Biomedical subjects

Song Hong

Publications and source records attributed to Song Hong.

26 records · Page 2Linked to original sources

PubMed2004

Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis.

Lipoxin A4 (LXA4) is a potent endogenous lipoxygenase-derived eicosanoid with antiinflammatory and proresolving properties. Supraphysiological levels of LXA4 are generated during infection by Toxoplasma gondii, which in turn reduces interleukin (IL) 12 production by dendritic cells, thus dampening Th1-type cell-mediated immune responses and host immunopathology. In the present work, we sought evidence for the structural basis of T. gondii's ability to activate LXA4 biosynthesis. Proteomic analysis of T. gondii extract (soluble tachyzoite antigen [STAg]), which preserves the immunosuppressive and antiinflammatory activity of the parasite, yielded several peptide matches to known plant lipoxygenases. Hence, we incubated STAg itself with arachidonic acid and found using LC-UV-MS-MS-based lipidomics that STAg produced both 15-HETE and 5,15-diHETE, indicating that T. gondii carries 15-lipoxygenase activity. In addition, T. gondii tachyzoites (the rapidly multiplying and invasive stage of the parasite) generated LXA4 when provided with arachidonic acid. Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties. Administration of plant 15-lipoxygenase generated endogenous LXA4 and mimicked the suppression of IL-12 production by splenic dendritic cells observed after T. gondii infection or STAg administration. Together, these results indicate that 15-lipoxygenase expressed by a pathogen as well as exogenously administered 15-lipoxygenase can interact with host biosynthetic circuits for endogenous "stop signals" that divert the host immune response and limit acute inflammation.

Animals↗

PubMed2004

The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase.

In mammals, lipoxygenases play key roles in inflammation by initiating the transformation of arachidonic acid into potent bioactive lipid mediators such as leukotrienes and lipoxins. In general, most bacteria are believed to lack lipoxygenases and their polyunsaturated fatty acid substrates. It is therefore of interest that an ORF (PA1169) with high homology to eukaryotic lipoxygenases was discovered by analysis of the whole-genome sequence of the opportunistic bacterial pathogen Pseudomonas aeruginosa. Using TLC and liquid chromatography-UV-tandem mass spectrometry (LC-UV-MS-MS), we demonstrate that PA1169 encodes a bacterial lipoxygenase (LoxA) that converts arachidonic acid into 15-hydroxyeicosatetraenoic acid (15-HETE). Although mammalian lipoxygenases are cytoplasmic enzymes, P. aeruginosa LoxA activity is secreted. Taken together, these results suggest a mechanism by which a pathogen-secreted lipoxygenase may modulate host defense and inflammation via alteration of the biosynthesis of local chemical mediators.

Amino Acid Sequence↗

PubMed2004

Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers.

The molecular basis for the beneficial impact of essential omega-3 (n-3) FA remains of interest. Recently, we identified novel mediators generated from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that displayed potent bioactions identified first in resolving inflammatory exudates and in tissues enriched with DHA. The trivial names resolvin (resolution phase interaction products) and docosatrienes were introduced for the bioactive compounds from these novel series since they possess potent anti-inflammatory and immunoregulatory actions. Compounds derived from EPA carrying potent biological actions (i.e., 1-10 nM range) are designated E series and denoted resolvins of the E series (resolvin E1 or RvE1), and those biosynthesized from the precursor DHA are denoted resolvins of the D series (resolvin D1 or RvD1). The number 1 designates the bioactive compounds in this family (#1-4). Bioactive members from DHA-containing conjugated triene structures or docosatrienes (DT) that possess immunoregulatory and neuroprotective actions were termed neuroprotectins. Aspirin treatment initiates a related epimeric series by triggering endogenous formation of the 17R-D series resolvins and docosatrienes. These epimers are denoted as aspirin-triggered (AT)-RvD and DT, and possess potent anti-inflammatory actions in vivo essentially equivalent to their 17S series pathway products. These include five distinct series: (i) 18R resolvins from EPA (i.e., RvE1); (ii) 17R series (AT) resolvins from DHA (RvD1 through RvD4); (iii) 17S series resolvins from DHA (RvD1 through RvD4), (iv) DT from DHA; and (v) their AT form 17R series DT. In this article, we provide an overview of the formation and actions of these newly uncovered pathways and products.

Animals↗

PubMed2004

Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis.

The molecular basis for the beneficial impact of essential omega-3 fatty acids is of considerable interest. Recently, novel mediators generated from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that displayed potent bioactions were first identified in resolving inflammatory exudates [J. Exp. Med. 192 (2000) 1197; J. Exp. Med. 196 (2002) 1025] and in tissues enriched with DHA [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677]. The trivial names Resolvin (resolution phase interaction products) and docosatrienes were introduced for the bioactive compounds belonging to these novel series because they demonstrate potent anti-inflammatory and immunoregulatory actions. The compounds derived from eicosapentaenoic acid carrying potent biological actions (i.e., 1-10 nM range) are designated E series, given their EPA precursor, and denoted as Resolvins of the E series (Resolvin E1 or RvE1), and those biosynthesized from the precursor docosahexaenoic acid are Resolvins of the D series (Resolvin D1 or RvD1). Bioactive members from DHA with conjugated triene structures are docosatrienes (DT) that are immunoregulatory [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677], and neuroprotective [J. Biol. Chem., 278 (2003) 43807; Proc. Natl. Acad. Sci. U.S.A. [submitted for publication]] and are termed neuroprotectins. The specific receptors for these novel bioactive products from omega-3 EPA and DHA are abbreviated Resolvin D receptors (i.e., ResoDR1), Resolvin E receptor (ResoER1; RER1), and neuroprotectin D receptors (NPDR), respectively, in recognition of their respective cognate ligands. Aspirin treatment impacts biosynthesis of these compounds and a related series by triggering endogenous formation of the 17R-D series Resolvins and docosatrienes. These novel epimers are denoted as aspirin-triggered (AT)-RvDs and -DTs, and possess potent anti-inflammatory actions in vivo essentially equivalent to their 17S series pathway products. Here, we provide a syntomy overview of the formation and actions of these newly uncovered pathways and products as well as highlight their role(s) as endogenous protective mediators generated in anti-inflammation and catabasis.

Animals↗

PubMed2003

Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.

Ischemic stroke triggers lipid peroxidation and neuronal injury. Docosahexaenoic acid released from membrane phospholipids during brain ischemia is a major source of lipid peroxides. Leukocyte infiltration and pro-inflammatory gene expression also contribute to stroke damage. In this study using lipidomic analysis, we have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model. Aspirin, widely used to prevent cerebrovascular disease, activates an additional pathway, which includes the 17R-resolvins. The newly discovered brain messenger 10,17S-docosatriene potently inhibited leukocyte infiltration, NFkappaB, and cyclooxygenase-2 induction in experimental stroke and elicited neuroprotection. In addition, in neural cells in culture, this lipid messenger also inhibited both interleukin 1-beta-induced NFkappaB activation and cyclooxygenase-2 expression. Thus, the specific novel bioactive docosanoids generated in vivo counteract leukocyte-mediated injury as well as pro-inflammatory gene induction. These results challenge the view that docosahexaenoate only participates in brain damage and demonstrate that this fatty acid is also the endogenous precursor to a neuroprotective signaling response to ischemia-reperfusion.

Animals↗

PubMed2003

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation.

Docosahexaenoic acid (DHA, C22:6) is highly enriched in brain, synapses, and retina and is a major omega-3 fatty acid. Deficiencies in this essential fatty acid are reportedly associated with neuronal function, cancer, and inflammation. Here, using new lipidomic analyses employing high performance liquid chromatography coupled with a photodiode-array detector and a tandem mass spectrometer, a novel series of endogenous mediators was identified in blood, leukocytes, brain, and glial cells as 17S-hydroxy-containing docosanoids denoted as docosatrienes (the main bioactive member of the series was 10,17S-docosatriene) and 17S series resolvins. These novel mediators were biosynthesized via epoxide-containing intermediates and proved potent (pico- to nanomolar range) regulators of both leukocytes reducing infiltration in vivo and glial cells blocking their cytokine production. These results indicate that DHA is the precursor to potent protective mediators generated via enzymatic oxygenations to novel docosatrienes and 17S series resolvins that each regulate events of interest in inflammation and resolution.

Animals↗

PubMed2003

Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense.

Signaling pathways instrumental in the temporal and spatial progression of acute inflammation toward resolution are of wide interest. Here a transgenic mouse with myeloid-selective expression of human lipoxin A4 receptor (hALX) was prepared and used to evaluate in vivo the effect of hALX expression. hALX-transfected HEK293 cells transmitted LXA4 signals that inhibit TNFalpha-induced NFkappaB activation. Transgenic FvB mice were generated by DNA injections of a 3.8 kb transgene consisting of the full-length hALX cDNA driven by a fragment of the hCD11b promoter. When topically challenged via dermal ear skin, hALX transgenic mice gave attenuated neutrophil infiltration (approximately 80% reduction) in response to leukotriene B4 (LTB4) plus prostaglandin E2 (PGE2) as well as approximately 50% reduction in PMN infiltrates (P<0.02) to receptor-bypass inflammation evoked by phorbol ester. The hALX transgenic mice gave markedly decreased PMN infiltrates to the peritoneum with zymosan and altered the dynamics of this response. Transgenic hALX mice displayed increased sensitivity with >50% reduction in PMN infiltrates to suboptimal doses (10 ng/mouse) of the ligand lipoxin A4 stable analog compared with <10% reduction of PMN in nontransgenic littermates. Soluble mediators generated within the local inflammatory milieu of hALX mice showed diminished ability to activate the proinflammatory transcription factor NFkappaB. Analyses of the lipid-derived mediators from exudates using LC-MS tandem mass spectroscopy indicated an altered profile in hALX transgenic mice that included lower levels of LTB4 and increased amounts of lipoxin A4 compared with nontransgenic littermates. Together these results demonstrate a gain-of-function with hALX transgenic mouse and indicate that ALX is a key receptor and sensor in formation of acute exudates and their resolution.

3T3 Cells↗

PubMed2002

Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.

Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA-derived 17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC(50) approximately 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40-80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.

Animals↗