Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis.

BACKGROUND: Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are unclear. OBJECTIVES: Here, we identified to explore the role and mechanism of lysophosphatidylcholine (LPC) on the pathogenesis of psoriasis. METHODS: The level of LPC in plasma and skin lesions and the expression of G2A on skin lesions of psoriasis patients were detected by enzyme-linked immunosorbent assay, liquid chromatography-tandem mass spectrometry, or immunohistochemistry, respectively. The glycolysis in the skin lesions of imiquimod (IMQ)-induced psoriasis-like mouse model was detected by extracellular acidification rate. LPC was subcutaneously injected into IMQ-treated mouse ears, and the phenotype as well as the glycolysis were evaluated. Exploring the effects and mechanism of LPC on keratinocytes and CD4+ T cells by culturing primary keratinocytes and CD4+ T in vitro. RESULTS: We found that LPC was significantly increased both in the plasma and skin lesions of psoriatic patients, while G2A, exerting an essential role in LPC-inducing biological functions, was increased in psoriatic lesions. The abundance of LPC was positively correlated with glycolytic activity in the psoriasis-like mouse model. LPC treatment facilitated psoriasis-like inflammation and glycolytic activity in skin lesions. Mechanistically, the LPC/G2A axis significantly triggered glycolytic activity and produced inflammatory factors in keratinocytes, and blockade of glycolysis abrogated LPC-induced expression of inflammatory mediators in keratinocytes. LPC activated STAT1, resulting in recognition and binding to the promoters of GCK and PKLR, which are glycolytic rate-limiting enzymes. Furthermore, the LPC/G2A axis directly benefited Th1 differentiation, which was dependent on LPC-induced glycolytic activity. Notably, LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL-1ß in keratinocytes-T cells coculture system. CONCLUSIONS: Taken together, our findings revealed the role of the LPC/G2A axis in the pathogenesis of psoriasis; targeting LPC/G2A is a potential strategy for psoriasis therapy.

Myristoyl lysophosphatidylcholine is a biomarker and potential therapeutic target for community-acquired pneumonia.

There is no gold standard for evaluating the severity of community-acquired pneumonia (CAP), and it is still based on a score. This study aimed to use the metabolomics method to find promised biomarkers in assessing disease severity and potential therapeutic targets for CAP. The result found that the metabolites in the plasma samples of CAP patients had significantly different between the acute phase and the remission phase, especially lysophosphatidylcholine (LPCs) in glycerophospholipids, whose levels are negatively linked to the severity of the disease. Subsequently, the two key metabolites of myristoyl lysophosphatidylcholine (LPC 14:0) and LPC 16:1 were screened. We analyzed the predictive performance of the two metabolites using Spearman-related analysis and ROC curves, and LPC14:0 showed more satisfactory diagnostic performance than LPC16:1. Then we explored the protective role and mechanism of LPC 14:0 in animal and cell models. The results showed that LPC 14:0 could inhibit the LPS-induced secretion of IL-1ß, IL-6, and TNF-α, lower the ROS and MDA levels, and decreased the depletion of SOD and GSH, thereby reducing lung tissue and cell damage, such as down-regulating the protein level in BALF, lung W/D ratio, MPO activity, and apoptosis. We found that LPC 14:0 inhibited LPS-induced inflammatory response and oxidative stress, and the above protection was achieved by inhibiting LPS-induced activation of the NLRP3 inflammasome. LPC 14:0 may serve as a novel biomarker for predicting the severity of CAP. In addition, our exploration of the role of LPC 14:0 in animal and cellular models has reinforced its promise as a therapeutic target to improve the clinical efficacy for CAP.

A Stably Established Two-Point Injection of Lysophosphatidylcholine-Induced Focal Demyelination Model in Mice.

Receptor-mediated lysophospholipid signaling contributes to the pathophysiology of diverse neurological diseases, especially multiple sclerosis (MS). Lysophosphatidylcholine (LPC) is an endogenous lysophospholipid associated with inflammation, and it could induce rapid damage with toxicity to myelin lipids, leading to focal demyelination. Here, a detailed protocol is presented for stereotactic two-point LPC injection that could directly cause severe demyelination and replicate the experimental demyelination injury quickly and stably in mice by surgical procedure. Thus, this model is highly relevant to demyelination diseases, especially MS, and it can contribute to the related advancing clinically-relevant research. Also, immunofluorescence and Luxol fast blue staining methods were used to depict the time course of demyelination in the corpus callosum of mice injected with LPC. In addition, the behavioral method was used to evaluate the cognitive function of mice after modeling. Overall, the two-point injection of lysophosphatidylcholine via a stereotaxic frame is a stable and reproducible method to generate a demyelination model in mice for further study.

Intranasal administration of fingolimod (FTY720) attenuates demyelination area in lysolecithin-induced demyelination model of rat optic chiasm.

BACKGROUND: Fingolimod (FTY720) is an oral immunosuppressive compound that has been prescribed to multiple sclerosis (MS) patients since 2010. The lipophilicity and low molecular weight of FTY720 allows it to cross blood brain barrier (BBB) and exert both peripheral and central effects. Previous reports showed that intranasal (IN) administration of drugs are the preferred non-invasive route, which bypasses BBB and improves their delivery and bioavailability in the central nervous system (CNS). Therefore, we aimed to compare the effects of IN and oral administrations of FTY720 on astrocyte activation and demyelination levels of optic chiasm in a focal demyelination model. METHODS: The experimental model was induced by injection of 2 µL lysolecithin 1% into the optic chiasm of male Wistar rats. The rats were treated by oral gavage or intranasal drop of FTY720 at dose of 0.3 mg/kg for 14 days. Astrocyte activation was analyzed using GFAP immunostaining, extent of demyelination, and myelination levels were measured by fluoromyelin staining, and MOG immunostaining, respectively. Then, the concentration of FTY720 was measured by high performance liquid chromatography (HPLC) method in brain tissues. RESULTS: Our data showed that IN administration of FTY720 significantly decreases astrocyte activation and demyelination levels in the optic chiasm compared to the oral administration route. In addition, the concentration of FTY720 was higher in the brain tissue of IN receiving rats compared to the oral treated group. CONCLUSION: It seems that IN administration of FTY720 may be a preferred route to decline the central inflammation and demyelination levels in the MS patients.

Effect of fluoxetine treatment on neurotoxicity induced by lysolecithin in male rats.

Demyelination disorder is an unusual pathologic event, which occurs in the central nervous system (CNS). Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the CNS, and it is the leading cause of disability in young adults. Lysolecithin (LPC) is one of the best toxin-induced demyelination models. In this study, a suitable model is created, and the effect of fluoxetine treatment is examined on this model. In this case, it was assumed that daily fluoxetine treatment had increased the endogenous remyelination in the LPC model. This study was focused on investigating the influence of the fluoxetine dose of 5 or 10 mg/kg per day for 1 and 4 weeks on LPC-induced neurotoxicity in the corpus callosum region. It was performed as a demyelinating model in male Wistar rats. After 3 days, fluoxetine was injected intraperitoneally (5 or 10 mg/kg per day) for 1 and 4 weeks in each group. After completing the treatment course, the corpus callosum was removed to examine the gene expression and histological analysis was performed. The results of the histopathological study of hematoxylin and eosin staining of the corpus callosum showed that in 1 and 4-week treatment groups, fluoxetine has reduced the level of inflammation at the LPC injection site (5 and 10 mg/kg per day). Fluoxetine treatment in the luxol fast blue (LFB) staining of the corpus callosum has been led to an increase in myelination capacity in all doses and times. The results of the genetic study showed that the fluoxetine has significantly reduced the expression level of tumor necrosis factor-α, nuclear factor κß, and induced nitric oxide synthase in comparison with the untreated LPC group. Also, the fluoxetine treatment has enhanced the expression level of the forkhead box P3 (FOXP3) gene in comparison with the untreated group. Fluoxetine has increased the expression level of myelination and neurotrophic genes such as myelin basic protein (MBP), oligodendrocyte transcription factor 2 (OLIG2), and brain-derived neurotrophic factor (BDNF). The outcomes demonstrated that fluoxetine reduces inflammation and strengthens the endogenous myelination in the LPC-induced demyelination model; however, supplementary studies are required for specifying the details of its mechanisms.

MALDI Mass Spectrometry Imaging in a Primary Demyelination Model of Murine Spinal Cord.

Destruction of myelin, or demyelination, is a characteristic of traumatic spinal cord injury and pathognomonic for primary demyelinating pathologies such as multiple sclerosis (MS). The regenerative process known as remyelination, which can occur following demyelination, fails as MS progresses. Models of focal demyelination by local injection of gliotoxins have provided important biological insights into the demyelination/remyelination process. Here, injection of lysolecithin to induce spinal cord demyelination is investigated using matrix-assisted laser desorption/ionization mass spectrometry imaging. A segmentation analysis revealed changes to the lipid composition during lysolecithin-induced demyelination at the lesion site and subsequent remyelination over time. The results of this study can be utilized to identify potential myelin-repair mechanisms and in the design of therapeutic strategies to enhance myelin repair.

Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells.

It has been shown that anti-inflammatory cytokines interleukin-35 (IL-35) and IL-10 could inhibit acute endothelial cell (EC) activation, however, it remains unknown if and by what pathways IL-35 and IL-10 could block atherogenic lipid lysophosphatidylcholine (LPC)-induced sustained EC activation; and if mitochondrial reactive oxygen species (mtROS) can differentiate mediation of EC activation from trained immunity (innate immune memory). Using RNA sequencing analyses, biochemical assays, as well as database mining approaches, we compared the effects of IL-35 and IL-10 in LPC-treated human aortic ECs (HAECs). Principal component analysis revealed that both IL-35 and IL-10 could similarly and partially reverse global transcriptome changes induced by LPC. Gene set enrichment analyses showed that while IL-35 and IL-10 could both block acute EC activation, characterized by upregulation of cytokines/chemokines and adhesion molecules, IL-35 is more potent than IL-10 in suppressing innate immune signatures upregulated by LPC. Surprisingly, LPC did not induce the expression of trained tolerance itaconate pathway enzymes but induced trained immunity enzyme expressions; and neither IL-35 nor IL-10 was found to affect LPC-induced trained immunity gene signatures. Mechanistically, IL-35 and IL-10 could suppress mtROS, which partially mediate LPC-induced EC activation and innate immune response. Therefore, anti-inflammatory cytokines could reverse mtROS-mediated acute and innate immune trans-differentiation responses in HAECs, but it could spare metabolic reprogramming and trained immunity signatures, which may not fully depend on mtROS. Our characterizations of anti-inflammatory cytokines in blocking mtROS-mediated acute and prolonged EC activation, and sparing trained immunity are significant for designing novel strategies for treating cardiovascular diseases, other inflammatory diseases, and cancers.

Protective effect of phosphatidylcholine on lysophosphatidylcholine-induced cellular senescence in cholangiocyte.

BACKGROUND: Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC-induced cytotoxicity causes senescence-associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC-induced cholangiocyte cytotoxicity. METHODS: MMNK-1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK-1 cells treated with LPC. RESULTS: The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK-1 treated with LPC. Moreover, SA-ß-gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)-8, IL-6, and C-C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. CONCLUSION: PC protects cholangiocytes against LPC-induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC-related carcinogenesis and its promotion.

Characterizing Structural Changes With Devolving Remyelination Following Experimental Demyelination Using High Angular Resolution Diffusion MRI and Texture Analysis.

BACKGROUND: Changes in myelin integrity are associated with the pathophysiology of many neurological diseases, including multiple sclerosis. However, noninvasive measurement of myelin injury and repair remains challenging. Advanced MRI techniques including diffusion tensor imaging (DTI), neurite orientation dispersion and density index (NODDI), and texture analysis have shown promise in quantifying subtle abnormalities in white matter structure. PURPOSE: To determine whether and how these advanced imaging methods help understand remyelination changes after demyelination using a mouse model. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Demyelination was induced in the thoracic spinal cord of 21 mice using the chemical toxin lysolecithin. FIELD STRENGTH/SEQUENCES: 9.4T ASSESSMENT: Imaging was done at day 7 (demyelination) and days 14 to 35 (ongoing remyelination) postsurgery, followed by histology. Image analysis focused on both lesions and peri-lesional areas where remyelination began. In histology, we quantified the complexity of tissue alignment using angular entropy, in addition to staining area. STATISTICAL ANALYSIS: Two-way analysis of variance was performed for assessing differences between tissue types and across timepoints, followed by post-hoc analysis to correct for multiple comparisons (P < 0.05). RESULTS: All diffusion and texture parameters were worse in lesions than the control tissue (P < 0.05) except orientation dispersion index (ODI) and neurite density index (NDI) over late remyelination. Longitudinally, ODI decreased and NDI increased persistently in both lesions and peri-lesion regions (P < 0.05). Fractional anisotropy showed a mild decrease at day 35 after increase, when lesion texture heterogeneity showed a trend to decrease (P > 0.05). Both lesion size and angular entropy decreased over time, and no change in any measure in the control tissue. DATA CONCLUSION: Diffusion and MRI texture metrics may provide compensatory information on myelin repair and ODI and NDI could be sensitive measures of evolving remyelination, deserving further validation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1750-1759.

Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin.

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease in the central nervous system (CNS) characterized by loss of oligodendrocytes, myelin axons, and neurons. Remyelination is an endogenous repair mechanism, which recovers the loss of myelin and is able to preserve functional axons. The hope is that the development of new treatments aiming at promoting remyelination will halt and potentially partially reverse the progressive neurological decline in MS. The development of such drugs requires adequate models. In this chapter, we will discuss the surgical procedure of injection of lysolecithin into ventral thoraco-lumbar spinal cord white matter of mice, which is particularly suitable for investigating remyelination using transgenic animals.

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model.

Neurotropin® (NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases.

Tg6F ameliorates the increase in oxidized phospholipids in the jejunum of mice fed unsaturated LysoPC or WD.

Mouse chow supplemented with lysophosphatidylcholine with oleic acid at sn-1 and a hydroxyl group at sn-2 (LysoPC 18:1) increased LysoPC 18:1 in tissue of the jejunum of LDL receptor (LDLR)-null mice by 8.9 ± 1.7-fold compared with chow alone. Western diet (WD) contained dramatically less phosphatidylcholine 18:1 or LysoPC 18:1 compared with chow, but feeding WD increased LysoPC 18:1 in the jejunum by 7.5 ± 1.4-fold compared with chow. Feeding LysoPC 18:1 or feeding WD increased oxidized phospholipids in the jejunum by 5.2 ± 3.0-fold or 8.6 ± 2.2-fold, respectively, in LDLR-null mice (P < 0.0004), and 2.6 ± 1.5-fold or 2.4 ± 0.92-fold, respectively, in WT C57BL/6J mice (P < 0.0001). Adding 0.06% by weight of a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) decreased LysoPC 18:1 in the jejunum of LDLR-null mice on both diets (P < 0.0001), and prevented the increase in oxidized phospholipids in the jejunum in LDLR-null and WT mice on both diets (P < 0.008). Tg6F decreased inflammatory cells in the villi of the jejunum, decreased dyslipidemia, and decreased systemic inflammation in LDLR-null and WT mice on both diets. We conclude that Tg6F reduces diet-induced inflammation by reducing the content of unsaturated LysoPC and oxidized phospholipids in the jejunum of mice.

Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

BACKGROUND: Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. METHODS: Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. RESULTS: A total of 110 subjects were enrolled (age 10.4 ±â€Š3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. CONCLUSIONS: LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.

Sulforaphane protected the injury of human vascular endothelial cell induced by LPC through up-regulating endogenous antioxidants and phase II enzymes.

Sulforaphane (SFN), which is an isothiocyanate (ITC) that is found in cruciferous vegetables, has received considerable attention because of its beneficial effects. In this study, the protection by SFN in the lysophosphatidylcholine (LPC)-induced injury of human vascular endothelial EA.hy.926 cells was investigated. ROS intensity was obtained by fluorescence microscopic imaging. Levels of MDA, GSH and the activity of SOD were determined spectrophotometrically. Expressions of GST, GSH-Px, TrxR and Nrf-2 proteins were measured by western blotting analysis. SFN largely decreased ROS production, similar to vitamin E. The MDA level was decreased by SFN to a level that was comparable to the negative group. Incubation with 0.5, 1.25, 2.5 µmol L(-1) SFN for 24 h restored the activity of SOD by 58%, 64%, and 123%, respectively. SOD activities were individually increased by 53%, 97%, 103% after treatment with 2.5 µmol L(-1) SFN for 12 h, 24 h, and 48 h, respectively. SFN restored and up-regulated the expressions of GST, GSH-Px and TrxR both in dose- and time-dependent ways. Although VE presents comparable induction of phase 2 enzymes as 1.25 µmol L(-1) SFN, it cannot induce the translocation of Nrf-2 to the nucleus. SFN protected the injury of vascular endothelial cell by LPC by enhancing anti-oxidative capabilities mediated by Nrf-2 translocation.

Sciatic nerve injury induces functional pro-nociceptive chemokine receptors in bladder-associated primary afferent neurons in the rat.

Visceral sensory afferents during disease or following injury often produce vague, diffuse body sensations, and pain referred to somatic targets. Alternatively, injury due to trauma or disease of somatic nerve targets can also lead to referred pain in visceral targets via a somatovisceral reflex. Both phenomenons are thought to be due to convergence of visceral and somatic afferents within the spinal cord. To investigate a potential peripheral influence for referred pain in visceral targets following somatic nerve injury, we examined whether a sciatic nerve injury known to produce hindpaw tactile hyperalgesia alters the frequency of micturition and the sensitivity of bladder-associated sensory neurons to pro-nociceptive chemokines. Adult female Sprague-Dawley rats received injections of cholera toxin B subunit conjugated to 555 into urinary bladder wall to retrogradely label visceral primary afferent neurons. After 7 days, the right sciatic nerve of these animals was subjected to a lysophosphatidylcholine (LPC)-induced focal demyelination injury. Pre- and post-injury tactile sensitivity in the hind paw and micturition frequency were assayed. Animals were allowed to survive for 14-28 days. Lumbosacral and lumbar dorsal root ganglia (DRG) ipsilateral to the nerve injury were acutely dissociated from sham and nerve injured animals. Bladder wall-associated sensory neurons identified via the retrograde marker were assayed for fluxes in intracellular calcium following administration of pro-nociceptive chemokines. The assayed chemokines included monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal cell derived factor-1 alpha (SDF1/CXCL12). LPC nerve injured animals exhibited tactile hyperalgesia and increased micturition frequency for at least 28 days. Focal demyelination of the sciatic nerve also increased the number of injured L4L5 and non-injured L6-S2 bladder-associated sensory neurons that responded to MCP1 and SDF1 when compared with sensory neurons derived from uninjured naïve and sham-injured control animals. Taken together, these data suggest that some visceral hypersensitivity states may have a somatic origin. More importantly, nociceptive somatovisceral sensation may be mediated by upregulation of chemokine signaling in visceral sensory neurons.

[Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced ventricular arrhythmias in rats].

OBJECTIVE: To investigate the effect of fluvastatin on lysophosphatidylcholine (LPC)-induced ventricular arrhythmias and its mechanism. METHODS: Twenty male SD rats were randomly allocated into two equal groups, namely LPC treatment group and fluvastatin pretreatment group. Langendorff apparatus was used for cardiac perfusion ex vivo with 5 µmol/L LPC for 5 min followed by washing for 30 min in LPC treatment group, and in fluvastatin pretreatment group, a 30-min perfusion with 10 µmol/L fluvastatin was administered before LPC perfusion. The LPC-induced nonselective cation current (I(NSC)) in the ventricular myocytes was recorded using the whole-cell voltage-clamp method. RESULTS: Fluvastatin significantly inhibited LPC-induced ventricular tachyarrhythmia/fibrillation and I(NSC). The small G-protein Rho inhibitor (C3) and Rho-kinase inhibitor (Y-27632) in the pipette solution also suppressed LPC-induced I(NSC). CONCLUSION: Fluvastatin offers cardiac protection against LPC by inhibiting LPC-induced I(NSC). LPC induces fatal arrhythmia via a Rho/Rho-kinase-mediated pathway.

The role of neutrophils in the pathogenesis of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is the major cause of transfusion related morbidity and mortality, world wide. Efforts to reduce or eliminate this serious complication of blood transfusion are hampered by an incomplete understanding of its pathogenesis. Currently, TRALI is thought to be mediated by donor alloantibodies directed against host leukocytes or the result of 2 distinct clinical events. For both proposed mechanisms, the neutrophil is the key effector cell. This article reviews TRALI pathophysiology, explores the role of the neutrophil, details practical information for appropriate diagnosis and promotes further studies into the pathogenesis of TRALI.

Efficient central nervous system remyelination requires T cells.

We demonstrate a role for immune functions in the spontaneous remyelination of central nervous system (CNS) axons after lysolecithin-induced demyelination in the spinal cord. Rag-1-deficient mice lack both B cells and T cells and show significantly reduced spontaneous remyelination compared with control mice of matching genetic background. Mice lacking or depleted of either CD4(+) T cells or CD8(+) T cells also exhibit reduced remyelination. These data indicate that T cells are necessary for efficient CNS remyelination. Thus, general nonspecific immunosuppression as a therapeutic approach for the treatment of CNS injury and demyelinating disease may have undesirable effects on subsequent tissue repair.

[Effects of lysophosphatidylcholine on expression of monocyte chemoattractant protein-1 in glomerular endothelial cells].

Glomerular endothelial cells(GEC) produce monocyte chemoattractant protein-1(MCP-1), which is considered to be an important factor for the recruitment of macrophages into the glomeruli. Recent reports have suggested an association between oxidized low-density lipoprotein(ox-LDL) and progression of glomerular disease. In this study, the effects of lysophosphatidylcholine(LysoPC), a modified phospholipid produced during LDL oxidation, on MCP-1 mRNA expression in cultured bovine GEC were examined. GEC from the 8th through 10th passages were used. LysoPC substantially increased expression of MCP-1 mRNA when compared to the control. These findings led us to examine the mechanism of LysoPC-induced MCP-1 expression in GEC. LysoPC-induced MCP-1 mRNA expression in GEC was suppressed by genistein and staurosporine. It was suggested that both the tyrosinekinase(TK) and proteinkinase C(PKC) pathways were involved in LysoPC-induced MCP-1 expression in GEC. MCP-1 mRNA induction by LysoPC was also attenuated by Vitamin E. This effect may be related to the beneficial effects of Vitamin E on experimental glomerular disease models. In conclusion, LysoPC increased MCP-1 expression in GEC. This phenomenon is believed to be mediated by both the TK and PKC signaling pathways, in contrast with other vascular endothelial cells. Vitamin E also attenuated LysoPC-induced MCP-1 expression in GEC.

Lysophosphatidylcholine as a ligand for immunoregulation.

Despite the recognized effects of lysophosphatidylcholine upon cells of the immune system and its association with inflammatory processes, its mechanism of action has remained poorly characterized. Our recent identification of the first lysophosphatidylcholine receptor as an immunoregulatory G protein-coupled receptor named G2A whose genetic ablation results in the development of inflammatory autoimmune disease has, therefore, provided a new perspective on the role of this lysophospholipid as a modulator of immune responses. This commentary discusses the biological properties of lysophosphatidylcholine as an immunoregulatory ligand for cells of the innate and adaptive arms of the immune system. Although we focus primarily on ligand interactions with G2A, we also discuss the issue of possible functional redundancy with other receptors with recently established ligand specificities towards phosphorylcholine-containing lysolipids including lysophosphatidylcholine.