Platelet-Activating Factor Raises Airway and Vascular Pressures and Induces Edema in Lungs Perfused with Platelet-Free Solution^1–3

Abstract

The effects of synthetic platelet-activating factor (PAF) on guinea pig lung were examined in isolated lungs perfused with platelet-free Krebs-Ringer solution. When PAF (1 microgram) was injected into the pulmonary artery (PA), it markedly increased airway pressure (maximal increase, 84.7%) and moderately raised PA pressure (maximal increase, 22.8%). The same dose also provoked a massive (29-fold) release of thromboxane B2 (TXB2), the stable metabolite of TXA2, into the perfusate, beginning before the increases in airway and PA pressures. The concentration of 6 keto-PGF1 alpha, the stable metabolite of prostacyclin, also increased (to 5 times control levels) about 70 s after peak release of TXB2. Indomethacin completely blocked TXB2 release, reduced the magnitude of airway pressure increase by 79%, and shortened its duration, as well as the duration of the PA pressure rise. Larger concentrations of PAF (3 and 10 micrograms) produced even greater increments in airway and PA pressures, but these were only moderately attenuated by indomethacin. Also, PAF increased extravascular lung water, as evidenced by increases in wet/dry lung weight and lung/body weight ratios. In a concentration of 0.1 microgram, PAF had no effects on airway or PA pressures, nor did it stimulate TXB2 or 6-keto-PGF1 alpha release. Lyso-PAF was similarly ineffective. We conclude that PAF induces airway constriction, pulmonary hypertension, and pulmonary edema in guinea pig lung independently of platelets. These effects are associated with stimulated synthesis of TXA2, but the mechanisms of their production remain to be determined.

Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

“…Previously ET-1 has been shown to be able to induce prostanoid, including TXA2 release from perfused guinea-pig lungs (De Nucci et al, 1988). Since the myotropic action of ET-1 can be attenuated by sulphidopeptide leukotriene and PAF receptor antagonists, and the contractile activity of these mediators in the guinea-pig lung is thought to depend on TXA2 formation (Engineer et al, 1978;Piper & Samhoun, 1981;Ueno et al, 1982;Hamasaki et al, 1984;Lefort et al, 1984;Chung et al, 1986;Jancar et at., 1989), i is reasonable to assume that the enhanced TXA2 formation in response to ET-1 might be, in part, a consequence of increased synthesis of PAF and sulphidopeptide leukotrienes. Indeed, preincubation of the parenchymal strips with the PAF receptor antagonists, BN 52021 and WEB 2086 or with FPL 55712 significantly diminished TXA2 release following addition of ET-1.…”

Mechanism of action of platelet activating factor in the pulmonary circulation: an investigation using a novel isotopic system in rabbit isolated lung

“…PAF causes pulmonary endothelial damage (Lewis et al, 1983;McManus & Pinckard, 1985), pulmonary oedema and vasoconstriction (Heffner et al, 1983;Hamasaki et al, 1984;Burhop et al, 1986;Christman et al, 1988), increased airway resistance and decreased lung compliance (Halonen et al, 1980;1981;Christman et al, 1988). Furthermore, PAF has been demonstrated to cause epithelial cell damage and an influx of inflammatory cells into airways and alveoli (Camussi et al, 1983a;Arnoux et al, 1988;Coyle et al, 1988;Lellouch-Tubiana et al, 1988;Sanjar et al, 1990).…”

“…For example, it is unclear whether oedema formation is due to a change in endothelial cell permeability or whether it is merely a consequence of increased hydrostatic pressure secondary to vasoconstriction (Heffner et al, 1983;Hamasaki et al, 1984;Burhop et al, 1986;Christman et al, 1988;Imai et al, 1988). To investigate the effects of PAF and other inflammatory mediators in the lung under constant flow conditions, we have developed a novel model using in vitro lung perfusion.…”

Effect of PAF on rat lung vascular permeability: role of platelets and polymorphonuclear leucocytes

“…Heffner et al (1983) showed that the perfusion of PAF together with platelets in isolated perfused lung in vitro caused an acute pulmonary hypertension and oedema which was attributed to TxA2 released from platelets. Hamasaki et al (1984) observed the same phenomenon in lungs perfused with a platelet-free solution and suggested that vascular permeability was not related to TxA2 synthesis. Bolin et al (1987) obtained similar increases of arterial pulmonary pressure following PAF treatment and 6" Macmillan Press Ltd, 1994 showed that platelets potentiated this phenomenon.…”