Acidosis has lethal consequences but alkalosis
Acidosis has lethal consequences, but alkalosis (due to chloride depletion, potassium depletion, and excess mineralocorticoid) is not tolerated as well (Luke and Galla, 2012). In this regard, efforts to restore pH to normal physiological level, in the most benign way should be the goal of researchers.
Compliance with ethical standards
Introduction A prime example of bioactive fatty glycoprotein iib iiia inhibitors is arachidonic acid (20:4n-6, AA), an omega-6 fatty acid that is found at relatively high levels in cells involved in innate immunity reactions, such as monocytes, macrophages and dendritic cells [, , ]. AA is the common precursor of the eicosanoids, a family of lipid mediators with fundamental roles in physiology and pathophysiology, particularly in inflammatory reactions [, , ]. The eicosanoids affect immune regulation by modulating cell activation at different points, including differentiation and migration, phagocytic capacity, and cytokine production [, , , ]. Similarly, docosahexaenoic acid (22:6n-3, DHA) and related long-chain omega-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA) and docosapentaenoic acid (22:5n-3, DPA), also found in major inflammatory cells, can be oxygenated to generate biomolecules known as protectins, resolvins, and maresins (collectively called specialized pro-resolving mediators, SPM), which account for much of the biological activity of omega-3 fatty acids, and are involved in the resolution phase of inflammation, clearance of apoptotic cells, tissue repair and regeneration, and anti-nociceptive actions . In addition, omega-3 fatty acids may promote anti-inflammatory reactions by themselves by acting on fatty acid-sensing receptors [12,13]. Fatty acid-derived mediators are produced during inflammation in two temporal waves with opposite effects, when cells switch the type of mediators produced from pro- to anti-inflammatory . Thus, the immediate production of proinflammatory AA-derived eicosanoids after the insult is progressively followed by accumulation of anti-inflammatory lipoxins and other pro-resolving lipid mediators derived from omega-3 fatty acids, a process that initiates resolution of inflammation and the return to homeostasis [11,14]. Thus, cells appear to possess intrinsic mechanisms to dampen inflammation to avoid excessive damage that might lead to irreversible injury. In addition to the expression of polyunsaturated fatty acid-metabolizing enzymes, availability of the fatty acid in free form is well established to constitute a limiting factor for the biosynthesis of eicosanoids and pro-resolving lipid mediators [1,15]. Such free fatty acid availability is provided by phospholipase A2s, the enzymes that cleave the sn-2 position of glycerophospholipids . Multiple PLA2 enzymes co-exist in a single cell, each exhibiting potentially different headgroup and/or fatty acid preferences. Acting frequently in a co-ordinate manner, cellular PLA2s provide a tight regulation of biological processes involving membrane phospholipid fatty acid rearrangement (Fig. 1). PLA2s are found in practically all types of organisms, and in mammals they are ubiquitously expressed throughout most cells and tissues, suggesting their importance in life processes. The variety of functions of PLA2s in physiology, far from being only circumscribed to activated states of immune cells, have become more evident in the last years with the study of the phenotypes of genetically-manipulated mice [16,17]. More than thirty enzymes with PLA2 activity have been described and, based on sequence similarities, they are currently classified in 16 groups, each containing several sub-groups . However, based on biochemical features these enzymes are frequently grouped into six major families: secreted phospholipase A2s (sPLA2), calcium-independent phospholipase A2s (iPLA2), cytosolic phospholipase A2s (cPLA2), platelet activating factor acetylhydrolases (PAF-AH, also known as lipoprotein-associated phospholipase A2, Lp-PLA2), lysosomal phospholipase A2 (L-PLA2) and the adipose phospholipase A (AdPLA2) [, , , , ]. Extensive in vitro kinetic studies have been recently carried out with most of these enzymes. Many of the studies have taken advantage of the analytical power of mass spectrometry-based lipidomics [, , , ], which provided valuable information as to the substrate preference of these enzymes. Nevertheless, factors that take part in the microenvironment of the enzymes, such as the complex membrane composition, compartmentalization of the enzyme and the different physiological and pathophysiological scenarios of the cell (including cross-talk between PLA2 forms), may produce as a result a variety of lipid molecules that orchestrate global responses and cannot be easily reproduced in in vitro assays.