Kinins and Respiratory Tract Diseases

REVIEW

Kinins and respiratory tract diseases

A. Trifilieff, A. Da Silva, J-P. Gies

Kinins and respiratory tract diseases. A. Trifilieff, A. Da Silva, J-P. Gies. ©ERS Jour Laboratoire de Neuroimmuno nals Ltd 1993. pharmacologie-Pulmonaire, INSERM CJF- ABSTRACT: Bradykinin and related kinins are peptidic hormones, formed in 9105, Universit~ Louis Pasteur-Strasbourg tissues and fluids during inflammation. Various functional sites have been pro I, Facult6 de pharmacie, Illkirch, France. posed as mediators of the biological effects of kinins, including the B , B and B 1 1 3 Correspondence: J-P. Gies receptors. The existence of the B1 and the B1 receptor has largely been con Laboratoire de Neuroimmuno-pharma firmed, whilst that of the B3 receptor is controversial and needs further confirma cologie-Pulmonaire tion. INSERM CJF-9105 The role of bradykinin in the pathophysiology of asthma is not well understood, Universit6 Louis Pasteur-Strasbourg I but bradykinin was proposed as a putative mediator of asthma, since asthmatic Facult6 de pharmacie subjects are hyperresponsive to bradykinin, and since immunoreactive kinins are BP 24, 67401 Illkirch Cedex increased in the bronchoalveolar lavage fluids of asthmatic patients. Kinins could France provoke bronchoconstriction by acting directly on smooth muscle and/or indirectly by their inflammatory properties. They may also contribute to the symptomatology Keywords: Asthma bronchial hyperresponsiveness of allergic and viral rhinitis, since they are the only mediators detected to date kin ins that are generated in nasal secretion during experimental and natural rhinovirus rhinitis colds. Moreover, they can induce relevant symptoms when applied to airway mucosa. Received: April 8 1992 It has also been proposed that coughing during treatment with angiotensin Accepted after revision December 28 1992 converting enzyme (ACE) inhibitors is linked to the action of kinins, since ACE Is able to degrade kinins, and since the effects of ACE Inhibitors are reduced by This work was supported by the Institut kinin antagonists. Due to their mitogenic properties, kinlns have been proposed to National de la San~ et de la Rechereche regulate lung carcinoma growth. Their action remains speculative, but some M6dicale, grants CRE 900504 and CJF findings are of great interest In order to define their role in these pathologies. 9105. Despite many studies in animals and In humans, the mode of action of kinins in airways Is still poorly understood. The recent cloning and sequenclng of the com plementary deoxyribonucleic acid (cDNA) of a human Bl receptor, and the avail ability of selective Bl antagonists will be useful for defining more precisely the action of kinins on airways functions. Eur Respir J., 1993, 6, 576-587.

The history of kinins began in 1909 when ABaous and in inflammatory responses of the aitway and in bronchial BARDIER [1] observed a transient fall in blood pressure in hyperresponsiveness. man after injection of fractions extracted from human urine. It was not until 40 yrs later that WERLE and BEREK [2] attributed the hypotensive effect of urine to the pres Kinin receptor subtypes ence of an enzyme, named "kallikrein", which could re lease a substance from plasma which was capable of Two receptor subtypes have been identified on the ba contracting smooth muscle. This generated material was sis of the kinin receptors literature since 1980, when E named "kallidin". At the same time, ROCHA Sn.vA et al. REooLI and BARABE [7] proposed the classification of B1 [3] coined the name "bradykinin" for a similar smooth and Bi kinin receptors based upon the relative bioassay muscle spasmogen liberated from plasma by the action potencies of a series of bradykinin analogues on vascular of trypsin. Bradykinin was subsequently characterized as smooth muscle preparations. Two different patterns of a nonapeptide [4] (table 1). The presence of kinins in agonist activities have been identified in the rabbit aorta the tracheobronchial tree [6], and their pharmacological (B1 tissue), and in the rabbit jugular vein (B2 tissue). In 10 properties, including the ability to increase vascular per B1 tissue, the agonist potencies are: des-Arg -kallidin > meability and secretion of mucus, to cause vasodilatation des-Arg9-bradykinin = kallidin » bradykinin; whereas or oedema, and to contract airway smooth muscle in vivo in B2 tissue the agonist potencies are: bradykinin = ka or in vitro, would suggest that these peptides are involved llidin »des-Arg10-kallidin > des-Arg9-bradykinin [7]. KININS AND AIRWAYS 577

Table 1. - Structure and classification of kinin agonlsts and antagonists

Name Structure Classification

Bradykinin (BK) Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Natural agonist Kallidin (KD) Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Natural agonist 9 Des-Arg -BK Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Natural B1 agonist 10 Des-Arg -KD Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Natural B1 agonist 9 8 Des-Arg -[Leu ]-BK Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu Synthetic B1 antagonist 7 [o-Phe ]-BK Arg-Pro-Pro-Gly-Phe-Ser-Phe-Phe-Arg Synthetic B2 antagonist 0 3 7 o-Arg [Hyp ,o-Phe ]-BK Am-Arg-Pro-Hyp-Gly-Phe-Ser-~-Phe-Arg Synthetic B2 antagonist 0 3 5 8 7 , • o-Arg [Hyp Thi ,n-Phe ]-BK A!i-Arg-Pro-Hyp-Gly-Thi-Ser-~-Thi-Arg Synthetic B2 antagonist 0 3 5 8 7 o-Arg [Hyp ,Leu • ,n-Phe ]-BK Am-Arg-Pro-Hyp-Gly-Leu-Ser-~-Leu-Arg Synthetic B2 antagonist 0 3 5 7 8 o-Arg [Hyp ,Thi ,n-Tic ,0ic ]-BK Au-Arg-Pro-Hyp-Gly-Thi-Ser-Iil;.-Oic-Arg Synthetic B2 antagonist 0 3 5 7 8 o-Arg [Hyp ,Thi ,n-Tic ,Tic ]-BK Au-Arg-Pro-Hyp-Gly-Thi-Ser-Iil;.-Tic-Arg Synthetic B2 antagonist 0 3 7 8 o-Arg [Hyp ,n-HypE(trans-propyl) ,0ic ]-BK Au-Arg-Pro-Hyp-Gly-Phe-Ser-HypE Synthetic B2 antagonist (trans-propyl)Oic-Arg

Hyp: trans-4-hydroxyproline; Thi: ~-(2-thienyl)-alanine; Tic: (1, 2, 3, 4-tetrahydroisoquinolin-3-yl-carbonyl); Oic: [(3aS, 7aS) octahydroindol-2-yl-carbonyl]. Underlined residues are of the D-series. Modified from [5] with permission.

B 1 receptors affinity for B2 receptors, at least two log units lower than kinin agonists, and can induce the release of histamine

Bradykinin B1 receptors are activated by the kinin from mast cells [26] by acting on a Grlike protein [27]. metabolites, des-Arg-kinins, induced by kininase I. In The most potent of the early series of B2 antagonists is o addition, effects mediated via B1 receptors can be com ArgO[Hyp3,Leu5·8,o-Phe7]-bradykinin (table 1) [28]. Re pc.iitively inhibited by the antagonist des-Arg9-[Leu8] cently, i.EMBECK et al. [29] have proposed new bradykinin B receptor antagonists, in which unusual amino acids bradykinin (table 1). In general, B1 receptors appear to be 2 distributed predominantly in vascular smooth muscle [7], have been inserted. The most potent of these compounds, although non-vascular localization also exists [8]. Inter o-Arg0[Hyp3,Thi5,o-Tic7,0ic8]-bradykinin (Hoe 140) (table

estingly, B1 responsiveness can be induced under inflam 1), has been used in many biological assays [30--32]. matory conditions or trauma [9, 10]. The mechanism by Hoe 140 does not act as a partial agonist, is selective for

which this up-regulation of response to B1 agonist occurs B2 receptors, has a similar affinity for B2 receptors as has not been entirely clarified, but may be due to de novo bradykinin, and is resistant to enzyme cleavage. There

synthesis of B1 receptors during incubation [9, 11], which fore, Hoe 140 is likely to contribute to the investigation may be mediated via the production of interleukin-1 [12]. of the pathophysiological role of bradykinin. A derived compound, showing a similar binding affinity, has been proposed by FARMER et al. [33], o-Arg0[Hyp3,ThP,o· 7 B2 receptors Tic ,Tic&]-bradykinin (NPC 16731) (table 1). These two B2 antagonists, Hoe 140 and NPC 16731, are conforma Most of the actions of kinins are mediated via the oc tionally constrained in the backbone of the four C cupancy of the B2 receptors. Specific binding of radio terminal residues. On the basis of these conformational labelled bradykinin to a variety of tissues and cell constraints, KYLE et al. [34] have proposed a series of populations has been demonstrated [13-18]. The affin bradykinin analogues, each having the generic primary 0 1 2 3 4 7 ity constant (K) for bradykinin binding has generally sequences o-Arg -Arg -Pro -Hyp -Gly -Phe5-Ser6-X - Y8- been reported to range from picomolar to nanomolar af Arg9, in which X and Y are chosen to obtain a ~-turn. finities, whilst maximum binding (B~~~.,,) varies from 10 to The most potent of these analogues has been obtained by 230 fmol per mg of protein or per 106 cells. Ligand the replacement of X-Y with the dipeptide N-acetyl-(o-4- binding has been shown to correlate with physiological hydroxyprolinetrans-propyl ether)-(Oic)-N'-methylarnide. functions in many tissues [19-22]. With the availability This compound, named NPC 17731, has the following 3 7 8 of B2 antagonists [23], a sizeable body of knowledge has sequence: o-ArgO[Hyp ,o-HypE(trans-propyl) ,0ic ]-BK been accumulated regarding the properties and regulation (table 1). of these receptors. The major characteristics of these Another route to developing more potent bradykinin early B antagonists is the replacement of proline' with a 2 receptor antagonists, has been to dimerize the early B2 3 7 8 o-phenylalanine residue in the bradykinin structure (table antagonist o-ArgD[Hyp ,o-Phe , Leu ]-BK, in which the 1). This modification has led to a series of compounds seryl6 residue had been replaced with a cystyl residue which antagonize the action of bradykinin in tissues to allow the dimerization performed with the thiol-specific thought to contain B receptors. However, these ana homobifunctional cross-linking agent bis logues have several limitations, since they are partial maleirnidohexane. The compound obtained (CP-0127) is agonists in various biological systems [24], and display an antagonist, approximately 50--100 times more potent some affinity for B1 receptors following their degradation than the parent compound, with pharmacological profiles by kininase I [25]. Moreover, these antagonists show low comparable to those of Hoe 140 and NPC 17731 [35]. 578 A. TRIFILIEFF, A. DA SILVA, J-P. GIES

anti-idiotype antisera (AlA 3). As expected, AlA 3 de The earlier B2 antagonists [23) have been used exten sively and and a complex picture of B creased the binding of (3H)-bradykinin to the guinea-pig in vivo in vitro, 2 receptors is emerging [36). Several studies have dem ileum receptor. Moreover, AlA 3 acts as an agonist at onstrated the presence of multiple classes of binding sites the B2 receptor, increasing the production of ino in tissues or cells [13, 14, 18, 37], and the different sitolphosphates on HF 15 fibroblasts and inducing secre effects of B2 antagonists in several bioassays imply the tion of prostaglandin E2 in murine SV-T2 cells. This multiplicity of bradykinin B2 receptors [38, 39]. Moreo secretion was inhibited by the addition of the B2 antago ver, the recent cloning of a B bradykinin receptor com nist o-Arg0[Hyp3,o-Phe7)-bradykinin. Therefore, anti 2 plementary deoxyribonucleic acid (cDNA), and the tis idiotypic antibody AlA 3 interacts specifically with the sue distribution of messenger ribonucleic acid (mRNA) B2 kinin receptor at the structural and functional level. encoding this receptor, suggest the possible existence of Unfortunately, the irnrnunoprint analysis was unsuccessful, probably due to the denaturation of the receptor during subtypes of B2 receptors [40). More recently, FARMER and eo-workers [41, 42) have proposed a new pulmonary gel electrophoresis. The anti-idiotypic approach, therefore, • receptor subtype, referred to as B3 But it must be kept provides a powerful tool to further characterize the kinin in mind that kinins exert complex indirect effects, which receptors. might depend on independent receptor mechanisms which are not blocked by antagonists [43], such as the release of histamine from rat mast cells [27, 44], and the release B3 receptors of epinephrine from the adrenal medulla [45J. The existence of the pulmonary B receptor is largely The cloning of the B2 bradykinin rat receptor predicted 3 a protein sequence of 366 amino acids having a molecu controversial. This new receptor has been proposed in lar mass of 41,696 Da. Hydrophobicity analysis reveals view of the weak inhibition produced by B1 and B2 an seven putative transmembrane domains consistent with the tagonists on bradykinin-induced bronchoconstriction in structure observed in the G protein-coupled receptor vivo, and the failure to antagonize the ability of bradyki family. Moreover, the sequence also contains three po nin to contract the epithelium-denuded guinea-pig trachea tential N-linked glycosylation sites in the predicted ex in vitro. Binding studies have conftrrned that antagonists tracellular domain (40], suggesting that rat bradykinin B are unable to displace specific binding in membrane 2 receptor is a glycoprotein. Following the cloning of this preparations [41). However, other groups have failed to rat B2 receptor, HESsE et al. [46] have cloned and se reproduce these results. In vivo experiments do not agree lCHINOSE quenced the cDNA of a B2 receptor from a human lung with those of JIN et al. [49] and and BARNES fibroblasts cell line. This cDNA encodes a 364 amino [50), who have shown that bradykinin-induced bron acid protein, which also has the characteristics of a seven choconstriction in the guinea-pig is inhibited by the B2 transmembrane domain G-protein coupled receptor. The antagonist o-Arg0[Hyp3,Thi5.S,o-Phe']-bradykinin. By di predicted amino acid sequence is 81% identical to the rat rect binding studies, we have shown that bradykinin receptor, and the three potential sites of glycosylation binding in the guinea-pig lung is similar to that found in present in the rat receptor are all conserved in the human other tissues [14), and shows a typical pattern of B2 one, suggesting high identity between the two species. receptors [18]. The failure of the B2 antagonists used by FARMER and eo-workers. [41] to antagonize bradykinin Analysis of the tissue distribution of the human B2 receptor suggests that the highest level of receptor· is in induced bronchoconstriction may be due to degradation kidney, lung and uterus. by carboxypeptidase N [25]. In fact, B2 antagonists have If cloning can determine the molecular weight and a short half-life in the guinea-pig lung in vivo [49]. give structural information as to the carbohydrate moie Moreover, the low afflnity of the B2 antagonists used can ties, it fails, however, to give any information as to the explain the weak inhibition observed. Indeed, Hoe 140 native form (i.e. glycosylated form). The production of [29, 31, 51, 52] and NPC 16731 [33], which have high anti-bradykinin antibodies would be useful to extend the affmities for kinin receptors, completely inhibit the action knowledge of the bradykinin receptor. Anti-bradykinin of bradykinin in guinea-pig airways in vivo or in vitro. antibodies might be regarded as a model structure for We have tested the action of NPC 17731 on bradykinin bradykinin receptors and can, therefore, be used as binding in the guinea-pig lung and trachea. This com immunogens to produce antibodies which are cross pound is able to completely displace the specific binding, reactive with the bradykinin receptor. Since all brady with an affinity comparable to that of bradykinin kinin antibodies described to date cross-react with des (Trifilieff A., Da Silva A., Landry Y., Gies J-P., submit Arg9-bradykinin [47], this anti-idiotypic approach cannot ted). Based on all of these observations, it would be be applied specifically to the B2 receptor. Recently, premature to conclude that bradykinin receptors in airways monoclonal anti-bradykinin antibodies have been de are different from other bradykinin B2 receptors. The existence of these putative B receptors needs confmna scribed (MBK 1, MBK 2, MBK 3) [48]. MBK 1 ap 3 pears to be specific for des-Arg9-bradykinin, and could be tion, perhaps using molecular cloning techniques. correlated with the B receptor system. MBK 3, which A comparaison of the relative potencies of Hoe 140, 1 does not bind to des-Arg9-bradykinin, has been correlated NPC 16731 and NPC 17731 in guinea-pig ileum, trachea with the B2 receptor system. MBK 2 did not conform and lung (table 2) reveals a similar binding affinity (in the to the profiles of any of the known kinin receptor nanomolar range) for the three compounds for B2 systems. Therefore, MBK 3 was used to produce receptors. In in vitro functional studies, all compounds KININS AND AIRWAYS 579

Table 2. - Relative potencies of the most potent B2 recaptor antagonists In different guinea-pig tissues Ileum Trachea Lung

Binding Functional Binding Functional Binding Functional affinity affinity affinity Antagonism AA Antagonism AA Antagonism AA

Hoe 140 nM [30J NC (53] No [53) nM [52] NC [52, 53) No [53) nM• Yes [52]

NPC 16731 nM [33) c [33] No [33) nM (33) c [33) No [33] NPC 17731 nM [34] c (34] No [34) nM• NC* No• nM*

•: parameters from our laboratory. nM: nanomolar; NC: non-competitive; C: competitive; AA: agonist activity. Functional parameters are measured in isolated organs, and represent the antagonism exerted by the compounds used against bradykinin-induced contraction. inhibited bradykinin-induced contraction in the ileum and subjects, but has little or no effect (cough and retrostemal trachea. In the trachea, Hoe 140 and NPC 17731 ap discomfort) in non-asthmatics. These observations have pear to act non-competitively, whereas NPC 16731 ex been reinforced by in vivo and in vitro studies. Brady erts a competitive antagonism. Therefore, the use of this kinin does not contract normal human bronchus [60], latter compound seems to be more appropriate for a study whereas bronchus from patients with airway obstruction of bradykinin receptors in airways. shows an increased sensitivity to bradykinin [61). These studies have recently been confirmed by Fuu.ER et al. [62]. Moreover, circulating plasma kinin is significantly Natural bradykinin antagonists increased in patients with severe bronchial asthma [63]. After allergen challenge in asthmatics, CmuSTIANSEN et al. Several natural compounds have been studied for po [64] found elevated amounts of tissue kallikrein and tential bradykinin antagonist activity (review [45]). The kinins in bronchoalveolar lavage fluids. This increase most promising natural antagonists have been extracted may be due to the slow rate of inhibition of human kal from the rhizome of Mandevilla velutina (Apocynaceae). likrein in the airway of asthmatic subjects [65). Inter Mandevilla velutina is a native plant of Brazil, and its preting lung volumes and capacities, NEWBALL et al. [59] rhizome is used in folk medicine for the treatment of in suggested that the bronchoconstrictor effect induced by flammatory states and for venomous snake bites. A crude intravenously injected bradykinin is localized at the level extract of its rhizome was found to functionally antago of the alveolar duct. This localization might lead to suf nize bradykinin-induced uterine contraction in the rat. ficient distortion or stimulation of pulmonary receptors to This action was reversible, and selective for bradykinin, cause the respiratory distress experienced by asthmatics. since the response to other agonists was unaffected [54]. This hypothesis is in agreement with the autoradiographic The extract was also found to be active in antagonizing localization of bradykinin receptors in human lung: the the contractile response induced by bradykinin and des smooth muscle of large airways is sparsely labelled, Arg9-bradykinin, mediated by both B and B receptors, in 1 2 whilst greater labelling was observed in the smaller air the rabbit vascular bed [55]. Purification of this extract ways [66]. gave five steroid glycoids (MV 8609, MV 8611, MV The mode of action of this bronchoconstrictor effect 8612, MV 9610), which antagonized the bradykinin-in in humans remains to be determined, but a cyclo duced contraction in rat uterus and guinea-pig ileum [56). oxygenase inhibitor (aspirin) does not affect broncho However, only MV 8612 appears to be a competitive constriction induced by bradykinin, whereas pre-inhalation antagonist, since the other compounds induce a decrease of ipratropium, a muscarinic antagonist, significantly re in the maximal response (54]. Despite the high doses duces this bronchoconstrictor response [62]. Moreover, (10-20 !lM) employed for these antagonistic actions, these bradykinin applied to mixed isolated human lung cells is findings strongly suggest that such steroids may consti unable to release prostaglandins and thromboxanes (67]. tute a new class of putative non-peptidic bradykinin an Therefore, the product of cyclo-oxygenase does not tagonists. appear to be involved in the bradykinin-induced bronchoconstriction in asthmatic subjects. Similar con Bradykinin and asthma clusions have been drawn for histamine [68]. The non adrenergic non-cholinergic (NANC) system seems to be Bronchoconstrictor effect involved in the action of kinins in the airways. But the contribution of NANC nerves is controversial regarding During the past 30 yrs, evidence that kinins are in the animal model used. It is not involved in the con volved in the pathogenesis of asthma has been accumu traction of ferret trachea [69], whereas it has been shown lating. Inhalation [57, 58], or intravenous injection [59], to play a role in the bradykinin-induced contraction of of bradykinin causes bronchoconstriction in asthmatic guinea-pig trachea (70]. In asthmatic patients, the 580 A. TRIFILIEFF, A. DA SILVA, J-P. GIBS

bronchoconstrictor effect of bradykinin is markedly in peptides in asthma. Kinins could possibly generate an hibited by cromolyn sodium and nedocromil sodium [71]. epithelium-derived relaxant factor (EpDRF) [82]. The Both of these drugs are able to inhibit the activation of EpDRF, which can be generated by many endogenous sensory nerves in airways [72]. Therefore, part of the substances (acetylcholine, serotonin, histamine) [83], may bronchoconstrictor response induced by bradykinin may be different from nitric oxide. It has not yet been iden be mediated via the NANC system. tified, but might be an inhibitory prostaglandin [83], and could regulate the bronchoconstrictor action of agonists. Epithelial damage observed in the respiratory tract of Bradykinin and inflammation asthmatic patients [84, 85] might perturb the liberation of EpDRF and would, therefore, explain the acute broncho Besides this bronchoconstrictor effect, bradykinin constriction observed in these patients. On the other could play a role in asthma via its pro-inflammatory hand, de novo synthesis of Bl receptors following tissue properties. The circulating level of immunoreactive damage [9, 10] could be invo ved in this hypersensitivity bradykinin increases three- to fourfold in a clinical model to kinins. However, a recent study has shown that the of acute inflammation (oral surgery), or in chronic 9 B1 agonist, des-Arg -bradykinin, has no effect on asth inflammation (rheumatoid arthritis) [73]. Furthermore, matic subjects [86]. myriad metabolic imbalances and minor traumas activate In addition, bradykinin could act on epithelium; elicit the cascade of events leading to the formation of kinins, a rapid and transient increase in ciliary beat frequency in and all components of this system have been reported cultured rabb.it tracheal epithelium (87], and increase from inflammatory exudates [74]. Allergic sheep, simi mucus secretion [88]. In cultured cells of human tracheal lar to asthmatic patients, respond to the inhalation of an mucosa, WIDDICOMBE et al. [89] showed that bradykinin antigen (Ascaris suum) with acute anaphylactic broncho could increase short-circuit current. These authors sug constriction, followed 6-8 h later by a late phase of gested that Na• absorption and Cl· secretion account for at increased airway resistance [75]. In addition, these ani least some of this increase. Both Na• absorption and CI· mals develop nonspecific airway hyperresponsiveness 2 secretion across the epithelium can lead to fluid move and 24 h following the challenge, and airway inflam ment into the airway from the lumen [90, 91 J. Auto mation as assessed by the number of oesinophils, radiographic studies [92], and selective application of neutrophils and macrophages in the bronchoalveolar bradykinin to submucosal or mucosal surfaces of dog lavages before and after the challenge by Ascaris suum. tracheal monolayers [93], have localized bradykinin A B antagonist, o-Arg0[Hyp3,o-Phe7]-bradykinin, had no 2 receptors on the apical and basolateral membranes of effect on the acute bronchial response to antigen, but epithelial cells. These receptors belong to the B;. subtype blocked bradykinin-induced bronchoconstriction in a dose [39, 94]. In human airways, the labelling of PHJBK was dependent manner. The antigen-induced increase in air sparse over the luminal surface of the epithelium, but was way responsiveness and the associated inflammatory dense in the lamina propria immediately subjacent to the responses that occur 2 h after the challenge were also basal epithelial cells layer [66]. blocked [76]. The sanie antagonist inhibited the bronchoconstriction, inflammation and mediator genera tion in the late phase responses (24 h) [77]. Moreover, Tachyphylaxis to bradykinin many inflammatory cells are able to generate kallikreins following stimulation by diverse compounds. Peritonial Repeated inhalation of bradykinin by asthmatic subjects rat mast cells, stimulated by catecholarnines, could lib is associated with a loss of bronchoconstrictor response erate an active kininogenase [78], and activation of hu [62, 95]. This tachyphylaxis may be due to the second man basophils by an anti-immunoglobin E (IgE) antibody ary generation of relaxant prostanoids, such as prostaglan generates kallikreins [79]. These data suggest a role for din ~ [96], but the inability of a cyclo-oxygenas inhibitor kinins in hyperresponsiveness and inflammation in the (flub1profen) to protect against the impairment of brady airways. kinin responsiveness provides convincing evidence that Bradykinin is able to increase microvascular leakage refractoriness to bradykinin does not result from the re of plasma proteins in guinea-pig airways by acting on lease of protective prostaglandins [95]. In dogs, brady a B2 receptor [50]. This effect on plasma leakage may kinin-induced bronchoconstriction is largely mediated by contribute significantly to airway oedema, and may be the activation of C-fibres [97], which liberate tachykinins involved in the development of bronchial hyperrespon (substance P, neurokinin A and B), which are potent siveness. In guinea-pigs, RooERS et al. [80] have dem bronchoconstrictor agents [98]. Depletion of these onstrated an interaction between kinin and the platelet neuropeptide stores could explain this tachyphylaxis, activating factor (PAF), which is a potent mediator of as has been proposed in humans for capsaicin [99], asthma [81). The late phase of this bradykinin-induced which had a similar effect to bradykinin on C-fibres leakage is mediated exclusively by PAF [80]. [100].

Effect of tracheal epithelium Bradykinin and upper airways

The actions of kinins on the tracheal epithelium might In recent years, evidence has accumulated to support be important in the understanding of the role of these the hypothesis that kinins may play a role in the KININS AND AIRWAYS 581

pathogenesis of inflammatory disease in the upper appropriate for use in humans. It is known that the fer airways. It has been demonstrated that these peptides are ret is a suitable model for studying infections with the generated in nasal secretions during allergic reactions influenza A virus. Study of this viral infection in this [101, 102). In addition, kinins are the only mediators animal showed that it is a convenient model to further detected in nasal secretions during experimental [103), or evaluate the role of kinins in the pathogenesis of upper natural rhinovirus colds [104). Kinin generation in these respiratory tract infections [113 ]. inflammatory responses correlates with the onset of symptoms. When adult volunteers, with and without na sal allergy, were challenged by the inhalation of brady Converting enzyme inhibitor induced-cough kinin, they developed unilateral obstruction of nasal and kinlns conductance, rhinorrhoea and a persistent sore throat [105, 106). These symptoms are independent of mast cell or A dry, non-productive cough and, less frequently, ex basophil mediator release [105, 107]. Similar studies, acerbation or development of asthma are well-recognized conducted by DoYLE et al. (108), were unable to entirely side-effects of angiotensin-converting enzyme (ACE) in confirm the symptoms evoked by bradykinin, but these hibitors (review [114]). Although its pathogenesis is un discrepancies may be a refle.ction of the different methods known, some properties of this class of drugs have been of challenge administration, and differences in subjectively described. ACE inhibitors may generate bronchoactive reported symptoms. mediators, such as prostaglandins (115], and may decrease Autoradiographic examination of human nasal mucosa the bronchodilatator effect of vasoactive intestinal peptide revealed that bradykinin binds specifically to small mus (VIP) or beta-agonists by preventing the accumulation of cular arteries, venous sinusoids and submucosal fibres cyclic adenosine monophosphate in smooth muscle [116]. [88). The identity of the fibres could not be determined, ACE inhibitors may also decrease the breakdown of but the authors suggested that they might be nociceptive substance P (117], and bradykinin [7], which are potent sensory nerve fibres. Other studies have shown that kinin bronchoconstrictor agents. Here, we review only the applied to human nasal mucosa produces an algesic re evidence for the kinin-mediated pharmacological activity sponse, which was not blocked by capsaicin desensitiza of ACE inhibitors. tion [109]. Therefore, sensory motor nerve fibres do not Despite one study, reporting that the antihypertensive appear to be involved in the action of kinins on the upper action of ACE inhibitors is not a kinin-dependent airways. In human nasal mucosa, kinins are also able mechanism [118], convincing evidence suggests that to increase vascular permeability, as measured by albumin bradykinin plays a major role in the side-effects of ACE and N-a-tosyl-L-arginine methyl ester (TAME)-esterase inhibitors. HoFFMAN et al. [119] demonstrated a stimula activities. This increase cannot be blocked by the com tion of vascular prostaglandin 12 synthesis by captopril, 0 3 7] petitive B2 receptor antagonist, o-Arg [Hyp ,o-Phe lisinopril and bradykinin, which was very strongly sup bradykinin, suggesting that B2 receptors are not involved pressed by a competitive B2 receptor antagonist (D Arg0[Hyp3,Thi5·8,o-Phe7]-bradykinin). Investigating the [110). The possibility of activation of B1 receptors can not be excluded. By studying glandular secretion in hu role of bradykinin in the infarct-limiting effect of the man nasal fragments in response to kinins, BARANIUK et ACE inhibitors, MAR.TORANA et al. [120] showed that the al. [88] reported the ability of B1 receptor antagonist (des effect of ramiprilat was reversed by the new B2 receptor Arg9-[Leu8]-bradykinin) to block this pro-secretory effect antagonist Hoe 140. These and other studies [121, 122) On the other hand, the failure of o-Arg0(Hyp3,o-Phe7] provide evidence for the involvement of kinins in the bradykinin to antagonize the effect of bradykinin on vas side-effects of ACE inhibitors. Thus, inhibition of ACE cular permeability, may be due to its degradation by would allow accumulation of bradykinin, provided that carboxypeptidase N [25], which has been shown to be this was a rate-limiting step in the metabolic pathway. one of the major enzymes in kinin degradation in nasal However, ACE inhibitors cause no [123], or only a mi secretions [111 ]. If a bradykinin-induced increase in nor increase [124, 125] in plasma level of bradyki glandular secretion, and possibly in vascular permeability, nin. Although this might, in part, be due to the technical seems to be mediated by the activation of B receptors problems in bradykinin determination, it might also sug 1 [88, 110), other effects on human nasal mucosa appear gest that ACE inhibitors induce an increase of tissue to be mediated by B2 receptors (109, 112). The cellular kinins rather than plasma kinins. events leading to all of the symptoms observed in nasal mucosa are still not known. The production of kinins during experimental or natu Bradykinin and lung cancer ral rhinovirus cold, together with their pharmacological properties, has led to the suggestion that these autacoids Lung cancer is the leading cause of cancer death, with may play a role in the pathogenesis of inflammatory dis approximately 90% of affected patients dying within one ease of the upper airways. In order to establish a defi year of diagnosis. On the basis of both clinical behav nite role for kinins in these disorders, however, it is iour and prognosis, lung cancers can be divided into small essential to intervene pharmacologically, in order to alter cell lung cancer (SCLC), and non-small cell lung cancer their activity and to observe the effects of such interven (NSCLC). Multiple neuropeptides, including vasopressin, tions on the symptoms. Unfortunately, many of the ap galanin, neurotensin, cholecystokinin, gastrin-releasing proaches for interfering with the kinin action are not peptide, and bradykinin, have been proposed to act as 582 A. TRIFILIEFF, A. DA SILVA, 1-P. GIES

paracrine or autocrine growth factors for SCLC and Conclusion NSCLC [126, 127]. The mitogenic action of bradykinin on human lung The effects of kinins on airways reviewed in this arti

fibroblasts has been known since the eighties [128, 129], cle are mediated mainly via activation of B2 receptors but at this period no possible role in carcinoma growth (table 3 and fig. 1). Concerning the contraction of tra had been described. A few years later, MAEoA et al. cheal smooth muscle, the putative B~ receptor [41, 42]

[130) reported, for the first time, the presence of brady can be classified as a B2 receptor L18, 49-52]. The kinin in human tumour ascites from a patient with gas knowledge of kinin receptors requires further investiga tions, but the recent cloning of a rat [40], and human B tric cancer. Thereafter, similar observations were reported 2 in various human malignant effusions [131], and in the receptor [46], and the development of potent antagonists plasma of advanced cancer patients [132]. [29-31, 33-35] lead us to expect substantial advances in The role of peptides in cancer has been more widely the understanding of the mechanism of kinin action. Ef studied in SCLC, probably since SCLC produce a greater fective hormone antagonists should have several charac number of neuropeptides (vasopressin, galanin, gastrin teristics, the principal being the possession of high affinity releasing peptide, and others) [133]. Moreover, SCLC are for the agonist receptor without any agonist activity. resisitant to chemotherapy, so that an increased under Receptor selectivity is also essential. Another criterion standing of SCLC growth regulation may identify novel for practical drug development is the long half-life of the targets for treatment. Bradykinin has been reported to antagonist in vivo, which generally correlates with a re· be the most potent peptide in increasing intracellular cal sistance to enzymatic degradation, especially critical for

cium in a number of SCLC cells lines [134], but other peptides. The new B2 bradykinin receptor antagonists peptides were also observed to produce a response [134, (Hoe 140, NPC 16731, and NPC 17731) possess all of 135]. Because of this heterogeneity, a specific bradyki these qualities, which makes them appropriate for further nin antagonist or antibody might not have a great anti investigation of the physiological and pathophysiological tumour effect. Future therapeutic strategies must role of kinins. recognize this heterogeneity in neuropeptide response, With regard to the mode of action of kinins in asthma, and the application of a combination of peptide antago the predominant mechanism (contraction of airway nists might be more useful. Alternatively, since all of smooth muscle, or intervention in the inflammatory these peptides utilize the same intracellular signal (i.e. an process) is still unknown. But the lack of a constrictor increase in calcium), another approach might be to inter effect due to bradykinin in airway smooth muscle of fere with this calcium signal. Promisingly, a recent study normal subjects (57, 58, 62) suggests that the broncho has shown that this strategy can be utilized success constrictor effect of bradykinin in asthmatic patients is fully using the experimental SCLC in a hamster model most likely indirect, probably mediated by inflammatory [136]. effects. In fact, kinins may play a role in all steps of What is the exact role of kinins in the clinical setting the inflammation cascade of asthma e.g. they can induce and in the pathogenesis of lung cancer? A dual action a hypersecretion of mucus [88], increase vascular perme could be suggested; due to their permeability-enhancing ability (50, 80], which accounts for the mobilization of properties, kinins could increase vascular permeability and inflammatory cells and oedema formation, and can also facilitate a greater supply of nutrients and oxygen to the act directly on inflammatory cells, such as mast cells [27, tumour cells [132]; or, alternatively, kinins could directly 44]. These different inflammatory actions could result in stimulate the proliferation of tumour cells [134,. 135]. the contraction of airway smooth muscle.

Table 3. - Action of kinlns in the airways

Site Action Receptor References

Bronchial smooth muscle Bronchoconstriction Ba [57-62, 86] Bronchorelaxation Ba [43] Vessels Vasodilatation Bl [7] Plasma exudation Ba [50, 80] Epithelium Secretion of mucus Bl (88] Generation of EpDRF Bl [82, 94] Increase in ciliary beat frequency B2 [87]

Mast cells Histamine secretion Protein G1-like [26, 27, 44] Eosinophils and neutrophils Proliferation Bz (76, 77] Cholinergic nerves Activation Bz (38, 62] NANC nerves Activation (rabbit, guinea-pig, dog) Bl [50, 71, 72]

EpDRF: epithelium derived relaxant factor; NANC: non-adrenergic non-cholinergic. Modified from [5] with pennission. KININS AND AIRWAYS 583

Histamine Mucus production Mucus production Mast cells

Eosinophlls ~ i :o p~ ~ '1'.~ '

Cholinergic 0~ ~ nerves C-fibre

Contraction

Fig. 1. - Schematic rcpresentaiion of possible levels of action of bradykinin In the airways. Bradykinin may induce the proliferation of neutrophils and eosinophils, the release of histamine from mast cells and the forma tion of oedema. Bradykinin may also increase mucus secretion by acting directly on submucosal glands or indirectly by the activation of C-fibres and cholinergic nerves. Finally, all of these inflammatory even ts could be followed by the contraction of airway smooth muscle. PAF: platelet activating factor; EpDRF: epit.he lium-derived relaxing factor. For references sec table 2. Modi!ied from (S) with permission.

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