Problemas de Cobertura y Sostenibilidad

The endothelium is a continuous layer of squamous ^ithelial cells. Post-capillary venules have the loosest functional organisation of the entire vascular system and a peculiar sensitivity to vasoactive substances. Changes in permeability are thou^t to result from ultrastructural reorganization of the inter-endothelial junctional region (Hulstrom & Svenjo, 1979) vhich increase the permeability to large molecules with little change in the permeability for small molecules (Curry & Michel, 1980). This change in gap junctions is thou^t to be the result of endothelial cell contraction (Majno et al, 1969). Three types of contractile fibres have been found within endothelial cells (Drenckhahn & Wagner, 1986). Sub-plasmalemmal and junctional webs of actin filaments are present in virtually all endothelial cells, but only the endothelial cells lining arterioles and vein valves contain the so-called stress fibres. The shape change of endothelial cells has been attributed to contraction of the actin-iryosin complexes (Northover, 1988).

In this context it is of interest that contracted endothelicil cells have been observed by electron microscopy in post-capillary venules of guinea pig lungs after ovalbumin anaphylaxis (I^an & Ryan, 1984). Furthermore, in vitro studies have recently demonstrated that PAF elicits reorganization of the microfilaments and causes the endothelial cells to loose intimai contact with each other (Bussolino et al, 1986) and induces marked changes in endothelial cell shape both in culture (Grigorian & I^^an, 1987) and in intact guinea pig vessels (Northover, 1989). PAF antagonists have been shown to inhibit

the changes induced ky PAF in cultured endothelial cell cytoskeletal structure (Bussolino et al, 1987) and the shape change in intact vessels (Northover, 1989).

In addition to changes in gap junctions, protein leakage across the vessel wall will be determined by blood supply, the hydrostatic pressure gradient across the vessel wall [so that vasodilators will enhance leakage (Williams & Morley, 1973) ] and will vary with cell accumulation, determined by chemical stimuli in the small venules.

In vivo, in experimMTtal aninals, PAF has been shown to induce increased vascular permeability, as revealed by extravasation of vital dye or radiolabelled pleisma protein, in a number of tissues. Ihe findings in the skin and bronchial circulation will be outlined as they are of relevance to the potential role of PAF in allergic inflammation. Ihe discussion is confined to the guinea pig, althou^ similar data has been accumulated in the ral±>it, rat and in primates. Changes have also been dDserved in the pulmonary circulation (Heffner et al, 1983) and the hamster cheek pouch (Bjork et al, 1983).

PAF has been shewn to cause plasma protein extravasation in guinea pig skin (Stimler et al, 1981; Paul & Page, 1983) in a dose related manner. Ihe response is complete within 15 to 30 minutes except with h i ^ doses vhere extravasation persists for 90 minutes (Morley et al, 1983). Ihe response is associated with platelet accumulation (Paul & Page, 1983) but the weal induced by PAF is platelet independent, since the response is not abrogated by anti-platelet antisera in guinea pigs (Paul et al, 1984) and occurs

in rat skin, a species vAiere platelets lack PAF receptors (Pirotzky et al, 1984). Furthermore, agents such as prostacyclin or stable analogues of prostacyclin such as ZK36374 (Ilcprost) potentiate PAF induced extravasation Wiilst inhibiting platelet function (Archer et al, 1984a). Ihe plasma protein extravasation response is also enhanced by vasodilator prostaglandins and verapamil, althou^ these drugs concomitantly reduce platelet accumulation (Morley et al, 1983; Paul et al, 1984). Pretreatment with antagonists, 5-HT antagonists, cyclo-oxygenase inhibitors and cytotoxic drugs vhich deplete neutrc^hils fail to modify the response, suggesting a direct effect of PAF on the vascular endothelium (Archer et al, 1985a; Fjellner & Hagermarker, 1985; Sciberras et al, 1987).

Ihe PPE response is inhibited by PAF antagonists (Hwang et al, 1985), beta agonists and alpha agonists (Morley et al, 1983) and by h^jarin

(Paul et al, 1984).

Ihese observations are consistent with the interpretation that PAF acts directly at the level of the vascular endothelium to cause increased vessel wall permeability. Ihe inference that PAF produces dysfunction of endothelial cells has been confirmed by transmission electron microsccpy vhich demonstrates such separation associated with passage of colloidal carbon particles across the endothelial lining of post capillary venules at sites of intradermal PAF administration (Dewar et al, 1984).

PAF also induces PPE in the bronchial circulation of the guinea pig (Evans et al, 1987; O'Donnell & Barnett, 1987). Ihe response is dose related, maximal 5 minutes after i.v. injection of PAF, and

independent of platelets as demonstrated by ej^)eriments with anti-platelet antisera (Evans et clL, 1987). Ihe response is unaltered by HI antagonists and inhibitors of cyclooxygenase and lipoxygenase (Evans et eil, 1987) but can be inhibited by PAF antagonists (Evans et al, 1987; Evans et al, 1988) and adrenaline (Boschetto et al, 1989).

PAF (8 nmol) siperfused onto guinea pig tracheal mucosa in vivo produced both an acute (Persson & Erjefalt, 1986) and a late phase vascular leakiness 5 hours after provocation (Persson et al, 1987) vhich has not as yet been reported with any other mediator.

In human skin, the intradermal injection of PAF also induces increased vascular permeability. Nanogram doses of PAF produce a weal and hence PAF may be assumed to induce increased vascular permeability of dermal vessels (Pinckard et al, 1980; Basran et al,

1983, 1984; Dewar et al, 1984; Archer et al, 1984a & b; 1985a; Henocq and Vargaftig, 1986; Chung et al, 1987; Michel et al, 1987; Sciberras et al, 1987, 1991). Certainly, histological examination of biopsied tissues removed at the time of the weal and flare response reveals stasis of dermal capillaries, together with ej^jansion of interstitied spaces, vhich are characteristic of oedema (Archer et al, 1985b).

Ihe weal induced by PAF is enhanced by vasodilator prostaglandins (Archer et al, 1984a), but unaffected by prednisolone or cyclooxygenase inhibitors (Pinckard et al, 1980; Archer et al, 1985a). However, PAF induced weal responses can be inhibited by PAF antagonists (Chung et al, 1987) and by the HI antagonists, azelastine (Lai et al, 1991), ketotifen (Chung et al, 1988) and terfenadine (Scibberas et al, 1991) but not by chlorpheniramine (Archer et al, 1985a).