High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) and is a potent mediator of inflammation. HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells. Here we report that Hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.

Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

Sepsis is the leading cause of death in critically ill patients in the United States. Yet the individual host response to septicemia is variable, depending on the patient's immune response, age, nutritional status, and coexisting conditions, as well as on the virulence of the organism and the size of the inoculum. This review examines evolving concepts of sepsis and discusses new and potential therapies. Recent clinical advances include therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit. Future therapies may be focused on modulating the immune response in the light of the characteristics of the specific pathogen, the genetic profile of the patient, and the duration of the disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMra021333

The pathophysiology and treatment of sepsis.

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.

The inflammatory reflex

High quality protocols facilitate proper conduct, reporting, and external review
 of clinical trials. However, the completeness of trial protocols is often
 inadequate. To help improve the content and quality of protocols, an
 international group of stakeholders developed the SPIRIT 2013 Statement
 (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT
 Statement provides guidance in the form of a checklist of recommended items to
 include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important
 information to promote full understanding of the checklist recommendations. For
 each checklist item, we provide a rationale and detailed description; a model
 example from an actual protocol; and relevant references supporting its
 importance. We strongly recommend that this explanatory paper be used in
 conjunction with the SPIRIT Statement. A website of resources is also available
 (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement,
 should help with the drafting of trial protocols. Complete documentation of key
 trial elements can facilitate transparency and protocol review for the benefit
 of all stakeholders.

https://www.bmj.com/content/bmj/346/bmj.e7586.full.pdf

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

Die Bedeutung des endogenen Opioidsystems fur die zell-vermittelte Immunfunktion nach hamorrhagischem Schock ist bislang nicht eindeutig geklart. Im Zusammenhang mit traumatischen Ereignissen haben einige Autoren immunstimulierende Effekte berichtet [4], wahrend andere Gruppen dem endogenen Opioidsystem eher immundepressive Eigenschaften zuschreiben [8]. Nach hamorrhagischem Schock kommt es zu zahlreichen endokrinen Veranderungen; erhohte Spiegel von ACTH, Kortison und β-endorphin sind nach hypotensivem Schock berichtet worden [6]. Trotz dieser endokrinen Veranderungen, ist das therapeutische Potential von endogenen Mediatoren oder Rezeptorenblockern fur die Immunsuppression nach hamorrhagischem Schock noch nicht intensiv erforscht worden [5]. Es ist bekannt, das hamorrhagischer Schock eine signifikante Depression der zell-vermittelten und humoralen Immunfunktion verursacht [3]. Des weiteren ist hamorrhagischer Schock ein wichtiger Faktor fur die Entstehung von multiplem Organversagen [1]. In dieser Studie wurden mannliche C3H/HeN Mause direkt nach kontrolliertem hamorrhagischem Schock (mittlerer arterieller Blutdruck 35 mmHg fur 60 min, anschliesende Blut- und Volumengabe) mit 1,0 mg Naloxon pro kg Korpergewicht (KG) behandelt. So wurde der Einflus des endogenen Opioidsystems blockiert und die Bedeutung dieses Mediatorsystems fur die zell-vermittelte Immunitat nach hamorrhagischem Schock konnte analysiert werden.

Naloxon verschlechtert die zell-vermittelte Immunfunktion nach hämorrhagischem Schock

https://www.nejm.org/doi/pdf/10.1056/NEJM200102013440518

Eugen Faist

Papers

Naloxon verschlechtert die zell-vermittelte Immunfunktion nach hämorrhagischem Schock

Multiple organ failure: pathophysiology,

Interleukin-10 as a protective cytokine produced during human septicemia and septic shock

Testosterone: the crucial mediator responsible for local wound immune dysfunction following hemorrhage,: 158

Prostaglandin edependent suppression of interleukin production in patients with major trauma