Scientific and clinical challenges in sepsis

Abstract

Advances in intensive care and antibiotics have prevented the spread of some infections, though sepsis mortality rates remain high. With failure of over thirty clinical trials, sepsis remains a scientific and clinical challenge in modern medicine. Sepsis is defined by the clinical signs of a systemic inflammatory response to infection. "Severe sepsis" is when these symptoms are associated with multiple organ dysfunction. These definitions of sepsis may be too broad and common to heterogeneous groups of patients who do not necessarily have the same disorder. This consideration has become especially evident in the clinical trials that have failed to obtain consistent results in similar studies of patients diagnosed with severe sepsis. In these trials, patients with infections caused by different microorganisms, and affecting different organs, have been combined under the general diagnosis of severe sepsis. The situation is analogous to attempting a clinical trial based on the general definition of cancer, combining all patients with tumor independent of the type of malignancy. In this consideration, it would not be very surprising that activated protein C, the only treatment in sepsis approved by the Food and Drug Administration, is projected for use in only a small subset of patients with severe sepsis. This article reviews novel inflammatory molecular aspects and the experimental anti-inflammatory strategies for sepsis, as they may represent particular pathological processes in specific subsets of patients.

Fig. (1). APC and the feed-back regulation of Thrombin

Thrombin activates protein C, which prevents further thrombin generation. Bacterial endotoxin stimulates the production of tissue factor on endothelium. This tissue factor triggers the proteolytic cascade resulting in thrombin generation and subsequent blood clotting/coagulation. Endotoxin also induces the release of a zymogen form of protein C from the liver into the systemic blood. Thrombin cleavage converts protein C into activated protein C, a highly active serine protease. Activated protein C cleaves several substrates including factor Va and factor VIIIa, which are proteases that process pro-thrombin to generate thrombin. Activated protein C therefore functions as a classical feed-back regulator of thrombin generation and coagulation. As such, activated protein C also attenuates inflammation induced by thrombin receptor-mediated platelet activation, and NF-κB activation in blood and endothelial cells.

Fig. (2). Glucocorticoids: endocrine-mediated systemic immune suppression

In the absence of glucocorticoid steroids, the glucocorticoid receptor is maintained in the cytosol as part of a large multi-subunit complex associated with the heat-shock protein HSP90. Glucocorticoid causes the dissociation of this complex, releasing the activated glucocorticoid receptor. The anti-inflammatory therapeutic effects of glucocorticoids are predominantly mediated by transrepression of characteristic transcription factors including NF-KB and AP1, while many side effects are mediated by transactivation of target genes. Current efforts are directed to design synthetic selective glucocorticoid receptor agonists (SEGRAs) to enhance this transrepression while preventing transactivation. Transactivation of the glucocorticoids induces the expression of factors like macrophage migration inhibitory factor (MIF), which counteracts the anti-inflammatory potential of the glucocorticoids.

Fig. (3). HMGB1: from the septic DAMP to the immune secretion

There are two potential mechanisms for cells to liberate HMGB1 into the extracellular milieu. Somatic cells contain large amounts of HMGB1 that is “passively released” into the extracellular milieu following cell membrane perturbation during cellular damage, unresolved apoptosis or necrosis. In this scenario, HMGB1 represents an intracellular protein adopted by the innate immune system to recognize tissue damage and initiate reparative response. Recent studies suggest that the immune system has copied this mechanism to activate innate responses and initiate tissue repair. The second mechanism can be an “active secretion” of HMGB1 from immune cells to mimic the necrotic process and activate innate immune response during an immunological challenge. From an immunological perspective, HMGB1 represents a characteristic “necrotic marker” or damage-associated molecular pattern (DAMP) molecule selected to activate the immune system.

Fig. (4). Nicotinic anti-inflammatory potential in sepsis

The vagus nerve can modulate the innate immune response and restrain inflammation through a physiological mechanism that can be translated into a pharmacological strategy. Since acetylcholine, the principal neuro-transmitter of the vagus nerve, signals through either muscarinic or nicotinic receptor, selective agonists (atropine, conotoxin, or mecamylamine) were used to identify the receptors involved in the control of macrophages. The vagus nerve and acetylcholine can restrain the production of pro-inflammatory cytokines from macrophages through a nicotinic acetylcholine receptor. Nicotine, a more selective cholinergic agonist, is more efficient than acetylcholine, and inhibits the production of pro-inflammatory cytokines from macrophages through a mechanism dependent on the alpha7nAChR.

Fig. (5). The Cytokine Code

The definition of sepsis is too broad and may not necessary represent a particular clinical entity. The situation is analogous to attempting a clinical trial based on the general definition of cancer, combining all patients with tumor independent of the type of malignancy. Inflammatory cytokines represent molecular messages that codify for a precise immune response against infection, trauma or injury. Similar to a molecular fingerprint, a “pathological” profile of cytokines production results in a characteristic constellation of clinical symptoms. Under this consideration, TNF represents a characteristic mediator of “septic shock”, whereas HMGB1 has been proposed as a prototype for severe sepsis. The characterization of this “cytokine code” will allow to associate particular molecular patterns for the characterization of discreet groups of patients or particular clinical entities generally lumped under the general definition of sepsis.