PAF-induced Paw Oedema Research Articles

Angiotensin peptides attenuate platelet-activating factor-induced inflammatory activity in rats

Angiotensin (Ang)—a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF.

Biotinylated heptapeptides substituted with a d-amino acid as platelet-activating factor inhibitors

Platelet-activating factor (PAF), a potent lipid mediator, is implicated in many inflammatory diseases, and therefore may serve as a direct target for anti-inflammatory drugs. We previously reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence markedly inhibit PAF-induced inflammation by direct binding, and that two synthetic fluorescence-labelled heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp and d-Lys-Trp-Tyr-Lys-Asp-Gly-Asp) with high stability in plasma specifically bind to PAF-like lipids (oxidized- and lyso-phosphatidylchoine). In this study, synthetic heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp) coupled to a biotin molecule through the N-terminal amino group and ε-amino group of N-terminus Lys, (Btn)KP6 and K(Btn)P6, respectively, and their biotinylated peptides substituted with d-Lys at the N-terminus, (Btn)dKP6 and dK(Btn)P6, respectively, were investigated for their effects on PAF-induced inflammation. In the experiments using a rat model of hind paw oedema, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 significantly inhibited PAF-induced paw oedema, with the highest inhibitory effect exhibited by dK(Btn)P6. The inhibitory effect of d-Tyr-d-Lys-d-Asp-Gly tetrapeptide on PAF-induced paw oedema was much lower than that of Tyr-Lys-Asp-Gly tetrapeptide. In the experiments using tryptophan fluorescence spectroscopy, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 bound to PAF dose-dependently, with dK(Btn)P6 showing the strongest binding affinity, indicating that its affinity appears to be closely correlated with its inhibitory effect on PAF-induced inflammation. These results suggest that direct binding of (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 to PAF can lead to marked inhibition of PAF-induced inflammation, and these agents, particularly dK(Btn)P6, may be useful as anti-inflammatory drugs targeting PAF with high stability in plasma.

An endothelin-3-related synthetic biotinylated pentapeptide as a novel inhibitor of platelet-activating factor

Platelet-activating factor (PAF), a potent proinflammatory mediator, is involved in many inflammatory diseases. We recently reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence inhibit PAF-induced inflammation by directly binding to PAF. In this study, we investigated the effect of two synthetic biotinylated peptides, both of which have a sequence similar to Tyr-Lys-Asp-Gly—an endothelin-3 (ET-3)-related biotinylated pentapeptide (Tyr-Lys-Asp-Lys-Glu, BPET3) and a scavenger receptor CD36-related biotinylated tetrapeptide (Tyr-Lys-Gly-Lys, BPCD36)—on PAF-induced inflammation by using a rat model of hind paw oedema. BPET3 markedly inhibited PAF-induced oedema in a dose-dependent manner, and the dose that caused 50% inhibition was estimated to be approximately 2.64nmol/paw. The inhibitory effect of BPCD36 on PAF-induced paw oedema was less than that of BPET3, while a synthetic biotinylated pentapeptide (Lys-Lys-Tyr-Asp-Glu) shuffling amino acid sequence of BPET3, an ET-1-related synthetic biotinylated pentapeptide (Leu-Met-Asp-Lys-Glu), or an ET-2-related synthetic biotinylated pentapeptide (Trp-Leu-Asp-Lys-Glu) did not inhibit PAF-induced paw oedema. Furthermore, intrinsic tryptophan fluorescence studies demonstrated that ET-3 specifically interacted with both PAF and its metabolite/precursor lyso-PAF. These results provide evidence that the Tyr-Lys-Asp region in both ET-3 and BPET3 is essential for marked inhibition of the peptide on PAF-induced inflammation, and strongly suggest that BPET3 may be useful as a novel anti-inflammatory drug targeting PAF.

Endothelin-3 at low concentrations attenuates inflammatory responses via the endothelin B2 receptor

The aim of this study was to clarify a role of endothelins (ETs: ET-1, -2, and -3) and their receptors (ETA, ETB1, and ETB2) in inflammatory responses. Male Wistar rats (180-220 g) were used. The effects of ETs in the absence or presence of the ETA antagonist BQ-123/the selective ETB2 antagonist BQ-788, and the effect of the selective ETB1 agonist IRL-1620 and the nonselective ETB agonist BQ-3020, on rat hind paw oedema induced by several proinflammatory substances were examined. The involvement of nitric oxide (NO) in the effects of ETs on the paw oedema was investigated using the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). ET-3, which acts mainly on ETB, at low concentrations specifically inhibited platelet-activating factor (PAF)-induced paw oedema, whereas neither ET-1 nor ET-2, both of which act on ETA and ETB, showed inhibitory activity. The inhibition by ET-1 and ET-3 (each 0.5 pmol/paw) in the presence of BQ-123 (66.4 ± 6.7 % and 65.4 ± 22.6 %, respectively), was comparable to that by ET-3 (0.5 pmol/paw) alone (65.4 ± 10.9 %), whereas neither ET-1 nor ET-3 in the presence of BQ-788 showed inhibitory activity. BQ-3020 (0.5 pmol/paw) inhibited the oedema by 50.9 ± 6.0 %, whereas IRL-1620 showed almost no activity. Additionally, L-NAME markedly attenuated the inhibitory effects of ET-3 on PAF-induced paw oedema. These results indicate that ETB2 may mediate NO production and attenuation of PAF-induced inflammatory responses. Moreover, ET-3 (0.5 pmol/paw) inhibited the oedema induced by ET-1 at higher dose and zymosan by 76.6 ± 11.0 and 85.4 ± 13.6 %, respectively, indicating that ET-3 at lower concentrations inhibits the paw oedema induced by various inflammatory substances. ET-3 at low concentrations may attenuate inflammatory responses via ETB2 activation and NO production.

Antiinflammatory and antiallodynic actions of the lignan niranthin isolated from Phyllanthus amarus: Evidence for interaction with platelet activating factor receptor

Previous studies have shown that the extracts obtained from Phyllanthus amarus, and some of the lignans isolated from it, exhibit pronounced antiinflammatory properties. In the present study, we have assessed whether the antiinflammatory actions of these lignans can be mediated by interaction with platelet activating factor (PAF) receptor or interference with the action of this lipid. The local administration of nirtetralin, phyltetralin or niranthin (30 nmol/paw), similar to WEB2170 (a PAF receptor antagonist, 30 nmol/paw), significantly inhibited PAF-induced paw oedema formation in mice. The extracts of P. amarus (100 μg/ml) and niranthin (30 μM), but not nirtetralin or phyltetralin (30 μM), decreased the specific binding of [ 3H]-PAF in mouse cerebral cortex membranes. Furthermore, both niranthin and WEB2170 displaced, in a concentration-dependent manner, the [ 3H]-PAF binding sites. The mean IC 50 values from these effects were 6.5 μM and 0.3 μM, respectively. Additionally, both niranthin and WEB2170 (30 nmol/paw) inhibited the increase of myeloperoxidase activity induced by PAF injection in the mouse paw. When assessed the mouse model of pleurisy induced by PAF, pretreatment with niranthin (100 μmol/kg, p.o.) or WEB2170 (1.7 μmol/kg, i.p.) significantly inhibited PAF-induced protein extravasations. Moreover, in the rat model of PAF-induced allodynia, both niranthin (30 nmol/paw) and WEB2170 (30 nmol/paw) treatment significantly inhibited PAF-induced allodynia. In addition, niranthin had a rapid onset and long-lasting antiallodynic action when compared with WEB2170. Collectively, the present findings suggest that niranthin exhibits antiinflammatory and antiallodynic actions which are probably mediated through its direct antagonistic action on the PAF receptor binding sites.

Th-P17:426 Fluorescence lifetime imaging of unstained human atherosclerotic plaques

Angiotensin (Ang)—a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF.

Action of Pluchea indica methanol extract as a dual inhibitor on PAF-induced paw oedema and gastric damage

Action of Pluchea indica methanol extract as a dual inhibitor on PAF-induced paw oedema and gastric damage

Action ofPluchea indica methanol extract as a dual inhibitor on PAF-induced paw oedema and gastric damage

The effect of the methanol fraction of Pluchea indica (P. indica) and certain standard drugs were evaluated on platelet activation factor (PAF)-induced inflammation, gastric necrosis, ulceration and haematological picture. Administration of PAF (i.v.) for 20 min produced significant alteration in haematological profiles, considerable inflammation, severe gastric mucosal vasocongestion, necrosis and ulceration. Pretreatment with either P. indica and certain standard drugs significantly inhibited inflammation and incidences of lowered gastric damage.

A rat seminal vesicle protein, sv iv reduces paf-induced bronchial and vascular effects

Angiotensin (Ang)—a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF.