Mechanisms of Resolution of Inflammation

Abstract

Abstract-The inflammatory response is an integral part of the innate immune mechanism that is triggered in response to a real or perceived threat to tissue homeostasis, with a primary aim of neutralizing infectious agents and initiating repair to damaged tissue. By design, inflammation is a finite process that resolves as soon as the threat of infection abates and sufficient repair to the tissue is complete. Resolution of inflammation involves apoptosis and subsequent clearance of activated inflammatory cells -a tightly regulated event. Chronic inflammation is a characteristic feature in virtually all inflammatory diseases, including atherosclerosis, and it is becoming increasingly clear that derangement of the processes usually involved in resolution of inflammation is an underlying feature of chronic inflammatory conditions. This review will draw on evidence from a range of diseases in which dysregulated inflammation is important, with particular emphasis on cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2011;31:1001-1006.)Key Words: atherosclerosis Ⅲ eicosanoids Ⅲ lipids Ⅲ NO Ⅲ resolution of inflammation I nflammation is a primary component of the immune system that is triggered by any stimulus that poses a real or perceived threat to tissue homeostasis. 1 The acute inflammatory process is characterized by rapid recruitment of granulocytes (ie, neutrophils, eosinophils, and basophils) to the inflammatory site; the relative contribution of these cell types is dependent on the location of the inflammatory site in question. The migration of granulocytes to inflammatory loci is a necessary requirement for the neutralization and removal of deleterious agents; these cells play a key role in the defense against bacterial, fungal, and viral infections and in resistance to parasitic invasion and the allergic response. Resolution of inflammation is perceived to occur by elimination of granulocytes and the eventual return of tissue mononuclear cell (macrophage and lymphocyte) numbers to basal levels. 2 For effective resolution to occur, cessation of proinflammatory signaling is a prerequisite that pre-empts removal of infiltrating granulocytes. During spontaneous resolution, neutrophils undergo apoptosis, a highly regulated cell death mechanism that prevents the release of histotoxic cellular contents. 3 Alterations in neutrophil cell surface markers and morphological changes during apoptosis correlate with increased recognition by professional phagocytes, such as macrophages, that mediate effective clearance of dying cells. 3,4 It is accepted that the resolution process is active, rather than passive, and is controlled by a range of tightly regulated biochemical and cellular mechanisms. 2 The acute inflammatory response is self-limiting and normally results in tissue restoration and the return of tissue homeostasis. Persistent inflammatory stimuli or dysregulation of mechanisms of the resolution phase results in chronic inflammation, 2 recognized to be a key underlying factor in the progression of a range of d...

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

“…In addition, deficient eNOS phosphorylation at Ser1177 and reduced eNOS expression and NO production also occurred in GK rats, demonstrating typical impairment of vasoendothelium in type 2 diabetes. [1][2][3][4][5] Importantly, the present study demonstrates that treatment Fucoidan improves endothelial dysfunction W Cui et al of GK rats with LMWF profoundly ameliorated these diabetes-associated disorders, based on the observations that (1) LMWF improved the basal blood pressure and shear stress-induced vasodilation, and protected mesentery integrity in diabetic rats; (2) LMWF ameliorated the pathological changes in endangium and the endothelium-dependent vasodilation, and upregulated NO synthesis in diabetic rats; and (3) mechanistically, LMWF induced an endothelium/ eNOS/NO-dependent vasorelaxation, in particular an enhancement of eNOS phosphorylation at Ser1177 in both Physiologically, endothelium has a fundamental role in maintenance of vascular function and homeostasis. [7][8][9] Under pathological circumstances, such as high glucose, hypertension, or oxidative stress, endothelial dysfunction characterized by a reduction in NO bioavailability is recognized as the hallmark of atherosclerotic diseases and prediction of cardiovascular events.…”

“…[7][8][9] Under pathological circumstances, such as high glucose, hypertension, or oxidative stress, endothelial dysfunction characterized by a reduction in NO bioavailability is recognized as the hallmark of atherosclerotic diseases and prediction of cardiovascular events. 4,5,7 Because of the multiple risk factors coexisting in diabetes, diabetes patients are more susceptible to endothelial dysfunction and lesions, and eventually suffer cardiovascular complications. eNOS has been identified as the enzyme responsible for most of the NO production in vasculature, and it may undergo a harmful change in its enzymology termed 'eNOS uncoupling' , ie, converting from formation of NO to generating O 2 -that further consumes NO, making toxic peroxynitrite (ONOO -) in diabetes.…”

“…[3][4][5] Loss of NO induces increased activity of proinflammatory transcription factors, such as nuclear factor kappa B, resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines, which further promote endothelial inflammation and atherosclerosis. 5,6 Therefore, the endothelial dysfunction caused by imbalance of NO bioavailability in early-stage diabetes has been implicated as a sign or a predictor of a future cardiovascular event. [6][7][8] Mechanistically, a disturbance in endothelial NO synthase (eNOS) activity, referred to as uncoupling of eNOS and downregulation of eNOS expression, 2,9 has been identified as an important pathogenic…”

“…1,2 It is well established that endothelium-derived nitric oxide (NO) maintains vascular homeostasis and health through vasodilation and protection of vasculature from various damaging agents. [3][4][5] Loss of NO induces increased activity of proinflammatory transcription factors, such as nuclear factor kappa B, resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines, which further promote endothelial inflammation and atherosclerosis. 5,6 Therefore, the endothelial dysfunction caused by imbalance of NO bioavailability in early-stage diabetes has been implicated as a sign or a predictor of a future cardiovascular event.…”

MyD88 in Mycobacterium tuberculosis infection

“…MyD88s-mediated inhibition of TLR signaling is selective for the NF-κB pathway and does not alter the activity of other pathways, like the one of transcription factor AP-1 [80]. Resolution of inflammation also involves apoptosis and subsequent clearance of activated inflammatory cells, in order to prevent a chronic inflammatory condition [81]. An aberrant inflammatory response ensues when MyD88 is absent, possibly due to a failure in the mechanism of regulation of inflammation.…”