https://journal.chestnet.org/article/S0012-3692(16)38415-X/pdf

Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis

Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

The pathogenesis of atherosclerosis: a perspective for the 1990s

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

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Cancer-related inflammation.

Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.

Inflammation in atherosclerosis

Career situation of first and presenting author Young investigator. Introduction Gout flares are characteristically mediated by the pro-inflammatory cytokine interleukin (IL)-1β.1 Uptake of monosodium urate (MSU) crystals by macrophages activates the nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, which converts intracellular pro-interleukin-1β (pro-IL-1β) to mature bioactive IL-1β by proteolytic cleavage. Deposition of MSU crystals alone is not sufficient to trigger a gout flare. In the presence of concomitant pro-inflammatory stimuli, i.e. Toll-Like Receptor (TLR) agonists, transcription of il-1β gene is induced and pro-IL-1β is rapidly converted into its active form. IL-1β binds to its receptor (IL-1R1) and induces a cascade of secondary inflammatory mediators including prostaglandins, cytokines and chemokines. Recently, OLT1177™, a β-sulfonyl nitrile compound, safe in humans, was shown to inhibit the NLRP3 inflammasome, reverse the metabolic cost of inflammation and inhibit joint inflammation in murine models of acute arthritis.2 3 Objectives To explore the mechanism by which oral OLT1177™ inhibits joint inflammation in humans with gout flares. Methods 29 patients with a gout flare were treated within 4 days after the start of the symptoms with three different doses of OLT1177™ for 7 days (EudraCT: 2016-000943-14). Blood was drawn at baseline, days 3, 7 and 14 (7 days after finishing treatment). Haematology, hsCRP and SAA were measured as markers for systemic inflammation. Plasma was collected for assessment of circulating cytokines. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured under unstimulated or stimulated conditions with a TLR ligands (Pam3Cys and LPS) in combination with MSU crystals after which intra- and extracellular cytokine production was assessed. Results Plasma IL-1β are increased in samples from intercritical gout patients and individuals with gout flares when compared to healthy controls (healthy controlshsCRP and SAA and acute phase proteins of individuals treated with OLT1177™ during a gout flare show a dose-dependent reduction during course of treatment. Circulating IL–1β and IL–6, but not TNFα, was reduced and stimulated cytokine production of PBMCs declined during treatment. In unstimulated PBMCs on day 3, ratio of intracellular pro-IL-1β and IL-1β revealed inhibition of the NLRP3 inflammasome by oral OLT1177™. Moreover, in vitro and ex vivo data show OLT1177™ spontaneously increases the level of IL-1 receptor antagonist (IL-1Ra). Conclusions Oral OLT1177™, safe in humans, inhibits inflammation and increases systemic IL-1Ra concentrations in patients with an acute gout flare by inhibiting the NLRP3 inflammasome product, IL–1b. References Dinarello CA. How interleukin-1beta induces gouty arthritis. Arthritis Rheum 2010;62(11):3140–4. Marchetti C, et al. OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci USA 2018;115(7):E1530–E1539. Marchetti C, et al. NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res Ther 2018;20(1):169. Acknowledgements We wish to acknowledge the gout patients who participated as well as Danielle Poeth and Dorine Baselmans for their commitment to the conduct of this study. Potential investigators conflict of interest DS is Founder and CEO of Olatec, CD is CSO and SAB member of Olatec, LJ is SAB member of Olatec. Disclosure of Interest None declared.

https://ard.bmj.com/content/annrheumdis/78/Suppl_1/A69.2.full.pdf

P159/O30 OLT1177™, an oral NLRP3 inflammasome inhibitor, inhibits acute joint inflammation and circulating IL 1β during gout flares in humans

Introduction: Activation of the NLRP3 inflammasome during acute myocardial infarction (AMI) mediates further inflammatory injury after reperfusion. Several NLRP3 inflammasome inhibitors have been s...

Abstract 18066: Novel NLRP3 Inflammasome Inhibitor OLT1177 Reduces Infarct Size in a Mouse Model of Myocardial Ischemia Reperfusion Injury

/pdf/editorial-cytokines-and-intestinal-mucosal-immunity-27nhp5hwuu.pdf

Charles A. Dinarello

Papers

P159/O30 OLT1177™, an oral NLRP3 inflammasome inhibitor, inhibits acute joint inflammation and circulating IL 1β during gout flares in humans

Abstract 18066: Novel NLRP3 Inflammasome Inhibitor OLT1177 Reduces Infarct Size in a Mouse Model of Myocardial Ischemia Reperfusion Injury

Editorial: Cytokines and Intestinal Mucosal Immunity.

IL‐1 Superfamily and Inflammasome

Interleukin 1alpha: a comprehensive review on the role of IL-1alpha in the pathogenesis and targeted treatment of autoimmune and inflammatory diseases