IntroductionA tight regulation of the immune/inflammatory system is crucial for maintaining the balance between protective and tissue-damaging responses.Systemic inflammatory response syndrome (SIRS) and sepsis are characterized by a loss of control over inflammatory responses, which can be provoked by a variety of causative agents and severe clinical insults.Sepsis is the most common cause of death in intensive care units worldwide and despite the extensive research we do not fully understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury.A number of different approaches have been investigated to try to treat and/or prevent septic shock associated with infections caused by Gram-negative bacteria.Antibiotics constitute a necessary part of the treatment of sepsis, but antibiotics alone, even used optimally, are not sufficient to dramatically reduce the mortality of septic patient, because antibiotics cannot control the complex systemic inflammation and dysregulated host responses.For this reason, considerable efforts have been expended in developing non-antibiotic forms of treatment.A wide variety of dietary plants including grains, berries, legumes, tea, beer, grape/wine, olive oil, chocolate/cocoa, coffee, walnuts, peanuts, spices, fruits, vegetables etc. contain polyphenols (Bravo, 1998).Polyphenols, with 8000 structural variants, are characterized by the presence of aromatic rings bearing one or more hydroxyl moieties, which have a pivotal role in mediating of its antioxidant properties.As antioxidants, polyphenols are normally produced by plants for their antibiotic and antifungal features (Leiro et al., 2004).Polyphenols are generally divided into six major groups: hydroxybenzoic acids, phenolic alcohols, hydroxycinnamic acids, lignans, flavonoids and stilbenes (e.g.resveratrol) (D'Archivio et al., 2007).Recently, a number of natural products or ingredients of traditional medicines and healthy foods such as resveratrol, curcumin, and catechins were extensively investigated and subjected to clinical trials as anti-inflammatory agents (Hatcher et al., 2008).Although the knowledge of absorption, bioavailability and metabolism of polyphenols is not entirely known, it appears that some polyphenols are bioactive and are absorbed in their native or modified form.After the metabolization of polyphenols by the microflora of the intestines, their absorbed forms may be detected in plasma in nanomolar concentration (Rahman et al., 2006).The active components of dietary phytochemicals (e.g.curcumin, resveratrol, capsaicin, catechins, vitamins, beta carotene and dietary fiber) are believed to suppress the www.intechopen.comSevere Sepsis and Septic Shock -Understanding a Serious Killer 380 inflammatory processes, moderate cell signaling pathways, proliferation, apoptosis, redox balance and most often appear to be protective against cancer, neurodegenerative disorders and cardiovascular diseases (Aggarwal & Shishodia, 2006;Rahman et al., 2006).Polyphenols can exert their anti-inflammatorical properties at multiple levels, through the modulation of MAPK, Akt and NF-κB signaling pathways, inhibition the production of inflammatory cytokines and chemokines, suppressing the activity of COX and iNOS and decreasing the production of ROS/RNS.MAPKs which play critical roles in inflammation are inhibited by catechins in macrophages (Ichikawa et al., 2004).Other dietary phytochemicals, namely curcumin, resveratrol and green tea polyphenols have been shown to modulate the MAP kinases and it was dependent on cell type and on the polyphenol used.Akt plays crucial roles in mammalian cell survival signalling and has been shown to be activated in various cancers (Chang et al., 2003).Activated Akt promotes cell survival by activating NF-κB signalling pathway (Romashkova & Makarov, 1999).Several phytochemicals including genistein (Li & Sarkar, 2002), curcuminoids (Aggarwal et al., 2006) and catechins (Tang et al., 2003) are known to suppress the activation of Akt, in this way inhibit cancer cell growth.Almost all cell types, when exposed to TNF-, LPS or other stimuli, activate NF-κB and AP-1 transcription factors, leading to the expression of inflammatory genes, such as COX-2, iNOS, cell adhesion molecules, inflammatory cytokines and chemokines.Thus, all the dietary agents that can suppress these transcription factors have the potential of inhibiting the expression of COX-2, iNOS, cell adhesion molecules, TNF-and interleukins.Several dietary components including green tea catechins (Gerhäuser et al., 2003), curcumin (Plummer et al., 1999), and resveratrol (Subbaramaiah et al., 1998) have been shown to suppress COX-2 and in this way to decrease the production of reactive oxygen species.iNOS, which is responsible for the release of free radical nitric oxide, was suppressed by several phytochemicals and dietary agents in RAW 264.7 macrophage cell line, stimulated with LPS and interferon-(IFN-) (Kim et al., 1998).Other sources of the antioxidant properties of polyphenols is their free radicals scavenger features, which is based on their structure (Joe & Lokesh, 1994, Babu & Liu, 2008).Furthermore, several polyphenols suppress lipid peroxidation through to maintain the cellular status of antioxidant enzymes like superoxide dismutase, catalase and glutathione peroxidase (Labinskyy et al., 2006;Reddy & Lokesh, 1992).Due to the NF-κB suppressing effect of polyphenols, some of them (e.g.curcumin, resveratrol, quercetin and green tee polyphenols) have been shown to decrease the expression of chemokines and cytokines (Hidaka et al., 2002, Kowalski et al., 2005).Recently, the anti-inflammatory properties of natural products or ingredients of traditional medicines and healthy foods were extensively investigated, but the solubility of these compounds is limited.Because of it, it is questionable whether their bioavailability could account for their pharmacological effect.Recent publications show that polyphenols in healthy foods or drinks such as chocolate, red wine, or beer are readily metabolized to phenolic acids and aldehydes by the microflora of the intestines, raising the possibility that these metabolites, rather than the original natural products or food ingredients, are responsible for their anti-inflammatory properties (Gonthier et al., 2003;Rios et al., 2003).In the present chapter we summarize our recent knowledge about the effect of natural polyphenols in systemic inflammatory conditions focusing on their metabolites and degradation products.These compounds could represent new potential clinical approaches in the therapeutic intervention of severe sepsis and septic shock.www.intechopen.com
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