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"Dwr B Vol L p p 74-'98. 1'47"

Pergamon Press

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A N A P H Y L A X I S AND THE R E L E A S E OF ACTIVE SUBSTANCES IN THE LUNGS PRISCILLA J. PIPER Department of Pharmacology, Royal College of Surgeons of England, Lincoln's Inn Fields, London, W.C.2.

1. INTRODUCTION The tissues in which anaphylaxis occurs vary between mammalian species but in this discussion of mediators released in anaphylaxis only the release during anaphylaxis in the lungs will be considered. Obviously it is of prime importance to know what mediators are released during anaphylaxis in human lung, what changes they produce in the circulation and other tissues and how these effects may be modified by drugs, but the limitations of experimental work in human subjects makes it necessary to study anaphylaxis, its effects and their modification in animal 'models'. Biologically active mediators may be released from the lung by various stimuli which may be immunological, mechanical or pathological (Piper and Vane, 1971). Therefore, anaphylaxis is only one of several types of stimuli which cause release of mediators from lung tissue. Since some of the mediators are released by all stimuli, perhaps there is a mechanism of release which is common to the various stimuli. When mediators are released in the lung, theoretically they may enter the pulmonary circulation, pass into the systemic circulation and could then act on other organs in the body. In addition to enzymes which control the synthesis of biologically active substances, the lung also contains efficient enzyme systems which inactivate some substances passing through the pulmonary circulation thus preventing them from reaching the systemic circulation (Vane, 1969). Whether or not some anaphylactic mediators are inactivated is not yet certain but will be discussed later. Changes in the lung occur during anaphylactic shock in some species but not all. In man and guinea pig the lung seems to be the major 'shock' organ and source of mediators; in mouse, cat, monkey, rat and calf biologically active substances may also be released from the lung although the lung is not the main target organ of anaphylaxis. Release of mediators from guinea pig lung during anaphylactic shock and the effects of drugs on this release have been very actively studied in the hope that the results might be relevant to anaphylaxis or to asthma in man but there are important differences in the mechanisms of anaphylaxis in guinea pig and human lung. For instance, the antibody in guinea pig is IgG, but it is IgE in man, and the relative sensitivity of bronchial smooth muscle to anaphylactic mediators differs between the two species. Anaphylactic shock which occurs immediately after the injection of antigen is a type I reaction involving the release of pharmacologically active substances from sensiti~.ed tissue cells (Gell and Coombs classification). The anaphylactic reactions to drugs such as penicillin are type III reactions and will not be discussed here. 2. MEDIATORS R E L E A S E D FROM LUNG 2.1. GUINEA PIG LUNG The signs of anaphylactic shock in the guinea pig are laboured breathing ('dyspnea'), sneezing, coughing, acceleration of respiration and heart rate, collapse and convulsions possibly followed by death. Guinea pigs have more airway smooth muscle than other species (Miller, 1947) and the smooth muscle fibers of the trachea and bronchi are attached to the inner surface of the cartilage (Sanyal and West, 1958). Contraction of 75

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these fibers in anaphylaxis may produce folding of the thick bronchial mucosa (Schultz and Jordan, 1911) resulting in airway obstruction in such a way that air can be forced into the lungs but cannot be expelled again (Dale, 1920). When the chest is opened post mortem the lungs are relatively bloodless, fully inflated and do not collapse (Auer and Lewis, 1910). Hypotension usually occurs in anaphylaxis but sometimes a rise in blood pressure accompanies anaphylactic bronchoconstriction and may be the result of hypoxia caused by bronchoconstriction (Auer and Lewis. 1910) and/or the action of one or more of the mediators released. 2.1.1. Histamine

Dale and Laidlaw (1910) described the similarity between anaphylaxis in the guinea pig and the effect of injected histamine, and Dale (1929) suggested that the release of histamine was responsible for the effects of anaphylaxis in the guinea pig. The importance of histamine was confirmed when Watanabe (1931) showed that the histamine content of guinea pig lung was reduced after anaphylaxis, and Bartosch et al. (1933) demonstrated the release of histamine during anaphylaxis in isolated perfused lungs in vitro. An increase in histamine and fall in histaminase levels in blood also occur during anaphylactic shock in the guinea pig in vivo (Code, 1937; Eilbeck and Smith, 1967). Guinea pig lung has numerous mast cells embedded between the smooth muscle cells of the bronchi and during anaphylaxis histamine is released from the granules of these mast cells (Mota and Vugman, 1956). Following administration of antigen to a sensitized guinea pig in vivo or isolated lungs in vitro, the release of histamine is short-lasting and appears within 30 sec of antigen challenge, reaches a maximum in 2 min and very little histamine is released after 30 min (Brocklehurst, 1960; Collier and James, 1967) (Fig. 1). 10 mPn I-

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FI(;. I. Release of mediators from isolated lungs of sensitized guineu pig. A ~trip of cat terminal ileum (CTI), a strip of rabbit aorta (RbA), a chick rectum (CR), a strip of guinea pig trachea (GPT), a rat s t o m a c h strip (RSS) and a rat colon (RC) were s u p e r f u s e d with the effluent from sensitized guinea pig isolated perfused lungs. All tissues except CTI were treated with combined a n t a g o n i s t s to histamine, acetylcholine, 5-HT and catecholamines. H i s t a m i n e (2 and 1 /~g/ml DIR) and PGE2 (E~, 50 ng/ml DIR) infused directly to the a s s a y tissues d e m o n s t r a t e d the selective sensitivity of the a s s a y s y s t e m . A n a p h y l a x i s in the lungs was induced by intra-arterial injection of o v a l b u m e n (EA 10 mg i.a.). Contractions of CTI d e m o n s t r a t e d release of histamine, RbA release of RCS, G P T release of SRS-A and CR, RSS and RC release of PGs. Time 10 min; vertical scale 5 cm. R e p r o d u c e d by Vane ( 197 la).

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Histamine is stored in the granules of mast cells in a complex with protein and heparin (Uvnas, 1974). So far the amine storage and release mechanism have only been studied in rat peritoneal mast cells, but mast cells from other species contain heparin and it seems possible that these cells store and release histamine in a similar way (Uvnas, 1974). Histamine release in response to antigen challenge is calciumdependent, requires an intact glycolytic pathway and involves the action of a serine esterase which is sensitive to di-isopropylfluorophosphate (DFP) (Schild, 1937, 1968; Mongar and Schild, 1958; Orange et al., 1971a). 2.1.2. Slow-Reacting Substance of Anaphylaxis With anaphylaxis in guinea pig isolated perfused lungs, Kellaway and Trethewie (1940) observed the release of another mediator (besides histamine) which caused slow, long-lasting contraction of guinea pig ileum. This 'other' mediator they called slow-reacting substance of anaphylaxis (SRS-A). Brocklehurst (1960) characterized the actions of SRS-A and showed that in the presence of atropine and mepyramine it caused slow contraction of guinea pig ileum. SRS-A appears in the effluent fluid from guinea pig isolated perfused lungs 30 sec after antigen challenge, reaches a maximum concentration after 4 min but is still released in appreciable amounts after 30 rain (Brocklehurst, 1960, 1970). SRS-A is also released into the circulation during anaphylaxis in guinea pig in vivo caused by intravenous administration of antigen (Collier and James, 1967; Stechschulte et al., 1973). The exact chemical structure of SRS-A has proved very difficult to elucidate and is still unknown. Brocklehurst (1968) described SRS-A as an acidic substance which is probably not a true lipid but which forms a loose association with lipid, protein and other molecules such as lecithin and becomes very unstable when these are removed. SRS-A has been distinguished from bradykinin, prostaglandin F2o, histamine, acetylcholine, 5-hydroxytryptamine, substance P a n d angiotensin (Berry and Collier, 1964) and also from neuraminic acid (,~ngg~rd et al., 1963). Austen, Orange and co-workers, working with SRS-A from rat peritoneal cavity and human lung, which shows no demonstrable difference from guinea pig SRS-A, have made valuable progress in purifying and identifying this substance. The release of SRS-A differs from that of histamine in that there are both biosynthetic and secretory stages involved in the release of SRS-A (Orange, 1974) whereas histamine is released from a preformed store. SRS-A appears to be formed and released by enzymic processes activated by union of antigen and antibody (Brocklehurst, 1970). SRS-A seems to be an unsaturated, acidic substance of low molecular weight (approx. 500) (Orange et al., 1973). It contains both hydroxyl and carboxylic acid groups and is biologically active at doses of less than a nanogram (Orange, 1974). Orange et al., (1974) have found that two preparations of arylsulphatase destroyed its activity and therefore concluded that SRS-A is a sulphate ester. The presence of a sulphate moiety in a substance reduces its volatility and prevents analysis by mass spectrometry, but analysis of a highly purified sample of SRS-A by spark-source mass spectrometry and electron probe showed the presence of sulfur in SRS-A (Orange et al., 1974). This observation was confirmed by Dawson et al. (1975) who administered radioactively labeled sulfur to sensitized guinea pigs and recovered the radioactivity in SRS-A prepared from their lungs after antigen challenge. The release of SRS-A from guinea pig and human lung is accompanied by an output of prostaglandins of the E and F series (Piper and Vane, 1969a; Piper and Walker, 1973), but Dawson and Tomlinson (1974) have shown that SRS-A and prostaglandins do not arise from a common precursor. The substrate giving rise to SRS-A is at present unknown. 2.1.3. Prostaglandins

When isolated lungs from sensitized guinea pigs are challenged in vitro, prostaglandins E2 and F2o are released and can be detected in the effluent fluid from the lungs (Piper and Vane, 1969a,b). Prostaglandin synthetase from sensitized guinea pig

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lungs is also able to synthesize prostaglandin D,. but this has not yet been detected in lung effluent fluid (Benzie et al., 1975). In addition to the parent prostaglandins (Math6 and Levine, 1973), Dawson and Tomlinson (1974) and Liebig et al. (1974) have detected the release of the prostaglandin metabolites 13,14-dihydro-15-keto-PGE., and 13,14,dihydro-PGF,~ during anaphylaxis in guinea pig isolated perfused lungs. The release of prostaglandins during anaphylaxis in oivo has not yet been directly demonstrated, but Collier and James (1967) found that aspirin-like drugs (inhibitors of prostaglandin synthetase) partially antagonized anaphylactic bronchoconstrictions in guinea pigs in vivo which strongly indicates the involvement of prostaglandins, and Strandberg and Hamberg (1974) have shown that output of urinary metabolites of prostaglandins almost doubled following anaphylactic shock. Prostaglandins of the E and F series are synthesized from arachidonic acid by the action of prostaglandin synthetase found in the lung (Angg/lrd and Samuelsson, 1965). Arachidonic acid is incorporated in phospholipids of the cell membrane and may be freed by the action of phospholipases and made available to prostaglandin synthetase (Kunze and Vogt, 1971). Prostaglandins are not stored in a preformed state in tissues and therefore release of these substances represents fresh synthesis (Piper and Vane. 1971 ). Benzie et al. (1975) have shown that lungs from sensitized guinea pigs contain more prostaglandin synthetase than lungs from control animals. Prostaglandins are released from lung tissue by a variety of stimuli which include anaphylaxis, injection or infusion of chemical substances and mild damage or distortion of cells caused by, e.g., embolism (Piper and Vane, 1971). These stimuli must therefore activate prostaglandin synthetase and make the substrate available to the enzyme perhaps by the action of phospholipase A (Kunze and Vogt, 1971). Whether prostaglandins are synthesized by a specific type of cell or by cells generally is not known. However, during challenge of peritoneal mast cells from sensitized rats a small amount of prostaglandin-like material was released in addition to histamine (Piper, unpublished) suggesting that perhaps mast cells in the lung may be a source of prostaglandins in anaphylaxis. Since prostaglandins are released by distortion of cells, Piper and Walker (1973) suggested that during anaphylaxis prostaglandins might be released from contracting bronchial smooth muscle. Evidence for this was found by Orehek et al. (1973) and Grodzinska et al. (1975) who showed release of prostaglandins during anaphylactic contraction of isolated trachea from a sensitized guinea pig and also when guinea pig trachea was contracted by histamine or acetylcholine. There is some evidence to suggest that prostaglandins may not be primary mediators of anaphylaxis. Prostaglandins are released from perfused lungs by other mediators of anaphylaxis such as histamine and SRS-A (Piper and Vane, 1969b; Palmer et al. 1973) and contraction of guinea pig isolated trachea by histamine causes a release of prostaglandin (Orehek et al., 1973; Grodzinska et al., 1975). This could indicate that the release of prostaglandins is secondary to that of the primary mediators, histamine and SRS-A. 2.1.4. R a b b i t A o r t a Contracting S u b s t a n c e ( R C S ) The release of prostaglandins during anaphylaxis in guinea pig perfused lungs was detected by immediate continuous bioassay of the effluent fluid (Piper and Vane, 1969a). However, subsequent ethyl acetate extraction followed by identification and quantification of prostaglandins by thin-layer chromatography showed that not all of the prostaglandin-like activity on the assay tissues was caused by prostaglandins. The non-extractable activity was due to an unstable substance with a half-life of 1-2 rain in Krebs solution and characterized only by the fact that it strongly contracted isolated strips of rabbit aorta in the presence of antagonists to histamine, acetyicholine, 5-HT and catecholamines; this substance was named rabbit aorta contracting substance (RCS) (Piper and Vane, 1969a,b; Palmer et al., 1973). The release of RCS has also been demonstrated during anaphylactic shock in anesthetized guinea pigs in vivo (Palmer et al., 1973).

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RCS is always released together with prostaglandins, and its release (and also that of prostaglandins) is blocked by non-steroid anti-inflammatory drugs such as aspirin or indomethacin (Piper and Vane, 1969b; Vane, 1971b). RCS is therefore a product of the prostaglandin synthetase system. Gryglewski and Vane (1972) produced RCS from dog spleen and showed that as the concentration of RCS declined that of prostaglandin increased, suggesting that RCS might be a precursor of prostaglandins. In fact, there are certain similarities between the biological actions of prostaglandins G2 and H2 (the cyclic endoperoxide precursors of prostaglandins E2 and F2,) and RCS, but their half-lives are different (Hamberg and Samueisson, 1973). Recently Hambert et al., (1975) have identified RCS produced by aggregation of platelets as a mixture of prostaglandin endoperoxides and thromboxane A2 so that at least part of RCS is a prostaglandin precursor. RCS is released by all the chemical and mechanical stimuli which release prostaglandins from guinea pig lung (Palmer et al., 1973), such as infusion of bradykinin and embolism. 2.l.5. Rabbit Aorta Contracting Substance Releasing Factor ( R C S - R F ) In addition to RCS, a stable substance is released during anaphylactic shock in guinea pig isolated perfused lungs which, when infused into nonsensitized lungs causes a release of RCS and prostaglandins but not histamine; this substance is known as rabbit aorta contracting substance releasing factor (RCS-RF). RCS-RF is stable to both freezing and boiling and is nondialyzable (Piper and Vane, 1969b). The release of RCS-RF is not inhibited by aspirin or indomethacin so it is unlikely to be a product of prostaglandin synthetase (Palmer et al., 1973). 2.1.6. Kinins

Brocklehurst and Lahiri (1962, 1963) demonstrated the release of bradykinin into the circulation of the guinea pig during anaphylactic shock by showing that kininogen levels in the blood fell during anaphylaxis. Collier and James (1967) showed that anaphylactic bronchoconstriction was lessened by making guinea pigs tachyphylactic to bradykinin before challenge and therefore indirectly confirmed the release of bradykinin during anaphylaxis. In 1966 Jonasson and Becker showed the release of kallikrein from guinea pig isolated perfused lungs during anaphylaxis but, in the absence of blood and therefore substrate, no release of bradykinin could be detected (Piper and Vane, 1969b). 2.1.7. Eosinophil Chemotactic Factor in Anaphylaxis ( E C F - A )

In addition to histamine and SRS-A a factor specifically chemotactic for guinea pig eosinophil leucocytes (ECF-A) is released during anaphylactic shock in either guinea pig isolated perfused lungs or chopped lung tissue from actively or passively sensitized animals (Kay et al., 1971). The releases of ECF-A and SRS-A follow a similar time-course and bear a similar response to dose of antigen given. 2.2. HUMAN LUNG The signs of anaphylaxis in man include acute respiratory distress, asphyxia, angioneurotic edema, severe hypotension and vascular collapse possibly leading to death. The respiratory distress may result from upper airway obstruction by laryngeal edema or severe bronchospasm (Sheffer, 1973). Post mortem examination of humans dying in anaphylactic shock shows changes in the lungs comparable with those seen in guinea pig, i.e. hyperinflation with alternating areas of emphysema and collapse (Layton and Cameron, 1971). Similar changes are seen in patients dying of status asthmaticus. Although systemic anaphylaxis in man and bronchial asthma are both type I reactions and there are similar pathological changes in the lungs in both conditions, the main difference seems to be that asthma is usually a localized reaction in the lungs. Both conditions may be partly explained in terms of mediators released by

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antigen-antibody reactions but it is important to realize that asthma is not synonymous with anaphylaxis in either man or animals although there are similarities between the two conditions, including involvement of the same mediators, which merit consideration. 2.2.1. H i s t a m i n e The release of histamine from human asthmatic lung and bronchial tissue during challenge with specific antigen was demonstrated by Schild et al. (1951) and confirmed by Brocklehurst (1960) who perfused and challenged segments of lung from allergic patients and showed the release of both histamine and SRS-A. Sheard et al. (1967) passively sensitized human chopped lung tissue with reaginic serum and detected the release of histamine and SRS-A when this tissue was challenged. Histamine was also released from human chopped sensitized or unsensitized lung tissue by mild mechanical stimulation (Piper and Walker, 1973). 2.2.2. S R S - A The release of SRS-A from human lung was first demonstrated by Brocklehurst (1960) who challenged lung tissue from an allergic (actively sensitized) patient. Since then others have used fragments of passively sensitized human lung tissue to produce SRS-A (Parish, 1967; Sheard et al., 1967; Orange et al., 1971a,b). SRS-A appeared in the plasma of asthmatic children when the patients were provoked with specific antigen administered by aerosol. The maximum concentration of SRS-A occurred 20 min after provocation (Orange and Langer, 1973). Since the antigen was administered by aerosol, the SRS-A detected in the circulation must have originated from the lungs as a result of antigen-antibody interaction on the surface of sensitized target cells. SRS-A formed in human lung tissue has similar actions to guinea pig SRS-A but until a pure preparation of SRS-A is available it is not possible to say that SRS-A's from the two species are identical. 2.2.3. P r o s t a g l a n d i n s Piper and Walker (1973) detected the release of prostaglandins E,, E2 and F2~ during antigen challenge of passively sensitized human lung tissue. The release of prostaglandins was not related to antigen dose. Gentle agitation of human chopped lung tissue whether sensitized or not also caused release of prostaglandins (Piper and Walker, 1973). This result suggests that conditions of tissue damage such as pulmonary embolism may also cause prostaglandin release. Recently, Gr6en et al., (1974) found indirect evidence of the release of prostaglandins from human lung in vivo. They showed an increase of up to eight-fold in the prostaglandin metabolite 15-keto-13,14-dihydroprostaglandin F2~ in peripheral venous blood soon after an allergen-provoked attack of asthma in patients with type I asthma. Since prostaglandins of E and F series are metabolized by 90-95 per cent in the pulmonary circulation of cat, dog, rabbit and guinea pig, both in vivo and in vitro, and maybe also in man in vivo (Ferreira and Vane, 1967d; Piper et al., 1970; Crutchley and Piper, 1974, 1975a,b) this strongly suggested that at least prostaglandin F2~ was released from the lung during asthmatic attack. However, Smith and Dunlop (1975) treated atopic asthmatic patients with indomethacin (inhibitor of prostaglandin synthetase) before challenge and found no significant change in per cent fall of fast expired volume (FEV) during challenge, which indicates that prostaglandins were not playing an important role in the bronchoconstriction of asthma. Whether prostaglandins are primary mediators of anaphylaxis or asthma will be further discussed later. 2.2.4. R C S In contrast to anaphylaxis in the guinea pig, no detectable amount of RCS was released from passively sensitized human lung tissue when challenged. However, RCS

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was released together with prostaglandins during mechanical stimulation of the chopped tissue (Piper and Walker, 1973). 2.2.5. E C F - A When human lung tissue which has been passively sensitized with homologous IgE antibody is challenged with antigen, ECF-A is released in addition to histamine and SRS-A (Kay et al., 1971). ECF-A, like histamine, is stored preformed in human lung tissue, possibly in mast cell granules (Wasserman et al., 1974a). The molecular weight of ECF-A is approximately 500 and it appears to be acidic peptide (Austen, 1974). The release of ECF-A requires an intact glycolytic pathway, divalent cations and activation of a DFP-sensitive esterase and is modulated by cyclic nucleotides in the same way as the release of histamine and SRS-A (Wasserman et al., 1974b). 2.2.6. K i n i n s There is little evidence available on the release of kinins during human anaphylaxis since most investigations have been carried out on fragments of human lung tissue in vitro in the absence of substrate for kinin formation. However, Abe et al. (1967) reported that the blood level of bradykinin is raised in severe bronchial asthma which suggests that kinins might also be formed during anaphylaxis in vivo. 2.3.

MONKEY LUNG

The 'shock' organ appears to vary with species of monkey, but when rhesus monkeys which have been either passively sensitized with human reaginic sera or actively sensitized to ascaris are challenged the lungs are involved in the anaphylactic response (Patterson et al., 1965; Patterson and Talbot, 1969; Patterson et al., 1970). Antigen-antibody responses in the bronchial tree seem to be the cause of the respiratory symptoms of anaphylaxis in this species and the changes are similar to those seen in asthma in man and include increase in respiratory frequency, decrease in tidal volume, edema of the bronchial mucosa and bronchoconstriction (Patterson and Talbot, 1969). Brocklehurst (1960) showed the release of histamine and SRS-A in perfused lungs from rhesus monkeys sensitized to ovalbumen. When atopic human serum was used to passively sensitize monkey lung tissue, histamine and SRS-A were subsequently released during challenge of the tissue (Ishizaka et al., 1970) and these mediators are also released from mast cells from lung during challenge (Ishizaka et al., 1972). During anaphylactic shock in vivo increased blood levels of histamine were detected (Patterson et al., 1965). Other mediators besides histamine and SRS-A may be involved in anaphylaxis in monkey lung but this has not been closely investigated. Since administration of bradykinin or prostaglandin F2, by aerosol to monkeys did not cause bronchoconstriction, these mediators do not seem to be of prime importance in anaphylaxis in monkeys (Patterson and Talbot, 1972; Patterson and Kelly, 1973).

2.4.

BOVINE L U N G

Calves have been sensitized to horse serum (Eyre et al., 1973) and anaphylaxis elicited either in isolated perfused lungs in vitro or in the intact anesthetized animal in vivo. During acute anaphylaxis the calves undergo respiratory changes including apnea or labored breathing, initial bradycardia and then tachycardia. The release of SRS-A has been detected during anaphylaxis in isolated perfused lungs of calves (Burka and Eyre, 1974). Plasma histamine increased during anaphylaxis in vivo, and Eyre et al. (1973) suggested that anaphylaxis in vivo may be caused by interaction of histamine, SRS-A and 5-HT. There was also evidence that prostaglandins may be involved in bovine anaphylaxis since meclofenamate, a potent prostaglandin synthetase inhibitor (Flower and Vane, 1974), suppressed anaphylactic shock by 80 per cent (Eyre et al., 1973). Greatly increased levels of kinins have been demonstrated in whole blood during anaphylaxis in calves (Eyre and Lewis, 1972) but may not play an important role in JPTB. \ol 3. No I--F

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bovine anaphylaxis (Eyre et al., 1973). Vagotomy lessened the apnea of anaphylaxis in calves suggesting the involvement of vagal afferent nerves. 3. RELEASE OF C A T E C H O L A M I N E S Collier and James (1966) and Collier et al. (1967) showed that bronchoconstriction caused by anaphylaxis or bradykinin in the guinea pig was greatly potentiated by /3-adrenoreceptor blockade. This was indirect evidence that catecholamines were released in anaphylaxis. Piper et al. (1967) provided direct evidence of this by showing by immediate bioassay techniques that when sensitized guinea pigs were challenged by intravenous injection of antigen catecholamines, mainly epinephrine, were released into the circulation from the adrenal medulla. In nonsensitized anesthetized guinea pigs the mediators of anaphylaxis, histamine, SRS-A (partially purified) and bradykinin when given intravenously all caused bronchoconstriction and a release of catecholamines from the adrenal medulla (Piper et al., 1967). Although bradykinin released epinephrine from the adrenal glands when administered into the arch of the aorta, the release of catecholamines by histamine and SRS-A appears to be associated with the latter's ability to cause bronchoconstriction, possibly reflexly via hypoxia (Gray and Diamond, 1957). Antagonism of bronchoconstriction due to histamine, bradykinin or SRS-A by mepyramine or aspirin-like drugs also inhibited the release of catecholamines by these substances, although the release of epinephrine produced by anaphylaxis was unaffected (Piper, 1969). A similar release of catecholamines may occur in humans during bronchoconstriction since asthmatics are very sensitive to /3-adrenoreceptor blocking drugs which can cause intense bronchoconstriction (McNeill, 1964). 4. ACTIONS OF MEDIATORS 4.1 HISTAMINE Histamine directly stimulates the H, receptors in the smooth muscle of the bronchial tree (Black et al., 1972) and also has a non-vagal effect on lung compliance, presumably by constriction of terminal airways in guinea pig (Mills and Widdicombe, 1970). However, Collier (1970b) reported that histamine contracts smooth muscle in all parts of the bronchial tree. Histamine either given intravenously or released during anaphylaxis stimulates 'lung irritant receptors' in the bronchial epithelium which are thought to cause vagal reflex hyperpnea and bronchoconstriction (Mills et al., 1969). The action of histamine released in anaphylaxis in vivo seems to be partly direct and partly due to neural stimulation (Mills and Widdicombe, 1970). The direct chemical effect of histamine on airway smooth muscle is sufficient to also stimulate 'irritant receptors'. Histamine can also paradoxically relax the trachea by stimulation of adrenergic receptors (James, 1969). Histamine causes bronchoconstriction in man when given intravenously or by inhalation (Samter, 1933; Curry, 1946; Herxheimer, 1949). In man vagal reflexes are important in the respiratory and bronchomotor effects of histamine (Buohuys et al., 1960). However, it has been widely assumed that the effects of histamine in guinea pig in vivo are caused only by direct effects of histamine on bronchial smooth muscle (Collier and James, 1967). Pulmonary blood vessels contain both Ht and Hz receptors and histamine has a dual mode of action in this vascular bed (Okpako, 1972). In the pulmonary circulation of the guinea pig isolated perfused lungs histamine causes vasoconstriction and an increase in pulmonary arterial pressure by stimulation of H, receptors. This action is converted to vasodilatation after antagonism of H, receptors by mepyramine (Okpako, 1972; Goadby and Phillips, 1973; Turker, 1973). The vasodilation is mediated by H2 receptors and is inhibited by burimamide. Histamine also causes a release of catecholamines by direct action on the adrenal medulla and this together with a reflex release of catecholamines caused by hypoxia

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will have a pressor effect such that an initial hypotension may be followed by a secondary rise in blood pressure (Piper et al., 1967). Histamine causes an increase in vascular permeability in blood vessels and produces leaking venules attributed to partial disconnection of the endothelium (Majno, 1974). This may happen in small blood vessels in the lung which would contribute to the formation of edema during anaphylaxis. When histamine is injected into the pulmonary circulation of guinea pig isolated perfused lungs prostaglandins are released into the effluent fluid from the lungs (Palmer et al., 1973), so that histamine released during anaphylactic shock may in turn contribute to the release of prostaglandins. However, whether prostaglandins are released as a direct action of histamine or as a result of contraction of bronchial smooth muscle has yet to be determined. 4.2. SRS-A Berry and Collier (1964) showed that a charcoal-purified sample of SRS-A from guinea pig lung caused bronchoconstriction in the same species in vivo. However, more recent studies with highly purified rat SRS-A showed that intravenous administration to an unanesthetized guinea pig decreased pulmonary compliance without appreciable change in pulmonary resistance (Drazen et al., 1973). Charcoal-purified SRS-A also contracts smooth muscle from the trachea and bronchioles of guinea pig and man respectively (Berry and Collier, 1964; Collier and Shorley, 1963). Smooth muscle from human bronchioles is contracted by much lower concentrations of SRS-A than is bronchial smooth muscle from any other species (Brocklehurst, 1970). Herxheimer and Streseman (1963) found that when SRS-A prepared from guinea pig was given by aerosol to human asthmatics it caused bronchoconstriction. SRS-A causes prolonged contraction of smooth muscle, especially after a long contact time. This indicates either that SRS-A causes changes in smooth muscle or becomes firmly attached to the tissue and is not easily destroyed (Brocklehurst, 1970). When SRS-A is more highly purified the smooth muscle contractions become shorter-lasting. When SRS-A is given intra-arterially to an anesthetized guinea pig it causes slight lowering of the blood pressure (Piper, 1969). However, when given intravenously SRS-A has a pressor effect but this may be a reflex effect of the bronchoconstriction which occurs, since both the pressor and bronchoconstrictor effects are antagonized by treatment with aspirin-like drugs (Berry and Collier, 1964; Piper, 1969). Stechschulte et al. (1973) showed that SRS-A caused increased vascular permeability in guinea pig skin. If SRS-A released during anaphylaxis causes a similar increase in vascular permeability in the pulmonary circulation it would contribute to edema formation. SRS-A from bovine lung contracted bovine isolated pulmonary vein (Burka and Eyre, 1974) and this may also occur in other species. Piper and Vane (1969b) showed that SRS-A caused release of prostaglandins and RCS from guinea pig isolated perfused lungs but, as with histamine, this might possibly be a result of contraction of bronchial smooth muscle. 4.3. PROSTAGLANDINS

The exact function in the lungs of the prostaglandins released in anaphylaxis seems hard to define since both E and F prostaglandins arc released and they have opposing direct actions on some smooth muscles. Sweatman and Collier (1968) showed that prostaglandin E2 relaxed human isolated bronchial smooth muscle whereas prostaglandin F2, contracted this tissue. Main (1964) showed relaxation of previously contracted bronchial smooth muscle of cat by prostaglandin E2. Rosenthale et al. (1970) showed the bronchodilator effects of prostaglandin E2 given by aerosol in guinea pig, dog and monkey in cico. The bronchoconstrictor effects of prostaglandin F2o in guinea pig were shown by Berry and Collier (1964). Smith and Cuthbert (1973) have studied the effects of prostaglandins in the lungs of both normal and asthmatic human subjects. When the prostaglandins were given by aerosol, prostaglandin E: was found to increase fast

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expired volume (FEV), whereas prostaglandin F2a decreased this function. However, when given intravenously prostaglandin E2 had variable effects on the airways of asthmatic patients (Smith, 1974). Math6 et al. (1974) found that asthmatic patients were 8000 times more sensitive to the bronchoconstrictor effects of prostaglandin F2~ given by aerosol than were healthy subjects. Smith and co-workers (personal communication) confirmed an increased sensitivity to prostaglandin F2~ but found that the increase was only 161-fold. Prostaglandin E~ is a vasodilator in a wide variety of vascular beds in a number of species (Horton, 1969), whereas the actions of prostaglandin F~ on the circulation are complex. F-type prostaglandins exert mild to moderate depressor actions in the cat and rabbit but are pressor in rat and dog (.~ngg~rd and Bergstrom, 1963; Horton and Main, 1963; DuCharme et al., 1968). In cats, an increase in right ventricular pressure suggested that there might be an increased pulmonary vascular resistance (,~ngg~rd and Bergstrom, 1963). In the guinea pig, anaphylaxis is accompanied by a marked rise in pulmonary arterial pressure but prostaglandins seem to play little part in this effect since indomethacin (an inhibitor of prostaglandin synthetase) had no effect on the pressor effect (Okpako, 1972). Piper and Vane (1971) suggested that a function of prostaglandins released in the lung might be to divert blood from underventilated areas of the lung to areas which are better ventilated. Since metabolites of prostaglandins are released during anaphylaxis in guinea pig lung both in vitro and in vivo (Math6 and Levine, 1973; Dawson and Tomlinson, 1974; Liebig et al., 1974) and during asthmatic attacks in humans, perhaps the metabolites have important actions in the lung. Dawson et al. (1974) have shown that 15-keto prostaglandin F~, is more potent than the parent prostaglandin in contracting human isolated bronchial smooth muscle. Similarly 15-keto prostaglandin E2 is more active in relaxing guinea pig isolated trachea than is prostaglandin E2 (Crutchley and Piper, 1975c). Prostaglandins are known to sensitize pain receptors in human skin to the actions of other agonists such as histamine and bradykinin (Ferreira, 1972). At least one of the pulmonary metabolites of prostaglandin E2 sensitizes guinea pig bronchial smooth muscle to contraction by histamine both in vitro and in vivo (Dawson, personal communication). Therefore perhaps one of the actions of prostaglandins and their metabolites released in anaphylaxis is to sensitize bronchial smooth muscle to the other mediators of anaphylaxis. Prostaglandins Et, E2 and F2, have been shown to increase levels of cyclic 3'5'-adenosine monophosphate (cAMP) in rat peritoneal mast cells and human lung fragments (Kaliner and Austen, 1974a; Tauber et al., 1973; Walker, 1973). In concentrations which raise the levels of cAMP exogenous prostaglandins inhibit the release of histamine and SRS-A during challenge of passively sensitized human lung fragments and rat peritoneal mast cells. There is evidence that endogenous prostaglandins modulate and tend to inhibit the release of SRS-A from human lung tissue, but no similar evidence was found for modification of histamine release (Walker, 1973). It seems possible that a feed-back mechanism might exist in lung tissue whereby kinins, SRS-A and histamine release prostaglandins from lung tissue (possibly as a result of bronchoconstriction) and prostaglandins then inhibit further mediator release. 4.4. RCS Although RCS is vasoconstrictor in vitro (Piper and Vane, 1969b; Palmer et al., 1973) it is not known what action RCS has on blood vessels in vivo. Similarly, RCS contracts human isolated bronchial muscle in vitro (Piper and Walker, 1973) but its action on the bronchial tree in vivo is not known. 4.5. RCS-RF RCS-RF appears to have little direct action on isolated smooth muscle but appears to exert its action in the pulmonary circulation to release other mediators. If RCS-RF is released into the circulation during anaphylaxis in vivo it might cause prolonged release of prostaglandins which could in turn affect the release of other mediators.

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4.6. KIrqlrqS Bradykinin generally causes vasodilatation and lowers systemic blood pressure (Rocha e Silva et al., 1949; Elliot et al., 1960). However, the hypotension caused by intravenous administration of bradykinin is sometimes followed by a rise in blood pressure (Collier and Shorley, 1963; Lecomte et al., 1964). This rise in blood pressure is probably due to release by bradykinin of catecholamines from the adrenal medulla which has been demonstrated in rabbit, rat, cat, dog and guinea pig (Lecomte et al., 1961; Feldberg and Lewis, 1964; Staszewska-Barczak and Vane, 1967; Piper et al., 1967) and/or ganglionic stimulation by bradykinin (Trendelenberg, 1966). Although bradykinin is hypotensive in the systemic circulation, it constricts the pulmonary vein in guinea pig and decreases perfusion of isolated lungs (Greef and Moog, 1964). Capillary permeability is increased by bradykinin and, although this was demonstrated in skin (Bhoola and Schachter, 1959; Elliot et al., 1960), a similar increase in vascular permeability may also occur in the lungs. In spontaneously breathing guinea pigs bradykinin causes tachypnea (Gjuris and Westerman, 1963, 1964) but, when given to anesthetized or spinalized guinea pigs prepared for use in the Konzett-Rossler preparation, bradykinin given intravenously causes a marked increase in air overflow volume (Collier et al., 1959). This is mainly due to decrease in lung compliance (Widdicombe, 1963) and may be explained by the fact that bradykinin selectively narrows the smaller airways and constricts the respiratory bronchioles (J~ink/il/i and Virtama, 1963). As mentioned above, bradykinin releases catecholamines and when given intravenously bradykinin first causes bronchoconstriction and then releases catecholamines which antagonize the bronchoconstriction (Piper et al., 1967). As with histamine, bradykinin paradoxically decreases intratracheal pressure, probably by adrenergic stimulation (James, 1969). Bradykinin contracts isolated bronchial smooth muscle from man and guinea pig in vitro but is more potent as a bronchoconstrictor agent in guinea pig in vivo than in vitro (Collier, 1970a). This suggests that part of its bronchoconstrictor action may be due to release of an intermediate substance. Since the bronchoconstrictor action of bradykinin in vivo is antagonized by non-steroid anti-inflammatory drugs (Collier et al., 1960) and these drugs are potent inhibitors of prostaglandin synthetase (Vane, 1971b), RCS or prostaglandins may be involved in bronchoconstriction caused by bradykinin (Collier, 1969; Palmer et al., 1973). Indeed bradykinin has been shown to release RCS and prostaglandins from guinea pig isolated perfused lungs and RCS in vivo (Palmer et al., 1973).

4.7. ECF-A Eosinophil chemotactic factor is selectively chemotactic towards eosinophils and it is interesting to note that ECF-A attracts cells which are capable of inactivating SRS-A by their arylsulphatase content (see later) (Austen, 1974). Thus the release of ECF-A may be another example of a feed-back mechanism occurring in anaphylaxis.

5. FATE OF BIOLOGICALLY ACTIVE SUBSTANCES R E L E A S E D Besides being able to activate or synthesize the mediators of anaphylaxis the lung has efficient enzyme systems which stimulate metabolism of various biologically active substances which enter the pulmonary circulation. Usually, the metabolites have less activity than the parent substances so that the pulmonary enzymes have a protective function by reducing the concentrations of potent compounds entering the systemic circulation. The metabolism of exogenous substances in the pulmonary circulation is well documented but less is known about metabolism of mediators released in anaphylaxis; the mediators may be suddenly released in such high concentrations that the enzymes may become saturated, or sensitization of the animal may modify the inactivating enzymic systems.

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5.1. HISTAMINE Histamine is not inactivated when passing through the pulmonary circulation of rats or dogs in vivo (Boileau et al., 1970; Ferreira, et al., 1973), or guinea pig or rat isolated perfused lungs (Alabaster, 1971; Piper, unpublished). This may be because there is no transport mechanism for histamine in the pulmonary blood vessels since histamine is easily metabolized by lung slices or homogenates from man. guinea pig. cat and rat (Lilja and Lindell, 1960, 1961; Bennett, 1965; Brown et al., 1959). 5.2. SRS-A There is little information concerning the fate of SRS-A in the pulmonary circulation except that a charcoal-purified sample of SRS-A infused into the pulmonary artery of isolated guinea pig lungs caused release of RCS and prostaglandins (Piper and Vane. 1969b). Since prostaglandins and SRS-A do not have the same precursor (Dawson and Tomlinson, 1974) this does not represent 'activation' of SRS-A but rather a release mechanism. SRS-A does not appear to be metabolized to any great extent in the pulmonary circulation since Stechschulte et al., (1973) found high concentrations in guinea pig plasma which was obtained from blood from cut blood vessels in the neck, which would be mainly arterial blood (having passed through the pulmonary vascular bed). 5.3. PROSTAGLANDINS

Exogenous prostaglandins of the E and F series are inactivated by 90-98 per cent on passage through the pulmonary circulation of cats, dogs and rabbits in vivo (Ferreira and Vane, 1967d; Crutchley and Piper, 1975a,b), and preliminary experiments suggest that similar inactivation occurs in man (Jose et al., 1975). The same prostaglandins are metabolized in the pulmonary circulation of guinea pig, rabbit and rat isolated lungs in vitro (Piper et al., 1970; Crutchley and Piper, 1974; Piper, unpublished). However, A-type prostaglandins do not seem to be inactivated in vivo (McGiff et al., 1969) and only to a small extent in vitro (Piper et al., 1970). In guinea pig isolated perfused lungs the metabolizing enzymes were not saturated by concentrations of prostaglandin ten times higher than that released in anaphylaxis (Piper et al., 1970). In the lungs of most species, including guinea pig and rabbit, the rate-limiting enzyme in the breakdown of prostaglandins is 15-OH prostaglandin dehydrogenase (,~ngg~rd, 1971; Samuelsson et al., 1971). Crutchley and Piper (1974, 1975a,b) used diphloretin phosphate to inhibit prostaglandin dehydrogenase both in vivo and in vitro and demonstrated the resulting potentiation of prostaglandin action. Prostaglandins released in anaphylaxis are metabolized since various prostaglandin metabolites have been detected during anaphylaxis in vivo and in vitro (Math6 and Levine, 1973; Liebig et al., 1974; Dawson and Tomlinson, 1974). However, diphloretin phosphate did not increase the amount of prostaglandin released during anaphylactic shock in guinea pig isolated perfused lungs (Piper, 1973, 1974). This indicates that prostaglandins released in anaphylaxis are metabolized at a different site from exogenous prostaglandins. Since the pulmonary metabolites of prostaglandins E2 and F:, contract the smooth muscle preparations used to assay prostaglandins, some of the prostaglandins released from isolated perfused lungs during anaphylaxis may already have been metabolized before entering the pulmonary circulation (Crutchley and Piper, 1975c). 5.4. KImNS Bradykinin is metabolized by peptidases in the blood which results in reduction of its biological activity IFerreira and Vane, 1967a): the half-life of bradykinin in the circulation of rats, cats and dogs is approximately 17 sec IFerreira and Vane, 1967a.b,c). In addition to metabolism in the blood, 80 per cent of bradykinin entering the pulmonary circulation of cats, dogs, sheep, rats and guinea pigs is inactivated during one passage through the lungs (Alabaster and Bakhle, 1972a,b; Biron, 1968; H6bert et

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al., 1972; Pojda and Vane, 1971). In the pulmonary circulation of rat isolated perfused lungs bradykinin is metabolized by enzymic hydrolysis of peptide bonds (Ryan et al.,

1968, 1969, 1970; Ryan and Smith, 1971). These authors found that bradykinin did not leave the vascular space and showed that the metabolizing enzymes are bound on or near the vascular endothelial cells, possibly in the caveoli. These findings suggest that a large amount of the bradykinin released into the pulmonary circulation during anaphylaxis is likely to be metabolized before entering the systemic circulation. 6. PHARMACOLOGICAL MODULATION OF ANAPHYLAXIS 6.1. PHYSIOLOGICAL ANTAGONISM

The antagonism of anaphylactic broncoconstriction by epinephrine was shown by Schild in 1937. This 'physiological antagonism' was further demonstrated in vivo by showing that/3-adrenoreceptor blocking drugs greatly enhanced the bronchoconstrictot effects of the anaphylactic mediators histamine, bradykinin and SRS-A (Collier and James, 1967; Collier et al., 1968). 6.2. INHIBITION OF RELEASE OF MEDIATORS

6.2.1. H i s t a m i n e a n d S R S - A The mechanism of action of catecholamines is more complex than simply 'physiological antagonism'. Schild (1936) showed that epinephrine suppressed the antigen-induced release of histamine from guinea pig lung. The mechanism began to be explained when Sutherland and Robison (1966) described the formation of cyclic 3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) by activation of membrane-bound adenylate cyclase with a-adrenoreceptor stimulating agents. In 1968 Lichtenstein and Margolis showed that/3-adrenoreceptor agents and methylxanthines protect cAMP from breakdown by phosphodiesterases and prevent the release of histamine during antigen challenge of human sensitized leukocytes. Assem and Schild (1969) found that isoprenaline (most potent), epinephrine, salbutamol, dopamine and orciprenaline (least potent) prevented the release of histamine from challenged human lung fragments. In human chopped lung tissue or nasal polyps, other agents besides /3-adrenoreceptor drugs and methylxanthines increase cAMP concentrations and there is a direct correlation between the increase in cAMP levels and inhibition of mediator release (Orange et al., 1971a; Kaliner et al., 1973). Prostaglandins E~, E~, F2°, A,, and cholera toxin all increase cAMP and inhibit antigen-induced release of histamine and SRS-A either by stimulating adenyl cyclase or inhibiting phosphodiesterase (Table 1) (Tauber et al., 1973; Kaliner et al., 1973). Disodium cromoglycate inhibits the antigen-induced release of histamine and SRS-A from human lung tissue in a dose-dependent manner (Sheard and Blair, 1970). It also prevents release of ECF-A (Kaliner and Austen, 1974b). This drug also inhibits the release of prostaglandins from human lung but only in doses which completely inhibit histamine and SRS-A output (Piper and Walker, 1973). Disodium cromoglycate does not inhibit mediator release in guinea pig lung (Cox et al., 1970). The mechanism of action of disodium cromoglycate is not completely understood but it is not acting either as a stimulator of adenyl cyclase or inhibitor of phosphodiesterase (Cox et al., 1970). The action of disodium cromoglycate is further discussed in the section 'antagonism of anaphylaxis'. Diisopropylfluorophosphate (DFP) and lack of calcium will prevent antigen-induced release of histamine (Mongar and Schild, 1958), SRS-A and ECF-A from human and guinea pig lung since the release mechanism is calcium-dependent and requires the activation of a DFP-sensitive serine esterase (Orange et al., 1971a,b; Mongar and Schild, 1958; Wasserman et al., 1974b, Austen, 1974; Schild, 1937, 1968). Release of SRS-A from lungs is prevented by diethylcarbamazine (Orange and Austen, 1969) and this drug also blocks prostaglandin release (Bakhle and Smith, 1972). Release of both

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TABLE 1. Inhibition o[ Release o[ M e d i a t o r s [rom L u n g Tissue During A n a p h y l a x i s Species

State of lung

Mediators

Inhibitors

Reference

Guinea pig

Perfused

Histamine

Epinephrine Hydrocortisone

SRS-A

Histamine

Calcium lack DFP Indomethacin Aspirin Non-steroid, antiinflammatory drugs Calcium lack and DFP Catecholamines Dinitrophenol Indomethacin Aspirin Non-steroid, antiinflammatory drugs ~-Adrenergic drugs

Schitd, 1936 Trethewie, 1957 Goadby and Smith, 1964 Brocklehurst, 1960

SRS-A

Methylxanthines Prostaglandin E, E2, F~,, A, Cholera toxin Disodium cromoglycate Calcium lack Colchicine Cytochalasin B /3-Adrenergic drugs

Prostaglandins and RCS Guinea pig Chopped

Histamine SRS-A Prostaglandins and RCS

Human

Chopped

ECF-A

Prostaglandins Monkey

Chopped

Histamine

SRS-A

Bovine

Chopped

Histamine SRS-A

Methylxanthines Prostaglandins E,, E2, F2,, A, Cholera toxin Disodium cromoglycate Calcium lack Colchicine Cytochalasin A /3-Adrenergic drugs Methylxanthines DFP Disodium cromoglycate Indomethacin Disodium cromoglycate Catecholamines Theophylline cAMP Chlorophenesin Catecholamines Theophylline cAMP Diethycarbamazine Chlorphenesin High molecular weight fractions PPP. High molecular weight fractions PPP.

Piper and Vane. 1969b Palmer et al., 1973 Mongar and Schild, 1958 Austen and Brocklehurst, 1960 Assem and Schild. 1969 Stechschulte et al.. 1967 Piper (unpublished) Piper (unpublished) Assem and Schild, 1969 Orange et al.. 1971a,b Kaliner et al., 1973 Tauber et al., 1973 Kaliner et al., 1973 Sheard and Blair, 1970 Orange et al., 1971b Orange, 1974 Orange. 1974 Assem and Schild, 1969 Orange et al., 1971a, b Kaliner et al., 1973 Tauber et al., 1973 Kaliner et al., 1973 Sheard and Blair, 1970 Orange et al., 1971b Orange, 1974 Orange, 1974 Wasserman et al., 1974b Orange and Austen. 1974 Orange and Austen, 1974 Piper and Walker, 1973 Ishizaka et al., 1971 Malley and Baecher, 1971 Ishizaka et al.. 1971

Malley and Baecher, 1971 Burka and Eyre, 1974 Burka and Eyre, 1974

h i s t a m i n e a n d S R S - A is b l o c k e d b y c o i c h i c i n e w h i c h m a y act b y i n h i b i t i n g r e l e a s e b u t n o t the i n t r a c e l l u l a r f o r m a t i o n of S R S - A ( O r a n g e , 1974). C h l o r o p h e n e s i n p r e v e n t e d the a n t i g e n - i n d u c e d r e l e a s e of h i s t a m i n e a n d S R S - A f r o m m o n k e y lung f r a g m e n t s w h i c h had b e e n s e n s i t i z e d with h u m a n reagin ( M a i l e y a n d B a e c h e r , 1971). T h e a c t i o n of c h l o r o p h e n e s i n was t h o u g h t to be d u e to a c t i v a t i o n of adenyl cyclase.

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The release of histamine and SRS-A from sensitized rat and primate lung tissue was inhibited by diethyicarbamazine (Orange et al., 1968; Ishizaka et al., 1971). Since the action of diethylcarbamazine was not prevented by propranolol, it could not be attributable to /3-adrenoreceptor stimulation. Diethylcarbamazine has been shown to relieve asthma and exercise-induced asthma (Salazar-Mailen, 1965; Sly and Matzen, 1974). Diethylcarbamazine also blocks the release of prostaglandins from rat isolated perfused lung (Bakhle and Smith, 1972) so that its therapeutic action in the lung may be to inhibit immunological release of mediators by an unknown mechanism. 6.2.2. E C F - A The release of ECF-A from human lung was modified in the same way as release of histamine and SRS-A by increased cAMP and cyclic guanosine 3'5'-monophosphate (cAMP) levels and cholinergic stimulation (Wasserman et al., 1974b). Disodium cromoglycate probably also inhibits the release of ECF-A from human lung (Kaliner and Austen, 1974b). The high molecular weight fractions of polyphloretin phosphate (PPP) inhibit release of histamine and SRS-A from rat mast cells (Strandberg, 1973) and bovine lung (Burka and Eyre, 1974). 6.2.3. P r o s t a g l a n d i n s a n d R C S The anaphylactic release of RCS and prostaglandins from guinea pig isolated perfused lung or human lung fragments was inhibited by anti-inflammatory drugs such as aspirin, indomethacin or mefenamate without blocking the release of histamine or SRS-A (Piper and Vane, 1969b; Palmer et al., 1973; Piper and Walker, 1973). Indeed Walker (1973) observed that the amount of SRS-A released on challenge of human lung was increased when the release of prostaglandins had been inhibited by indomethacin. Smith and Dunlop (1975), however, found that indomethacin did not affect the reduction in fast expired volume in 1 sec (FEV,), during antigen challenge of asthmatics. The release of RCS during anaphylaxis in guinea pig in vivo was prevented by treating the animal with aspirin (Palmer et al., 1973). This also abolished the release of RCS caused by bradykinin. The inhibition by non-steroid anti-inflammatory drugs of release of RCS (and prostaglandins) measured by direct bioassay methods in vivo explains the partial protection against anaphylaxis seen with these drugs in guinea pig in vivo (Collier et al., 1968). Aitken and Sanford (1972) and Eyre et al. (1973) found that meclofenamate protected calves against acute systemic anaphylaxis whereas mepyramine or methysergide were either totally or partially ineffective. These authors interpreted these results as showing inhibition of SRS-A and bradykinin, but an alternative conclusion would be that meclofenamate blocked the release of RCS and prostaglandins which might be important mediators in anaphylaxis in the calf (Bakhle and Vane, 1974). The release of RCS-RF was not blocked by anti-inflammatory drugs (Palmer et al., 1973) and no inhibitor of its release has yet been found. 6.3. ENHANCEMENT OF MEDIATOR RELEASE The immunological release of anaphylactic mediators from lung tissue in vitro may be enhanced by various pharmacological means (Table 2). Just as an increase in cAMP concentration causes inhibition of mediator release, decreased levels of cAMP result in enhanced release, a-Adrenoreceptor stimulation of human lung tissue increases the antigen-induced release of histamine and SRS-A (Orange et al., 1971a). This result may be due to activation of a cell-bound ATPase (Coffey et al., 1971) caused by a-adrenoreceptor stimulation. Low concentrations of prostaglandin E, and F2, cause increased release of histamine and SRS-A on challenge of human sensitized lung fragments (Tauber et al., 1973). This is accompanied by decreased tissue levels of cAMP but as this effect was not blocked by phenoxybenzamine it was not due to stimulation of a-adrenoreceptors.

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TABLE2. Enhancement o f Release o f Mediators from Lung Tissue Species

State of lung

Human

Chopped

Guinea pig

Chopped

Human

Chopped

Mediators

Inhibitors

Reference

Histamine SRS-A

~ -Adrenergic drugs Low concentrations of prostaglandins E~, F2. Acetylcholine Carbamylcholine

Orange et al.. 197 la

Succinate Maleate Low doses of cytochalasin B Cytochalasin A

Austen and Brocklehurst, 1961 Orange et al., 1971a Orange, 1974

Histamine SRS-A ECF-A Histamine SRS-A Histamine

Tauber et al., 1973 Kaliner et al., 1972, 1973

Cholinergic stimulation of human sensitized lung and nasal polyp tissue with acetylcholine and carbamylcholine results in increased release of histamine SRS-A and ECF-A on challenge (Kaliner et al., 1972, 1973); this is not caused by reduction in cAMP, but by an increase in cGMP, since cholinergic stimulation increases cGMP in guinea pig and human lung slices (Stoner et al., 1973). Any cholinergic stimulation during anaphylaxis in vivo might result in increased release of mediators. Maleate or succinate increases the antigen-induced release of histamine and SRS-A from guinea pig sensitized lung slices (Austen and Brocklehurst, 1961) and maleate enhances release from human lung fragments (Orange et al., 1971a). The structural configuration of the dibasic acids seems to be critical but the mechanism of the enhancement is not understood (Orange and Langer, 1973). The fungal metabolites cytochalasin A and B affect the release of histamine and SRS-A in different ways. Low doses of cytochalasin B enhance, but higher doses inhibit, histamine release whereas this material causes only a dose-dependent inhibition of SRS-A release. Cytochalasin A enhances histamine release and inhibits SRS-A output in a dose-dependent manner (Orange, 1974). Enhancement of histamine release may be due to facilitated exocytosis and the inhibition of SRS-A release to inhibition of a membrane transport mechanism (for references see Orange, 1974). The actions of the cytochalasins appear to indicate that immunological release of histamine and SRS-A involves both shared and independent biochemical steps. 6.4. ANTAGONISM OF ACTION OF ANAPHYLACTIC MEDIATORS

6.4.1. H i s t a m i n e The bronchoconstrictor action of histamine is mediated through H1 receptors and is antagonized by mepyramine. Both the histamine-induced contraction of isolated bronchial or tracheal smooth muscle from man or guinea pig and bronchoconstriction in vivo are blocked by mepyramine. (Collier et al., 1960; Berry and Collier, 1964). 6.4.2. B r a d y k i n i n a n d S R S - A The bronchoconstrictor actions of bradykinin and SRS-A (charcoal purified) in guinea pig in vivo are antagonized by non-steroid anti-inflammatory drugs such as aspirin and fenamates (Collier et al., 1963; Collier et al., 1960; Berry and Collier, 1964; Collier and James, 1967; Collier et al., 1968). Bradykinin- or SRS-A-induced contraction of human or guinea pig isolated tracheal or bronchial smooth muscle is also antagonized by these drugs but higher concentrations are required in vitro than in vivo (Berry and Collier, 1964; Sweatman and Collier, 1968). Since both bradykinin and SRS-A release prostaglandins and RCS from guinea pig lung (Piper and Vane, 1969a, 1971; Palmer et al., 1973) the action of the anti-inflammatory drugs in vivo may be to inhibit the release of prostaglandins and RCS by bradykinin and SRS-A rather than to directly antagonize their action.

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The guinea pig ileum-contracting activity of SRS-A derived from human lung and rat peritoneal cavity is destroyed by arylsulphatase (Orange et al., 1974). Sodium 7-(3-(4acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy) 4-oxy-8-propyl-4H- I-benzopyran-2-carboxylate (FPL 55712) is a potent and specific inhibitor of the action of SRS-A from guinea pig or human lung and rat peritoneal cavity on guinea pig ileum in vitro (Augstein et al., 1973) but seems to have little action in vivo. 6.4.3. P r o s t a g l a n d i n s Polyphloretin phosphate (PPP) and diphloretin phosphate (DPP) and a dibenzoxapine (SC 19220) selectively antagonize the cardiovascular and gastrointestinal actions of prostaglandins in vivo and on isolated gastrointestinal smooth muscle (Eakins et al., 1970, 1973: Sanner, 1971). PPP blocks the contraction of PGF2,, on human bronchial smooth muscle but leaves the relaxant effect of PGE_~ unchanged (Math6 et al., 1971). 6.5. PHARMACOLOGICAL ANTAGONISM OF ANAPHYLAX1S Collier and James (1967) treated sensitized anesthetized guinea pigs in vivo with a combination of aspirin or meclofenamate and mepyramine before challenge with antigen. This treatment suppressed most but not all of the anaphylactic bronchoconstriction. The authors concluded that the residual bronchoconstriction was due to unknown bronchoconstrictor factor(s). Disodium cromoglycate inhibits anaphylaxis in human lung fragments by preventing the release of histamine and SRS-A, presumably from mast cells (Sheard et al., 1967). Disodium cromoglycate also prevents the release of prostaglandins during anaphylaxis in human lung tissue but only at doses which almost completely inhibit the release of histamine and SRS-A (Piper and Walker, 1973). During anaphylaxis in the rat, bronchoconstriction can occur although the lung is not the 'target' organ in this species, and disodium cromoglycate inhibits this anaphylactic bronchoconstriction (Church et al., 1972). Disodium cromoglycate inhibits the release of histamine from rat peritoneal mast cells caused either by antigen challenge or by phospholipase A (Cox et al., 1970) and may therefore exert a similar action on mast cells in the lung. However, disodium cromoglycate has no protective action during anaphylaxis in guinea pig chopped lung during challenge (Cox et al., 1970; Assem and Mongar, 1970). The exact mode of action of disodium cromoglycate is unknown but the fact that it inhibited the release of mediators from mast cells by phospholipase A suggests that it may act on an enzyme or enzyme substrate activated by the antigen-antibody reaction to prevent the release of mediators (Cox et al., 1970). There is some evidence that the anti-inflammatory steroids butazoiidine and h'ydrocortisone reduce the amount of histamine and SRS-A released from guinea pig lung during anaphylaxis (Trethewie, 1957; Goadby and Smith, 1964). The animals used in these experiments had been sensitized with low doses of antigen. Cortisone and hydrocortisone suppressed the response of guinea pig isolated intestinal smooth muscle to histamine and SRS-A (Trethewie, 1958; Goadby and Smith, 1964). Church et al. (1972) inhibited anaphylactic bronchoconstriction in the rat with dexamethasone but gave no evidence whether this was due to inhibition of mediator release or antagonism of their bronchoconstrictor action. 7. DISCUSSION Antigen-challenge of lungs or lung tissue from several species, including man, results in the release of a-number of mediators which have potent biological actions. However, the effects of anaphylaxis are not entirely due to the direct actions of the mediators released but also to stimulation of nervous components, the 'lung irritant receptors'. The mediators may either be released from preformed stores such as histamine or ECF-A or synthesized de n o v o as a result of antigen-antibody union, as are SRS-A and prostaglandins, for example. Between species there seems to be some variation in

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quantity and types of mediators released but histamine and SRS-A are released from the lung of species in which this organ is the 'target' of anaphylaxis. Not all of the substances released in anaphylactic shock seem to be primary mediators of anaphylaxis but may in turn be released by those primary mediators. Histamine, SRS-A, ECF-A and kallikrein are released from human or guinea pig lung during anaphylaxis and certainly histamine and SRS-A are primary mediators. Catecholamines are secondary mediators in the guinea pig and are released into the circulation during anaphylaxis probably either by a direct action of histamine, SRS-A or bradykinin on the adrenal medulla and/or reflexly as a result of hypoxia caused by the bronchoconstrictor action of these substances. Similar mechanisms for catecholamine release probably exist in other species. Prostaglandins may also be secondary mediators or anaphylaxis, perhaps released by anaphylactic contraction of bronchial smooth muscle, as a result of hypoxia (Said et al., 1974) or as a result of histamine, SRS-A or bradykinin entering the pulmonary circulation. In the guinea pig, stimuli which release prostaglandins also release RCS. Since this substance is not released by anaphylactic shock in either human or rat lung, RCS (and likewise RCS-RF) may only be produced in anaphylaxis involving IgG antibodies. In describing the various functions of the mediators released during anaphylaxis in the lung, it seems that several negative feed-back mechanisms may exist either in the whole animal in vivo or in chopped lung tissue in vitro or perhaps in both systems. Histamine, bradykinin and SRS-A are bronchoconstrictor, and catecholamines released during anaphylaxis act to reverse this bronchoconstriction. Also in chopped lung catecholamines inhibit the anaphylactic release of histamine, SRS-A and ECF-A, but whether catecholamines released in anaphylaxis tend to cause similar inhibition in vivo is not known. Similarly, prostaglandins inhibit mediator release in challenged chopped lung and may possibly do so in vivo. ECF-A may exert another negative feed-back mechanism against the action of SRS-A. This substance is released together with SRS-A and is chemotactic towards eosinophils which contain arylsulphatase, an enzyme which destroys the activity of SRS-A. It seems, therefore, that release of the primary mediators of anaphylaxis triggers a series of events which tend either to reverse the bronchoconstriction caused by anaphylactic mediators or to inhibit their release. Prostaglandins of the E and F series are recent additions to the list of anaphylactic mediators and their possible functions in the lung merits discussion. Since pretreatment of sensitized guinea pigs with aspirin does not greatly lessen anaphylaxis, and prostaglandins of the E and F series often have directly opposing actions, it is difficult to explain why they should be released in anaphylaxis. The release of prostaglandin metabolites also occurs from perfused lungs and suggests that the parent prostaglandins have an action and are metabolized before entering the pulmonary circulation. Prostaglandin metabolites themselves may be important in anaphylaxis, and certainly 15-keto metabolites of prostaglandin E: and F.,~ are more potent in relaxing or contracting bronchial smooth muscle than are the parent prostaglandins. Prostaglandins are not circulating hormones and their local action in the lung may be the maintenance of ventilation/perfusion ratios. For instance, prostaglandin F2~ might be released in areas of bronchoconstriction and hypoxia and cause vasoconstriction in these areas, whereas prostaglandin E_, may cause bronchodilatation and vasodilatation in areas of the lung which are better ventilated. Prostaglandins may potentiate the action of anaphylactic mediators in the lung since they have been shown to potentiate the actions of inflammatory mediators in human and guinea pig skin and increase passive cutaneous anaphylaxis in guinea pig (Ferreira, 1972; Williams and Morley, 1973). Sensitization with antigen may modify the enzymes controlling both synthesis and metabolism of prostaglandins since an increased concentration of prostaglandin synthetase has been found in sensitized lungs. The anaphylactic response may be modified by potentiating or inhibiting mediator release or by antagonizing the actions of the mediators. In lung fragments cholinergic and adrenergic stimulation have opposite effects on mediator release. Release may be

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enhanced by cholinergic drugs causing increased levels of cGMP and inhibited by B-adrenoreceptor stimulants which increase cAMP. Release of anaphylactic mediators is also inhibited by mechanisms which do not affect cellular levels of cyclic nucleotides. In the case of disodium cromoglycate for example, the exact mechanism is unknown, but may be inhibition of an enzyme activated by antigen-antibody union. Prostaglandin release is prevented by inhibition of the synthesizing enzymes. The effects of anaphylaxis in guinea pig in vivo may be very strongly reduced by pretreatment with a combination of antagonists of the actions of the individual mediators. However, the antagonism of bradykinin and SRS-A bronchoconstriction by non-steroid anti-inflammatory agents may at least be partly due to inhibition of a prostaglandin-mediated step in the reaction. The marked inhibition of anaphylaxis in the calf in vivo by mefenamic acid also suggests that prostaglandins may be important in this species. Steroids inhibit anaphylactic bronchoconstriction in the rat but the mechanism of their action is not understood. The lung has functions other than gas exchange and contains enzyme systems for the synthesis, release and metabolism of biologically active substances. Anaphylaxis is just one of the conditions in the lung which lead to mediator release. Some of the mediators may also be metabolized by enzyme systems in the lung after having a local action; others are not metabolized and survive to enter the systemic circulation where they may have other actions. REFERENCES ABE, K., WATANABE, N., KUMAGAI, N., Motnu, T., SEW, T. and YOSHINAGA, K. (1967) Circulating plasma kinin in patients with bronchial asthma. Experientia, 23: 626-627. ArrKEN, M. M. and SANFORD, J. (1972) Modification of acute systemic anaphylaxis in cattle by drugs and by vagotomy. J. comp. Pathol. 82: 247-256. ALABASTER, V. A. (197 l) The Metabolism of Vasoactive Substances by the Lung. Ph.D. Thesis, University of London. ALABASTER, V. A. and BAKHLE, Y. S. (1972a) The inactivation of bradykinin in the pulmonary circulation of isolated lungs. Br. J. Pharmac. 45: 299-309. ALABASTER, V. A. and BAKI-ILE, Y. S. (1972b) Converting enzyme and bradykininase in the lung. Cir. Res. Suppl II, 30 and 31: 72-81. ANGGARD. E. (1971) Studies on the analysis and metabolism of the prostaglandins. Ann. N.Y. Acad. Sci. 180: 2O0-213. ANGGARD. E. and BERGSTROM. S, (1963) Biological effects of an unsaturated trihydroxy acid (PGF2o) from normal swine lung. Acta physiol, scand. 58: 1-12. ~,NC.GARD, E. and SAMUELSSON,B. (1965) Biosynthesis of prostagiandins from arachidonic acid in guinea-pig lung. J. biol. Chem. 240: 3518-3521. ~,NGGARD, E., BERGQVIST, U., H6OBEItG, B., JOI-IANSSON, K., TnON, I. L. and UVNAS, B. (1963) Biologically active principles occurring on histamine release from cat paw, guinea-pig lung and isolated rat mast cells. Acta physiol, scand. 59: 97-110. ASSEM, E. S. K, and MONGAR, J. L. (1970) Inhibition of allergic reactions in man and other species by cromoglycate. Int. Archs. Allergy appl. Immun. 38: 68-77. ASSEM. E. S. K. and SCHILD, H. O. (1969) Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitized human lung. Nature, 224: 1026-1029. AUER, J. and LEWIS, P. L. (1910) The physiology of the immediate reaction of anaphylaxis in the guinea-pig. J. exp. Med. 12: 151-175. AUGSTEIN. J., FARMER, J. B., LEE, T. B., SHEARD, P. and TATTERSAL, M. L. (1973) Selective inhibitor of slow reacting substance of anaphylaxis. Nature, New Biol. 245: 215-217. AUSTEN, K. F. (1974) A review of immunological biochemical and pharmacological factors in the release of chemical mediators from human lung. In: Asthma: Physiology, Immunopharmacology and Treatment, pp. 109-122, AUSTEN, K. F. and LICHTENS'TEIN, M., (eds.), Academic Press, London. AUSTEN, K. F. and BROCKLEHURST, W. E. (1960) Inhibition of the anaphylacetic release of histamine from chopped guinea-pig lung by chymotrypsin substrates and inhibitors. Nature, 186: 866-868. AUSTEN. K. F. and BROCKLEHURST, E. W. (1961) Anaphylaxis in chopped guinea-pig lung. II. Enhancement of the anaphylactic release of histamine and slow-reacting substance by certain dibasic aliphatic acids and inhibition by monobasic fatty acids. J'. exp. Med. 113: 541-557. BAKHLE. Y. S. and SMITH, T. W, (1972) Release of spasmogenic substances induced by vasoactive amines from isolated lungs. Br. J. Pharmac. 46: 543-544P. B AKHLE. Y. S. and VANE. J. R. (1974) Pharmacokinetic function of the pulmonary circulation. Physiol. Rev. .~1: 1007-1045, BARTOSCH. R.. FELDBERG. W. and NAGEL. E. (1933) Weitere Versuche uber das Freiwerden eines histaminahnlichen Stoffes aus der durchstromten Lunge sensibilisieter Meerschweinchen beim Auslosen einer anaphylaktischen Lungenstarre. Archly. Physiol. 231: 616--629.

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