Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia.

Fischer, E.; Marano, Michael A.; Zee, Kimberly J. Van; Rock, Craig S.; Hawes, A S; Thompson, W. A.; DeForge, Laura; Kenney, J S; Remick, Daniel G.; Bloedow, Duane C.

doi:10.1172/jci115748

Cited by 325 publications

(128 citation statements)

References 22 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…administration of high doses of bacteria (12,13). However, the clinical relevance of such models is doubtful in light of the acute and fulminant course and the lack of a local infectious source.…”

Section: Discussionmentioning

confidence: 99%

“…TNF and IL-1␤ have highly overlapping biological activities and synergize in inducing systemic toxicity in animals in vivo (10,11). Elimination of either TNF or IL-1 activity during severe bacteremia in baboons largely prevents lethality, suggesting that excessive systemic production of these cytokines is of pivotal importance for the development of organ injury during the sepsis syndrome (12,13). However, evidence indicates that the local production of proinflammatory cytokines is crucial for the clearance of bacterial infections from the lung.…”

Section: Mice All Il-1rmentioning

confidence: 99%

See 1 more Smart Citation

TNF-α Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia

Rijneveld

Florquin

Branger

et al. 2001

The Journal of Immunology

112

106

View full text Add to dashboard Cite

To determine the role of IL-1 in the host defense against pneumonia, IL-1R type I-deficient (IL-1R−/−) and wild-type (Wt) mice were intranasally inoculated with Streptococcus pneumoniae. Pneumonia resulted in elevated IL-1α and IL-1β mRNA and protein levels in the lungs. Survival rates did not differ between IL-1R−/− and Wt mice after inoculation with 5 × 104 or 2 × 105 CFU. At early time points (24 and 48 h) IL-1R−/− mice had 2-log more S. pneumoniae CFU in lungs than Wt mice; at 72 h bacterial outgrowth in lungs was similar in both groups. Upon histopathologic examination IL-1R−/− mice displayed a reduced capacity to form inflammatory infiltrates at 24 h after the induction of pneumonia. IL-1R−/− mice also had significantly less granulocyte influx in bronchoalveolar lavage fluid at 24 h after inoculation. Since TNF is known to enhance host defense during pneumonia, we determined the role of endogenous TNF in the early impairment and subsequent recovery of defense mechanisms in IL-1R−/− mice. All IL-1R−/− mice treated with anti-TNF rapidly died (no survivors (of 14 mice) after 4 days), while 10-day survival in IL-1R−/− mice (control Ab), Wt mice (anti-TNF), and Wt mice (control Ab) was 7 of 13, 3 of 14, and 12 of 13, respectively. These data suggest that TNF is more important for host defense against pneumococcal pneumonia than IL-1, and that the impaired early host defense in IL-1R−/− mice is compensated for by TNF at a later phase.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Mice All Il-1rmentioning

confidence: 99%

TNF-α Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia

Rijneveld

Florquin

Branger

et al. 2001

The Journal of Immunology

112

106

View full text Add to dashboard Cite

show abstract

“…Whereas high levels of circulating cytokines belonging to the IL-1 superfamily are associated with increased mortality in patients with septic shock (33), the IL-1 receptor antagonist (IL-1RA) inhibits IL-1 signal transduction (34). By functional receptor blockade, the recombinant form of the human protein [rhIL-1RA (35)] exerted beneficial effects in a broad range of experimental trials of systemic inflammation and sepsis (36)(37)(38)(39). Subsequently, a number of clinical studies investigated the value of rhIL-1RA as therapeutic option in patients with sepsis, severe sepsis or septic shock (40)(41)(42)(43)(44).…”

Section: Early Modulation Of Pro-inflammatory Mediators: History Of Rmentioning

confidence: 99%

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

et al. 2016

View full text Add to dashboard Cite

Sepsis and septic shock are associated with high mortality rates and remain a serious menace for the critically ill patient. Concurrent activation of pro-and anti-inflammatory pathways and an excessive cytokine release represent initial key features in the deregulation of the humoral and cellular antimicrobial defense. Research of the last decades addressed both the ebullient inflammation as well as the resulting longterm failure of the host immunity. While the reestablishment of an adequate immune-competence is still under investigation, many promising experimental trials to limit the inflammatory response during sepsis were challenged by missing beneficial effects in clinical studies. Nevertheless, due to advanced knowledge about the complex regulation of inflammatory mediators and their overlapping involvement in other potentially life-threatening diseases, further evaluation of these approaches in relevant subgroups could help to identify critically ill patients with potential benefit from anti-inflammatory therapies.

show abstract

“…In models of severe systemic infection or inflammation produced by i.v. administration of high doses of bacteria or bacterial products such as endotoxin, excessive production of proinflammatory cytokines significantly contributes to organ failure and death, as reflected by findings that neutralization of either TNF or IL-1 activity markedly reduced mortality in these systemic challenge models (13)(14)(15). However, in experiments in which an at least initially localized infection was induced, including pneumonia and peritonitis, the local activity of proinflammatory cytokines appeared important for antibacterial host defense at the site of the infection (16 -19).…”

Section: Il-10-deficient Mice Demonstrate Multiple Organ Failure and mentioning

confidence: 99%

IL-10-Deficient Mice Demonstrate Multiple Organ Failure and Increased Mortality DuringEscherichia coliPeritonitis Despite an Accelerated Bacterial Clearance

Sewnath¹,

Olszyna

Birjmohun³

et al. 2001

The Journal of Immunology

151

View full text Add to dashboard Cite

To determine the role of endogenous IL-10 in local antibacterial host defense and in the development of a systemic inflammatory response syndrome during abdominal sepsis, IL-10 gene-deficient (IL-10−/−) and wild-type (IL-10+/+) mice received an i.p. injection with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-10 concentrations in peritoneal fluid and plasma. The recovery of E. coli from the peritoneal fluid, blood, and lungs was diminished in IL-10−/− mice, indicating that endogenous IL-10 impaired bacterial clearance. Despite a lower bacterial load, IL-10−/− mice had higher concentrations of TNF, macrophage inflammatory protein-2 and keratinocyte in peritoneal fluid and plasma, and demonstrated more severe multiple organ damage as indicated by clinical chemistry and histopathology. Furthermore, IL-10−/− mice showed an increased neutrophil recruitment to the peritoneal cavity. To examine the role of elevated TNF levels in the altered host response in IL-10−/− mice, the effect of a neutralizing anti-TNF mAb was determined. Anti-TNF did not influence the clearance of E. coli in either IL-10+/+ or IL-10−/− mice. Furthermore, anti-TNF did not affect leukocyte influx in the peritoneal fluid, multiple organ damage, or survival in IL-10+/+ mice. In IL-10−/− mice, anti-TNF partially attenuated neutrophil recruitment and multiple organ damage, and prevented the increased lethality. These data suggest that although endogenous IL-10 facilitates the outgrowth and dissemination of bacteria during E. coli peritonitis, it protects mice from lethality by attenuating the development of a systemic inflammatory response syndrome by a mechanism that involves inhibition of TNF release.

show abstract

Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia.

Cited by 325 publications

References 22 publications

TNF-α Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia

TNF-α Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

IL-10-Deficient Mice Demonstrate Multiple Organ Failure and Increased Mortality DuringEscherichia coliPeritonitis Despite an Accelerated Bacterial Clearance

Contact Info

Product

Resources

About