Novel insights for systemic inflammation in sepsis and hemorrhage

Abstract

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.

Figure 1

Nicotinic anti-inflammatory pathways. The inflammatory response to the infection, hemorrhage, or tissue trauma is mediated through the pathways of cytokine HMGB1, TNF, and interleukins which are released from immunized cells of lymph system including spleen tissue. Such immune pathway can be modulated by vagus nerve via its acetylcholine transmitter through either muscarinic or nicotinic receptor. A nicotinic acetylcholine receptor (α7nAChR) agonist, such as nicotine, or transmitter released from vagus nerve stimulation, can inhibit the inflammation through restraining the production of proinflammatory cytokines from lymphocyte macrophage line. As cholinergic selective, nicotine is more efficient than acetylcholine in anti-inflammatory response through α7nAChR-dependent mechanism.

Figure 2

Inflammatory response of HMGB1 and its attenuation by ethyl pyruvate. HMGB1 is liberated from macrophages into the extracellular milieu following cell membrane perturbations during sepses, hemorrhage, and injury. HMGB1-mediated nitric oxide (NO) leakages the endothelial line leading to a high permeability. NFKB signally stimulated by HMGB1 in macrophage regulates the release of TNF cytokine and interleukins. Inflammatory shock and animal death result due to vascular collapse and cytokine toxicity of the organ tissues. By attenuating the HMGB1 pathways with hextend-ethyl pyruvate (HEP), animals may improve survival with the dependent dosage.