Experimental Therapeutic Strategies for Severe Sepsis

Abstract

Severe sepsis is the leading cause of mortality in intensive care units. The limited ability of current therapies to reduce sepsis mortality rates has fueled research efforts for the development of novel treatment strategies. Through the close collaboration between clinicians and scientists, progress can be seen in the struggle to develop effective therapeutic approaches for the treatment of sepsis and other immune and inflammatory disorders. Indeed, significant advances in intensive care, such as lung protective mechanical ventilation, improved antibiotics, and superior monitoring of systemic perfusion, are improving patient survival. Nonetheless, specific strategies that target the pathophysiological disorders in sepsis patients are essential to further improve clinical outcomes. This article reviews current clinical management approaches and experimental interventions that target pleiotropic or late-acting inflammatory mediators like caspases, C5a, MIF, and HMGB1, or the body's endogenous inflammatory control mechanisms such as the cholinergic anti-inflammatory pathway. These inflammatory mediators and anti-inflammatory mechanisms, respectively, show significant potential for the development of new experimental therapies for the treatment of severe sepsis and other infectious and inflammatory disorders.

Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection

“…These interesting findings pointed out to the a7 nAChR as the master regulator of inflammation at the peripheral level. a7 nAChR receptor activation modulates multiple intracellular signal transduction cascades in monocytes and macrophages that downregulate the nuclear translocation of NF-kB and the expression of Toll-like receptor-4 (TLR4), thus suppressing the transcription of pro-inflammatory cytokines [1,101,102]. Moreover, a7 nAChR activation could inhibit NF-kB in monocytes and macrophages through the phosphorylation of the inhibitor of NF-kB (IkB) [103].…”

“…The cholinergic anti-inflammatory pathway was proven to be effective not only in sepsis [102], but also in a wide plethora of diseases with a strong inflammatory component like ischemia/ reperfusion [105][106][107], rheumatoid arthritis [108,109] or pancreatitis [110,111]. The selective a7 nAChR agonist GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], initially developed for the treatment of AD [112,113], has been shown as a strong modulator of inflammation.…”

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

“…Sepsis/septic shock is characterized by profound hypotension, progressive metabolic acidosis, systemic inflammatory response syndrome (SIRS), tissue damage and multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS) and/or acute lung injury (ALI), or even death. Although its pathophysiology is not well defined, monocytes orchestrate the innate immunity response to Gram-positive and Gram-negative bacteria by expressing a variety of inflammatory cytokines, including tumour necrosis factor (TNF)-a and interleukin (IL)-6, which are considered to play an essential role in the pathogenesis of sepsis [2][3][4][5][6].…”

Anti-Inflammatory Role of Natural Polyphenols and Their Degradation Products

“…These toxic effects occur by direct action of TNF-on host cells and by the interaction with a cascade of other endogenous mediators including IL-1, IL-6 and interferon-gamma (Tracey & Cerami, 1993;Tracey & Cerami, 1994). Similar to TNF-and HMGB1, several proinflammatory cytokines and factors, such as IL-1 (Dinarello, 1994), IL-6, IL-8 (Calandra et al, 1990;Hotchkiss et al, 2000) macrophage migration inhibitory factor (Parrish et al, 2008) and lysophosphatidylcholine (Kabarowski et al, 2001), contribute to the pathogenesis and progression of sepsis. Sepsis is characterized by a surge of the pro-inflammatory cytokines TNF-and IL-1 at the early stage.…”