Sepsis is the leading cause of death in many intensive care units. It is the 12th leading cause of death in the United States and the incidence is increasing rapidly because of the growing number of immunosuppressed patients. Although the general consensus has been that sepsis represents a disorder due to uncontrolled inflammation, the failure of numerous anti- inflammatory strategies has led to a rethinking of this concept. Recent evidence in both animal models and in clinical studies of patients dying of sepsis and multiple organ failure indicates that sepsis causes extensive apoptotic cell death of lymphocytes throughout the body. This loss in lymphocytes may impair the ability of patients to eradicate infection and predispose to secondary infections. Interestingly, patients with inherited defects in lymphocytes have infections with many of the same organisms as patients in the intensive care unit. Furthermore, these patients also have difficulty eradicating infections. Recent studies in which lymphocyte apoptosis was prevented by two independent methods, i.e., overexpression of the anti-apoptotic protein Bcl-2 or administration of drugs that prevent cell death proteases (caspase inhibitors), have shown a marked improvement in sepsis survival. The focus of this investigation is to determine, using transgenic mice models and adoptive transfer of lymphocytes, which lymphocyte subsets, i.e., CD4 helper T cells, CD8 cytotoxic T cells, or B cells, are critical for sepsis survival. The changes in lymphocyte effector function that occur in survivors vs. non-survivors will also be determined. Two other potential mechanisms of immune suppression in sepsis will be examined including: 1) effects of apoptotic cells to induce anti-inflammatory responses and, 2) a shift in the pattern of cytokine expression from the pro-inflammatory Th1 to the anti- inflammatory Th2.
| Francois, Bruno; Jeannet, Robin; Daix, Thomas et al. (2018) Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 3: |
| Drewry, Anne M; Fuller, Brian M; Skrupky, Lee P et al. (2015) The presence of hypothermia within 24 hours of sepsis diagnosis predicts persistent lymphopenia. Crit Care Med 43:1165-9 |
| Drewry, Anne M; Hotchkiss, Richard S (2015) Sepsis: Revising definitions of sepsis. Nat Rev Nephrol 11:326-8 |
| Hutchins, Noelle A; Unsinger, Jacqueline; Hotchkiss, Richard S et al. (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224-33 |
| Fuller, Brian M; Mohr, Nicholas M; Hotchkiss, Richard S et al. (2014) Reducing the burden of acute respiratory distress syndrome: the case for early intervention and the potential role of the emergency department. Shock 41:378-87 |
| Walton, Andrew H; Muenzer, Jared T; Rasche, David et al. (2014) Reactivation of multiple viruses in patients with sepsis. PLoS One 9:e98819 |
| Drewry, Anne M; Samra, Navdeep; Skrupky, Lee P et al. (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42:383-91 |
| Hotchkiss, Richard S; Monneret, Guillaume; Payen, Didier (2013) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13:862-74 |
| Drewry, Anne M; Fuller, Brian M; Bailey, Thomas C et al. (2013) Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: a case-control study. Crit Care 17:R200 |
| Takasu, Osamu; Gaut, Joseph P; Watanabe, Eizo et al. (2013) Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 187:509-17 |
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