The Mechanisms of Organ Dysfunction During Severe Infection

DOI
  • Kotani Joji
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Hirata Jun-ichi
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Goshima Masahiro
    Department of Gastroenterological Surgery, Kobe University Graduate School of Medicine
  • Yamada Mariko
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Matsudaira Munenori
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Ohya Munehiko
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Kirita Manabu
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Yoshinaga Kazumasa
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine
  • Marukawa Seishiro
    Department of Emergency and Critical Care Medicine, Hyogo College of Medicine

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Other Title
  • 周術期重症感染症の病態と治療  重症感染症における臓器障害の発生機序

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Prolonged cell survival through delayed apoptosis in circulating neutrophils and massive apoptosis induction in bone marrow cells has been demonstrated in patients and mice with systemic inflammation. Since neutrophils possess a variety of means of inducing tissue injury, delayed apoptosis of neutrophils may be implicated in the pathogenesis of persistent inflammatory states, which, in turn, might be implicated in multiple organ dysfunction syndrome.; Because the cells generated via myelopoiesis in the bone marrow, i.e. neutrophils, are a critical first line of defense against bacterial infection, the induction of apoptosis in these cells may contribute to consequent immunosuppression during the late phases of inflammatory states. Using a mouse model of acute endotoxemia, we demonstrated that the apoptotic tendency in myeloid cells is minimized as they undergo differentiation and that mature neutrophils eventually become resistant to apoptosis. This observation may be explained by the fact that TNFR-p55 plays a pro-apoptotic role in immature myeloid cells, but not in mature myeloid cells or peripheral neutrophils, via a mechanism other than the modulation of membrane-associated TNFR and Fas expression. We also demonstrated that unactivated mouse neutrophils abundantly express Bax, a death-promoting Bcl-2 homologue, but do not express anti-apoptotic Al or Mcl-1 proteins, consistent with the a short survival time of normal resting mouse neutrophils. In addition, the findings that Al was strongly induced and that Bax was constantly expressed may help to explain the prolonged survival time of activated mouse neutrophils.

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