Role of eicosanoids in PAF‐induced increases of the vascular permeability in rat airways

1 We have used 125I-labelled fibrinogen (I-FN) in experiments monitoring plasma extravasation from vessels within guinea-pig trachea and peripheral lung tissue in response to platelet activating factor (PAF) and bradykinin (BK). Retained tissue radioactivity derived from I-FN was detected by direct measurement and by autoradiography. 2 Both PAF and BK caused concentration-dependent increases in radioactivity in trachea and peripheral lung, with PAF being approximately 1000 times more potent than BK at both sites. On a wet weight basis, mean tracheal leakage responses to PAF and BK were approximately 6 times and 2 times greater respectively than those in peripheral lung. Furthermore, in trachea, the maximal response to PAF was nearly twice that to BK, although they were approximately equiactive in peripheral lung. Autoradiograms showed that both agonists caused increases in peripheral bronchial circulation microvascular permeability to I-FN. No evidence for leakage in alveolar wall capillaries or in pulmonary blood vessels was observed. Quantitation of such autoradiographic data will allow a comprehensive evaluation of the effects of putative asthma mediators on microvascular permeability throughout the respiratory tree.

Section: Discussionsupporting

confidence: 80%

Quantitative assessment of increased airway microvascular permeability to ¹²⁵I‐labelled plasma fibrinogen induced by platelet activating factor and bradykinin

Pedersen

Rigby

Goldie

1991

“…Furthermore, when higher doses of endothelin-1 (1 nmol kg-') and PAF (1.9 nmol kg-l) were injected simultaneously, markedly increased protein extravasation was detected in the airways, pancreas, duodenum and stomach. Interestingly, combined administration of endothelin-1 plus PAF evoked a significant increase in protein extravasation in the pulmonary parenchyma, where the classical inflammatory mediators fail to produce changes in macromolecular permeability (Maron, 1982;Grega et al, 1986;Sirois et al, 1990). The permeability effect of endothelin-1 was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Effects of endothelin‐1 on vascular permeability in the conscious rat: interactions with platelet‐activating factor

Filep¹,

Sirois

Rousseau

et al. 1991

106

The objectives of the present experiments were to assess the effects of endothelin‐1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet‐activating factor (PAF) in vascular responses to endothelin‐1 and to examine the vascular effects of combined administration of endothelin‐1 and PAF in conscious rats. Intravenous bolus injection of endothelin‐1 (0.1–2 nmol kg−1) resulted in a dose‐dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose‐dependent increase in haematocrit values. Endothelin‐1 (0.1 and 1 nmol kg−1) increased dose‐dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin‐1 treatment. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg−1, i.v.) or BN 52021 (10 mg kg−1, i.v.) reduced the endothelin‐1 (1 nmol kg−1)‐induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin‐1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin‐1. When low doses of endothelin‐1 (0.1 nmol kg−1) and PAF (0.19 nmol kg−1) were administered simultaneously, enhanced protein extravasation was detected in the upper and lower bronchi, whereas neither endothelin‐1 nor PAF by themselves affected vascular permeability in these tissues. These changes occurred in the absence of significant changes in MABP. Combined administration of higher doses of endothelin‐1 (1 nmol kg−1) and PAF (1.9 nmol kg−1) resulted in marked increases (up to 530%) in protein extravasation in the airways, pancreas, stomach and duodenum. The effect of endothelin‐1 on permeability was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney. Combined injection of endothelin‐1 and PAF resulted in a slight, but significant increase in MABP. The present findings show that endothelin‐1 is capable of increasing vascular permeability in selected vascular beds including the airways, gastrointestinal tract and kidney, and suggest that PAF may mediate, in part, its action on permeability, but not its hypotensive action. The present data also suggest that endothelin‐1 and PAF can act in concert to increase vascular permeability in rat airways and gastrointestinal tract.

“…Thus, in rats, the vascular reactivity of the pulmonary vessels to complement activation contrasted with the sensitivity of the systemic vessels. Recently, Sirois et al (1990) reported that PAF increased vascular permeability in rat trachea and bronchi, as in other systemic vessels, but not in rat lungs. Our results agree with this observation.…”

Section: Discussionmentioning

confidence: 99%

Dissociation between the effects of zymosan on the systemic and pulmonary vessels of the rat

Damas

Lagneaux

1991

1 Zymosan, an activator of the alternative complement pathway, (2 to 16mgkg-1) injected intravenously via the tail vein of anaesthetized rats, dose-dependently increased the vascular permeability of lung parenchyma, as measured by the accumulation of 1251-labelled albumin in lungs. 2 Pretreatment of the animals with cyclo-oxygenase inhibitors, indomethacin or ketoprofen (3 mg kg 1) or with the lipoxygenase and cyclo-oxygenase inhibitor, BW755C (40mgkg-') abolished the vascular permeability changes induced by zymosan (16mg kg-1). Neither, the PAF antagonist, WEB 2086 (10mg kg-1) nor the antagonists of mast cell amines, mepyramine and methysergide (3mg kg-) affected the plasma exudation in lungs. Zymosan did not induce any accumulation of labelled albumin in lungs of rats made leucopenic by rabbit anti-neutrophil serum. 3 Zymosan (16mgkg-1) increased the haematocrit. This increase was not modified by indomethacin but reduced by WEB 2086. 3 Intravenous injection of zymosan (3 and 8 mgkg ')in anaesthetized rats transiently increased right ventricular blood pressure and pulmonary arterial pressure, accelerated respiratory rate and decreased systemic blood pressure. 5 WEB 2086 largely reduced the systemic hypotension but did not affect the increase of pulmonary vascular resistance. Indomethacin inhibited the increase of blood pressure in the right ventricle and the modification of the respiratory rate. This drug did not inhibit but increased the systemic hypotension induced by zymosan. 6 Zymosan (16mg kg-) reduced serum complement haemolytic activity by 46%. 7 These data suggest that the pulmonary vascular changes induced by intravascular complement activation with zymosan in rats are mediated by neutrophils and prostanoids while the systemic vascular effects depend mainly on PAF.