta clamping in a rat model. J. Surg. Res. 129:190–5.CrossRefGoogle Scholar
  89. 89.
    Kelly KJ. (2003) Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 14:1549–58.CrossRefGoogle Scholar
  90. 90.
    Hanayama R, Miyasaka K, Nakaya M, Nagata S. (2006) MFG-E8-dependent clearance of apoptotic cells, and autoimmunity caused by its failure. Curr. Dir. Autoimmun. 9:162–72.PubMedGoogle Scholar
  91. 91.
    Hart SP, Dransfield I, Rossi AG. (2008) Phagocytosis of apoptotic cells. Methods. 44:280–5.CrossRefGoogle Scholar
  92. 92.
    Tendler DA. (2003) Acute intestinal ischemia and infarction. Semin. Gastrointest. Dis. 14:66–76.PubMedGoogle Scholar
  93. 93.
    Matthay MA, et al. (2003) Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am. J. Respir. Crit. Care. Med. 167:1027–35.CrossRefGoogle Scholar
  94. 94.
    Martin TR, Nakamura M, Matute-Bello G. (2003) The role of apoptosis in acute lung injury. Crit. Care. Med. 31:S184–8.CrossRefGoogle Scholar
  95. 95.
    Perl M, Lomas-Neira J, Chung CS, Ayala A. (2008) Epithelial cell apoptosis and neutrophil recruitment in acute lung injury — a unifying hypothesis? What we have learned from small interfering RNAs. Mol. Med. 14:465–75.CrossRefGoogle Scholar
  96. 96.
    Swan R, et al. (2007) Polymicrobial sepsis enhances clearance of apoptotic immune cells by splenic macrophages. Surgery. 142:253–61.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Akihisa Matsuda
    • 1
    • 2
  • Asha Jacob
    • 1
    • 2
  • Rongqian Wu
    • 1
    • 2
  • Mian Zhou
    • 1
    • 2
  • Jeffrey M. Nicastro
    • 2
  • Gene F. Coppa
    • 2
  • Ping Wang
    • 1
    • 2
  1. 1.Laboratory of Surgical ResearchThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of SurgeryNorth Shore University Hospital and Long Island Jewish Medical CenterManhassetUSA

Personalised recommendations