Release Of Platelet-activating Factor Research Articles

Topical Photodynamic Therapy Generates Bioactive Microvesicle Particles: Evidence for a Pathway Involved in Immunosuppressive Effects

Although effective in treating actinic damage, topical photodynamic therapy (PDT) has been shown to be immunosuppressive through unknown mechanisms, which could potentially limit its effectiveness. Multiple types of environmental stressors, including PDT, can produce the immunosuppressive lipid mediator platelet-activating factor (PAF). Because PAF can produce subcellular microvesicle particles (MVPs), these studies tested whether PDT can generate PAF and MVP release and whether these are involved in PDT-induced immunosuppression. Previously, topical PDT using blue light and 5-aminolevulinic acid was found to be a potent stimulus for PAF production in mice and human skin explants and human patients, and we show that experimental PDT also generates high levels of MVP. PDT-generated MVPs were independent of the PAF receptor but were dependent on the MVP-generating enzyme acid sphingomyelinase. Patients undergoing topical PDT treatment to at least 10% of body surface area showed local and systemic immunosuppression as measured by inhibition of delayed-type hypersensitivity reactions. Finally, using a murine model of contact hypersensitivity, PDT immunosuppression was blocked by genetic and pharmacologic inhibition of acid sphingomyelinase and genetic inhibition of PAF receptor signaling. These studies describe a mechanism involving MVP through which PDT exerts immunomodulatory effects, providing a potential target to improve its effectiveness.

UVB-Induced Microvesicle Particle Release and Its Effects on the Cutaneous Microenvironment.

Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.

Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers

This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs) elicited acute, shock-like symptoms in mice, associated with increased plasma PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These symptoms were completely prevented by prophylactic PAF receptor inhibition or Kupffer cell depletion. Assessment of varied si-NP chemistries confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on carrier endosome disruptive function. 4T1 tumor-bearing mice, which exhibit increased circulating leukocytes, displayed greater sensitivity to these toxicities. PAF-mediated toxicities were generalizable to commercial delivery reagent in vivo-jetPEI® and an MC3 lipid formulation matched to an FDA-approved nanomedicine. These collective results establish Kupffer cell release of PAF as a key mediator of siRNA nanocarrier toxicity and identify PAFR inhibition as an effective strategy to increase siRNA nanocarrier tolerated dose.

Synthesis of Human Neutrophil Extracellular Traps Contributes to Angiopoietin-Mediated In Vitro Proinflammatory and Proangiogenic Activities.

Neutrophil extracellular traps (NETs) are composed of nuclear DNA in a web-like structure extruded from neutrophils in response to either bacterial infection or inflammation. We previously reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of both angiopoietins (Ang1 and Ang2) to induce proinflammatory activities, such as synthesis and release of platelet-activating factor, upregulation of β2 integrin complex (CD11/CD18), and neutrophil chemotaxis. In contrast, only Ang1 but not Ang2 is capable of promoting translational and transcriptional activities in neutrophils. In this article, we addressed whether Ang1 and/or Ang2 could modulate the release of NETs and if they contribute to angiopoietin-mediated proinflammatory activities. We observed that Ang1 and Ang2, alone or combined (10 nM, 3 h), increase NET synthesis and release by ≈2.5-fold as compared with PBS-treated neutrophils. The release of NETs is Tie2 dependent and requires downstream intracellular participation of PI3K, p38, and p42/44 MAPK pathways; reactive oxygen species production; intracellular calcium store depletion; and protein arginine deiminase 4 activation. These isolated NETs induced neutrophil and endothelial cell activation, leading to neutrophil adhesion onto human extracellular matrix and HUVEC and in vitro formation of capillary-like tubes by endothelial cells. Our study reports the capacity of Ang1 and Ang2 to promote the release of NETs and that these NETs contribute to angiopoietin-mediated in vitro proinflammatory and proangiogenic activities.

Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis.

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators by mast cells and basophils. Although anaphylaxis is often under-communicated and thus underestimated, its incidence appears to have risen over recent decades. Drugs are among the most common triggers in adults, being analgesics and antibiotics the most common causal agents. Anaphylaxis can be caused by immunologic or non-immunologic mechanisms. Immunologic anaphylaxis can be mediated by IgE-dependent or -independent pathways. The former involves activation of Th2 cells and the cross-linking of two or more specific IgE (sIgE) antibodies on the surface of mast cells or basophils. The IgE-independent mechanism can be mediated by IgG, involving the release of platelet-activating factor, and/or complement activation. Non-immunological anaphylaxis can occur through the direct stimulation of mast cell degranulation by some drugs, inducing histamine release and leading to anaphylactic symptoms. Work-up of a suspected drug-induced anaphylaxis should include clinical history; however, this can be unreliable, and skin tests should also be used if available and validated. Drug provocation testing is not recommended due to the risk of inducing a harmful reaction. In vitro testing can help to confirm anaphylaxis by analyzing the release of mediators such as tryptase or histamine by mast cells. When immunologic mechanisms are suspected, serum-sIgE quantification or the use of the basophil activation test can help confirm the culprit drug. In this review, we will discuss multiple aspects of drug-induced anaphylaxis, including epidemiology, mechanisms, and diagnosis.

An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance.

Glucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC-GR complex with the receptor and exert their actions. On activation the GC-GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.

Oxidative Stress and Suicidal Erythrocyte Death

Eryptosis, the suicidal erythrocyte death, is characterized by cell shrinkage, membrane blebbing, and phosphatidylserine translocation to the outer membrane leaflet. Phosphatidylserine at the erythrocyte surface binds endothelial CXCL16/SR-PSOX (CXC-Motiv-Chemokin-16/Scavenger-receptor-for-phosphatidylserine-and-oxidized-low-density-lipoprotein) and fosters engulfment of affected erythrocytes by phagocytosing cells. Eryptosis serves to eliminate infected or defective erythrocytes, but excessive eryptosis may lead to anemia and may interfere with microcirculation. Clinical conditions with excessive eryptosis include diabetes, chronic renal failure, hemolytic uremic syndrome, sepsis, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, glutamate cysteine ligase modulator deficiency, and Wilson's disease. Eryptosis is triggered by a wide variety of xenobiotics and other injuries such as oxidative stress. Signaling of eryptosis includes prostaglandin E₂ formation with subsequent activation of Ca(2+)-permeable cation channels, Ca(2+) entry, activation of Ca(2+)-sensitive K(+) channels, and cell membrane scrambling, as well as phospholipase A2 stimulation with release of platelet-activating factor, sphingomyelinase activation, and ceramide formation. Eryptosis may involve stimulation of caspases and calpain with subsequent degradation of the cytoskeleton. It is regulated by AMP-activated kinase, cGMP-dependent protein kinase, Janus-activated kinase 3, casein kinase 1α, p38 kinase, and p21-activated kinase 2. It is inhibited by erythropoietin, antioxidants, and further small molecules. It remains uncertain for most disorders whether eryptosis is rather beneficial because it precedes and thus prevents hemolysis or whether it is harmful because of induction of anemia and impairment of microcirculation. This will address the significance of eryptosis, further mechanisms underlying eryptosis, and additional pharmacological tools fostering or inhibiting eryptosis.

Effects of platelet-activating factor and its differential regulation by androgens and steroid hormones in prostate cancers

Background:Platelet-activating factor (PAF) is an arachidonic acid metabolite that plays an important role in cell proliferation, migration and neoangiogenesis, but whether it is involved in the progression of prostate cancer remains undiscovered.Methods:Clinical prostate specimens were investigated with immunohistochemistry method and in vitro cell experiments referred to MTS cell proliferation assay, invasion and migration experiment, quantitative real-time RT–PCR assay, western blotting analysis and ELISA assay.Results:Platelet-activating factor synthetase, lyso-PAF acetyl transferase (LPCAT1), increased significantly in castration-resistant prostate cancer (CRPC) specimens and CRPC PC-3 cells than that in controls. Intriguingly, PAF induced invasion and migration of PC-3 cells but not LNCaP cells. The PAF receptor antagonist inhibited proliferation of LNCaP and PC-3 cells. Dihydrotestosterone (DHT) treatment caused a decrease in LPCAT1 expression and PAF release in LNCaP cells, which could be blocked by androgen receptor antagonists. Finally, DHT increased LPCAT1 expression and PAF release in PC-3 cells in a Wnt/β-catenin-dependent manner.Conclusion:For the first time, our data supported that PAF might play pivotal roles in the progression of prostate cancer, which might throw a new light on the treatment of prostate cancer and the prevention of the emergence of CRPC.

B cell activating factor (BAFF) and platelet activating factor (PAF) could both be markers of non-IgE-mediated reactions

Background B cell activating factor (BAFF) is a member of the tumor necrosis factor superfamily and an important regulator of peripheral B cell survival, maturation and immunoglobulin class-switch recombination. Many studies suggest that BAFF might be a new mediating mechanism in foodrelated inflammation. Higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be particularly involved in non-IgE-mediated reactions [1]. According to Finkelman there are 2 pathways of systemic anaphylaxis: antigens can cause systemic anaphylaxis in mice through the classic pathway by cross-linking IgE bound to mast cell FceRI, stimulating histamine and PAF release, or the alternative pathway by forming complexes with IgG that cross-link macrophage FcgRIII, stimulating only PAF release [2]. The aim of this study is to evaluate the correlation between BAFF and PAF in non-atopic subjects.

Effect of mammalian lignans on fMLP-induced oxidative bursts in human polymorphonuclear leucocytes.

We examined the effects of mammalian lignans, enterolactone, prestegane B and 2,3-dibenzylbutane-1,4-diol (DBB) on superoxide production and luminol-dependent chemiluminescence (LCL) response in human polymorphonuclear leucocytes (PMNs). The three lignans had no direct effect on the responses of human PMNs. DBB and prestegane B enhanced the superoxide production and LCL response induced by formylmethionyl-leucyl-phenylalanine (fMLP), but enterolactone inhibited fMLP-induced effects. The effects of DBB were stronger than those of prestegane B and the effects of DBB were inhibited by bromophenacyl bromide, mepacrine, N-(6-aminophenyl)-5-chloro-1-naphthalene, sulphonamide and trifluoroperazine, but not by gossypol, nordihydroguaretic acid, indomethacin, staurosporine, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride or (R,S)-2-methoxy-3-(octadecyl-carbamoyloxy)-propyl-2-(2-thiazoli o)-ethylphosphate. These results suggest that DBB primes the responses of human PMNs, and the priming effect is caused by the activation of phospholipase A2--and Ca(2+)-calmodulin-pathways, but not by the activation of lipoxygenase, cyclo-oxygenase and protein kinase C or by the release of platelet activating factor.

PAF formation by human gastrointestinal mucosa/submucosa in-vitro: release by ricinoleic acid, and inhibition by 5-aminosalicylic acid.

Human isolated gastrointestinal mucosa/submucosa incubated with ricinoleic acid (12.5-100 micrograms mL-1) or the calcium ionophore A23187 (10 micrograms mL-1) released platelet-activating factor (PAF) as determined by a scintillation proximity assay after extraction and purification. 5-Aminosalicylic acid (25-100 micrograms mL-1) inhibited PAF release by ricinoleic acid in a concentration-dependent manner, and 50 micrograms mL-1 reduced the effect of A23187. We suggest that PAF may play a role in the laxation and mucosal damage by ricinoleic acid released from castor oil.

Nonredundant Roles for Basophils in Immediate- and Delayed-onset Allergic Reactions

Basophils circulate in the peripheral blood under physiological conditions, and they are recruited to affected tissues in allergic reactions, albeit in small numbers. Because of their rarity (less than 1% of peripheral blood leukocytes are basophils), and their similarity to mast cells, basophils have often been considered the lesser relatives of mast cells. Moreover, because basophils have been so difficult to identify, mice were erroneously believed for a long time to lack them. Therefore, the assumption that basophils have only redundant roles has remained unquestioned until recently. The flow-cytometric identification of basophils in mice and the development of in vivo models and reagents useful for their functional analyses have greatly advanced the field of basophil research. Previously unrecognized roles of basophils, dis- tinct from those of mast cells, have been shown in allergic responses and the regulation of acquired immunity. In this re- view, we mainly focus on roles of basophils in immediate- and delayed-onset allergic reactions. Basophils are crucial ini- tiators, rather than effectors, in the development of IgE-mediated, chronic cutaneous allergic inflammation, which is char- acterized by the massive infiltration of eosinophils and neutrophils and can be elicited even in the absence of mast cells and T cells. Basophils are dispensable for the induction of IgE-mediated systemic anaphylaxis, unlike mast cells, but play a major role in IgG-mediated passive and active systemic anaphylaxis, through the release of platelet-activating factor in response to stimulation with antigen-IgG immune complexes. Thus, basophils and their products appear to be promising therapeutic targets for allergic disorders.

Endothelial progenitor cells express PAF receptor and respond to PAF via Ca 2+-dependent signaling

Endothelial progenitor cell (EPC) therapy is a promising approach to promote angiogenesis and endothelial repair in patients with cardiovascular diseases (CVD). However, their release of proinflammatory mediators may compromise the therapeutic efficacy. Little is known about the role of Platelet-Activating Factor (PAF) in EPC functional response. Here, we investigated the expression of PAF receptor (PAF-R) in early EPC and the release of PAF under stimulation with factors involved in endothelial dysfunction. Results indicated that early EPC express the PAF-R and respond to PAF signaling via a transient increase of cytoplasmic Ca 2+ concentration. EPC release PAF in a time dependent manner upon stimulation with tumor necrosis factor-α (TNF-α) or high-glucose concentration with a peak at 30 min and 10 min ( p < 0.01 vs. control), respectively. PAF, starting at concentration of 50 ng/ml, exerted a detrimental effect on EPC number with a concomitant increase of p38 activity. Furthermore, both the reduction of early EPC number and the enhanced p38 activity induced by PAF were abolished by CV3988, a PAF receptor antagonist. These novel findings, revealing that early EPC respond to PAF signaling, unveil an inflammatory pathway that may play a crucial role in the outcome of cardiovascular cell therapy with EPC.

Endothelial Cell Prostaglandin I2 and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A2β Knockout Mouse

Damage and activation of lung endothelium can lead to interstitial edema, infiltration of inflammatory cells into the interstitium and airways, and production of inflammatory metabolites, all of which propagate airway inflammation in a variety of diseases. We have previously determined that stimulation of human microvascular endothelial cells from lung (HMVEC-L) results in activation of a calcium-independent phospholipase A(2) (iPLA(2)), and this leads to arachidonic acid release and production of prostaglandin I(2) (PGI(2)) and platelet-activating factor (PAF). We stimulated lung endothelial cells isolated from iPLA(2)beta-knockout (KO) and wild type (WT) mice with thrombin and tryptase to determine the role of iPLA(2)beta in endothelial cell membrane phospholipid hydrolysis. Thrombin or tryptase stimulation of WT lung endothelial cells resulted in increased arachidonic acid release and production of PGI(2) and PAF. Arachidonic acid release and PGI(2) production by stimulated iPLA(2)beta-KO endothelial cells were significantly reduced compared to WT. Measured PLA(2) activity and PGI(2) production by iPLA(2)beta-KO cells were suppressed by pretreatment with (R)-bromoenol lactone (R-BEL), which is a selective inhibitor of iPLA2gamma. In contrast to the increase in PAF production induced by stimulation of WT endothelial cells, none was observed for KO cells, and this suggests that endothelial PAF production is entirely dependent on iPLA(2)beta activity. Because inflammatory cell recruitment involves the interaction of endothelial cell PAF with PAF receptors on circulating cells, these data suggest that iPLA(2)beta may be a suitable therapeutic target for the treatment of inflammatory lung diseases.

Platelet-Activating Factor and Evidence of Oxidative Stress in the Bronchoalveolar Fluid of Thoroughbred Colts during Race Training

Inflammatory airway disease (IAD) is prevalent in young racehorses during training, being the 2nd most commonly diagnosed ailment interrupting training of 2-year-old Thoroughbred racehorses. That stabling and exercise cause oxidative stress, release of platelet-activating factor (PAF) and inflammation in airways of Thoroughbred colts. Colts in breeding farms (NC, n = 45), stabled for 30 days (EC, n = 40), and race trained (EX, n = 34). Cytological profile and parameters of bronchoalveolar lavage fluid (BALF) related to oxidative stress, bioactivity of the proinflammatory mediator PAF, catalase activity, and alveolar macrophage function. Percentages of neutrophils and eosinophils in the BALF of the EX group were higher (5.4 +/- 6.4% versus 0.9 +/- 1.2%) than the upper limits for normal horses (3-5%). BALF from the EX group (45.6 +/- 2.8 cells/microL of BALF) also displayed significantly (P = .017) higher total nucleated cell count. PAF bioactivity and the total protein concentration in the BALF were higher in the EX group (0.0683 +/- 0.076 versus 0.0056 +/- 0.007 340 : 380 nm ratio P = .0039, 0.36 +/- 0.30 versus 0.14 +/- 0.15 mg of proteins/mL of BALF P < .001). Concentration of BALF hydroperoxides was higher in the EC group (104.7 +/- 80.0 versus 35.2 +/- 28.0 nmol/mg of proteins, P = .013) and catalase activity was higher in the EX group (0.24 +/- 0.16 versus 0.06 +/- 0.02 micromol H2O2/min/mg of proteins, P = .0021). Alveolar macrophage phagocytosis (P = .048) as well as production of superoxide anion (P = .0014) and hydrogen peroxide (P = .0011) were significantly lower in EX group. Further studies should be performed to elucidate the role of PAF in the pathophysiology of IAD. Its presence in bronchoalveolar fluid of young athletic horses makes it a potential therapeutic target to be investigated.

Blood-brain barrier breakdown by PAF and protection by XQ-1H due to antagonism of PAF effects

Hypoxia and reoxygenation set in motion a series of events, including blood-brain barrier breakdown. We examined the content and effect of platelet-activating factor (PAF), which was increased in the rat brain microvessel endothelial cells (RBMECs) during hypoxia and reoxygenation. MTT method was used to assay cell damage; ELISA analysis was used to estimate PAF release after hypoxia and reoxygenation injury; and RT-PCR and Western blotting method were used to assess gene and protein expressions of inducible nitric-oxide synthase (iNOS) in RBMECs under PAF damage. PAF affected intracellular free Ca 2+ levels, increasing [Ca 2+] i, which caused up-regulation of iNOS. We also examined the blood-brain barrier protective effect of XQ-1H, a novel ginkgolide B derivative. Pretreatment with XQ-1H (10 µM and 3 µM) for 24 h significantly antagonized PAF receptor and inhibited the increase in intracellular calcium concentration and the up-regulation of iNOS in response to PAF under hypoxia and reoxygenation in vitro.

HCl-activated neural and epithelial vanilloid receptors (TRPV1) in cat esophageal mucosa

To test whether transient receptor potential channel vanilloid subfamily member-1 (TRPV1) mediates acid-induced inflammation in the esophagus, a tubular segment of esophageal mucosa was tied at both ends, forming a sac. The sac was filled with 0.01 N HCl (or Krebs buffer for control) and kept in oxygenated Krebs buffer at 37 degrees C. The medium around the sac (supernatant) was collected after 3 h. Supernatant of the HCl-filled sac abolished contraction of esophageal circular muscle strips in response to electric field stimulation. Contraction was similarly abolished by supernatant of mucosal sac filled with the TRPV1 agonist capsaicin (10(-6) M). These effects were reversed by the selective TRPV1 antagonist 5'-iodoresiniferatoxin (IRTX) and by the platelet-activating factor (PAF) receptor antagonist CV9388. Substance P and CGRP levels in mucosa and in supernatant increased in response to HCl, and these increases were abolished by IRTX and by tetrodotoxin (TTX) but not affected by CV9388, indicating that substance P and CGRP are neurally released and PAF independent. In contrast, the increase in PAF was blocked by IRTX but not by TTX. Presence of TRPV1 receptor was confirmed by RT-PCR and by Western blot analysis in whole mucosa and in esophageal epithelial cells enzymatically isolated and sorted by flow cytometry or immunoprecipitated with cytokeratin antibodies. In epithelial cells PAF increased in response to HCl, and the increase was abolished by IRTX. We conclude that HCl-induced activation of TRPV1 receptors in esophageal mucosa causes release of substance P and CGRP from neurons and release of PAF from epithelial cells.

Erythrocyte programmed cell death

Eryptosis, the suicidal death of erythrocytes, is characterised by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are recognised by macrophages, which engulf and degrade the affected cells. Reported triggers of eryptosis include osmotic shock, oxidative stress, energy depletion, ceramide, prostaglandin E(2), platelet activating factor, hemolysin, listeriolysin, paclitaxel, chlorpromazine, cyclosporine, methylglyoxal, amyloid peptides, anandamide, Bay-5884, curcumin, valinomycin, aluminium, mercury, lead and copper. Diseases associated with accelerated eryptosis include sepsis, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency, hemolytic uremic syndrome and Wilsons disease. Eryptosis may be inhibited by erythropoietin, adenosine, catecholamines, nitric oxide (NO) and activation of G-kinase. Most triggers of eryptosis except oxidative stress are effective without activation of caspases. Their signalling involves formation of prostaglandin E(2) with subsequent activation of cation channels and Ca2+ entry and/or release of platelet activating factor (PAF) with subsequent activation of sphingomyelinase and formation of ceramide. Ca2+ and ceramide stimulate scrambling of the cell membrane. Ca2+ further activates Ca2+-sensitive K+ channels leading to cellular KCl loss and cell shrinkage and stimulates the protease calpain resulting in degradation of the cytoskeleton. Eryptosis allows defective erythrocytes to escape hemolysis. On the other hand, excessive eryptosis favours the development of anemia. Thus, a delicate balance between proeryptotic and antieryptotic mechanisms is required to maintain an adequate number of circulating erythrocytes and yet avoid noneryptotic death of injured erythrocytes.

Basophils Are Back!

In this issue of Immunity, Tsujimura et al. (2008) report that the release of platelet-activating factor by basophils stimulated with immunoglobulin G1 (IgG1)-antigen immune complexes contributes substantially to the expression of an IgG1-dependent alternative pathway of systemic anaphylaxis in mice.

Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

Acute pancreatitis (AP) causes release of platelet-activating factor (PAF), which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF is a cell surface secretion of bioactive lipid, which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R). Studies showed that PAF participate in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP. PAF has also been implicated as a key mediator in the progression of severe AP, which can lead to complications and unacceptably high mortality rates. Several classes of compounds show significant PAF-RAs, and significant local and systemic effects on reducing inflammatory changes. As a preventive treatment, PAF-RA could block a series of PAF-mediated inflammatory injury and thus improve the prognosis of AP. This review introduces the important role of PAF-RA in the treatment of AP.