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Mast Cell Mediators and their Effect on Airway Smooth Muscle
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
5-HETE is also a lipoxygenase product resulting from stimulation of human lung mast cells.137 5-HETE has weak bronchoconstricting effects on human airway in vitro.138 It is able to induce mucus production109 and, thus, may affect airway patency both directly and indirectly. 5-HETE is also chemotactic for both neutrophils139 and eosinophils,140 but is less potent than LTB4. Overall, the effect of 5-HETE on human airway tone is likely small in comparison to the other lipoxygenase products.
Eicosanoids and the Uterine Cervix
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
Tanaka et al.65 prepared microsomal pellets from term and nonpregnant human cervices; following incubation with radioactive arachidonic acid, products were extracted into organic solvent and separated by thin-layer chromatography. Predominantly 6-keto-F1α was identified and considerably more was present at term delivery, compared with the nonpregnant cervix. PGE2 and PGD2 were formed in smaller amounts than 6-keto-F2α. The products were not further identified by other detection methods. 6-Keto-PGF2α formation was, however, prevented by the inclusion in the incubates of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, a known prostacyclin synthetase inhibitor. Very few investigations have been performed on the lipoxygenase-derived products of arachidonic acid by the human uterine cervix. Saeed and Mitchell63 studied the generation of products following [14C]arachidonic acid incubation with supernatants of human uterine cervix from nonpregnant women. They tentatively identified 5-HETE, 12-HETE, and the lactone of 5-HETE and could inhibit the formation of these products with the lipoxygenase inhibitor, nordihydroguairaetic acid. Indomethacin did not inhibit the formation of these products. 12-Lipoxygenase activity has also been identified in the squamous epithelial region of the cervix and subcellular fractionation showed highest levels in the microsomal fraction. 12-Hydroperoxyeicosatetraenoic acid and 12-HETE were identified following incubation with [14C]arachidonic acid. This activity was inhibited by nordihydroguaiaretic acid and eicosatetranoic acid.66 An investigation not yet confirmed by other investigators is that of Hillier and Coad,67 who showed that passive stretching of the fibrous inner zone of the nonpregnant human cervix under a constant load increased the synthesis of PGE2 and PGF2α measured by RIA (Table 3). The cells responsible for the increased synthesis have not been determined, and the contribution of smooth muscle and other cell types urgently requires investigation. General heightened cellular activity of cervix cells at term might suggest that synthesis under the influence of stretching may be increased at term in the cervix as well as the amnion and the uterus. Whether increased PG synthesis in cervix under load is concerned with the alteration in matrix proteins that has been noted when nonreproductive tissues are exposed to mechanical stretch is unknown, but is worthy of investigation in human cervix.90
Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy
Published in Drug Metabolism Reviews, 2023
Mohammed A. W. ElKhatib, Fadumo Ahmed Isse, Ayman O. S. El-Kadi
Regarding 5-HETE, it has been reported to exert pro-inflammatory and vasoconstrictive functions (Burhop et al. 1988). Also, it has been demonstrated that it contributes to Ang II-mediated hypertrophy (Revermann et al. 2011). In this regard, 5-LOX inhibitor, LP105, attenuated Ang II-mediated hypertrophy in mice lacking ApoE. This was exhibited by the LP105 ability to reduce heart-to-body weight ratio, decrease heart rate, as well as inhibit the Ang II-induced increased aortic diameter and weight (Revermann et al. 2011). Another study reported that selenium was able to ameliorate diabetic CH via 5-LOX and 5-HETE downregulation (Dhanya et al. 2014).
Beneficial effect of n-3 polyunsaturated fatty acids on inflammation and analgesic use in psoriatic arthritis: a randomized, double blind, placebo-controlled trial
Published in Scandinavian Journal of Rheumatology, 2018
S Kristensen, EB Schmidt, A Schlemmer, C Rasmussen, MB Johansen, JH Christensen
While the changes in LTB4 and LTB5 formation indicate an anti-inflammatory action of the n-3 PUFA supplement, it is unknown whether the induced changes in formation of 5-HETE and 5-HEPE are of clinical relevance. Furthermore, it should be kept in mind that there may be a significant intraindividual variability in the formation of leukotrienes and, furthermore, maximal capacity was determined after stimulation. Although the formation of leukotrienes is believed to reflect the inflammatory potential, its importance for the overall granulocyte inflammatory activity in vivo is uncertain.
Nanosized silver, but not titanium dioxide or zinc oxide, enhances oxidative stress and inflammatory response by inducing 5-HETE activation in THP-1 cells
Published in Nanotoxicology, 2020
Wing-Lam Poon, Jetty Chung-Yung Lee, Kin Sum Leung, Harri Alenius, Hani El-Nezami, Piia Karisola
During infection and inflammation, cellular polyunsaturated fatty acids (PUFAs) may undergo oxidation to produce the important lipid signaling molecules, eicosanoids, either enzymatically by lipoxygenase (LOX), cyclooxygenase (COX) and cytochrome P450 (CYP) enzymes, or non-enzymatically by cellular ROS induced free radical chain reactions (Dennis and Norris 2015). In general, the tested nanoparticles did not cause severe enzymatic PUFA oxidation, probably because we used sub-toxic doses of the nanoparticles. Yet, we showed that n-Ag induced elevation in the 5-HETE: AA ratio at 24 h, implicating increasing 5-HETE production from AA oxygenation in the cell even at such low n-Ag concentration. 5-HETE is generated exclusively through the LOX pathway, especially by the 5-lipoxygenase (5-LOX) isoform. Inflammatory stimuli can activate purinergic receptor or toll-like receptor (TLR) to mobilize 5-LOX and/or cytosolic phospholipase A2 (cPLA2) to move from the cytosol to the nuclear membrane. At the nuclear membrane, AA is released by cPLA2 and passed to 5-LOX by FLAP (Dennis and Norris 2015), which can be eventually converted to 5-HETE or leukotrienes, which both are pro-inflammatory chemoattractants but their actions are mediated through different receptors and signaling cascades (O'Flaherty et al. 1998; Powell and Rokach 2005). 5-HETE may be converted to the potent chemoattractant 5-oxo-ETE under respiratory burst, oxidative stress and cell death. Both oxidized lipids are recognized by the G-protein coupled receptor OXE to mediate inflammatory and chemotactic responses. In particular, eosinophils have been suggested as the primary target of 5-oxo-ETE (Powell and Rokach 2013). Here, we did not see signs of specific eosinophils chemotaxis based on the microarray data. Considering the rather gentle status of oxidative stress, it was likely that 5-HETE was still the predominate form inside of cells exposed to n-Ag at 24 h. Some 5-HETEs are found esterified in the nuclear and non-nuclear membranes, which are functionally distinct from the free 5-HETEs. Clark et al. showed that stimulation by N-formyl-methionine-leucine-phenylalanine and priming with cytochalasin B, GM-CSF, or LPS triggers fast formation of esterified 5-HETE which could enhance superoxide and IL-8 production in neutrophils (Clark et al. 2011). In the current study, we have also found increasing levels of mitochondrial superoxide and a set of differentially expressed chemokine genes (CCL3, CXCL2, CXCL1, CXCL3 and CCL17) exclusively induced by exposure to n-Ag. Previously, we showed that n-Ag caused vast, statistically significant transcriptomic changes in differentiated THP-1 cells when compared to non-stimulated controls. In particular, the specific differentially expressed genes were mainly involved in type I interferon antiviral response likely via TLR7 activation, inflammasome activation and chemotaxis (Poon et al. 2017). Notwithstanding here, we showed exclusive induction of cellular 5-HETE production by exposure to n-Ag. It is likely that these responses are linked and collaborating to orchestra more severe inflammation in the cell compared to the other nanoparticles.