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Unne Stenram - One of the best experts on this subject based on the ideXlab platform.

  • beneficial effects of platelet activating Factor Receptor antagonist web 2170 on 90 minute hepatic inflow interruption
    European Journal of Gastroenterology & Hepatology, 1994
    Co-Authors: Bengt Jeppsson, Hubert O Heuer, C H Hakansson, Katarina Svanberg, Sune Svanberg, Unne Stenram
    Abstract:

    Objective: To study the effects of different doses of platelet activating Factor Receptor antagonist WEB 2170 on animal survival, haemodynamics, reperfusion and ultrastructural changes in the ischaemic liver in rats undergoing 90-min total hepatic inflow interruption (THII). Design: Sixty-five rats were divided into five groups. All animals underwent 90-min THII. Group 1 served as controls. Group 2 underwent THII alone. Group 3 received an intravenous injection of 1 mg/kg WEB 2170 prior to THII. Group 4 received a bolus injection of 3 mg/kg WEB 2170 before THII. Group 4 received a bolus injection of 3 mg/kg WEB 2170 before THII. Group 5 received 3 mg/kg WEB 2170 before, during and after THII. The liver reperfusion index using laser Doppler flowmetry, the time of ischaemic liver initiative reperfusion, and scanning electron microscopy were performed to evaluate the results of different dose schedules. Setting: Lund University Hospital, Lund, Sweden. Results: Animal survival rate, liver reperfusion index, the time of ischaemic liver initiative reperfusion and ultrastructural damage of the ischaemic liver were markedly improved in the groups treated with WEB 2170 compared with the non-treated 90-min THII group. The best result was obtained in the group receiving the three separate doses. Conclusion: In the 90-min THII model, WEB 2170 protects the liver from ischaemia-reperfusion injury and the spread of damage to the post-stasis splanchnic organs. These beneficial effects may be extended to hepatic transplantation or major resections of the liver. (Less)

Jeffrey B. Travers - One of the best experts on this subject based on the ideXlab platform.

  • Systemic chemotherapy is modulated by Platelet-Activating Factor-Receptor agonists.
    Mediators of Inflammation, 2015
    Co-Authors: Ravi P. Sahu, Matheus Ferracini, Jeffrey B. Travers
    Abstract:

    Chemotherapy is used to treat numerous cancers including melanoma. However, its effectiveness in clinical settings is often hampered by various mechanisms. Previous studies have demonstrated that prooxidative stressor-mediated generation of oxidized lipids with Platelet-Activating Factor-Receptor (PAF-R) agonistic activity induces systemic immunosuppression that augments the growth of experimental melanoma tumors. We have recently shown that treatment of murine B16F10 melanoma cells in vitro or tumors implanted into syngeneic mice and treated intratumorally with various chemotherapeutic agents generated PAF-R agonists in a process blocked by antioxidants. Notably, these intratumoral chemotherapy-generated PAF-R agonists augmented the growth of secondary (untreated) tumors in a PAF-R dependent manner. As both localized and systemic chemotherapies are used based on tumor localization/stage and metastases, the current studies were sought to determine effects of PAF-R agonists on systemic chemotherapy against experimental melanoma. Here, we show that systemic chemotherapy with etoposide (ETOP) attenuates the growth of melanoma tumors when given subsequent to the tumor cell implantation. Importantly, this ETOP-mediated suppression of melanoma tumor growth was blocked by exogenous administration of a PAF-R agonist, CPAF. These findings indicate that PAF-R agonists not only negatively affect the ability of localized chemotherapy but also compromise the efficacy of systemic chemotherapy against murine melanoma.

  • Systemic Platelet-Activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis.
    Cancer growth and metastasis, 2014
    Co-Authors: Patrick C. Hackler, Jeffrey B. Travers, Raymond L. Konger, Sarah Reuss, Ravi P. Sahu
    Abstract:

    Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated Factor-Receptor (PAF-R) agonistic activity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxi-dized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system.

  • Systemic Platelet-Activating Factor-Receptor activation augments experimental lung cancer growth and metastasis (LB496)
    The FASEB Journal, 2014
    Co-Authors: Ravi P. Sahu, Raymond L. Konger, Patrick C. Hackler, Jeffrey B. Travers
    Abstract:

    ABSTRACT: Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated Factor-Receptor (PAF-R) agonistic activ -ity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxidized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system.

  • Loss of the platelet activating Factor Receptor in mice augments PMA-induced inflammation and cutaneous chemical carcinogenesis.
    Carcinogenesis, 2012
    Co-Authors: Ravi P. Sahu, Jeffrey B. Travers, Amal Kozman, Sonia C. Dasilva, Samin Rezania, Kellie C. Martel, Simon Warren, Raymond L. Konger
    Abstract:

    Although Platelet-Activating Factor (PAF) is a well-known acute inflammatory mediator, little is known regarding the role of PAF in chronic inflammation. Phorbol esters are known to stimulate PAF production. Moreover, the ability of repeated applications of phorbol esters to induce a sustained inflammatory response is crucial to their tumorigenic activity. We therefore examined whether PAF acts as a mediator of phorbol ester-induced inflammation and tumorigenesis. While PAF Receptor knockout mice (PAFR (−/−)) showed an expected but modest reduction in the acute inflammatory response to phorbol 12-myristate 13-acetate (PMA), these mice exhibited a surprising increase in inflammation following chronic PMA application. This increased inflammation was documented by a number of findings that included: increased skin thickness, increased myeloperoxidase activity and expression and increased expression of known inflammatory mediators. Interestingly, vehicle-treated PAFR(−/−) mice also exhibited modest increases in levels of inflammatory markers. This suggests that the platelet activating Factor Receptor (PAFR) acts to suppress chronic inflammation in response to other stimuli, such as barrier disruption. The idea that chronic PAFR activation is anti-inflammatory was documented by repetitive topical PAFR agonist administration that resulted in reduced myeloperoxidase activity in skin. We next utilized a 7,12-dimethylbenz(a)anthracene/PMA carcinogenesis protocol to demonstrate that PAFR (−/−) mice exhibit significantly increased tumor formation and malignant progression compared with wild-type control mice. These studies provide evidence for two important, unexpected and possibly interrelated pathological roles for the PAFR: first, the PAFR acts to suppress PMA-induced chronic inflammation; secondly, the PAFR acts to suppress neoplastic development in response to chemical carcinogens.

  • Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the Platelet-Activating Factor Receptor
    Journal of Clinical Investigation, 2005
    Co-Authors: Qiwei Zhang, T Shimizu, Satoshi Ishii, Nico Mousdicas, Qiaofang Yi, Mohammed Al-hassani, Steven D. Billings, Susan M. Perkins, Katherine M. Howard, Jeffrey B. Travers
    Abstract:

    Staphylococcus aureus infections are known triggers for skin inflammation and can modulate immune responses. The present studies used model systems consisting of Platelet-Activating Factor Receptor-positive and -negative (PAF-R-positive and -negative) cells and PAF-R-deficient mice to demonstrate that staphylococcal lipoteichoic acid (LTA), a constituent of Gram-positive bacteria cell walls, acts as a PAF-R agonist. We show that LTA stimulates an immediate intracellular Ca 2 + flux only in PAF-R-positive cells. Intradermal injections of LTA and the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine (CPAF) induced cutaneous inflammation in wild-type but not PAF-R-deficient mice. Systemic exposure to LTA or CPAF inhibited delayed-type hypersensitivity (DTH) reactions to the chemical dinitrofluorobenzene only in PAF-R-expressing mice. The inhibition of DTH reactions was abrogated by the addition of neutralizing antibodies to IL-10. Finally, we measured levels of LTA that were adequate to stimulate PAF-R in vitro on the skin of subjects with infected atopic dermatitis. Based on these studies, we propose that LTA exerts immunomodulatory effects via the PAF-R through production of the Th2 cytokine IL-10. These findings show a novel mechanism by which staphylococcal infections can inhibit Thi reactions and thus worsen Th2 skin diseases, such as atopic dermatitis.

L. Holzapfel - One of the best experts on this subject based on the ideXlab platform.

  • confirmatory platelet activating Factor Receptor antagonist trial in patients with severe gram negative bacterial sepsis a phase iii randomized double blind placebo controlled multicenter trial
    Critical Care Medicine, 1998
    Co-Authors: J F Dhainaut, Alain Tenaillon, Michele Hemmer, Pierre Damas, Le Y Tulzo, Peter Radermacher, Mariedenise Schaller, J P Sollet, M Wolff, L. Holzapfel
    Abstract:

    Objective To determine the efficacy and safety of using natural Platelet-Activating Factor Receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. Design A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. Setting Fifty-nine academic medical center intensive care units in Europe. Patients Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. Interventions Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. Measurements and Main Results The patients were well matched at study entry for severity of illness and for risk Factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p = .50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p = .29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p = .06). The number of adverse events reported were not different between the two groups. Conclusions A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial. (Crit Care Med 1998; 26:1963-1971)

  • Platelet-Activating Factor Receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group.
    Critical Care Medicine, 1994
    Co-Authors: Jean-françois Dhainaut, Alain Tenaillon, Yves Le Tulzo, Benoît Schlemmer, Jean-pierre Solet, Michel Wolff, L. Holzapfel, Fabrice Zeni, Didier Dreyfuss, Jean-paul Mira
    Abstract:

    Objective:To evaluate the safety and efficacy of a natural Platelet-Activating Factor Receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome.Design:Prospective, randomized, placebocontrolled, double-blind, phase III, multicenter clinical trial.Setting:Twenty-

T Shimizu - One of the best experts on this subject based on the ideXlab platform.

  • Platelet-Activating Factor Receptor knockout mice are protected from MPTP-induced dopaminergic degeneration
    Neurochemistry International, 2013
    Co-Authors: Eun-joo Shin, Yoon Hee Chung, Duy Khanh Dang, Bae Dong Jung, Dae Hun Park, T Shimizu
    Abstract:

    Abstract Platelet-Activating Factor (PAF), a potent mediator of inflammatory and immune responses, plays various roles in neuronal functions. However, little is known about the role of PAF/Platelet-Activating Factor Receptor (PAF-R) in Parkinson’s disease. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in significant increases in PAF species in the striatum of wild-type mice. These increases paralleled PAF-R gene expression in wild-type mice. Although nuclear Factor kappa B (NF-κB) DNA-binding activity was increased significantly in MPTP-treated wild-type mice, this increase was not significant in PAF-R antagonist ginkgolide B (GB)-treated mice or PAF-R knockout (PAF-R −/− ) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, significantly ameliorated the dopaminergic deficits induced by MPTP in wild-type mice. MPTP treatment significantly increased oxidative damage, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglial cells, and microglial differentiation of the M1 type in the striatum of wild-type mice. Consistently, PDTC significantly attenuated MPTP-induced behavioral impairments in wild-type mice. However, dopaminergic deficits, oxidative damage, reactive microglial cells, and behavioral impairments induced by MPTP were not significantly observed in GB-treated mice or PAF-R −/− mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R −/− mice, indicating that NF-κB is a critical target for neurotoxic modulation of PAF-R. We propose for the first time that PAF/PAF-R can mediate dopaminergic degeneration via an NF-κB-dependent signaling process.

  • Amino acid residues critical for endoplasmic reticulum export and trafficking of Platelet-Activating Factor Receptor.
    Journal of Biological Chemistry, 2009
    Co-Authors: Nobuaki Hirota, T Shimizu, Daisuke Yasuda, Tomomi Hashidate, Teruyasu Yamamoto, Satoshi Yamaguchi, Teruyuki Nagamune, Takahide Nagase, Motonao Nakamura
    Abstract:

    Several residues are conserved in the transmembrane domains (TMs) of G-protein coupled Receptors. Here we demonstrate that a conserved proline, Pro247, in TM6 of Platelet-Activating Factor Receptor (PAFR) is required for endoplasmic reticulum (ER) export and trafficking after agonist-induced internalization. Alanine-substituted mutants of the conserved residues of PAFRs, including P247A, were retained in the ER. Because a PAFR antagonist, Y-24180, acted as a pharmacological chaperone to rescue ER retention, this retention is due to misfolding of PAFR. Methylcarbamyl (mc)-PAF, a PAFR agonist, did not increase the cell surface expression of P247A, even though another ER-retained mutant, D63A, was effectively trafficked. Signaling and accumulation of the Receptors in the early endosomes were observed in the mc-PAF-treated P247A-expressing cells, suggesting that P247A was trafficked to the cell surface by mc-PAF, and thereafter disappeared from the surface due to aberrant trafficking, e.g. enhanced internalization, deficiency in recycling, and/or accelerated degradation. The aberrant trafficking was confirmed with a sortase-A-mediated method for labeling cell surface proteins. These results demonstrate that the conserved proline in TM6 is crucial for intracellular trafficking of PAFR.

  • Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the Platelet-Activating Factor Receptor
    Journal of Clinical Investigation, 2005
    Co-Authors: Qiwei Zhang, T Shimizu, Satoshi Ishii, Nico Mousdicas, Qiaofang Yi, Mohammed Al-hassani, Steven D. Billings, Susan M. Perkins, Katherine M. Howard, Jeffrey B. Travers
    Abstract:

    Staphylococcus aureus infections are known triggers for skin inflammation and can modulate immune responses. The present studies used model systems consisting of Platelet-Activating Factor Receptor-positive and -negative (PAF-R-positive and -negative) cells and PAF-R-deficient mice to demonstrate that staphylococcal lipoteichoic acid (LTA), a constituent of Gram-positive bacteria cell walls, acts as a PAF-R agonist. We show that LTA stimulates an immediate intracellular Ca 2 + flux only in PAF-R-positive cells. Intradermal injections of LTA and the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine (CPAF) induced cutaneous inflammation in wild-type but not PAF-R-deficient mice. Systemic exposure to LTA or CPAF inhibited delayed-type hypersensitivity (DTH) reactions to the chemical dinitrofluorobenzene only in PAF-R-expressing mice. The inhibition of DTH reactions was abrogated by the addition of neutralizing antibodies to IL-10. Finally, we measured levels of LTA that were adequate to stimulate PAF-R in vitro on the skin of subjects with infected atopic dermatitis. Based on these studies, we propose that LTA exerts immunomodulatory effects via the PAF-R through production of the Th2 cytokine IL-10. These findings show a novel mechanism by which staphylococcal infections can inhibit Thi reactions and thus worsen Th2 skin diseases, such as atopic dermatitis.

  • Platelet-Activating Factor Receptor
    Journal of Biochemistry, 2002
    Co-Authors: Zen-ichiro Honda, Satoshi Ishii, T Shimizu
    Abstract:

    The human Platelet-Activating Factor Receptor gene exists as a single copy on chromosome 1. Two 5′-noncoding exons (Exon 1 and 2) has distinct transcription initiation sites and promoters. These exons are alternatively spliced to a common splice acceptor site on exon 3 that contains a total coding regions. The transcript 1 is expressed ubiquitously with an emphasis of differentiated eosinophilic cell line (Eol-1), and leukocytes. On the other hand, the transcript 2 is expressed tissue-specifically. The latter is not expressed in leukocytes or brain. The transcript 1 has three tandem repeats of NF-κB, and SP-1 site, and responded to various inflammatory reagents including PAF itself, lipopolysaccharide, or phorbol ester. By northern blotting of tissue or cells with various nutritional or hormonal treatments, the PAF Receptor messages are up-regulated. Estrogen increased the expression of the PAF Receptor in human endometrial glandular cells, and vitamin A (retinoic acid) or thyroid hormone treatment up-regulates the PAF Receptor expression only tissues with transcript 2. By various in vivo and in vitro transcriptional assays (CAT reporter assay, gel mobility shift assay), we identified estrogen responsible element, and hormone responsive element. The PAF Receptor hormone responsive element is composed of three direct repeated TGACCT-like hexamer motifs with 2 and 4 bp spaces, and the two upstream and two downstream motifs were identified as response elements for RA and T3.

  • Roles of cytosolic phospholipase A(2) and Platelet-Activating Factor Receptor in the Ca-induced biosynthesis of PAF.
    Biochemical and Biophysical Research Communications, 2000
    Co-Authors: Hideo Shindou, Satoshi Ishii, Naonori Uozumi, T Shimizu
    Abstract:

    Abstract Casein-elicited peritoneal exudate cells (PEC), mainly consisted of neutrophils, were collected from Platelet-Activating Factor Receptor-knock-out (PAFR-KO), cytosolic phospholipase A2 knock-out (cPLA2-KO), and wild-type (WT) mice. After stimulation of PEC with calcium ionophore A 23187, PAF levels were measured by radio-ligand binding assay using Receptor-rich membrane fraction prepared from the PAF Receptor transgenic mice. We found that the level of PAF production by PEC was not different between WT and PAFR-KO mice. On the other hand, cPLA2-KO mice were deficient in the PAF production. These results provide the direct evidence while cPLA2 is essential in the production of PAF, PAF Receptor deficiency has little effect on the PAF production.

Sonia Jancar - One of the best experts on this subject based on the ideXlab platform.

  • Platelet activating Factor Receptor antagonists improve the efficacy of experimental chemo- and radiotherapy.
    Clinics, 2018
    Co-Authors: Ildefonso Alves Da Silva Junior, Luciana Nogueira De Sousa Andrade, Sonia Jancar, Roger Chammas
    Abstract:

    Platelet activating Factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important Factor in tumor outcomes. Platelet activating Factor acts by specific binding to its Receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating Factor Receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages [...]

  • Platelet-Activating Factor Receptor Ligands Protect Tumor Cells from Radiation-Induced Cell Death.
    Frontiers in Oncology, 2018
    Co-Authors: Ildefonso Alves Da Silva Junior, Barbara Dalmaso, Suellen Herbster, Ana Paula Lepique, Sonia Jancar
    Abstract:

    : Irradiation generates oxidized phospholipids that activate Platelet-Activating Factor Receptor (PAFR) associated with pro-tumorigenic effects. Here, we investigated the involvement of PAFR in tumor cell survival after irradiation. Cervical cancer samples presented higher levels of PAF-Receptor gene (PTAFR) when compared with normal cervical tissue. In cervical cancer patients submitted to radiotherapy (RT), the expression of PTAFR was significantly increased. Cervical cancer-derived cell lines (C33, SiHa, and HeLa) and squamous carcinoma cell lines (SCC90 and SCC78) express higher levels of PAFR mRNA and protein than immortalized keratinocytes. Gamma radiation increased PAFR expression and induced PAFR ligands and prostaglandin E2 (PGE2) in these tumor cells. The blocking of PAFR with the antagonist CV3938 before irradiation inhibited PGE2 and increased tumor cells death. Similarly, human carcinoma cells transfected with PAFR (KBP) were more resistant to radiation compared to those lacking the Receptor (KBM). PGE2 production by irradiated KBP cells was also inhibited by CV3988. These results show that irradiation of carcinoma cells generates PAFR ligands that protect tumor cells from death and suggests that the combination of RT with a PAFR antagonist could be a promising strategy for cancer treatment.

  • Clearance of Apoptotic Cells by Macrophages Induces Regulatory Phenotype and Involves Stimulation of CD36 and Platelet-Activating Factor Receptor
    Mediators of Inflammation, 2013
    Co-Authors: Matheus Ferracini, Francisco J. Rios, Mateus Pecenin, Sonia Jancar
    Abstract:

    Phagocytosis of apoptotic cells (efferocytosis) induces macrophage differentiation towards a regulatory phenotype (IL-10high/IL-12p40low). CD36 is involved in the recognition of apoptotic cells (AC), and we have shown that the Platelet-Activating Factor Receptor (PAFR) is also involved. Here, we investigated the contribution of PAFR and CD36 to efferocytosis and to the establishment of a regulatory macrophage phenotype. Mice bone marrow-derived macrophages were cocultured with apoptotic thymocytes, and the phagocytic index was determined. Blockage of PAFR with antagonists or CD36 with specific antibodies inhibited the phagocytosis of AC (~70–80%). Using immunoprecipitation and confocal microscopy, we showed that efferocytosis increased the CD36 and PAFR colocalisation in the macrophage plasma membrane; PAFR and CD36 coimmunoprecipitated with flotillin-1, a constitutive lipid raft protein, and disruption of these membrane microdomains by methyl-β-cyclodextrin reduced AC phagocytosis. Efferocytosis induced a pattern of cytokine production, IL-10high/IL-12p40low, that is, characteristic of a regulatory phenotype. LPS potentiated the efferocytosis-induced production of IL-10, and this was prevented by blocking PAFR or CD36. It can be concluded that phagocytosis of apoptotic cells engages CD36 and PAFR, possibly in lipid rafts, and this is required for optimal efferocytosis and the establishment of the macrophage regulatory phenotype.

  • Apoptotic cells contribute to melanoma progression and this effect is partially mediated by the Platelet-Activating Factor Receptor.
    Mediators of Inflammation, 2012
    Co-Authors: André Luis Lacerda Bachi, Sonia Jancar, Lívia Caires Dos Santos, S. Nonogaki, Miriam Galvonas Jasiulionis
    Abstract:

    There is evidence that the Platelet-Activating Factor Receptor (PAFR) is involved in the clearance of apoptotic cells by macrophages, and that this is associated with anti-inflammatory phenotype. Our group has previously shown that coinjection of a large number of apoptotic cells can promote tumor growth from a subtumorigenic dose of melanoma cells. Here, we studied the involvement of the PAFR in the tumor growth promoting effect of apoptotic cells. A sub-tumorigenic dose of melanoma cells (Tm1) was coinjected with apoptotic Tm1 cells, subcutaneously in the flank of C57Bl/6 mice, and the volume was monitored for 30 days. Animals received the PAFR antagonists, WEB2170 or PCA4248 (5 mg/kg body weight) or vehicle, by peritumoral daily injection for 5 days. Results showed that PAFR antagonists significantly inhibited the tumor growth induced by the coinjection of a sub-tumorigenic dose of melanoma cells together with apoptotic cells. This was accompanied by inhibition of early neutrophil and macrophage infiltration. Addition of (Platelet-Activating Factor) to this system has no significant effect. PAFR antagonists did not affect the promoting effect of carrageenan. We suggest that the recognition of apoptotic cells by phagocytes leads to activation of PAFR pathways, resulting in a microenvironment response favorable to melanoma growth.

  • Platelet-Activating Factor Receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy
    BMC Cancer, 2010
    Co-Authors: Soraya Imon De Oliveira, Luciana Nogueira De Sousa Andrade, Roger Chammas, Ana Cláudia Onuchic, Sueli Nonogaki, Patricia Dias Fernandes, Mônica De Campos Pinheiro, Ciro Rohde, Sonia Jancar
    Abstract:

    Background Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-Activating Factor Receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma.