scholarly journals New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey B. Travers ◽  
Joyce G. Rohan ◽  
Ravi P. Sahu
Keyword(s):  
Cell Damage ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Lipid Mediator ◽  
Organ Systems ◽  
Paf Receptor ◽  
Bioactive Agents ◽  
Novel Therapeutic Strategies ◽  
Pathologic Processes ◽  
The Relationship

Described almost 50 years ago, the glycerophosphocholine lipid mediator Platelet-activating factor (PAF) has been implicated in many pathologic processes. Indeed, elevated levels of PAF can be measured in response to almost every type of pathology involving inflammation and cell damage/death. In this review, we provide evidence for PAF involvement in pathologic processes, with focus on cancer, the nervous system, and in photobiology. Importantly, recent insights into how PAF can generate and travel via bioactive extracellular vesicles such as microvesicle particles (MVP) are presented. What appears to be emerging from diverse pathologies in different organ systems is a common theme where pro-oxidative stressors generate oxidized glycerophosphocholines with PAF agonistic effects, which then trigger more enzymatic PAF synthesis via the PAF receptor. A downstream consequence of PAF receptor activation is the generation and release of MVP which provide a mechanism to transmit PAF as well as other bioactive agents. The knowledge gaps which when addressed could result in novel therapeutic strategies are also discussed. Taken together, an enhanced understanding of the PAF family of lipid mediators is essential in our improved comprehension of the relationship amongst the diverse cutaneous, cancerous, neurologic and systemic pathologic processes.

scholarly journals Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression

2002 ◽  
Vol 195 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Jeffrey P. Walterscheid ◽  
Stephen E. Ullrich ◽  
Dat X. Nghiem
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Immune Suppression ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Cellular Damage ◽  
Uv Exposure ◽  
Delayed Type Hypersensitivity ◽  
Lipid Mediator ◽  
Paf Receptor

Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E2, interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.

scholarly journals Expression of human platelet-activating factor receptor gene in EoL-1 cells following butyrate-induced differentiation

1995 ◽  
Vol 305 (3) ◽  
pp. 829-835 ◽  
Author(s):  
T Izumi ◽  
S Kishimoto ◽  
T Takano ◽  
M Nakamura ◽  
Y Miyabe ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Platelet Activating Factor ◽  
Allergic Inflammation ◽  
Genomic Analysis ◽  
Receptor Protein ◽  
Cell Surface Expression ◽  
Lipid Mediator ◽  
Mrna Accumulation ◽  
Leukaemia Cell Line ◽  
Paf Receptor

Platelet-activating factor (PAF) is a potent lipid mediator of allergic inflammation through its interaction with eosinophils. Expression of the PAF receptor is modulated by many agents, including those responsible for cell differentiation. We report here that differentiation of a human eosinophilic leukaemia cell line, EoL-1, by sodium n-butyrate is associated with induction of PAF receptor gene expression, as indicated by: PAF receptor mRNA accumulation; increases in the binding of [3H]WEB 2086, a PAF antagonist; analysis of cell-surface expression of PAF receptor protein using a monoclonal anti-(PAF receptor) antibody; and augmentation of PAF-induced increase in the intracellular concentration of calcium. Using cDNA cloning, the receptor expressed in EoL-1 cells was identified as ‘Transcript 1’, one of two transcripts which was previously reported from human genomic analysis (Mutoh, Bito, Minami, Nakamura, Honda, Izumi, Nakata, Kurachi, Terano and Shimizu (1993) FEBS Lett. 322, 129-134). The PAF-induced calcium response and phosphoinositide turnover were decreased by pertussis toxin (PTX) treatment, suggesting that these signals are coupled largely with PTX-sensitive G-protein(s) in EoL-1 cells. These systems may provide a useful experimental model with which to investigate the relationship between eosinophilic differentiation and PAF receptor induction, and the role of eosinophils in allergic responses.

scholarly journals A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation

2008 ◽  
Vol 294 (6) ◽  
pp. H2775-H2784 ◽  
Author(s):  
Peter J. Leary ◽  
Surender Rajasekaran ◽  
R. Ray Morrison ◽  
Elaine I. Tuomanen ◽  
Thomas K. Chin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Protective Effects ◽  
Loss Of Function ◽  
Wild Type ◽  
Intracellular Ca ◽  
Paf Receptor

Controversy exists as to whether platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, can actually protect the heart from postischemic injury. To determine whether endogenous activation of the PAF receptor is cardioprotective, we examined postischemic functional recovery in isolated hearts from wild-type and PAF receptor-knockout mice. Postischemic function was reduced in hearts with targeted deletion of the PAF receptor and in wild-type hearts treated with a PAF receptor antagonist. Furthermore, perfusion with picomolar concentrations of PAF improved postischemic function in hearts from wild-type mice. To elucidate the mechanism of a PAF-mediated cardioprotective effect, we employed a model of intracellular Ca2+ overload and loss of function in nonischemic ventricular myocytes. We found that PAF receptor activation attenuates the time-dependent loss of shortening and increases in intracellular Ca2+ transients in Ca2+-overloaded myocytes. These protective effects of PAF depend on nitric oxide, but not activation of cGMP. In addition, we found that reversible S-nitrosylation of myocardial proteins must occur in order for PAF to moderate Ca2+ overload and loss of myocyte function. Thus our data are consistent with the hypothesis that low-level PAF receptor activation initiates nitric oxide-induced S-nitrosylation of Ca2+-handling proteins, e.g., L-type Ca2+ channels, to attenuate Ca2+ overload during ischemia-reperfusion in the heart. Since inhibition of the PAF protective pathway reduces myocardial postischemic function, our results raise concern that clinical therapies for inflammatory diseases that lead to complete blockade of the PAF receptor may eliminate a significant, endogenous cardioprotective pathway.

Lysophosphatidylcholine transduces Ca2+ signaling via the platelet-activating factor receptor in macrophages

1997 ◽  
Vol 272 (1) ◽  
pp. H17-H24 ◽  
Author(s):  
T. Ogita ◽  
Y. Tanaka ◽  
T. Nakaoka ◽  
R. Matsuoka ◽  
Y. Kira ◽  
...  
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Platelet Activating Factor ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Peritoneal Macrophages ◽  
Free Calcium ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Paf Receptor ◽  
Web 2086

To clarify the molecular mechanism underlying the lysophosphatidylcholine (LPC) signaling, we studied the effect of LPC on the intracellular free calcium concentration ([Ca2+]i) in murine peritoneal macrophages. LPC when added alone induced biphasic elevation of [Ca2+]i, which consisted of a rapid increase followed by sustained elevation. LPC, when added with equimolar cholesterol, induced only the rapid increase in [Ca2+]i, which was blocked by WEB-2086, a selective platelet-activating factor (PAF) receptor antagonist. These results suggest LPC exerts a specific Ca2+ signaling. The sustained elevation reflected the cell lysis. Furthermore, we confirmed its pathway in a more specific manner using cloned PAF receptors expressed in Chinese hamster ovary cells. LPC induced an elevation of [Ca2+]i in a concentration-dependent manner only when the PAF receptor had been expressed, and the elevation of [Ca2+]i was blocked by WEB-2086. Taken together, LPC transduces Ca2+ signaling via the PAF receptor. Activation of the PAF receptor by LPC may indicate its novel important role in the pathogenesis of atherosclerosis.

scholarly journals Consumption of Enriched Yogurt with PAF Inhibitors from Olive Pomace Affects the Major Enzymes of PAF Metabolism: A Randomized, Double Blind, Three Arm Trial

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 801
Author(s):  
Maria Detopoulou ◽  
Agathi Ntzouvani ◽  
Filio Petsini ◽  
Labrini Gavriil ◽  
Εlizabeth Fragopoulou ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Lipid Mediator ◽  
Olive Pomace ◽  
Double Blind ◽  
Promising Alternative ◽  
Catabolic Enzymes ◽  
Platelet Activating Factor Acetylhydrolase ◽  
The Impact ◽  
By Products ◽  
Apparently Healthy

Platelet-activating factor (PAF), a proinflammatory lipid mediator, plays a crucial role in the formation of the atherosclerotic plaque. Therefore, the inhibition of endothelium inflammation by nutraceuticals, such as PAF inhibitors, is a promising alternative for preventing cardiovascular diseases. The aim of the present study was to evaluate the impact of a new functional yogurt enriched with PAF inhibitors of natural origin from olive oil by-products on PAF metabolism. Ninety-two apparently healthy, but mainly overweight volunteers (35–65 years) were randomly allocated into three groups by block-randomization. The activities of PAF’s biosynthetic and catabolic enzymes were measured, specifically two isoforms of acetyl-CoA:lyso-PAF acetyltransferase (LPCATs), cytidine 5′-diphospho-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT) and two isoforms of platelet activating factor acetylhydrolase in leucocytes (PAF-AH) and plasma (lipoprotein associated phospholipase-A2, LpPLA2). The intake of the enriched yogurt resulted in reduced PAF-CPT and LpPLA2 activities. No difference was observed in the activities of the two isoforms of lyso PAF-AT. In conclusion, intake of yogurt enriched in PAF inhibitors could favorably modulate PAF biosynthetic and catabolic pathways.

scholarly journals A Case of IgG4-Related Kidney Disease Developing While on Steroid Treatment for Autoimmune IgG4 Pancreatitis

2021 ◽  
Vol 9 ◽  
pp. 232470962110265
Author(s):  
Jonathan Vincent M. Reyes ◽  
Dawn Maldonado ◽  
Aaron S. Stern ◽  
Maritza Brown
Keyword(s):  
Kidney Disease ◽  
Inflammatory Process ◽  
Systemic Disease ◽  
Multiple Organ ◽  
Steroid Treatment ◽  
Autoimmune Process ◽  
Immunoglobulin G4 ◽  
Organ Systems ◽  
The Relationship ◽  
Steroid Sparing

IgG4 (immunoglobulin G4)-related systemic disease is an autoimmune process affecting multiple organ systems. This inflammatory process can present as but not limited to pancreatitis, cholangitis, or unspecified kidney disease. In this case, our patient developed IgG4-related kidney disease while already on a prolonged steroid course for IgG4-related pancreatitis. The patient ultimately had renal recovery after starting a higher dose of prednisone, but also developed steroid-related complications. This case further highlights the relationship between IgG4 diseases now termed IgG4-related systemic disease. This case brings to light the need for further investigative research into ideal steroid dosing, as well as steroid-sparing agents for IgG4-related systemic disease.

scholarly journals Identification of platelet-activating factor as the inflammatory lipid mediator in CCl4-metabolizing rat liver

2001 ◽  
Vol 42 (4) ◽  
pp. 587-596
Author(s):  
Gopal K. Marathe ◽  
Kathleen A. Harrison ◽  
L. Jackson Roberts ◽  
Jason D. Morrow ◽  
Robert C. Murphy ◽  
...  
Keyword(s):  
Rat Liver ◽  
Platelet Activating Factor ◽  
Lipid Mediator

scholarly journals Lack of Platelet-Activating Factor Receptor Attenuates Experimental Food Allergy but Not Its Metabolic Alterations regarding Adipokine Levels

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Nathália Vieira Batista ◽  
Roberta Cristelli Fonseca ◽  
Denise Perez ◽  
Rafaela Vaz Sousa Pereira ◽  
Juliana de Lima Alves ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Allergy ◽  
Inflammatory Process ◽  
Platelet Activating Factor ◽  
Oral Challenge ◽  
Tissue Loss ◽  
Lack Of Information ◽  
Paf Receptor ◽  
Rolling Leukocytes

Platelet-activating factor (PAF) is known to be an important mediator of anaphylaxis. However, there is a lack of information in the literature about the role of PAF in food allergy. The aim of this work was to elucidate the participation of PAF during food allergy development and the consequent adipose tissue inflammation along with its alterations. Our data demonstrated that, both before oral challenge and after 7 days receiving ovalbumin (OVA) diet, OVA-sensitized mice lacking the PAF receptor (PAFR) showed a decreased level of anti-OVA IgE associated with attenuated allergic markers in comparison to wild type (WT) mice. Moreover, there was less body weight and adipose tissue loss in PAFR-deficient mice. However, some features of inflamed adipose tissue presented by sensitized PAFR-deficient and WT mice after oral challenge were similar, such as a higher rate of rolling leukocytes in this tissue and lower circulating levels of adipokines (resistin and adiponectin) in comparison to nonsensitized mice. Therefore, PAF signaling through PAFR is important for the allergic response to OVA but not for the adipokine alterations caused by this inflammatory process. Our work clarifies some effects of PAF during food allergy along with its role on the metabolic consequences of this inflammatory process.

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