Blockade of Apoptosis as a Rational Therapeutic Strategy for the Treatment of Sepsis

Ayala, Alfred; Wesche-Soldato, Doreen E.; Perl, Mario; Lomas-Neira, Joanne; Swan, Ryan Z.; Chung, Chun‐Shiang

doi:10.1002/9780470059593.ch4

Cited by 24 publications

(22 citation statements)

References 45 publications

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“…In particular, an increased leukocyte apoptosis has been observed in septic patients [5]. Two major apoptotic pathways are activated: the extrinsic or death receptor-initiated caspase-8 mediated pathway, involving the superfamily of TNF receptor members; and the intrinsic or mitochondria-initiated caspase-9 pathway, which interplays between pro-apoptotic and anti-apoptotic members of the BCL-2 family [6]. …”

Section: Introductionmentioning

confidence: 99%

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Upregulation of the pro-apoptotic genes BID and FAS in septic shock patients

et al. 2010

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IntroductionLymphocyte apoptosis has been suggested to play a central role in sepsis pathophysiology, and studies in animal models demonstrated that blocking this pathway improves outcome. However, no routine biomarkers of apoptosis are so far available in patients. Thus, the aim of our study was to assess the different biomarkers of apoptosis putatively usable on a routine basis in septic shock.MethodsThirteen septic shock patients (sampled twice between days 1 to 2 and days 3 to 5 after diagnosis of shock) and 15 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis was measured in lymphocyte subpopulations using flow cytometry (Annexin-V binding, activated caspase-3 and Bcl-2 expressions). Representative pro-apoptotic and anti-apoptotic gene expressions were assessed by quantitative reverse-transcription PCR. Monocyte HLA-DR expression and lymphocyte subpopulation cell counts were measured as markers of sepsis-induced immune dysfunctions. To test for statistical significance, the Mann-Whitney U test was used with correction by the number of tests performed.ResultsFlow cytometric measurements of apoptosis in septic shock patients showed an increased Annexin-V binding on CD4+ T cells and an increased active caspase-3 expression on B cells only at days 3 to 5 (sixfold change and twofold change, respectively). Gene expression analysis showed an increased BCL-XL mRNA and an upregulation of the pro-apoptotic genes BID and FAS in septic shock patients (10-fold change and fivefold change, respectively) compared with healthy controls.ConclusionsThe present study highlights the difficulties encountered in monitoring apoptosis on a routine basis in septic patients, whereas in the same sampling conditions and on the same patients, HLA-DR expression and lymphocyte subpopulation cell counts showed characteristics described in the literature. However, pro-apoptotic genes BID and FAS appear to constitute promising apoptosis markers in our hands.

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Section: Introductionmentioning

confidence: 99%

“…Interestingly, numerous studies in animal models of sepsis showed that blocking programmed cell death improves outcome after septic challenge [6]. This approach could thus represent a potential innovative therapeutic strategy in septic shock.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the pro-apoptotic genes BID and FAS in septic shock patients

et al. 2010

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“…PPAR- γ activation during the onset of sepsis inhibits inflammatory gene expression and can negatively interfere with proinflammatory transcription factor signaling pathways in inflammatory cells, resulting in the prevention of sepsis progression via an attenuation of the hyperinflammatory response. The body diminishes the harmful effects of the late phase of sepsis by producing anti-inflammatory cytokines and enhancing immune paralysis via immune cell apoptosis [22, 23]. Hotchkiss and colleagues showed that the depletion of lymphocytes is the central pathogenic event during sepsis and is a major contributor to poor outcomes following sepsis [22, 24–27].…”

Section: Discussionmentioning

confidence: 99%

“…The body diminishes the harmful effects of the late phase of sepsis by producing anti-inflammatory cytokines and enhancing immune paralysis via immune cell apoptosis [22, 23]. Hotchkiss and colleagues showed that the depletion of lymphocytes is the central pathogenic event during sepsis and is a major contributor to poor outcomes following sepsis [22, 24–27]. Compared with the major (Pro) allele, the minor (Ala) allele of PPAR- γ is less biochemically active; therefore, we speculated that the improved survival and outcome of Ala carriers might be due to an attenuation of T cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The Pro12Ala Polymorphism of PPAR-γGene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population

Wang

et al. 2014

PPAR Research

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Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P = 0.622 for genotype; P = 0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P = 0.014 for allele and P = 0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P = 0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P < 0.001). Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis.

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“…Se ha observado, en forma particular, un aumento de la apoptosis de células efectoras inmunes 45 . Dos importantes vía para la apoptosis son activadas: la extrínseca o mediada por el receptor iniciador de muerte caspasa-8, que involucra la superfamilia de los receptores de FNT; y la vía intrínseca o vía caspasa-9 mitocondrial, que interactúa con los miembros pro-apoptosis y los anti-apoptosis de la familia de los BCL-2 46 . Se ha descrito además un shift desde un fenotipo inmune TH1 hacia un fenotipo TH2 anérgico, y se ha sugerido que podría existir una regulación hacia arriba de proteínas inhibitorias, ó una regulación hacia abajo de proteínas co-estimuladoras 47 .…”

Section: Discussionunclassified