Experimental Models of Sepsis and Their Clinical Relevance

Poli-de-Figueiredo, Luiz Francisco; Garrido, Alejandra G.; Nakagawa, Naomi Kondo; Sannomiya, Paulina

doi:10.1097/shk.0b013e318181a343

Cited by 217 publications

(193 citation statements)

References 42 publications

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“…Given that Gramnegative infection and administration of LPS in humans and animals result in a systemic inflammatory response (28,31) which partially mimics features of early sepsis, we tested the capacity of GXM to influence the course of LPS-induced sepsis (32). Healthy mice were treated with 100 g of GXM 60 min before or 15 min after LPS administration.…”

Section: Gxm Improves Survival Of Endotoxemic Micementioning

confidence: 99%

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

et al. 2013

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b Capsular material of the opportunistic fungus Cryptococcus neoformans is composed mainly of a polysaccharide named glucuronoxylomannan (GXM). In this study, the effects of GXM were analyzed in an in vivo experimental system of lipopolysaccharide (LPS)-induced shock. Endotoxic shock was induced in mice by a single intraperitoneal injection of LPS from Escherichia coli. GXM treatment reduced the mortality of mice at early stages. Mice treated with LPS alone showed markedly increased plasma levels of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6, whereas mice that were also treated with GXM showed significantly lower plasma levels of these cytokines. This effect was related to a marked suppression of Akt and IB␣ activation. Importantly, the inhibitory effect of GXM on proinflammatory cytokine secretion was reproduced by treatment with wortmannin, an inhibitor of the Akt transcription pathway. Our results indicate that GXM has a beneficial effect on endotoxic shock, resulting in a significant increase in the rate of survival by dampening the hyperinflammatory response.

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Section: Gxm Improves Survival Of Endotoxemic Micementioning

confidence: 99%

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

et al. 2013

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“…Conversely, the gene encoding the antimicrobial peptide cathelicidin is TLR-inducible via a vitamin Ddependent pathway in human but not mouse macrophages (8). Moreover, mice are relatively resistant to LPS-mediated toxicity (9), and many therapeutic agents that reduce inflammation and mortality in mouse septic shock models show no benefit clinically (10) or even increase mortality (e.g., nitric oxide antagonists) (11).…”

mentioning

confidence: 99%

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages

Schroder

Irvine

Taylor

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

274

284

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Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies differences in the transcriptional responses of primary human and mouse macrophages to the Toll-like receptor (TLR)–4 agonist lipopolysaccharide (LPS). By using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5′ ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologues were identified as “divergently regulated”). We further demonstrate concordant regulation of human-specific LPS target genes in primary pig macrophages. Divergently regulated orthologues were enriched for genes encoding cellular “inputs” such as cell surface receptors (e.g., TLR6, IL-7Rα) and functional “outputs” such as inflammatory cytokines/chemokines (e.g., CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. Functional consequences of divergent gene regulation were confirmed by showing LPS pretreatment boosts subsequent TLR6 responses in mouse but not human macrophages, in keeping with mouse-specific TLR6 induction. Divergently regulated genes were associated with a large dynamic range of gene expression, and specific promoter architectural features (TATA box enrichment, CpG island depletion). Surprisingly, regulatory divergence was also associated with enhanced interspecies promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change.

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“…The cecal ligation and puncture (CLP) model and its variants (8) induce a systemic inflammatory response from a polymicrobial abdominal infection. CLP, unlike surrogates like endotoxin injection (31), recreates sepsis progression most similarly to humans, with comparable hemodynamic and inflammatory profiles (8).…”

mentioning

confidence: 99%

Cecal ligation and puncture accelerates development of ventilator-induced lung injury

Yehya

Xin

Oquendo

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. Adult male Sprague-Dawley rats were subject to CLP or sham operation and, after 12 h, underwent injurious mechanical ventilation (tidal volume 30 ml/kg, positive end-expiratory pressure 0 cmH 2O) for either 0, 60, or 120 min. Biochemical and physiological measurements, as well as computed tomography, were used to assess injury at 0, 60, and 120 min of ventilation. Before ventilation, CLP rats had higher levels of alveolar neutrophils and interleukin-1␤. After 60 min of ventilation, CLP rats had worse injury as evidenced by increased alveolar inflammation, permeability, respiratory static compliance, edema, oxygenation, and computed tomography. By 120 min, CLP and sham rats had comparable levels of lung injury as assessed by many, but not all, of these metrics. CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1␤. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI.sepsis; acute lung injury NONPULMONARY SEPSIS IS A leading cause of acute respiratory distress syndrome (15); however, the etiology of the lung injury from sepsis is unclear. This is confounded by the fact that many septic patients with respiratory failure require mechanical ventilation, which itself causes injury from regional overdistension and cyclic reopening of atelectatic lung (22). This ventilator-induced lung injury (VILI) is characterized by epithelial (7, 9) and endothelial (12, 37) dysfunction, with barrier failure leading to alveolar flooding. Because sepsis and VILI share similar proinflammatory cytokine profiles (34), it is possible that an initial septic insult predisposes lungs for secondary injury from VILI.Characterization of potential interaction between sepsis and VILI requires appropriate animal models that both recapitulate the proinflammatory cascade seen in humans and allow for the testing of a priming septic insult on development of subsequent VILI. The cecal ligation and puncture (CLP) model and its variants (8) induce a systemic inflammatory response from a polymicrobial abdominal infection. CLP, unlike surrogates like endotoxin injection (31), recreates sepsis progression most similarly to humans, with comparable hemodynamic and inflammatory profiles (8).Exogenous endotoxin administration is well established to predispose lung to further injury (5, 39)...

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Experimental Models of Sepsis and Their Clinical Relevance

Cited by 217 publications

References 42 publications

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages

Cecal ligation and puncture accelerates development of ventilator-induced lung injury

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