Natural resolution of inflammation

Abstract

Inflammation is a protective response essential for maintaining human health and for fighting disease. As an active innate immune reaction to challenge, inflammation gives rise to clinical cardinal signs: rubor, calor, dolor, tumor and functio laesa. Termination of acute inflammation was previously recognized as a passive process; a natural decay of pro‐inflammatory signals. We now understand that the natural resolution of inflammation involves well‐integrated, active, biochemical programs that return tissues to homeostasis. This review focuses on recent advances in the understanding of the role of endogenous lipid mediators that modulate cellular fate and inflammation. Biosynthesis of eicosanoids and other lipids in exudates coincides with changes in the types of inflammatory cells. Resolution of inflammation is initiated by an active class switch in lipid mediators, such as classic prostaglandins and leukotrienes, to the production of proresolution mediators. Endogenous pro‐resolving lipid mediators, including arachidonic acid‐derived lipoxins, aspirin‐triggered lipoxins, ω3‐eicosapentaenoic acid‐derived resolvins of the E‐series, docosahexaenoic acid‐derived resolvins of the D‐series, protectins and maresins, are biosynthesized during the resolution phase of acute inflammation. Depending on the type of injury and the type of tissue, the initial cells that respond are polymorphonuclear leukocytes, monocytes/macrophages, epithelial cells or endothelial cells. The selective interaction of specific lipid mediators with G protein‐coupled receptors expressed on innate immune cells (e.g. G protein‐coupled receptor 32, lipoxin A4 receptor/formyl peptide receptor2, chemokine‐like receptor 1, leukotriene B4 receptor type 1 and cabannoid receptor 2) induces cessation of leukocyte infiltration; vascular permeability/edema returns to normal with polymorphonuclear neutrophil death (mostly via apoptosis), the nonphlogistic infiltration of monocyte/macrophages and the removal (by macrophages) of apoptotic polymorphonuclear neutrophils, foreign agents (bacteria) and necrotic debris from the site. While an acute inflammatory response that is resolved in a timely manner prevents tissue injury, inadequate resolution and failure to return tissue to homeostasis results in neutrophil‐mediated destruction and chronic inflammation. A better understanding of the complex mechanisms of lipid agonist mediators, cell targets and actions allows us to exploit and develop novel therapeutic strategies to treat human inflammatory diseases, including periodontal diseases.

What is the Contribution of Genetics to Periodontal Risk?

“…It is suggested in the literature that even the immune response level mounted at the early stage of gingivitis is the determinant factor of periodontitis progression and not the presence of specific bacteria known for their virulent properties (34,35). The host response level can vary widely without affecting the SO, and there is no real specific value for the host response level for SO to occur.…”

“…However as the system is always in some sort movement, it can swing into an aberrant immune function (one can observe this as an AgP case) or it can swing into a resolving or resolution phase (slow periodontal progression of many CP cases). Both the aberrant and resolution type host responses for periodontitis have been suggested in the literature (28,34,35). …”

“…SO is based on (i) amplification of disease activity by positive feedback, (ii) balancing of disease activity by negative feedback, (iii) amplification of random fluctuations (all three situations are obvious causes of nonlinearity) and (iv) on multiple local interactions of the system's components. In other words, periodontitis can fluctuate or move between an aberrant immunological reaction state and a resolving state (resolution) (34,35).…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…Both, DHA and eicosapentanoic acid are Ω-3 polyunsaturated fatty acids (PUFAs). Interestingly, despite the fact that inflammation resolution (and hence the production of inflammation resolution mediators) is a physiological process, aspirin-triggered inflammation resolution mediators have been reported (LXA4) [41]. Therefore, resolution mediators are not only produced during the physiological independent co-ordinated inflammation resolution process, but can also be triggered by NSAIDs such as aspirin.…”

“…AA is converted to various potent lipid mediators by cyclooxygenases (COX) and lipoxygenases to produce prostaglandins and leukotrienes. Indeed, COX enzymes convert AA into 10 subclasses of prostaglandins that are important in inflammation, while excessive production of prostaglandins and leukotrienes is correlated with progression from acute to chronic inflammation [41].…”