Determination of the safety and efficacy of therapeutic neutralization of tumor necrosis factor-α (TNF-α) using AZD9773, an anti-TNF-α immune Fab, in murine CLP sepsis

Newham, Peter; Ross, Daniel W.; Ceuppens, Peter; Das, Shampa; Yates, James; Betts, Catherine J.; Reens, Jaimini; Randall, Kevin J.; Knight, Richard; McKay, Jennifer S.

doi:10.1007/s00011-013-0683-3

Cited by 21 publications

(11 citation statements)

References 32 publications

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“…Serum TNF-α profiles over time are different after CLP between A/J and C57BL/6J mice; therefore, we infer it could be dissimilar between rats and mice [ 21 ]. Moreover, TNF-α neutralization does not improve survival in mouse CLP model [ 22 – 24 ]. This underlines that serum TNF-α levels are not necessarily linked to severity of insult in this model.…”

Section: Discussionmentioning

confidence: 99%

Sepsis modeling in mice: ligation length is a major severity factor in cecal ligation and puncture

Ruiz

Vardon‐Bounes

Merlet-Dupuy

et al. 2016

ICMx

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BackgroundThe cecal ligation and puncture (CLP) model, a gold standard in sepsis research, is associated with an important variability in mortality. While the number of punctures and needle size is well described in CLP animal studies, the length of cecal ligation is often not. The relationship between cecal ligation and survival in mice is briefly reported in the literature; therefore, we devised an investigation in mice of the consequences of three standardized cecal ligation lengths on mortality and the severity of the ensued sepsis.MethodsMale C57BL/6J mice underwent standardized CLP. The cecum was ligated at 5, 20, or 100 % of its total length and further perforated by a single 20-G puncture. Mortality was analyzed. We assessed blood lactate, serum creatinine levels, and serum cytokines (TNF-α, IL-1β, IL-6, and IL-10) after procedure in a control group and in ligated mice.ResultsMortality was directly related to ligation length: median survival was 24 h for the “100 %” group and 44 h for the “20 %” group. Blood lactate increased proportionally with the ligation length. At 6 h post-procedure, pro-inflammatory cytokines significantly increased in the ligated group with significantly higher serum levels of IL-6 in the 100 % group compared to the other ligated groups. The 20 % group exhibited the characteristics of septic shock with hypotension below 65 mmHg, pro-inflammatory balance, organ dysfunction, and hyperlactatemia.ConclusionsCecal ligation length appears to be a major limiting factor in the mouse CLP model. Thus, this experimental model should be performed with high consistency in future protocol designs.

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Section: Discussionmentioning

confidence: 99%

Sepsis modeling in mice: ligation length is a major severity factor in cecal ligation and puncture

Ruiz

Vardon‐Bounes

Merlet-Dupuy

et al. 2016

ICMx

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“…However, numerous clinical trials failed to demonstrate clear statistical benefits [51][52][53][54][55][56][57]. As sepsis involves the presence of a pathogen, the inability to control the infection when TNF signaling is abrogated might account for the failure seen in these clinical trials.…”

Section: Tnf the Master Regulator Of Inflammationmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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“…In septic patients plasma levels of TNFα were significantly higher in patients that died compared to the surviving group [63], making TNFα an interesting target for therapy. Neutralizing it with an antibody fragment against TNFα in experimental sepsis resulted in significantly increased survival rates [64]. However, a similar treatment only slightly improved survival in patients with sepsis [65], suggesting that there is redundancy in inflammatory signaling.…”

Section: Role Of Oxidative Phosphorylation In Acute Inflammationmentioning

confidence: 99%

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

Lee

Hüttemann

2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

130

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Mitochondrial dysfunction is increasingly recognized as an accomplice in most of the common human diseases including cancer, neurodegeneration, diabetes, ischemia/reperfusion injury as seen in myocardial infarction and stroke, and sepsis. Inflammatory conditions, both acute and chronic, have recently been shown to affect mitochondrial function. We here discuss the role of oxidative phosphorylation (OxPhos), focusing on acute inflammatory conditions, in particular sepsis and experimental sepsis models. We discuss mitochondrial alterations, specifically suppression of oxidative metabolism and the role of mitochondrial reactive oxygen species in disease pathology. Several signaling pathways including metabolic, proliferative, and cytokine signaling affect mitochondrial function and appear to be important in inflammatory disease conditions. Cytochrome c oxidase (COX) and cytochrome c, the latter of which plays a central role in apoptosis in addition to mitochondrial respiration, serve as examples for the entire OxPhos system since they have been studied in more detail with respect to cell signaling. We propose a model in which inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, including Tyr304 phosphorylation of COX catalytic subunit I. This results in inhibition of OxPhos, a reduction of the mitochondrial membrane potential, and consequently a lack of energy, which can cause organ failure and death as seen in septic patients.

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Determination of the safety and efficacy of therapeutic neutralization of tumor necrosis factor-α (TNF-α) using AZD9773, an anti-TNF-α immune Fab, in murine CLP sepsis

Cited by 21 publications

References 32 publications

Sepsis modeling in mice: ligation length is a major severity factor in cecal ligation and puncture

Sepsis modeling in mice: ligation length is a major severity factor in cecal ligation and puncture

A New Venue of TNF Targeting

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

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