Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

Silva, Fabiano Pinheiro da; Nizet, Victor

doi:10.1007/s10495-009-0320-3

Cited by 88 publications

(65 citation statements)

References 127 publications

(126 reference statements)

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“…Under classic conditions, apoptosis was proposed to be an inflammationindependent form of cell death (58). However, it is now clear that cells die via complex mechanisms, and that apoptotic cells can undergo secondary necrosis if not rapidly cleared by phagocytes (59). It is also clear that, during these responses, injured cells elaborate a number of danger signals, which can induce inflammation by activating Toll-like receptor 3 and Ctype lectin receptors (59).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is now clear that cells die via complex mechanisms, and that apoptotic cells can undergo secondary necrosis if not rapidly cleared by phagocytes (59). It is also clear that, during these responses, injured cells elaborate a number of danger signals, which can induce inflammation by activating Toll-like receptor 3 and Ctype lectin receptors (59). In accord with this scenario, the cell death response in this oxidant injury model has been extensively studied and shown to have features of both apoptosis and necrosis (14,60,61).…”

Section: Discussionmentioning

confidence: 99%

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The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

Sohn

Kang²,

Mizunuma³

et al. 2010

Am J Respir Crit Care Med

117

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Rationale: Prolonged exposure to 100% O 2 causes hyperoxic acute lung injury (HALI), characterized by alveolar epithelial cell injury and death. We previously demonstrated that the murine chitinase-like protein, breast regression protein (BRP)-39 and its human homolog, YKL-40, inhibit cellular apoptosis. However, the regulation and roles of these molecules in hyperoxia have not been addressed. Objectives: We hypothesized that BRP-39 and YKL-40 (also called chitinase-3-like 1) play important roles in the pathogenesis of HALI. Methods: We characterized the regulation of BRP-39 during HALI and the responses induced by hyperoxia in wild-type mice, BRP-39-null (2/2) mice, and BRP-39 2/2 mice in which YKL-40 was overexpressed in respiratory epithelium. We also compared the levels of tracheal aspirate YKL-40 in premature newborns with respiratory failure. Measurements and MainResults: These studies demonstrate that hyperoxia inhibits BRP-39 in vivo in the murine lung and in vitro in epithelial cells. They also demonstrate that BRP-39 2/2 mice have exaggerated permeability, protein leak, oxidation, inflammatory, chemokine, and epithelial apoptosis responses, and experience premature death in 100% O 2 . Lastly, they demonstrate that YKL-40 ameliorates HALI, prolongs survival in 100% O 2 , and rescues the exaggerated injury response in BRP-39 2/2 animals. In accord with these findings, the levels of tracheal aspirate YKL-40 were lower in premature infants treated with hyperoxia for respiratory failure who subsequently experienced bronchopulmonary dysplasia or death compared with those that did not experience these complications.Conclusions: These studies demonstrate that hyperoxia inhibits BRP-39/YKL-40, and that BRP-39 and YKL-40 are critical regulators of oxidant injury, inflammation, and epithelial apoptosis in the murine and human lung.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

Sohn

Kang²,

Mizunuma³

et al. 2010

Am J Respir Crit Care Med

117

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“…Unbridled production of inflammatory immune mediators during severe sepsis can result in capillary leakage, tissue injury, lethal organ failure, and mitochondrial dysfunction leading to inhibition of oxidative respiration (6,12,18,51,62). The overt loss of immune cells by extensive cell death compromises the host's ability to eradicate the infectious agent, leading to unchecked replication of the pathogen (31,50). During respiratory F. novicida infection in mice, the rapid rate of bacterial replication is followed by systemic dissemination and bacteremia (40,54).…”

mentioning

confidence: 99%

Vaccination with an Attenuated Strain of Francisella novicida Prevents T-Cell Depletion and Protects Mice Infected with the Wild-Type Strain from Severe Sepsis

Sharma

Mishra

et al. 2009

Infect Immun

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Francisella tularensis is the causative agent of zoonotic tularemia, a severe pneumonia in humans, and Francisella novicida causes a similarly severe tularemia in mice upon inhalation. The correlates of protective immunity, as well as the virulence mechanisms of this deadly pathogen, are not well understood. In the present study, we compared the host immune responses of lethally infected and vaccinated mice to highlight the host determinants of protection from this disease. Intranasal infection with an attenuated mutant (Mut) of F. novicida lacking a 58-kDa hypothetical protein protected C57BL/6 mice from a subsequent challenge with the fully virulent wild-type strain U112 via the same route. The protection conferred by Mut vaccination was associated with reduced bacterial burdens in systemic organs, as well as the absence of bacteremia. Also, there was reduced lung pathology and associated cell death in the lungs of vaccinated mice. Both vaccinated and nonvaccinated mice displayed an initial 2-day delay in upregulation of signature inflammatory mediators after challenge. Whereas the nonvaccinated mice developed severe sepsis characterized by hypercytokinemia and T-cell depletion, the vaccinated mice displayed moderated cytokine induction and contained increased numbers of ␣␤ T cells. The recall response in vaccinated mice consisted of a characteristic Th1-type response in terms of cytokines, as well as antibody isotypes. Our results show that a regulated Th1 type of cell-mediated and humoral immunity in the absence of severe sepsis is associated with protection from respiratory tularemia, whereas a deregulated host response leading to severe sepsis contributes to mortality.

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“…Although a great deal of preclinical and clinical trials have been carried out testing the efficacy and safety of various anti-sepsis agents (e.g., anti-cytokine and anti-endotoxin antibodies, steroids, antithrombin, insulin and inhibition of apoptosis), these investigations have not resulted in the development of effective clinical treatments (2)(3)(4)(5). Apoptosis plays an important role in the pathobiology of sepsis (20)(21)(22)(23)(24)(25). Reduction of apoptosis by overexpression of the anti-apoptotic Bcl-2 protein or inhibition of pro-apoptotic molecules such as caspases, Fas-ligand, TNF-R or TRAIL has been proven to be beneficial in septic animals (26)(27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Expression and characterization of recombinant human milk fat globule-EGF factor VIII

Qiang

et al. 2011

Int J Mol Med

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Abstract. Apoptosis plays an important role in the pathobiology of sepsis. The opsonizing protein milk fat globule-EGF factor VIII (MFG-E8) is involved in apoptotic cell clearance. Our previous studies have shown that administration of rat MFG-E8-containing exosomes or recombinant murine MFG-E8 (rmMFG-E8) is protective in a rat model of sepsis induced by cecal ligation of puncture (CLP). However, one obstacle hampering the development of MFG-E8 as a therapeutic agent for septic patients is the potential immunogenicity of animal proteins in humans. The purpose of this study, therefore, was to express recombinant human MFG-E8 (rhMFG-E8) and characterize its biological activity. Using an E. coli system, we successfully expressed and purified the mature molecule of human MFG-E8 (Leu24-Cys387). The purity of rhMFG-E8 was over 99% and it was immunoreactive for specific antihuman MFG-E8 antibodies. Amino acid sequence analysis by LC-MS/MS identified the purified protein as human MFG-E8. Using primary rat peritoneal macrophages, we showed that rhMFG-E8 markedly increased peritoneal macrophage phagocytosis of apoptotic thymocytes, which was as effective as commercial rmMFG-E8. To determine the biological activity of rhMFG-E8 in vivo, male adult rats were subjected to sepsis by CLP. rhMFG-E8 or rmMFG-E8 were administered intravenously at the time of CLP. Our results demonstrated that both rhMFG-E8 and rmMFG-E8 reduced thymocyte apoptosis and plasma levels of lactate and IL-6 at 20 h after CLP, and improved the 10-day survival rate. Thus, we have successfully expressed and purified biologically active rhMFG-E8. Our newly-expressed rhMFG-E8 is highly effective in the rat model of sepsis.

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Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

Cited by 88 publications

References 127 publications

The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

Vaccination with an Attenuated Strain of Francisella novicida Prevents T-Cell Depletion and Protects Mice Infected with the Wild-Type Strain from Severe Sepsis

Expression and characterization of recombinant human milk fat globule-EGF factor VIII

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