Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis.

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.

The IL-1 family and inflammatory diseases.

IL-1 and its related family member IL-18 are primarily proinflammatory cytokines by their ability to stimulate the expression of genes associated with inflammation and autoimmune diseases. For IL-1 (IL-1alpha and IL-1beta), the most salient and relevant properties are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A and inducible nitric oxide synthase (iNOS). This accounts for the large amount of prostaglandin-E2 (PGE2), platelet activating factor and nitric oxide (NO) produced by cells exposed to IL-1 or in animals or humans injected with IL-1. Another important member of the proinflammatory IL-1 family is IL-18. IL-18 is also an important player in autoimmune disease because of its ability to induce IFNgamma, particularly in combination with IL-12 or IL-15. Both IL-1 and IL-18 increase the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on mesenchymal cells and vascular-cell adhesion molecule-1 (VCAM-1) on endothelial cells. This latter property promotes the infiltration of inflammatory and immunocompetent cells into the extravascular space. IL-1 and IL-18 are also an angiogenic factors by increasing the expression of vascular endothelial growth factor; IL-1 and IL-18 thus play a role in pannus formation and blood vessel supply. The strongest case for the importance of IL-1 in disease processes come from the administration of the IL-1 receptor antagonist, also a member of the IL-1 family and IL-18 binding protein (IL-18BP), a constitutively expressed and secreted protein that binds and neutralizes IL-18. Data from the human genome project have revealed other members of the IL-1 family. However, these appear to be antagonists rather than agonists. IL-1 also acts as an adjuvant during antibody production and stimulates bone marrow stem cells for differentiation in the myeloid series. IL-1 is distinct from tumor necrosis factor (TNF); IL-1 and TNFalpha share several biological properties but the salient difference is that TNF receptor signaling induces programmed cell death whereas IL-1 receptor signaling does not. In fact, IL-1 is a hematopoietic growth factor and IL-1 was administered to humans to reduce the nadir of white blood cells and platelets in patients during bone-marrow transplantation. This property, of IL-1 is not observed in the responses to TNFalpha. Furthermore, in animal models of destructive rheumatoid arthritis, IL-1 is necessary but TNFalpha is not.

Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor.

OBJECTIVE: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: Research laboratory at a university. SUBJECTS: Male, Wistar rats (8-9 wks old; n = 83). INTERVENTIONS: In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. MEASUREMENTS AND MAIN RESULTS: LPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration. CONCLUSIONS: The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Antiasthmatic effects of Picrorhiza kurroa: androsin prevents allergen- and PAF-induced bronchial obstruction in guinea pigs.

In the Ayurvedic medicine, Picrorhiza kurroa Royle ex Benth. is used for the treatment of liver and lung diseases. Using different chemical and pharmacological methods, we could identify the phenol glycoside androsin as active compound preventing allergen and platelet-activating factor induced bronchial obstruction in guinea pigs in vivo (10 mg/kg p.o.; 1 h prior to the inhalation challenge). Histamine release from human polymorphonuclear leukocytes in vitro was inhibited by other compounds yet to be identified.

Effect of cetirizine on cutaneous reactions to PAF, kallikrein and serum in patients with chronic urticaria.

The effects of oral administration of the antihistamine cetirizine on the weal and flare caused by intradermal injection of platelet activating factor (PAF-acether), kallikrein, histamine and the patient's own serum were investigated in 10 patients with chronic urticaria. Cetirizine markedly reduced the weal and flare induced by all these agents as measured 12 min after the injections. The delayed reactions observed after injection of PAF, kallikrein and serum were also inhibited by cetirizine at 6 hours. In addition, reactions which were present 20 h after injection of the agent before administration of cetirizine were found to be inhibited at the same point in time after cetirizine treatment. These effects might explain the good inhibitory clinical effect of cetirizine on the patients' urticaria. No side-effects were noted during the treatment.

Late appearance of phospholipid platelet-activating factor and leukotriene B4 in human skin after repeated antigen challenge.

Inflammatory mediators were assessed in supernatants of chamber fluids from eight ragweed- or grass-sensitive subjects during antigen-induced cutaneous inflammatory responses. Platelet activating factor (PAF) accumulated at concentrations of 1 pm to 90 mumol/L in six of eight subjects beginning at 3 hours and continuing for 9 hours after antigen challenge. Leukotriene B4 (LTB4) was detectable at cutaneous sites of antigen challenge in five of five subjects throughout the 9-hour period at levels from 1 to 36 nmol, a range of 38% to 80% of which were omega-oxidation metabolites. Histamine levels peaked in the first hour at 106 +/- 18 ng/ml and decreased to a plateau of 11 to 13 ng/ml at 3 to 9 hours after antigen challenge. No PAF and only very low levels of LTB4 (0.1 to 1.3 nmol) and of histamine (less than 2 ng/ml) were detected at buffer-control sites during the 9 hours of study. Continuous antigen exposure thus results in the persistent release of histamine and LTB4 and the late appearance of PAF, all of which may contribute to the chronicity of allergic disorders and may have a bearing on the IgE-mediated, late-phase cutaneous response.

[Renal diseases and platelet activating factor]. / Maladies rénales et platelet-activating factor.

The platelet-activating factor (PAF) is a molecule produced by several types of cells (monocytes, platelets, polynuclears, eosinophils and endothelial cells) and by different organs (lungs, heart, kidney). Its action concerns many inflammatory phenomena such as allergy, cerebral, cardiac or renal ischemia. The discovery of specific antagonists helped us to understand the pathophysiological effects of PAF in man. As PAF is involved in the mechanism of proteinuria and many other nephropathies, the use of antagonists for the treatment of such disorders seems valuable.

Effect of a PAF antagonist, BN52063, on antigen-induced, acute, and late-onset cutaneous responses in atopic subjects.

Platelet-activating factor (PAF) is a potent phospholipid that has been implicated as a mediator of allergic inflammatory responses, since it may induce a biphasic response and eosinophil infiltration in the skin that is reminiscent of antigen-induced reactions after cutaneous administration in man. We have studied the effect of a PAF antagonist, the ginkgolide mixture, BN52063, to determine the role of PAF in antigen-induced cutaneous responses in a double-blind, placebo-controlled, crossover study in 10 atopic subjects. Two hours after ingestion of BN52063 (120 mg), the wheal-and-flare response to intradermal PAF (200 ng), but not to histamine (1 micrograms), was inhibited, as previously described in nonatopic subjects. The late-onset component of the response to allergen (8 hours after injection) was significantly attenuated from 2.89 +/- 0.76 cm3 to 1.41 +/- 0.58 cm3 (p less than 0.05). Although the early wheal response was reduced in 50% of subjects, it was not significant overall, nor was there any significant reduction in the flare response. These observations suggest that PAF contributes to the late inflammatory response to allergen that is known to be associated with an inflammatory cell (predominantly eosinophil) infiltrate. This lends support to the idea that PAF is a mediator of allergic inflammation and that PAF antagonists may have a therapeutic role in allergic diseases.

Pharmacology of the late response to allergen and its relevance to asthma prophylaxis.

Inhalation of allergen by sensitised asthmatics results in an acute increase of airways resistance that, in some individuals, is succeeded by a response of late-onset. Late-onset responses are associated with an increased airway reactivity to constrictor stimuli that lasts for several days and hence may be akin to exacerbation of clinical asthma. For this reason, much attention has been given to inhibition of late-onset reactions by glucocorticosteroids or by cromoglycate. Such effects have been cited as evidence of anti-asthma efficacy for these drugs and also for ketotifen, as might be anticipated from prophylactic efficacy in clinical asthma. More recently, a similar inhibitory effect has been demonstrated for theophylline, which is in marked contrast to beta-adrenoceptor agonists, which have long been known not to inhibit expression of late-onset reactions. The profile of drug sensitivity observed for late-onset reactions precludes mast cell stabilisation as an adequate explanation, since late-onset reactions are unaffected by beta-adrenoceptor agonists, notwithstanding the potency of such drugs as inhibitors of mast cell secretion; furthermore, late-onset reactions can be inhibited by nonsteroidal anti-inflammatory drugs, even though such drugs can enhance mast cell secretion. Rather, present evidence favours platelet-activating factor (PAF, Paf-acether, AGEPC) as a primary determinant of late-onset reactions, especially since responses to this material can be inhibited by cromoglycate, glucocorticosteroids, ketotifen and theophylline, and since there is substantial evidence that PAF has properties that could account for exacerbation of asthma.

Acute effects of intratracheal administration of platelet-activating factor in baboons.

The bronchomotor effect of intratracheal administration of PAF-acether (60 micrograms X kg -1) was investigated in 37 curarized baboons mechanically ventilated with constant volume and frequency. PAF-acether caused an immediate bronchoconstriction as assessed by a marked increase in peak inspiratory pressure with no change in static pulmonary compliance and chest X-rays. There was a concomitant fall in arterial PO2 and a significant increase in ventilated unperfused lung zones. A decrease of circulating platelets and leucocytes was also observed. Local anesthesia with lidocaine and atropine did not prevent PAF-acether-induced bronchoconstriction although both markedly reduced the bronchial response to histamine. Albuterol significantly reduced the bronchial response to PAF-acether. Pretreatment with aspirin (80 mg X kg -1 iv) did not prevent the bronchoconstriction caused by PAF-acether, and intravenous or intratracheal arachidonic acid caused no bronchial response. Thus the role of cyclooxygenase metabolites of arachidonic acid in PAF-acether-induced bronchoconstriction is unlikely. In conclusion, an acute bronchoconstriction probably not triggered by stimulation of irritant receptors of the airways and associated with aggregation of platelet takes place subsequent to intratracheal administration of PAF-acether. These data suggest that PAF-acether might play a role in the pathogenesis of human asthma.