Period of Irreversible Therapeutic Intervention during Sepsis Correlates with Phase of Innate Immune Dysfunction

Cauvi, David M.; Song, Donghuan; Vázquez, Daniel; Hawisher, Dennis; Bermúdez, José; Williams, Michael R.; Bickler, Stephen W.; Coimbra, Raúl; Maio, Antonio De

doi:10.1074/jbc.m112.359562

Cited by 26 publications

(42 citation statements)

References 71 publications

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“…Indeed, Flo et al previously showed that E. coli infection induced a robust expression of Lcn2 in hepatocytes, 14 and Wu et al reported that both bronchial epithelial cells and type II pneumocytes produced significant amounts of Lcn2 following pulmonary infection. 16 Conversely, we found that the kinetic expression of CRAMP in liver and lung followed an expression pattern similar to that observed for most of the inflammatory cytokines and neutrophil infiltration, 21 indicating that neutrophils may represent the main source of CRAMP in hepatic and pulmonary tissues following CLP-induced sepsis. Although CRAMP has also been detected in several other cell types such as monocytes and respiratory epithelial cells, 36 we cannot discard the possibility that other cells may contribute to some extent to CRAMP expression in these two tissues.…”

Section: Discussionsupporting

confidence: 68%

“…35 We have previously observed that the initial recruitment of neutrophils within the first 6 h of CLP was followed by a rapid decline in the number of these granulocytes in both liver and lung. 21 We showed in this report that Lcn2 expression rapidly increased and reached a plateau expression a few hours after CLP (6 and 3 h for liver and lung, respectively). These results indicate that the kinetic of Lcn2 expression is not likely explained by the presence of neutrophils in these two tissues, but rather by other types of stimulated cells.…”

Section: Discussionmentioning

confidence: 50%

“…In our previous study, we showed that the anti-inflammatory cytokine IL-10 was not hampered by LPS injection in CLP-treated animals. 21 We therefore postulated that a reduction of LPS-induced TNF-a and IFN-b expression after CLP may be the result of an excess production of IL-10 during the immunosuppressive stage. Interestingly, recent studies have reported that IL-10 was capable of inducing the production of Lcn2 in macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Our previous studies have shown that IL-10 expression remained elevated in the liver and even significantly increased in the lung of LPS-injected CLP-treated animals compared with LPS-treated SO mice. 21 Elevated expression of IL-10 was also found in the spleen of LPS-treated septic animals (CLP + LPS) compared with LPS-treated SO mice (Supplementary Figure 1B). We therefore tested whether or not IL-10 controls Lcn2 expression in the context of an inflammatory response.…”

Section: Il-10 Potentiates Lps-mediated Lcn2 Gene and Protein Expressionmentioning

confidence: 93%

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Sustained expression of lipocalin-2 during polymicrobial sepsis

et al. 2014

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Sepsis is a major healthcare problem and a leading cause of death worldwide. There is no dependable diagnosis, and treatment for this condition remains mainly supportive. The etiology of sepsis is related to an overwhelming inflammatory response. In this regard, the antimicrobial protein lipocalin-2 (Lcn2) has been associated with several inflammatory conditions, but its contribution to polymicrobial sepsis is unclear. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and Lcn2 mRNA levels and protein expression were measured in liver and lung tissues. We observed that Lcn2 expression was robustly induced in liver and lung of C57BL/6 J (B6) mice, and remained elevated during the stage of innate immune dysfunction observed in sepsis. This response was different in A/J mice, suggesting a contribution of the genetic background, probably due to differences in IL-10 expression between these two mouse strains. Indeed, IL-10 was found to regulate Lcn2 expression in both primary and J774A.1 macrophages. Thus, Lcn2 expression is highly regulated during CLP-induced sepsis, suggesting that this antimicrobial protein could have a role as a potential biomarker for the diagnosis of sepsis.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Il-10 Potentiates Lps-mediated Lcn2 Gene and Protein Expressionmentioning

confidence: 93%

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Sustained expression of lipocalin-2 during polymicrobial sepsis

et al. 2014

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“…Animals also exhibit hypothermia during experimental abdominal sepsis (60)(61)(62), and therefore hypothermia has been proposed as an effective indicator of mortality (63). Indeed, our model of polymicrobial IAI shows strong association between hypothermia and mortality at 24 h postinfection.…”

Section: Figmentioning

confidence: 79%

Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus

et al. 2016

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c Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model of Candida albicans-Staphylococcus aureus intra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement for C. albicans morphogenesis. However, the contribution of virulence factors coregulated during the yeast-tohypha transition is unknown. This also raised the question of whether other Candida species that are unable to form hyphae are as virulent as C. albicans during polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida (NAC) species with various morphologies and C. albicans transcription factor mutants (efg1/efg1 and cph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed that S. aureus coinoculated with C. krusei or C. tropicalis was highly lethal, similar to C. albicans, while S. aureus-C. dubliniensis, S. aureus-C. parapsilosis, and S. aureus-C. glabrata coinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E 2 (PGE 2 ) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation with C. albicans strains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that select Candida species, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE 2 acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability of C. albicans to induce mortality from an intra-abdominal polymicrobial infection. I ntra-abdominal infection (IAI) is a broad term used to describe numerous infections caused by the invasion of microorganisms into the abdominal cavity. These infections can range from appendicitis to complicated peritonitis and are initiated by microbes entering the abdominal cavity through a variety of routes, including bowel perforation, laparotomy, intestinal hernias, and insertion of medical devices such as peritoneal catheters (reviewed in reference 1). These infections often are polymicrobial in nature, which complicates diagnosis and treatment. Accordingly, infections with multiple microbes can result in amplified pathogenicity, also known as "infectious synergism" (2-4), which may accelerate disease progression or protect microbes from host responses (5), resulting in higher morbidity and mortality (6, 7).Polymicrobial IAIs involving fungi result in mortality rates between 50 and 75%, compared to 10 to 30% for polymicrobial bacterial infections (8-11). The majority of polymicrobial fungal IAIs are caused by Candida albicans (12, 13). However, IAIs caused by non-albicans Candida (NAC) species are becoming more common (14). C. al...

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CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

et al. 2016

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Eur. J. Immunol. 2017. 47: 119-130 Macrophages play an essential role in controlling bacterial infection, as they efficiently eliminate pathogens, provide a significant source of cytokines, and represent and link between innate and adaptive immunity [6]. Both the environmental milieu and cellular mitochondrial metabolism [7] can alter the functional polarization of macrophages, which can be broadly classified as classically activated (M1) and alternatively activated (M2) [8]. M1 macrophages triggered by IFN-γ alone or in combination with bacterial LPS are characterized by the production of type 1 inflammatory cytokines and bactericidal mediators such as nitric oxide and reactive oxygen intermediates. Thus, M1 macrophages play a dominant role in controlling acute infections, but also have the potential to induce a cytokine storm that is associated with tissue injury. In contrast, M2 macrophages triggered by IL-4/IL-13, glucocorticoids, IL-10, or immune complexes produce elevated amounts of anti-inflammatory cytokines and Th2-recruiting chemokines. M2 macrophages exhibit efficient phagocytic activity as well as increased expression of arginase 1, and therefore contribute to tissue healing and resolution of harmful inflammation. However, prolonged M2 polarization can generate a survival niche that leads to chronic microbial infection [9]. Initial overwhelming inflammatory responses, followed by macrophage dysfunction during the later stages of infection, have been widely observed in patients with severe sepsis. This probably occurs due to a switch in the macrophage phenotype from M1 to M2, implying a close association between macrophage phenotype and the progression of sepsis [10].The transmembrane protein CD46 was initially identified as a co-factor for complement factor I, which is involved in protecting host cells from autologous complement-mediated attack [11]. CD46 also serves as a receptor for several pathogens including measles virus [12] (Fig. 1A). Systemic meningococcal dissemination was well controlled in the WT mice, but not in the CD46 +/+ mice (Fig. 1B).To investigate whether this phenomenon was a general response to gram-negative bacterial infection, we repeated the experiments, challenging the mice with E. coli LPS. A non-lethal dose (20 mg/kg) for WT mice led to 67% mortality in CD46 +/+ mice within 4 days (Fig. 1C). A reduction in body weight, a common indicator of the severity of sepsis, was observed in the CD46 +/+ mice. Body weight was maintained in WT mice even though an initial decline was observed (Fig. 1D). The levels of circulatory cytokines IL-10, IL-6, and TNF, which are closely associated with sepsis severity and a fatal outcome [27], were significantly higher in the CD46 +/+ mice than in the WT mice upon meningococcal infection (Fig. 1E). Stronger cytokine responses were also observed in CD46 +/+ mice, compared to that in WT mice, following LPS challenge even though the effect was transient and lost after 24 h for IL-10 and TNF ( hand, LPS degradation in vivo might also contribute t...

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Period of Irreversible Therapeutic Intervention during Sepsis Correlates with Phase of Innate Immune Dysfunction

Cited by 26 publications

References 71 publications

Sustained expression of lipocalin-2 during polymicrobial sepsis

Sustained expression of lipocalin-2 during polymicrobial sepsis

Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus

CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

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