Sterile inflammation (SI) is a bona fide inflammatory response with all the clinical features of redness, heat, pain, and loss of function. All the cellular components of the acute inflammatory response, such as a neutrophilic infiltrate, macrophage

activation and cytokine production are also present. The best understood initiator of SI is necrotic cell death with the release of a large and diverse number of molecules that are usually present in the intracellular space. These are termed damage-associated molecular patterns (DAMPs), and Table 1 provides a selected list. The biology of DAMPs is important to understanding the development of SI, and it is also interesting click here because DAMPs were originally proposed on theoretical basis. Other less well-understood initiators are oxidative and metabolic stress. The central concept in SI inflammation is that DAMPs and related molecules activate two interrelated pathways (Fig. 1). The first pathway results in transcriptional up-regulation, and it is provided by toll-like

receptors (TLRs) and other receptors with the MyD88 signaling domain. This is via NF-kβ signaling, and it is considered a priming step. In the absence of additional signals, the pro-interleukin (IL)1-β produced is inactive and remains inside the cell. Diverse signals can provide the second signal resulting in caspaspe-1 activation, proteolytic cleavage of pro-IL-1β into the active form, and its secretion from Non-specific serine/threonine protein kinase the cell. Some of the signals that activate NLRP3

are ATP via the P2X7 receptor and reactive oxygen species.[1] A vital realization has been that the same www.selleckchem.com/products/Bortezomib.html PAMP receptor, for example, TLR4, can be activated by both PAMPs and DAMPs. In the case of TLR4, this can occur by exogenous lipopolysaccharide (LPS), or endogenous hyaluronic acid. This inflammasome-mediated inflammatory response is very proximal in the inflammatory cascade and can initiate all the cellular and in vivo features associated with inflammation ranging from minor local inflammation to a lethal systemic inflammatory response. It may seem surprising that an inflammatory response initiated tissue injury results in greater tissue injury, but this has been demonstrated in many experimental systems, and it also occurs in rare hereditary syndromes with hyper-activation of this pathway, as well as in genetically modified mice with constitutively active NLPR3.[2, 3] This also provides the rational for therapeutic intervention, and it is speculated to be the reason for requiring a two signal system of activation that is not seen for other cytokines. In the liver, SI is particularly important because a wide range of disease such as alcoholic hepatitis (alcoholic steatohepatitis [ASH]), non-alcoholic hepatitis (non-alcoholic steatohepatitis [NASH]), drug-induced liver injury (DILI), and ischemia reperfusion (IR) have SI as a major component to their pathology.