TARGETED DELIVERY OF siRNA TO CELL DEATH PROTEINS IN SEPSIS

Brahmamdam, Pavan; Watanabe, Eizo; Unsinger, Jacqueline; Chang, Katherine; Schierding, William; Hoekzema, Andrew; Zhou, Tony; McDonough, Jacquelyn S.; Holemon, Heather; Heidel, Jeremy D.; Coopersmith, Craig M.; McDunn, Jonathan E.; Hotchkiss, Richard S.

doi:10.1097/shk.0b013e318194bcee

Cited by 43 publications

(32 citation statements)

References 45 publications

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“…FACS is also able to discriminate the expression of surface molecules from intracellular antigens: intracellular levels of TLR2 and TLR4 in NK cells from septic patients were increased compared to healthy subjects (79). Moreover, FACS allows the analysis of cell cycle phases and apoptosis, the programmed cell death mechanism known to play a key role in sepsis-associated tissue injury and immunoparalysis (84). …”

Section: Resultsmentioning

confidence: 99%

Immune Cell Phenotype and Function in Sepsis

Rimmelé

Payen²,

Cantaluppi³

et al. 2016

Shock

140

119

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Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis. The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of non extracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed. A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8 and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes and the cell function.

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Section: Resultsmentioning

confidence: 99%

Immune Cell Phenotype and Function in Sepsis

Rimmelé

Payen²,

Cantaluppi³

et al. 2016

Shock

140

119

View full text Add to dashboard Cite

show abstract

“…Perhaps, if the comparisons were restricted to a particular cell class, such as circulating lymphocytes or monocytes, a much better correlation of the genomic response between mice and humans might have existed. In this regard, the dramatic upregulation in mouse lymphocytes of the genes encoding pro-apoptotic B cell lymphoma 2 (BCL-2) family members and downregulation of genes encoding anti-apoptotic BCL-2 family members has also been documented in lymphocytes from patients with sepsis 170,171 . The significance of this correlation for a particular class of genes in mice and humans is highlighted by the fact that apoptosis is a key pathogenic mechanism in sepsis.…”

Section: Figurementioning

confidence: 99%

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

2013

Self Cite

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Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease.

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“…Based on the observations that caspase-3, caspase-8 and caspase-9 molecules were activated, they concluded that both the extrinsic or death receptor apoptotic pathway (caspase-3 and caspase-8) as well as the mitochondrial apoptotic pathway (caspase-9) were involved in the lymphoid cell apoptotic process (20). Although lymphocyte caspase-3 activity was found to be increased, several preclinical trauma and sepsis studies did not find evidence to support a role for TNF or Fas ligand activation of the death receptor as the trigger which initiated the apoptotic response (21,22). Nonetheless, blockade of the extrinsic caspase-3 or the mitochondrial caspase-9 apoptotic pathways was effective in preventing sepsis or trauma-induced lymphoid tissue apoptosis (22).…”

Section: Discussionmentioning

confidence: 99%

Early Trauma-Hemorrhage–Induced Splenic and Thymic Apoptosis Is Gut-Mediated and Toll-Like Receptor 4-Dependent

Tiesi

Reino²,

Mason³

et al. 2013

Shock

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Immune depression after trauma-hemorrhage has been implicated as an important factor in the pathogenesis of sepsis and septic-organ failure. Although recent studies have implicated immune cell apoptosis as an important factor in the evolution of this post-trauma immune suppressed state, neither the initial triggers that induce this response nor the cellular pathways through which these triggering pathways act have been fully defined. Thus, the current study tests the hypothesis that acute splenic and thymic immune cell apoptosis developing after trauma-hemorrhagic shock (T/HS) is due to gut-derived factors carried in intestinal lymph and that this T/HS lymph-induced immune depressed state is mediated through TLR4. The first set of experiments documented that T/HS caused both thymic and splenic immune cell apoptosis as measured by TUNEL and caspase-3 immunohistochemistry and that this increase in apoptosis was totally abrogated by mesenteric lymph duct ligation. In subsequent experiments, mesenteric lymph collected from animals subjected to T/HS or trauma-sham shock (T/SS) were injected into TLR4 deficient (TLR4mut) mice or their wild-type (WT) littermates. T/HS, but not T/SS, lymph caused splenic apoptosis in the WT mice. However, the TLR4mutmice were resistant to T/HS lymph-induced splenic apoptosis. Furthermore, the WT, but not the TLR4mutmice developed splenic apoptosis after actual T/HS. In conclusion, gut-derived factors appear to initiate a sequence of events that leads to an acute increase in splenic and thymic immune cell apoptosis and this process is TLR4-dependent.

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TARGETED DELIVERY OF siRNA TO CELL DEATH PROTEINS IN SEPSIS

Cited by 43 publications

References 45 publications

Immune Cell Phenotype and Function in Sepsis

Immune Cell Phenotype and Function in Sepsis

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

Early Trauma-Hemorrhage–Induced Splenic and Thymic Apoptosis Is Gut-Mediated and Toll-Like Receptor 4-Dependent

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