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Circulation of fluid between plasma, interstitium and lymph
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
The increased cytosolic Ca2+ raises the Ca2+-calmodulin level, which stimulates endothelial NO synthase activity (Section 9.4). Although small amounts of NO can lower permeability (by scavenging toxic O2 radicals), high levels of NO are pro-inflammatory (Figure 11.28). NO activates soluble guanylyl cyclase, which produces cyclic guanosine monophosphate (cGMP). cGMP is a permeability-raising messenger that activates phosphodiesterase 2 (PDE2) (Figure 11.30). Because PDE2 is more abundant in venular than arterial endothelium, this helps localize the inflammatory response to venules. PDE2 degrades cyclic adenosine monophosphate (cAMP), an anti-inflammatory, barrierenhancing messenger, so a fall in cAMP raises permeability. Conversely, cAMP-raising agonists, such as the β adrenergic receptor agonists isoprenaline and terbutaline, attenuate gap formation and inflammation. The anti-inflammatory action of cAMP is mediated by two pathways: (1) cAMP activates protein kinase A (PKA), which inhibits myosin contraction (Section 9.7); (2) cAMP activates the factor exchange protein directly activated by cAMP 1 (EPAC1), which activates pathways that stabilize the junctional strands and actin cyto- skeleton. A fall in cAMP therefore favours gap formation by loosening the intercellular junction and by endothelial contraction (retraction). In intact venules, junction loosening seems the more important factor because inhibitors of myosin light chain kinase, a key initiator of contraction, do not block the inflammatory response. By contrast, active contraction is important in cultured endothelial cells, a much used but potentially misleading research ‘model’.
An updated patent review of autotaxin inhibitors (2017–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Zehui Tan, Hongrui Lei, Ming Guo, Yuxiang Chen, Xin Zhai
Autotaxin (ATX), also known as ecto-nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) or lysophospholipase D (lysoPLD), is a secreted enzyme playing a primary role in the hydrolysis of extracellular lysophosphatidyl choline (LPC) into the phospholipid derivative lysophosphatidic acid (LPA)[1]. LPA is a bioactive signaling lipid that exerts significant effects on cell behavior by acting on specific G-protein coupled receptors (GPCRs) LPA1-LPA6[2]. Accumulating evidence suggests that downregulation of LPA signaling is effective in various diseases, such as tumor metastasis [3,4], fibrosis [5,6], pruritus[7], multiple sclerosis[8], inflammation [9,10], autoimmune conditions[11], metabolic syndrome [12], and so on. Consequently, the development of small-molecule inhibitors targeting the ATX‐LPA axis turns out to be an attractive therapeutic strategy in the treatment of relevant diseases.
Adipokines as therapeutic targets in breast cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2018
Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a member of the nucleotide pyrophosphatase/phosphodiesterase family of enzymes and is secreted as a catalytically active glycoprotein. ATX was identified as an autocrine motility factor for tumor cells in the early 1990s, and it has found to be identical to lysophospholipase D in the serum [15]. ATX generates lysophosphatidate (LPA), a bioactive phospholipid, from lysophosphatidylcholine (LPC) by hydrolyzing choline from the head group. LPA binds to its receptor and induces various cellular processes via activation of phospholipase C, and the MAPK, PI3K, and (alkaline phosphatase) PhoA pathways [16]. The LPA receptor is a G-protein-coupled receptor, and at least six LPA receptors (LPA1–LPA6) have been identified. LPA1–LPA3 belong to the EDG family (LPA1-EDG2, LPA2-EDG4, LPA3-EDG7), while the structure of LPA4–LPA6 is similar to that of the P2Y nucleotide receptor [17]. ATX-LPA signaling has been reported to be associated with tumor formation, progression, and metastasis [18]. ATX is generated from many cell types including platelets, endothelial cells, fibroblasts, and adipocytes. Among them, ATX secreted by adipocytes specifically affects fat expansion and plasma LPA levels [19].