Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Ashare, Alix; Powers, Linda S.; Butler, Noah S.; Doerschug, Kevin C.; Monick, Martha M.; Hunninghake, Gary W.

doi:10.1152/ajplung.00231.2004

Cited by 84 publications

(73 citation statements)

References 41 publications

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“…Van den Berg et al [15] assessed the cytokine levels in a murine model with S. aureus bacteremia and showed that levels of IL-1, IL-6, and TNF-α in serum were significantly elevated. Ashare et al [20] also suggested that levels of TNF-α and IL-1β in liver homogenates were increased in septic mice. However, the correlations among these cytokines in S. aureus-induced bacteremia are poorly understood.…”

Section: Il-1β Il-6 and Tnf-αmentioning

confidence: 97%

Inflammatory responses and histopathological changes in a mouse model of Staphylococcus aureus-induced bloodstream infections

Zhou

Shijing

et al. 2017

J Infect Dev Ctries

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Introduction: Staphylococcus aureus-induced bloodstream infections (BSIs) remain a prevalent clinical challenge and the underlying pathogenesis is still poorly understood. The aim of this study was to investigate the inflammatory responses and histopathological changes in BSIs in mice. Methodology: Male C57BL/6 mice were inoculated with S. aureus intravenously to induce BSIs. The survival rate, weight loss, and murine sepsis scores (MSS) were monitored in BSI and phosphate-buffered saline (PBS) control mice. Blood samples and tissue homogenates were plated on agar plates to determine the bacterial burden. Inflammatory proteins and cytokines were determined by enzyme-linked immunosorbent assay (ELISA) kits. Histopathologic changes were assessed by pathological inflammation score (PIS) and macroscopic and microscopic examinations. Results: BSI mice induced by 4.5 × 10 8 CFU/mL S. aureus showed ~70% survival rate, higher sepsis scores, significantly decreased body weight, elevated levels of white blood cell (WBC) counts, C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Prominent correlations were found between elevated CRP and PCT levels as well as among IL-1β, IL-6, and TNF-α. Pathological changes and higher PIS were also observed in BSI mice. Conclusions: Our results demonstrate that inflammatory proteins (PCT and CRP) and cytokines (IL-6, IL-1β and TNF-α) play an important role in the inflammatory responses and histopathological changes in S. aureus-induced BSIs.

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Section: Il-1β Il-6 and Tnf-αmentioning

confidence: 97%

Inflammatory responses and histopathological changes in a mouse model of Staphylococcus aureus-induced bloodstream infections

Zhou

Shijing

et al. 2017

J Infect Dev Ctries

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“…In contrast, overexpression of regulatory cytokines, such as IL-10, may induce overt immunosuppression and thereby increase mortality (67,68). Therefore, an imbalance in the relative production of proinflammatory or antiinflammatory cytokines can lead to serious pathological consequences (69,70).…”

Section: Figurementioning

confidence: 99%

Individual Genetic Variations Directly Effect Polarization of Cytokine Responses to Superantigens Associated with Streptococcal Sepsis: Implications for Customized Patient Care

Nooh

Nookala

Kansal

et al. 2011

The Journal of Immunology

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Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II–DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II–DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vβ repertoires, the presentation of Strep-SAgs by the protective HLA-II–DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II–DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti–IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.

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“…technique to detect bacterial translocation in sepsis. PCR is more sensitive than standard plating techniques in that it can quantify exact numbers of bacteria and is able to detect lowlevel bacteremia (31,32). In addition, sepsis is associated with an active cellular and humoral response, resulting in bacterial killing.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor–1 Levels Contribute to the Development of Bacterial Translocation in Sepsis

Hunninghake¹,

Doerschug²,

Nymon³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)-1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis. Objectives: We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation. Methods: Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry. Measurements and Main Results:We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels. Conclusions: These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.

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Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Abstract: Anti-inflammatory response is associated with mortality and severity of infection in sepsis.

Cited by 84 publications

References 41 publications

Inflammatory responses and histopathological changes in a mouse model of Staphylococcus aureus-induced bloodstream infections

Inflammatory responses and histopathological changes in a mouse model of Staphylococcus aureus-induced bloodstream infections

Individual Genetic Variations Directly Effect Polarization of Cytokine Responses to Superantigens Associated with Streptococcal Sepsis: Implications for Customized Patient Care

Insulin-like Growth Factor–1 Levels Contribute to the Development of Bacterial Translocation in Sepsis

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