Serial cytokine levels in patients with severe sepsis

Wu, Huang-Pin; Chen, Chian-Kuang; Chung, Kian Fan; Tseng, Jo-Chi; Hua, Chung-Ching; Liu, Yu-Chih; Chuang, Duen-Yau; Yang, Chung-Han

doi:10.1007/s00011-009-0003-0

Cited by 101 publications

(89 citation statements)

References 38 publications

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“…This phenotype is thought to result mainly from suppression of hematopoiesis by elevated inflammatory cytokines such as TNF-␣ and IFN-␥ and from engulfment of hematopoietic cells by BM macrophages. 39 The serum concentrations of these cytokine levels in HLH are usually quite higher than those with sepsis, 40 suggesting that these extremely high levels of cytokines should be critical in the pathogenesis of HLH. In the present study, we show that HLH patients have low numbers of HSCs, and that HSCs from HLH patients down-regulate CD47 and are prone to be engulfed by macrophages more actively than normal HSCs.…”

Section: Discussionmentioning

confidence: 99%

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis

Kuriyama

Takenaka

Kohno

et al. 2012

Blood

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Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein ␣ (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSCspecific CD47 down-regulation might be critical for HLH development. (Blood. 2012;120(19):4058-4067) IntroductionHemophagocytic lymphohistiocytosis (HLH) is a syndrome with excessive immune activation characterized by deregulated engulfment of hematopoietic cells by macrophages in the BM. Patients with HLH display hemophagocytosis, pancytopenia, and various inflammatory symptoms, including high fever, acute liver failure, and splenomegaly. [1][2][3][4] HLH is classified into primary HLH and secondary HLH. Primary HLH, also known as familial hemophagocytic lymphohistiocytosis, shows clear familial inheritance or genetic causes, including mutations in the perforin (PRF1), syntaxin 11 (STX11), and RAB27A genes. [5][6][7][8][9] In primary HLH, natural killer cells and/or cytotoxic T lymphocytes fail to eliminate the targets in response to inflammatory reactions, and the resulting sustained inflammatory responses induce deregulated activation of macrophages. In secondary HLH, macrophages are activated in association with infections and malignant disorders. 4 The key pathogenic feature of HLH is hypercytokinemia including IFN-␥, TNF-␣, IL-6, and M-CSF, which may activate macrophages to engulf blood cells. 3 These cytokines are produced mainly by natural killer cells and cytotoxic T lymphocytes, and might stimulate BM macrophages to engulf erythrocytes, leukocytes, platelets, and their precursors in the BM.The question is, if hypercytokinemia causes activation of macrophages to engulf blood cells, why does such activation occur specifically in BM macrophages and induce severe hypocellularity and pancytopenia? Engulfment is triggered by the binding of specific recept...

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Section: Discussionmentioning

confidence: 99%

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis

Kuriyama

Takenaka

Kohno

et al. 2012

Blood

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“…Interestingly, confusion is an associated factor with increased levels of the pro-inflammatory cytokine IL-6, while arterial hypotension has a stronger association with increased levels of the anti-inflammatory cytokine IL-10. Moreover, in patients with severe sepsis or septic shock, increased IL-10 levels in blood were associated with a poorer prognosis [12][13][14][15]. Hyponatraemia and hyperglycaemia were associated with increased levels of different cytokines: hyponatraemia with IL-6, and hyperglycaemia with IL-10.…”

Section: Discussionmentioning

confidence: 99%

Factors associated with inflammatory cytokine patterns in community-acquired pneumonia

Martínez¹,

Menéndez²,

Reyes³

et al. 2010

Eur Respir J

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Raised systemic levels of interleukin (IL)-6 and IL-10 cytokines have been associated with poorer outcome in community-acquired pneumonia. The aim of our study was to identify potential associated factors with increased levels of IL-6, IL-10, or both cytokines.We performed a prospective study of 685 patients admitted to hospital with communityacquired pneumonia. IL-6 and IL-10 were measured in blood in the first 24 h.30-day mortality increased from 4.8% to 11.4% (p50.003) when both cytokines were higher than the median. Independent associated factors with an excess of IL-6 were neurologic disease, confusion, serum sodium ,130 mEq?L -1 , pleural effusion, and bacteraemia. The associated factors for an excess of IL-10 were respiratory rate o30 breaths?min -1, systolic blood pressure ,90 mmHg and glycaemia o250 mg?dL -1 . The independent associated factors for an excess of both cytokines were confusion, systolic blood pressure ,90 mmHg, pleural effusion and bacteraemia. Protective factors were prior antibiotic treatment and pneumococcal vaccination.Different independent factors are related to an excess of IL-6 and IL-10. Confusion, hypotension, pleural effusion and bacteraemia were associated with the inflammatory profile with the highest mortality rate, whereas anti-pneumococcal vaccination and previous antibiotic treatment appeared to be protective factors.

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“…Plasma TNF, IL-1b, IL-6 and IL-8 are important mediators of the inflammatory response in SIRS and sepsis and correlate partially with mortality and severity in septic patients [33][34][35]. However, several large clinical trials show that increased survival has not been achieved by targeting these cytokines selectively [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load

Egge

Barratt‐Due

Nymo

et al. 2015

Clinical and Experimental Immunology

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SummaryCombined inhibition of complement and CD14 is known to attenuate bacterial-induced inflammation, but the dependency of the bacterial load on this effect is unknown. Thus, we investigated whether the effect of such combined inhibition on Escherichia coli-and Staphylococcus aureus-induced inflammation was preserved during increasing bacterial concentrations. Human whole blood was preincubated with anti-CD14, eculizumab (C5-inhibitor) or compstatin (C3-inhibitor), or combinations thereof. Then heat-inactivated bacteria were added at final concentrations of 5 3 10 4 21 3 10 8 /ml (E. coli) or 5 3 10 7 24 3 10 8 /ml (S. aureus). Inflammatory markers were measured using enzyme-linked immunosorbent assay (ELISA), multiplex technology and flow cytometry. Combined inhibition of complement and CD14 significantly (P < 0.05) reduced E. coli-induced interleukin (IL)-6 by 40-92% at all bacterial concentrations. IL-1b, IL-8 and macrophage inflammatory protein (MIP)-1a were significantly (P < 0.05) inhibited by 53-100%, and the effect was lost only at the highest bacterial concentration. Tumour necrosis factor (TNF) and MIP-1b were significantly (P < 0.05) reduced by 80-97% at the lowest bacterial concentration. Monocyte and granulocyte CD11b were significantly (P < 0.05) reduced by 63-91% at all bacterial doses. Lactoferrin was significantly (P < 0.05) attenuated to the level of background activity at the lowest bacterial concentration. Similar effects were observed for S. aureus, but the attenuation was, in general, less pronounced. Compared to E. coli, much higher concentrations of S. aureus were required to induce the same cytokine responses. This study demonstrates generally preserved effects of combined complement and CD14 inhibition on Gram-negative and Grampositive bacterial-induced inflammation during escalating bacterial load. The implications of these findings for future therapy of sepsis are discussed.

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Serial cytokine levels in patients with severe sepsis

Abstract: IL-6 and IL-10 were the key cytokines in the pathogenesis of severe sepsis. IL-6 was comparatively more associated with septic shock and IL-10 was comparatively more associated with mortality.

Cited by 101 publications

References 38 publications

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis

Factors associated with inflammatory cytokine patterns in community-acquired pneumonia

The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load

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