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Endothelial cells (EC) are the simple squamous epithelium that lines blood and lymphatic vessels. The endothelium partitions the blood from the intima and media of the arteries and veins and from the interstitium of tissues throughout the body. The endothelium is responsible for determining the movement of macromolecules and also directionalizes circulating cells from the blood into extra vascular tissues.
The major endocrine functions of the endothelium are to regulate the vascular tone, this is done through the production of vasoconstrictive and vasodilatory molecules such as, endothelin [ET]-1 (La and Reid, 1995)and nitric oxide respectively(Moncada et al., 1987; Palmer et al., 1987); to regulate platelet function; maintain blood fluidity and finally to control inflammation. Other functions include a number of cellular activities such as maintaining homeostatsis of solutes, hormones and macromolecules and preventing the formation of thrombus. (Cines et al., 1998; van Hinsbergh, 1997)
Endothelial dysfunction can be due to cell injury which can be induced by a number of different mechanisms which include bacterial(Schouten et al., 2008), oxidative stress through abnormal regulation of reactive oxygen species, environmental irritants such as smoking (Oida et al., 2003) and hyperlipidaemia (Toma et al., 2009).
Therefore EC dysfunction can lead to compromise of vasoregulation, increased blood coagulation, promote infiltration of inflammatory cells and lipids into the intima, dysregulation of the production of nitric oxide and increase smooth muscle cell migration and proliferation. The endothelium is responsive to stimuli from circulating blood, neighbouring cells and tissues. Loss of normal function both biochemical and physiological is associated with disease. Although the exact mechanism leading to dysfunction is still unkown.
Under normal conditions the production of Nitric oxide(NO) by the vascular endothelium is important in the regulation of blood flow. Vascular action of NO includes direct vasodilation, indirect vasodilation, anti-thrombotic effects, anti-inflammatory effects and anti-proliferative effects.
NO is a signalling molecule that is produced by the endothelial isoform of nitric oxide synthase (eNOS). In the vascular system NO activates a cascade of events that lead to the relaxation of smooth muscle which in turn leads to a decrease in blood pressure. (Palmer et al., 1987). NO serves as a potent neurotransmitter at neurone synapses. In normal physiology NO is known to have an anti-inflammatory effect but can be a pro-inflammatory mediator in irregular conditions so therefore can be implicated in the immune response. (Beckman and Koppenol, 1996) NO is a contributing factor to the non-adhesive properties of the vascular endothelium meaning that it inhibits platelet adhesion to vascular endothelium so therefore is responsible for blood flow .(Radomski et al., 1987)
Inflammation can be defined as a protective localised response of tissue that eradicates the agents or debris or injury that cause the inflammation and can be linked intimately to repair. i.e. the recruitment and activation of leukocytes. During a normal inflammatory response highly unstable superoxide radicals are generated by leukocytes. This leads to the release of nitric oxide from endothelial cells to form a lesser potent radical known as peroxynitrite.
Atherosclerosis is formation of lipid deposits in the tunica media which is associated with damage to the endothelial lining. The cells involved in atherosclerosis are the endothelial cells, monocytes, macrophages and platelets. The mediators invovled are oxidative LDL, growth factors and reactive oxygen species. Atherosclerosis can be dangerous since a restricted blood flow can lead to vital organs being deprived of oxygen and nutrients which could lead to necrosis of tissue. Both early and advanced formation of atherosclerosis can be associated with endothelial cell dysfunction. (Pettersson et al., 1993; Ross, 1999)
has been proposed to be a key contributor to post-traumatic oxidative damage mainly because its highly reactive decomposition products nitrogen dioxide (·NO2), hydroxyl radical (·OH) and carbonate radical (CO3·−). These PN-derived radicals can oxidize proteins, nitrate tyrosine residues (Alvarez and Radi, 2003), induce cell membrane lipid peroxidation ([Beckman et al., 1990], [Hall, 2004] and [Kruman et al., 1997]) and cause single-strand DNA breaks ([Salgo et al., 1995] and [Szabo, 1996]).
Peroxynitrite (PN) is generated by the reaction between nitric oxide (NO) and anion superoxide (O2-). It is a powerful oxidant that can readily react with many cellular components. PN breaks down into highly reactive products, nitrogen dioxide (·NO2), hydroxyl radical (·OH) and carbonate radical (CO3·−). These PN derived radicals can oxidise proteins, cause single stand DNA breaks,
P38 is activated by cellular stress. Four members of the p38 group of MAP kinases have been characterised and clones. They are p38 also known as p38α(Han et al., 1994) p38β (Jiang et al., 1996) p38γ (or ERK6, SAPK3) (Lechner et al., 1996) and p38δ (or SAPK4)(Jiang et al., 1997).
The p38 Mitogen activated pathway kinase (MAPK) signalling pathway plays an important role in inflammation and other physiological processes. Inhibitors of p38 α and β MAPK block production of the major inflammatory cytokines i.e. Tumour Necrosis Factor (TNF) α and IL-1. The major function of the pathway is post transcriptional control of inflammatory gene expression. Many of the mRNAs are unstable because of AU-rich elements in the 3' untranslated region. Signalling in the p38 pathway counteracts these and therefore stabilises the mRNAs by prevent their otherwise rapid degeneration. (Saklatvala, 2004). Inhibiting the p38 MAPK pathway leads to suppression of the production of the key mediators in inflammation it is seen as an obvious target for therapy of chronic inflammatory diseases.
MAPKs are activated by dual phosphorylation specificity kinases by phosphorylation of threonine and tyrosine in a Thr-Xaa-Tyr motif in a loop near the active site. In p38 the intervening amino acid is Gly.