Ryan Swan

Alpert Medical School - Brown University, Providence, RI, United States

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Publications (10)43.31 Total impact

  • 05/2009: pages 205 - 229; , ISBN: 9783527626151
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    ABSTRACT: Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1(-/-) mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1(-/-) mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.
    Proceedings of the National Academy of Sciences 04/2009; 106(15):6303-8. · 9.81 Impact Factor
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    ABSTRACT: The inability of present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. This review will examine the concept that a portion of the immune and organ dysfunctions encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the apoptotic response, but also the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor stimuli as either an apoptotic, inflammatory and/or necrotic signal. We hope the discussion of such studies provides not only new insight into the pathobiology of sepsis, but also suggests possible therapeutic targets for the management of this devastating condition.
    Current Pharmaceutical Design 06/2008; 14(19):1853-1859. · 3.31 Impact Factor
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    ABSTRACT: The inability of present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. This review will examine the concept that a portion of the immune and organ dysfunctions encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the apoptotic response, but also the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor stimuli as either an apoptotic, inflammatory and/or necrotic signal. We hope the discussion of such studies provides not only new insight into the pathobiology of sepsis, but also suggests possible therapeutic targets for the management of this devastating condition.
    Current pharmaceutical design 02/2008; 14(19):1853-9. · 4.41 Impact Factor
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    ABSTRACT: Macrophage phagocytosis of apoptotic cells induces an anti-inflammatory macrophage phenotype. Immune cell apoptosis is widespread in sepsis; however, it is unknown whether sepsis alters the capacity of macrophages to clear this expanded population. We hypothesize that sepsis will enhance splenic macrophage phagocytosis of apoptotic immune cells, potentially contributing to immunosuppression. Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP). Apoptosis was induced in mouse thymocytes by dexamethasone incubation. At multiple time points after CLP/sham, splenic and peritoneal macrophages were isolated, plated on glass coverslips, co-incubated with apoptotic thymocytes, and fixed and the coverslips were then Giemsa stained. Splenic macrophages were also isolated 48 hours after CLP/sham, stained with the red fluorescent dye PKH26, and co-incubated with green fluorescent dye CFSE-stained apoptotic thymocytes and then coverslips were fixed and counterstained with DAPI. The macrophage phagocytic index (PI) was calculated for both staining methods. The PI of CLP splenic macrophages was significantly higher than sham by 24 hours, and this difference was sustained through 48 hours. Studies suggest that apoptotic cell clearance leads to an anti-inflammatory macrophage condition, which together with our findings in septic macrophages, may point at a process that contributes to septic immune suppression.
    Surgery 09/2007; 142(2):253-61. · 3.37 Impact Factor
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    ABSTRACT: Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1(+)CD11b(+) population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1(+) cells effectively suppress antigen-specific CD8(+) T cell interferon (IFN) gamma production but only modestly suppress antigen-specific and nonspecific CD4(+) T cell proliferation. GR-1(+) cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell-dependent and depression of Th1 cell-dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain-containing adaptor-inducing IFN-beta, or the IFN-alpha/beta receptor, is required for complete GR-1(+)CD11b(+) expansion. GR-1(+)CD11b(+) cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.
    Journal of Experimental Medicine 07/2007; 204(6):1463-74. · 13.21 Impact Factor
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    ABSTRACT: Recent research has yielded many interesting and potentially important therapeutic targets in sepsis. Specifically, the effects of antagonistic anti-cytokine therapies (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 [IL-1]) and anti-endotoxin strategies utilizing antibodies against endotoxin or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS-binding protein) have been studied. Unfortunately, these approaches often failed clinically, and in many cases, the efficacy of these treatments was dependent on the severity of sepsis. Recently, clinical trials using insulin to lock blood glucose levels and activated protein C treatment have showed that while they provided some survival benefit, their efficacy does not appear to be predicated solely upon anti-inflammatory effects. Here, we will review work done in animal models of polymicrobial sepsis and clinical findings that support the hypothesis that apoptosis in the immune system is a pathologic event in sepsis that can be a therapeutic target. In this respect, experimental studies looking at the septic animal suggest that loss of lymphocytes during sepsis may be due to dysregulated apoptosis and that this appears to be brought on by a variety of mediators effecting 'intrinsic' as well as 'extrinsic' cell death pathways. From a therapeutic perspective this has provided a number of novel targets for clinically successful current, as well as future therapies, such as caspases (caspase inhibition/protease inhibition), pro-apoptotic protein-expression (via administration and/or over-expression of Bcl-2) and the death receptor family Fas-FasL (via. FasFP [fas fusion protein] and the application of siRNA against a number pro-apoptotic factors).
    Current drug targets 05/2007; 8(4):493-500. · 3.93 Impact Factor
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    ABSTRACT: Apoptosis is an important mechanism during the immunopathogenesis of sepsis. Early programmed cell death of lymphocytes substantially impairs innate and adaptive immunity reducing the capacity to ward off the invading pathogen. Apoptosis of parenchymal cells (e.g. in the lung, liver and gut) may also promote organ failure and death. Several experimental therapeutic strategies have now been developed to beneficially influence these mechanisms; however, their potential clinical benefit is yet to be evaluated.
    Drug Discovery Today Disease Mechanisms 02/2007; 4(4):223-230.
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    ABSTRACT: Over time it has become clear that, much like other organ systems, the function and responsiveness of the immune system is impaired during the course of sepsis and that this is a precipitous event in the decline of the critically ill patient/animal. One hypothesis put forward to explain the development of septic immune dysfunction is that it is a pathological result of increased immune cell apoptosis. Alternatively, it has been proposed that the clearance of increased numbers of apoptotic cells may actively drive immune suppression through the cells that handle them. Here we review the data from studies involving septic animals and patients, which indicate that loss of immune cells, as well as non-immune cells, in some cases, is a result of dysregulated apoptosis. Subsequently, we will consider the cell death pathways, i.e. 'extrinsic' and/or 'intrinsic', which are activated and what cell populations may orchestrate this dysfunctional apoptotic process, immune and/or non-immune. Finally, we will discuss potentially novel therapeutic targets, such as caspases, death receptor family members (e.g. tumour necrosis factor, Fas) and pro-/anti apoptotic Bcl-family members, and approaches such as caspase inhibitors, the use of fusion proteins, peptidomimetics and siRNA, which might be considered for the treatment of the septic patient.
    Novartis Foundation symposium 02/2007; 280:37-49; discussion 49-52, 160-4.
  • Intensive Care Medicine 06/2006; 32(5):637-8. · 5.26 Impact Factor

Publication Stats

381 Citations
43.31 Total Impact Points

Institutions

  • 2007–2009
    • Alpert Medical School - Brown University
      • Department of Surgery
      Providence, RI, United States
    • University of Rhode Island
      • Department of Cell and Molecular Biology
      Kingston, RI, United States
  • 2006–2009
    • Rhode Island Hospital
      Providence, Rhode Island, United States