3D model (JSmol)
|Molar mass||280.408 g·mol−1|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
12-Hydroxyheptadecatrenoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was first detected and structurally defined by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.
- 1 Production
- 2 Further metabolism
- 3 Activities and clinical significance
- 4 See also
- 5 References
Cyclooxygenase-1 and cyclooxygenase-2 metabolize arachidonic acid to the 15-hydroperoxy, 20 carbon prostaglandin (PG) intermediate, PGG2, and then to the 15-hydroxy, 20 carbon intermediate, prostaglandin H2 (PGH2). Thromboxane synthase further metabolizes PGH2 to the 20 carbon product, Thromboxane A2, the 17 carbon product, 12-HHT, and the 3 carbon product Malonyldialdehyde. Platelets express cycloxygenase and thromboxane synthase enzymes, producing PGG2, PGH2, and TXA2 in response to platelet aggregating agents such as thrombin; these metabolites act as autocrines by feeding back to promote further aggregation of their cells of origin and as paracrines by recruiting nearby platlets into the response as well as exerting effects on other nearby tissues such as contracting blood vessels. These effects combine to trigger blood clotting and limiting blood loss. 12-HHT is a particularly abundant product of these pro-clotting responses, accounting for about one third of the total amount of arachidonic acid metabolites formed by physiologically stimulated human platelets. Its abundant production during blood clotting, the presence of cyclooxygenases and to a lesser extent thromboxane synthase in a wide range of cell types and tissue, and its production by other pathways imply that 12-HHT has one or more important bioactivities relevant to clotting and, perhaps, other responses.
Various cytochrome P450 enzymes (e.g. CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2S1, and CYP3A4) metabolize PGG2 and PGH2 to 12-HHT and MDA. While the latter studies were conducted using recombinant cytochrome enzymes or sub-fractions of disrupted cells, the human monocyte, a form of blood circulating leukocyte, increases its expression of CYP2S1 when forced to differentiate into a macrophage phenotype by interferon gamma or lipopolysaccharide (i.e. endotoxin); associated with these changes, the differentiated macrophage metabolized arachidonic acid to 12-HHT by a CYP2S1-dependent mechanism. Future studies, therefore may show that cytochromes are responsible for 12-HHT and MDA production in vivo.
PGH2, particularly in the presence of ferrous iron (FeII), ferric iron (FeIII), or hemin, rearranges non-enzymatically to a mixture of 12-HHT and 12-HHT's 8-cis isomer, i.e., 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid. This non-enzymatic pathway may explain findings that cells can make 12-HHT in excess of TXA2 and also in the absence of active cycloxygenase and/or thromboxane synthase enzymes.
12-HHT is further metabolized by 15-hydroxyprostaglandin dehydrogenase (NAD+) in a wide variety of human and other vertebrate cells to its 12-oxo (also termed 12-keto) derivative, 12-oxo-5Z,8E,10E-heptadecatrienoic acid (12-oxo-HHT or 12-keto-HHT). Pig kidney tissue also converted 12-HHT to 12-keto-5Z,8E-heptadecadienoic acid (12-oxo-5Z,8E-heptadecadienoic acid) and 12-hydroxy-heptadecadienoic acid.
Acidic conditions (pH~1.1-1.5) cause 12-HHT to rearrange in a time- and temperature-dependent process to its 5-cis isomer, 12-hydroxy-5E,8E,10E-heptadecatrienoic acid.
Activities and clinical significance
Fourteen years after the first publication on its detection in 1973, 12-HHT was reported to stimulate fetal bovine aortic and human umbilical vein endotheleal cells to metabolize arachidonic acid to Prostacyclin I2 (PGI2), a powerful inhibitor of platelet activation and stimulator of Vasodilation (see Prostacyclin synthase); it did not, however, alter arachidonic acid metabolism in human platelets. Shortly thereafter, 12-HHT was reported to inhibit the chemotaxis-blocking effect of a human monocyte-derived factor on human moncytes while the immediate metabolite of 12-HHT, 12-oxo-HT, was reported to stimulate the chemotasis of human neutrophils. and to inhibit platelet aggregation responses to various agents by stimulating platelets to raise their levels of Cyclic adenosine monophosphate (cAMP), an intracellular signal that serves broadly to inhibit platelet activation. These studies were largely overlooked; in 1998 and 2007 publications, for example, 12-HHT was regarded as either inactive or without significant biological activity. Nonetheless, this early work suggested that 12-HHT may serve as a contributor to monocyte- and neutrophil-based inflammatory responses and 12-oxo-HT may serve as a counterpoise to platelet aggregation responses elicited or promoted by TXA2. Relevant to the latter activity, a later study showed that this inhibitory effect was due to the ability of 12-oxo-HT to act as a partial antagonist of the Thromboxane receptor: it blocks TXA2 binding to its receptor and thereby the responses of platelets and possibly other tissues to TXA2 as well as agents that depend on stimulating TXA2 production for their activity. Thus, 12-HHT forms simultaneously with, and by stimulating PGI2 production, inhibits TXA2-mediated platelet activation responses while 12-oxo-HT blocks TXA2 receptor binding to reduce not only TXA2-induced thrombosis and blood clotting but possibly also vasospasm and other actions of TXA2. In this view, thromboxane synthase leads to the production of a broadly active arachidonic acid metabolite, TXA2, plus two other arachidonic acid metabolites, 12-HHT and 12-oxo-HT, that serve indirectly to stimulate PGI2 production or directly as a receptor antagonist to moderate TXA2's action, respectively. This strategy may be essential for limiting the deleterious thrombotic and vasospastic activities of TXA2.
12-HHT is a BLT2 receptor agonist
Leukotriene B4 (i.e. LTB4) is an arachidonic acid metabolite made by the 5-lipoxygenase enzyme pathway. It activates cells through both its high affinity (Dissociation constant [Kd] of 0.5-1.5 nM) Leukotriene B4 receptor 1 (BLT1 receptor) and its low affinity BLT2 receptor (Kd=23 nM); both receptors are G protein coupled receptors that, when ligand-bound, activate cells by releasing the Gq alpha subunit and pertussis toxin-sensitive Gi alpha subunit from Heterotrimeric G proteins. BLT1 receptor has a high degree of ligand-binding specificity: among a series of hydroxylated eicosanoid metabolites of arachidonic acid, it binds only LTB4, 20-hydroxy-LTB4, and 12-epi-LTB4; among this same series, BLT2 receptor has far less specificity in that it binds not only LTB4, 20-hydroxy-LTB4, and 12-epi-LTB4 but also 12(R)-HETE and 12(S)-HETE (i.e. the two stereoisomers of 12-Hydroxyeicosatetraenoic acid) and 15(S)-HpETE and 15(S)-HETE (i.e. the two stereoisomers of 15-Hydroxyicosatetraenoic acid). The BLT2 receptor's relative affinities for finding LTB4, 12(S)-HETE, 12(S)-HpETE, 12(R)-HETE, 15(S)-HETE, and 20-hydroxy-LTB4 are ~100, 10, 10, 3, 3, and 1, respectively. All of these binding affinities are considered to be low and therefore indicating that some unknown ligand(s) might bind BLT2 with high affinity. In 2009, 12-HHT was found to bind to the BLT2 receptor with ~10-fold higher affinity than LTB4; 12-HHT did not bind to the BLT1 receptor. Thus, the BLT1 receptor exhibits exquisite specificity, binding 5(S),12(R)-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid (i.e. LTB4) but not LTB4's 12(S) or 6Z isomers while the BLT2 receptor exhibits a promiscuous finding pattern. Formyl peptide receptor 2 is a relevant and well-studied example of promiscuous receptors. Initially thought to be a second and low affinity receptor for the neutrophil tripeptide chemotactic factor, N-formyl-met-leu-phe, subsequent studies showed that it was a high affinity receptor for the arachidonic acid metabolite, lipoxin A4, but also bound and was activated by a wide range of peptides, proteins, and other agents. BLT2 may ultimately prove to have binding specificity for a similarly broad range of agents.
The production of LTB4 and expression of BLT1 by human tissues are largely limited to bone marrow-derived cells such as the neutrophil, eosinophil, mast cell, and various types of lymphocytes and accordingly are regarded primarily as contributing to the many human defensive and pathological (ulcerative colitis, arthritis, asthma, etc.) inflammatory responses which are mediated by these cell types. Drugs that inhibit LTB4 production or binding to BLT1 are in use or development for the latter diseases. In contrast, the production of 12-HH2 and expression of BLT2 receptors by human tissues is far wider and more robust than that of the LTB4/BLT2 receptor axis. Recent studies indicate that the role(s) of the 12-HHT/BLT2 receptor axis in human physiology and pathology may be very different than those of the LTB4/BLT1 axis.
Recent studies on 12-HHT/BLT2 receptor activities
Inflammation and allergy
12-HHT stimulates chemotactic responses in mouse bone marrow mast cells, which naturally express BLT2 receptors, as well as in Chinese hamster ovary cells made to express these receptors by transfection. These findings suggest that the 12-HHT/BLT2 receptor pathway may support the pro-inflammatory (i.e. chemotactic) actions of the LTB4/BLT1 pathway.
On the other hand, the immortalized human skin cell line HaCaT expresses BLT2 receptors and responds to ultraviolet B (UVB) radiation by generating toxic reactive oxygen species which in turn cause the HaCaT cells to die by activating apoptotic pathways in a BLT2 receptor-dependent reaction. Topical treatment of mouse skin with a BLT2 receptor antagonist, LY255283, protects against UVB radiation-induced apoptosis and BLT2-overexpressing transgenic mice exhibited significantly more extensive skin apoptosis in response to UVB irradiation. Furthermore, 12-HHT inhibits HaCaT cells from synthesizing interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in response to UVB radiation. These results suggest that the 12-HHT/BLT2 axis can act to suppress inflammation by promoting the orderly death of damaged cells and blocking IL-6 production. Opposition between the pro-inflammatory LTB4/BLT1 and anti-inflammatory actions of the 12-HHT/BLT2 axes occurs in another setting. In a mice model of ovalbumin-induced allergic airway disease, 12-HHT and its companion cyclooxygenase metabolites, Prostaglandin E2 and Prostaglandin D2, but not 12 other lipoxygenase or cycloxygenase mebolites showed a statistically significantly increase in bronchoalveolar lavage fluid levels after intratracheal ovalbumin challenge; after this challenge, only 12-HHT, among the monitored BLT2 receptor-activating ligands (LTB4, the 12(S) stereoisomer of 12-HETE, and 15(S)-HETE) attained levels capable of activating BLT2 receptors. Also, BLT2 knockout mice exhibited a greatly enhanced response to ovalabumin challenge. Finally, BLT2 receptor expression was significantly reduced in allergy-regulating CD4+ T cells from patients with asthma compared to healthy control subjects. Unlike LTB4 and its BLT1 receptor, which are implicated in contributing to allergen-based airway disease in mice and humans, 12-HHT and its BLT2 receptor appear to suppress this disease in mice and may do so in humans. While further studies to probe the role of the 12-HHT/BLT2 axis in human inflammatory and allergic diseases, the current studies indicate that 12-HHT, acting through BLT2, may serve to promote or limit, inflammatory and to promote allergic responses.
High dose aspirin treatment (aspirin, at these doses, inhibits cyclooxygenases-1 and -2 to block their production of 12-HHT), thromboxane synthase knockout, and BLT2 receptor knockout but not TXA2 receptor knockout impair keratinocyte-based re-epithelialization and thereby closure of experimentally induced wounds in mice while a synthetic BLT2 receptor agonist accelerats wound closure not only in this mouse model but also in the db/db mouse model of obesity, diabetes, and dyslipidemia due to leptin receptor deficiency. 12-HHT accumulated in the wounds of the former mouse model. Companion studies using an in vitro scratch test assay indicated that 12-HHT stimulated human and mouse keratinocyte migration by a BLT2 receptor-dependent mechanism that involved the production of tumor necrosis factor α and metalloproteinases. These results indicate that the 12-HHT/BLT2 receptor axis is a critical contributor to wound healing in mice and possibly humans. The axis operates by recruiting the movement of keratinocytes to close the wound. This mechanism may underlie the suppression of wound healing that accompanies the high dose intake of aspirin and, based on mouse studies, other non-steroidal anti-inflammatory agents (NSAID) in humans. Synthetic BLT2 agonists may be useful for speeding the healing of chronic ulcerative wounds, particularly in patients with, for example diabetics, that have impaired wound healing.
A large number of studies have associated BLT2 and, directly or by assumption, 12-HHT in the survival, growth, and/or spread of various human cancers. See 'Leukotriene B4 receptor 2 for the associations of BLT2 and/or 12-HHT with stimulating the malignant behavior of prostate cancer, urinary bladder cancer, breast cancer, thyroid gland follicular carcinoma, kidney renal cell carcinoma, bladder transitional cell carcinoma, esophageal cancer, pancreatic cancer, and colon cancer.
- Leukotriene B4 receptor 2
- Leukotriene B4 receptor 1
- Leukotriene B4
- 12-Hydroxyeicosatetraenoic acid
- 15-hydroxyicosatetraenoic acid
- Wlodawer, P; Samuelsson, B (1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. PMID 4723909.
- Hamberg, M; Samuelsson, B (1974). "Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 71 (9): 3400–4. doi:10.1073/pnas.71.9.3400. PMC 433780. PMID 4215079.
- Wong, S. L.; Wong, W. T.; Tian, X. Y.; Lau, C. W.; Huang, Y (2010). Prostaglandins in action indispensable roles of cyclooxygenase-1 and -2 in endothelium-dependent contractions. Advances in Pharmacology. 60. pp. 61–83. doi:10.1016/B978-0-12-385061-4.00003-9. ISBN 9780123850614. PMID 21081215.
- Sadowitz, P. D.; Setty, B. N.; Stuart, M (1987). "The platelet cyclooxygenase metabolite 12-L-hydroxy-5, 8, 10-hepta-decatrienoic acid (HHT) may modulate primary hemostasis by stimulating prostacyclin production". Prostaglandins. 34 (5): 749–63. doi:10.1016/0090-6980(87)90297-8. PMID 3124219.
- Plastaras, J. P.; Guengerich, F. P.; Nebert, D. W.; Marnett, L. J. (2000). "Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde". The Journal of Biological Chemistry. 275 (16): 11784–90. doi:10.1074/jbc.275.16.11784. PMID 10766802.
- Hecker, M; Ullrich, V (1989). "On the mechanism of prostacyclin and thromboxane A2 biosynthesis". The Journal of Biological Chemistry. 264 (1): 141–50. PMID 2491846.
- Bui, P; Imaizumi, S; Beedanagari, S. R.; Reddy, S. T.; Hankinson, O (2011). "Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids". Drug Metabolism and Disposition. 39 (2): 180–90. doi:10.1124/dmd.110.035121. PMC 3033693. PMID 21068195.
- Frömel, T; Kohlstedt, K; Popp, R; Yin, X; Awwad, K; Barbosa-Sicard, E; Thomas, A. C.; Lieberz, R; Mayr, M; Fleming, I (2013). "Cytochrome P4502S1: A novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques". Basic Research in Cardiology. 108 (1): 319. doi:10.1007/s00395-012-0319-8. PMID 23224081.
- John, H; Cammann, K; Schlegel, W (1998). "Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid". Prostaglandins & Other Lipid Mediators. 56 (2–3): 53–76. doi:10.1016/s0090-6980(98)00043-4. PMID 9785378.
- Matsunobu, T; Okuno, T; Yokoyama, C; Yokomizo, T (2013). "Thromboxane a synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand". The Journal of Lipid Research. 54 (11): 2979–87. doi:10.1194/jlr.M037754. PMC 3793602. PMID 24009185.
- Hecker, M; Ullrich, V (1988). "12(S)-Hydroxy-5,8,10 (Z,E,E)-heptadecatrienoic acid (HHT) is preferentially metabolized to its 12-keto derivative by human erythrocytes in vitro". Eicosanoids. 1 (1): 19–25. PMID 3272822.
- Bergholte, J. M.; Soberman, R. J.; Hayes, R; Murphy, R. C.; Okita, R. T. (1987). "Oxidation of 15-hydroxyeicosatetraenoic acid and other hydroxy fatty acids by lung prostaglandin dehydrogenase". Archives of Biochemistry and Biophysics. 257 (2): 444–50. doi:10.1016/0003-9861(87)90589-3. PMID 3662534.
- Agins, A. P.; Thomas, M. J.; Edmonds, C. G.; McCloskey, J. A. (1987). "Identification of 12-keto-5,8,10-heptadecatrienoic acid as an arachidonic acid metabolite produced by human HL-60 leukemia cells". Biochemical Pharmacology. 36 (11): 1799–805. doi:10.1016/0006-2952(87)90241-3. PMID 3107571.
- Höhl, W; Stahl, B; Mundkowski, R; Hofmann, U; Meese, C. O.; Kuhlmann, U; Schlegel, W (1993). "Mass determination of 15-hydroxyprostaglandin dehydrogenase from human placenta and kinetic studies with (5Z, 8E, 10E, 12S)-12-hydroxy-5,8,10-heptadecatrienoic acid as substrate". European Journal of Biochemistry / FEBS. 214 (1): 67–73. doi:10.1111/j.1432-1033.1993.tb17897.x. PMID 8508808.
- Hofmann, U; Seefried, S; Meese, C. O.; Mettang, T; Hübel, E; Kuhlmann, U (1990). "Measurement of 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid and its metabolite 12-oxo-5Z,8E,10E-heptadecatrienoic acid in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry". Analytical Biochemistry. 189 (2): 244–8. doi:10.1016/0003-2697(90)90115-p. PMID 2281869.
- Campbell, P. B.; Tolson, T. A. (1988). "Modulation of human monocyte leukotactic responsiveness by thromboxane A2 and 12-hydroxyheptadecatrienoic acid (12-HHT)". Journal of Leukocyte Biology. 43 (2): 117–24. doi:10.1002/jlb.43.2.117. PMID 3422086.
- Okuno, T; Iizuka, Y; Okazaki, H; Yokomizo, T; Taguchi, R; Shimizu, T (2008). "12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2". The Journal of Experimental Medicine. 205 (4): 759–66. doi:10.1084/jem.20072329. PMC 2292216. PMID 18378794.
- Ruf, A; Mundkowski, R; Siegle, I; Hofmann, U; Patscheke, H; Meese, C. O. (1998). "Characterization of the thromboxane synthase pathway product 12-oxoheptadeca-5(Z)-8(E)-10(E)-trienoic acid as a thromboxane A2 receptor antagonist with minimal intrinsic activity". British Journal of Haematology. 101 (1): 59–65. doi:10.1046/j.1365-2141.1998.00669.x. PMID 9576182.
- Yokomizo, T; Kato, K; Terawaki, K; Izumi, T; Shimizu, T (2000). "A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders". The Journal of Experimental Medicine. 192 (3): 421–32. doi:10.1084/jem.192.3.421. PMC 2193217. PMID 10934230.
- Tager, A. M.; Luster, A. D. (2003). "BLT1 and BLT2: The leukotriene B(4) receptors". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 69 (2–3): 123–34. doi:10.1016/s0952-3278(03)00073-5. PMID 12895595.
- Yokomizo, T; Kato, K; Hagiya, H; Izumi, T; Shimizu, T (2001). "Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2". Journal of Biological Chemistry. 276 (15): 12454–9. doi:10.1074/jbc.M011361200. PMID 11278893.
- Yokomizo, T (2015). "Two distinct leukotriene B4 receptors, BLT1 and BLT2". Journal of Biochemistry. 157 (2): 65–71. doi:10.1093/jb/mvu078. PMID 25480980.
- Bäck, M; Powell, W. S.; Dahlén, S. E.; Drazen, J. M.; Evans, J. F.; Serhan, C. N.; Shimizu, T; Yokomizo, T; Rovati, G. E. (2014). "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". British Journal of Pharmacology. 171 (15): 3551–74. doi:10.1111/bph.12665. PMC 4128057. PMID 24588652.
- Anwar, Y; Sabir, J. S.; Qureshi, M. I.; Saini, K. S. (2014). "5-lipoxygenase: A promising drug target against inflammatory diseases-biochemical and pharmacological regulation". Current Drug Targets. 15 (4): 410–22. doi:10.2174/1389450114666131209110745. PMID 24313690.
- Fourie, A. M. (2009). "Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase". Current Opinion in Investigational Drugs. 10 (11): 1173–82. PMID 19876785.
- Hicks, A; Monkarsh, S. P.; Hoffman, A. F.; Goodnow Jr, R (2007). "Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: Preclinical and clinical developments". Expert Opinion on Investigational Drugs. 16 (12): 1909–20. doi:10.1517/135437188.8.131.529. PMID 18042000.
- Miyata, A; Yokoyama, C; Ihara, H; Bandoh, S; Takeda, O; Takahashi, E; Tanabe, T (1994). "Characterization of the human gene (TBXAS1) encoding thromboxane synthase". European Journal of Biochemistry / FEBS. 224 (2): 273–9. doi:10.1111/j.1432-1033.1994.00273.x. PMID 7925341.
- Ryu, H. C.; Kim, C; Kim, J. Y.; Chung, J. H.; Kim, J. H. (2010). "UVB radiation induces apoptosis in keratinocytes by activating a pathway linked to "BLT2-reactive oxygen species"". Journal of Investigative Dermatology. 130 (4): 1095–106. doi:10.1038/jid.2009.436. PMID 20090768.
- Lee, J. W.; Ryu, H. C.; Ng, Y. C.; Kim, C; Wei, J. D.; Sabaratnam, V; Kim, J. H. (2012). "12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity". Experimental & Molecular Medicine. 44 (6): 378–86. doi:10.3858/emm.2012.44.6.043. PMC 3389076. PMID 22391335.
- Matsunaga, Y; Fukuyama, S; Okuno, T; Sasaki, F; Matsunobu, T; Asai, Y; Matsumoto, K; Saeki, K; Oike, M; Sadamura, Y; Machida, K; Nakanishi, Y; Kubo, M; Yokomizo, T; Inoue, H (2013). "Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia". The FASEB Journal. 27 (8): 3306–14. doi:10.1096/fj.12-217000. PMID 23603839.
- Singh, R. K.; Tandon, R; Dastidar, S. G.; Ray, A (2013). "A review on leukotrienes and their receptors with reference to asthma". Journal of Asthma. 50 (9): 922–31. doi:10.3109/02770903.2013.823447. PMID 23859232.
- Watanabe, M; Machida, K; Inoue, H (2014). "A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung". Expert Review of Respiratory Medicine. 8 (4): 381–3. doi:10.1586/17476348.2014.908715. PMID 24742066.
- Liu, M; Saeki, K; Matsunobu, T; Okuno, T; Koga, T; Sugimoto, Y; Yokoyama, C; Nakamizo, S; Kabashima, K; Narumiya, S; Shimizu, T; Yokomizo, T (2014). "12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor". The Journal of Experimental Medicine. 211 (6): 1063–78. doi:10.1084/jem.20132063. PMC 4042643. PMID 24821912.
- Kaushal, M; Gopalan Kutty, N; Mallikarjuna Rao, C (2007). "Wound healing activity of NOE-aspirin: A pre-clinical study". Nitric Oxide. 16 (1): 150–6. doi:10.1016/j.niox.2006.07.004. PMID 16978891.
- Gus-Brautbar, Y; Panigrahy, D (2014). "Time heals all wounds--but 12-HHT is faster". The Journal of Experimental Medicine. 211 (6): 1008. doi:10.1084/jem.2116insight1. PMC 4042644. PMID 24890114.