Pro-inflammatory mediators

The key factor in the development of sepsis is inflammation. Inflammation is intended to be a local and contained response to infection or injury. Infection or injury is controlled through pro- and anti-inflammatory mediators. Pro-inflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue.1,13-16 In order to control the intensity and duration of the inflammatory response, antiinflammatory mediators are released that act to regulate pro-inflammatory mediators.15-16 The balance between pro- and anti-inflammatory mediators localizes infection/injury of host tissue.13-16 However, systemic responses ensue when equilibrium in the inflammatory process is lost. 

The inflammatory process in sepsis is linked to the coagulation system. Pro-inflammatory mediators maybe procoagulant and antifibrinolytic, whereas anti-inflammatory mediators may be fibrinolytic. A key factor in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Protein C levels are decreased in septic patients. 

Rhule, A. et al., Panax notoginseng attenuates LPS-induced pro-inflammatory mediators in RAW264.7 cells, J Ethnopharmacol, 106, 121, 2006. 

The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modem techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin-1(3 (IL-1(3), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1 a, (3 (MIP-la,[3)J, MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family... 

Several classes of drugs can be potentially used to reduce the release of pro-inflammatory mediators by SECs and KCs in the fibrotic process. 

CN177 Wallace, F. A., E. A. Miles, and P. C. Calder. Activation state alters the effect of dietary fatty acids on pro-inflammatory mediator production by murine macrophages. Cytokine 2000 12(9) 1374-1379. 

Endotoxaemia. - Exposure to bacterial endotoxin (lipopolysaccharide) can induce the production of pro-inflammatory mediators (e.g. tumour necrosis factor a and interleukin 1), culminating in septic shock profound vasodilation... 

Numerous studies have indicated that pro-inflammatory mediators (cytokines) are involved in the destruction of the insulin-producing p-cells of the pancreas in the development of type I diabetes. Tabatabaie et al. introduced cytokines and PBN into the pancreas of rats. The analysis of pancreatic extracts revealed that the cytokines stimulate the formation of lipid radicals. Radical generation did not occur in rats treated with streptozotocin, which destroys the P-cells.33 Evidence for the role of radicals in diabetes has also been provided by spin trapping studies in pancreatic homogenates, showing that streptozotocin, which is often used to induce the condition in laboratory animals, stimulates OH production.332 Other workers, using EPR to observe the decay of a spin probe in the abdomen of mice (at 1.2 GHz), have demonstrated that strep-... 

In a related study, resveratrol significantly reduced colonic injury, neutrophil infiltration, and drastically reduced the PGD2 concentration by inhibiting COX-2, but not affecting COX-1 [Martin et al., 2004]. It appears that the antiinflammatory activity of resveratrol may be realized through the inhibition of both COX-1 and COX-2-mediated pro-inflammatory signaling, suppression of pro-inflammatory mediator production, as well as from its potent antioxidative effects. 

Pro-inflammatory mediators, such as prostaglandins (PGs), nitric oxide (NO), and cytokines are involved in carcinogenesis [Kundu and Surh, 2005 Perwez... 

TGF-p. Inhibits the production of pro-inflammatory mediators in vitro and in vivo. Stimulates biosynthesis of smooth-muscle cells in vascular wall... 

Lastly, eicosanoids are important pro-inflammatory mediators derived from membrane metabolism. PLA2 plays a key role in the production of eicosanoids, derived from arachi-donic acid of the phospholipids contained in the cell membrane (40,41). As mentioned earlier, arachidonic acid is liberated from the membrane-bound phospholipids by several forms of PLA2 and is the substrate for COX-1, COX-2, and 12-lipoxygenases (LOX) involved in vascular inflammation. 

Shahbakhti, H., Watson, R.E.B., Azurdia, R.M., Ferreira, C., Garmyn, M., and Rhodes, L.E., Effects of systemic omega-3 fatty acids on basal and UVR-induced expression of pro-inflammatory mediators TNF-a, IL-1/3, IL-6, IL-8 and PGE2 in human skin, Photochem. Photobiol., 80, 231-5,... 

With one exception sepsis therapy focusing primarily on the pro-inflammatory mediators has not produced positive results (Zeni et al., 1997). Hence, targeting the sepsis cascade at earlier steps may yield better outcomes. 

Infection, injury and trauma initiate a series of immune reactions to overcome the effects of various pro-inflammatory mediators resulting in repair of injured tissues and wound healing. The arbiter of this response is the brain, which communicates with the immune system via neurotransmitters, cytokines and hormones (Figure 38.1). Activation of... 

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