THE INTERNATIONAL SYMPOSIUM
"EICOSANOIDS, ASPIRIN AND ASTHMA"
(partial) translation : | Français/French |  :-)
AIANE : Coordinating Center: Department of Medicine
University School of Medicine
31 066 Krakow, ul. Skawinska 8, Poland
tel. 004812 56 28 40, fax 004812 56 57 86

Principal Investigator: A. Szczeklik (Krakow)
Project Officer: : R. Pauwels (Ghent)

Participants:
M. Vaz Azevedo (Porto), S. Bianco (Milano), J. Bousquet (Montpellier),
B. Dahlén (Stockholm), S.T. Holgate (Southampton), G.J. Huchon (Paris),
L. Jager (Jena), M. Joseph (Lille), M.L. Kowalski (Lodz),
G. Kunkel, (Berlin), T.H. Lee (London), P. Magyar (Budapest),
G. Patriarca (Roma), R. Pauwels (Ghent), C. Picado (Barcelona),
T. Popov (Sofia), S. Rak (Uppsala), J. Rozniecki (~6dz),
M. Schmitz Schumann (Davos), B. Satkauskas (Vilnius), E.O. Terho (Turku),
D. Vervloet (Marseille), A. de Weck (Fribourg)

Coordinating Center Team: A. Szczeklik, E. Nizankowska, K. Sladek

About 300 clinicians, pharmacologists, molecular biologists and biochemists from 24 countries met together at the International Symposium "Eicosanoids, Aspirin and Asthma" on May 1 3 in Cracow. The meeting was organized by Professors Andrew Szczeklik and Richard Gryglewski on behalf of AIANE and Jagiellonian Medical Research Centre. The introductory lecture was delivered by Sir John Vane, who for his discovery of the mechanism of action of aspirin like drugs through their inhibition of prostaglandin biosynthesis, was awarded Nobel Prize in 1982. Invited world experts reviewed eicosanoids biochemistry, their metabolic pathways and the means of pharmacological intervention. A special session was devoted to expression of the eicosanoids genes. Presentation of basic mechanisms operating in bronchial asthma formed a background for detailed discussions on pathogenesis of aspirin intolerance. The clinical sessions turned attention to different symptomatology of aspirin induced asthma (AIA), its clinical course and diagnostic procedure. Methodological issues, including provocation challenges and measurement of the mediators in body fluids were addressed. New methods of treatment were thoroughly discussed with particular attention being paid to antileukotriene drugs.

Eicosanoid pathways

Sir John Vane reviewed the interactions between the diverse group of nonsteroidal antiinflammatory drugs (NSAIDs) and the enzyme cyclooxygenase which we now know exists in two isoforms: COX 1 and COX 2 (PGHS 1 and PGHS 2). The constitutive isoform, COX 1 has clear physiological function: its activation leads, for instance, to the production of prostacyclin which when released by the endothelium is anti thrombogenic and by the gastric mucosa is cytoprotective. The inducible isoform, COX 2 is activated by inflammatory stimuli and by cytokines in migratory and other cells, and probably the anti inflammatory actions of NSAID are due to inhibition of this isoform of COX. The range of activities of NSAIDs against COX 1 compared to COX 2 nicely explains the variations in the side effects of NSAID at their anti inflammatory doses. Piroxicam and indomethacin, which produce the highest gastrointestinal toxicity, have much higher potency against COX 1 than against COX 2. Drugs that strongly inhibit COX 2, but not COX 1, will have potent anti inflammatory activity with fewer side effects in the stomach and kidney. Nimesulid may be an example of such a drug. Newer anti COX 2 substances like L 745,337 have almost no side effects on stomach. Overexpression of COX 2, during ovulation and labour and in skin and colo rectal cancers, may be lowered by anti COX 2 drugs, creating, perhaps, the new therapeutic strategies in some pathological states in humans. Thus, identification of selective inhibition of COX 1 and COX 2 will not only provide an opportunity to test new hypotheses but also lead to advances in therapy.

The three dimensional structure of COX, or prostaglandin H synthase (PGHS), was summarized by Daniel Picot (Paris, France). The catalytic domain of PGHS contains the two main activities of the protein: the cyclooxygenase, which catalyses the interconversion of arachidonic acid into prostaglandin G2 and the peroxidase, which reduces PGG2 in prostaglandin H2. Theses two activities are spatially distinct. Another domain, the membrane binding domain, forms an opening to a long and narrow channel by which the substrate, arachidonic acid, enters the cyclooxygenase active site. The third domain EGF like module with unknown function, probably stabilizes two subunits of PGHS dimer. The long and narrow COX channel plays an important role in a mechanism of action of NSAIDs. From the powerful method of protein crystallography we now know that inhibitors like aspirin, flurbiprofen or indomethacin could be deeply buried in this channel. Since 1991, when the second isoenzyme of PGHS was discovered, many laboratories have been working on structural and functional differences of these two proteins. So far, sequence comparison has shown that the two structures are very similar, the difference in the active site region is minimal, although there is a possibility of selective inhibition of the two isoforms.

Until recently, little was known about the intracellular sites of localization of the enzymes responsible for eicosanoid biosynthesis (PLA2, COX. 5 LO. etc.). Marc Peters Golden (Ann Arbor, MI, USA) presented recent work from his own and other laboratories, which refuted the existing paradigm that the plasma cell membrane is a key site of localisation of these enzymes. He demonstrated that the nucleus is a centrally important site for eicosanoids synthesis and action. Initiation of leukotriene (LT) synthesis from arachidonic acid requires the interaction of 5 lipooxygenase (5 LO) and its activating protein (FLAP). Anthony Ford Hutchinson (Dorval, QUE, Canada), who discovered FLAP, gave during the Symposium, a description of its role in the initial stage of leukotriene biosynthesis and presented structures of new compounds which interfere with leukotriene generation and action. It is now known that FLAP is constitutively localized primarily at the nuclear envelope and that 5 LO redistributed from cytosolic or euchromatin region of the nucleus is also present at that site following activation. Interestingly, a number of other eicosanoid forming enzymes have also been localized at the nuclear envelope, including COX 2, thromboxane A2 synthase and LTC4 synthase. Moreover, cytosolic PLA2, the important arachidonyl selective phospholipase A2 translocates to the nuclear envelope upon activation in some cells. Marc Peters Golden suggested that the nuclear envelope has been organized to serve as the site at which many of the enzymes mediating arachidonic acid hydrolysis and metabolism are clustered.

Arachidonic acid could be metabolised not only by COX 1 or COX 2 but also via cytochrome P450 route. John McGiff (Valhalla, NY, USA) pointed to the possible interactions of that two distinct metabolic pathways of arachidonic acid. He demonstrated that in the rat kidney angiotensin II stimulates the generation of Tumor Necrosis Factor (TNFa) which in conjunction with lipopolysaccharide (LPS) switches the predominant pathway of oxygenation of arachidonate from cytochrome P450 (CYP) to the cyclooxygenase route, meaning the replacement of the major renal AA metabolite, i.e. 20 hydroxyeicosatetraenoic acid (20-HETE) with prostaglandin E2. Would cytotoxins be capable of switching their routes of AA metabolism in other organs, then it might well be that in patients with aspirin induced asthma their lungs exposed to cytotoxins or viral toxins did generated predominantly PGE2, becoming thus "PGE2 addicted". Any COX inhibitor by removing PGE2 could not only produce passive bronchoconstriction because of lack of PGE2, but also it might increase the efficacy of the CYP route with overproduction of bronchoconstrictor 20 HETE. This could be a new hypothetical mechanism of aspirin induced asthma.

Paola Patrignani (Chieti, Italy) presented alternative mechanisms of F2 isoprostane biosynthesis in humans. Isoprostanes are prostaglandin isomers formed in situ on cell membrane phospholipids by a non enzymatic, free radical catalyzed lipid peroxidation of arachidonic acid. The most abundant PGF2 isprostane produced in man is 8 epi PGF2a. It has vasoconstrictor and mitogenic activity. Dr Patrignani demonstrated the potential for a different, enzymatic, cyclooxygenase dependent component in isoprostane biosynthesis during platelet and monocyte activation as both dexamethasone, an inhibitor of PGHS 2 biosynthesis as well as L 745,337, a selective inhibitor of the cyclooxygenase activity of PGHS 2, reduced 8 epi PGF2a production in response to LPS. These novel findings suggest that inhibition of the biosynthesis of 8 epi PGF2a may integrate into the spectrum of pharmacological effects of new selective PGHS 2 inhibitors.

The possibile interactions between eicosanoids and nitric oxide (NO) in the experimental acute lung injury were discussed by Richard Gryglewski (Cracow, Poland). Overproduction of NO by the inducible izoenzyme (iNOS) is supposed to be responsible for vasoplegia in endotoxic shock. NOS inhibitors like NG-monomethyl L arginine were introduced into clinic for treatment of septic shock. Dr Gryglewski reported, that inhibition of NOS prior to injection of lipopolysaccharide (LPS) from E. coli to rats is detrimental, and leads to sudden death among the symptoms of acute injury to the lung. This LPS pneumotoxicity seems to be mediated by thromboxane A2; it could be opposed by pneumoprotective action of NO. Conclusion is, that in endotoxic lung, NO fights back the toxicity of arachidonate metabolites.

Expression of eicosanoid genes

In the opening lecture, Peter Barnes (London, UK) pointed out that COX 2 protein is induced in human lung epithelial cells, and probably several other cell types, after exposure to the proinflammatory cytokines, such as IFNg, IL 1ß, TNFa. Induction of COX 2 is accompanied by the release of the COX metabolites PGE2, PGF2a, 6 0XO PGF1a and minimal amounts of TXB2. Its increased expression is preceded by an increase in COX 2 mRNA and an increased rate transcription, and inhibited by dexamethasone. Transcription factor NF KB plays a key role in the expression of COX 2. There are at least two KB sites in the promoter region of human COX 2 and it appears that the upstream site has the leading regulatory role. On the opposite, glucocorticoids inhibit NF KB activity, by increasing synthesis of the inhibitory protein IKB a. Thus, glucocorticoids may inhibit COX 2 expression by blicking the activation of NF KB by different proinflammatory cytokines. Dr Barnes stressed that from clinical point of view, airway epithelial cells are activated by inhaled oxidants like ozone or NO, as well as rhinoviruses, the commonest precipitators of asthmatic exacerbations. All of them activate NF KB, which in turn, increases the transcription of inflammatory genes, such as inducible NO synthase, COX 2 and chemokines and thus raises the production of NO, eicosanoids and proinflammatory cytokines.

Lysophosphatidylcholine might be an important signal molecule involved in the regulation of vasoprotective endothelial genes, suggested Kenneth Wu (Houston, TX, USA). He presented evidence that IysoPC induces COX 2 in human endothelial cells by a transcriptional mechanism. Adenovirus mediated transfer of cyclooxygenase gene might prevent artherial thrombosis. Dr Wu presented results of his experiments in which delivery of recombinant adenovirus, containing human COX 1 gene, restored COX 1 activity, augmented prostacyclin synthesis and prevented thrombus formation in a porcine angioplasty model.

Numerous epidemiological and animal studies show that NSAIDs, inhibitors of both COX 1 and COX 2, can be effective anti neoplastic agents. Daniel L.Simmons (Provo, UT, USA) presented experimental evidence indicating that NSAIDs stimulate apoptosis, or programmed cell death, through induction of certain proteins. At present neither do we know which COX isoenzymes need to be inhibited to cause apoptosis, nor which metabolites produced by COX are critical for this process to occur.

The ability to remove or alter with precision a single one of the thousands of genes in the body and to transmit this mutation to all subsequent progeny was a science fiction dream only a few years ago. But today this technique is part of a routine procedure for creating animal models that can be used to study the patophysiology and therapy of diseases in humans. The experiments of Colin D. Funk (Philadelphia, PA, USA) with 5 LO deficient (5 LO / ) mice by gene targeting provided convincing evidence for the involvement of 5 LO products in allergic inflammation. Although 5 LO /-mice displays no obvious abnormalities under normal physiological conditions, following ovalbumin sensitisation and challenge its bronchial hyperresponsiveness as well as percentage of eosinophils in BAL fluid become significantly reduced. These results point out to the importance for the involvement of 5 LO products in the development of airway hyperresponsiveness and inflammatory cell recruitment.

Basic mechanisms in bronchial asthma as related to aspirin intolerance A series of state of the art lectures in this session created a solid background for further presentations on pathogenesis of AIA. William Cookson (Oxford, UK) covered the most recent developments in the rapidly growing field of genetics of asthma, Leo Fabbri (Ferrara, Italy) addressed the issue of inflammatory process affecting airways, John Oates (Nashville, TN, USA) discussed in detail the action of PGE2 on immune and allergic responses, including new data on prostaglandin receptors in bronchi, Klaus Rabe (Hamburg, Germany) reviewed pharmacology of eosinophils with special reference to leukotriene production, while Paul O'Byrne (Hamilton, ONT, Canada) summarized evidence for participation of LTs in allergen and exercise-induced asthma, suggesting that exercise refractoriness, abolished by pretreatment with indomethacin, may be caused by LTs stimulated prostaglandin inhibitory release.

There is more to asthma than just invasion by inflammatory cells. The word is: remodelling. It is revealed, according to Jean Bousquet (Montpellier, France) by: pseudo thickening of basement membrane due to collagen deposition, fragmentation of superficial elastic fibers, hyperplasia of collagen fibers as well as abnormal fibronectin, laminin and hyaluronic acid deposition in airways, and an increase of growth factors in asthma epithelium. Airways remodelling may contribute to a steeper rate of decline of FEV1 in intrinsic asthma (as is frequently the case in AIA) than in allergic asthma of earlier onset. Thus, asthma means also intensive process of healing and repair.

Viral infections are emerging as the most common factor of morbidity attributable to asthmatic exacerbations and they might even share with allergen a common mechanistic pathway in airway response. Frans Nijkamp (Utrecht, Netherlands) demonstrated involvement of nitric oxide in his experimental model of parainfluenza 3 virus induced airway inflammation. He pointed out that during contraction of bronchi, both nitric oxide and prostaglandin E2 are produced. Nitric oxide reacts with the reactive oxygen species formed during arachidonic acid conversion, and takes away the feedback system; this action further promotes the production of prostaglandin E2. Robert Lemanske (Madison, WI, USA) suggested that the mechanism by which both allergen exposure and viral infection could induce airway obstruction is through augmentation of cytokine production that results in upregulation of resident or inflammatory cell functions. Genetic susceptibility to virus induced chronic airway dysfunction is characterised by high gene expression of IL 4 and IL 5 in airways and low gene expression of IL 2 and IF y (so called TH2 vs TH1 profile predominating). The increased IL 5 production leads to enhanced eosinophil recruitment which contributes to the observed alterations in airway physiologic responses.

Pathogenesis of AIA

Attacks of asthma precipitated by aspirin like drugs are due to the inhibition of COX in airways of the sensitive patients. This idea, first proposed 22 years ago, has been well established. It is based on the following evidence: 1) In aspirin-sensitive patients NSAIDs with anti cyclooxygenase activity invariably precipitate bronchoconstriction, while NSAIDs deprived of this activity are well tolerated; 2) There is positive correlation between the potency of NSAIDs to inhibit COX in vitro and their potency to induce asthmatic attacks; 3) After aspirin desensitization, cross desensitisation to other NSAIDs, that inhibit COX, also occurs.

Over the last few years cysteine leukotrienes (cys LTs) emerged as major mediators in AIA. Indeed, following aspirin-precipitated reactions their levels rise in nasal secretions, urine and lungs. Andrew Szczeklik (Cracow, Poland) presented evidence that aspirin triggered cys LTs rise in airways is specific for AIA. He summarized results of the joint study, carried out with John Oates group of Vanderbilt University, in which bronchial segmental challenge with L lysine aspirin was performed in 11 patients with AIA and 14 patients tolerant to aspirin (ATA). At baseline the two groups did not differ with respect to BAL fluid concentrations of COX products, cys LTs or IL 5. Fifteen minutes after aspirin instillation there was statistically significant rise in cys LTs, IL 5 and eosinophil number in AIA, but not in ATA patients. Suprisingly, in the groups studied, aspirin exerted different effect on COX metabolites. It depressed PGE2 and TXB2 in both groups, however PGD2, PGF2a and 9a 11 p PGF2a decreased only in ATA patients. Such a characteristic disturbance in eicosanoid balance, produced by aspirin in patients intolerant to this drug, might explain precipitation of asthma attacks. These results of Cracow Nashville team found support in observations presented by Sally Wenzel (Denver, CO, USA). She evaluated 5 AIA and 5 ATA patients with bronchoalveolar lavage before and after endobronchial instillation of indomethacin. The drug produced a marked increase of cys LTs only in AIA patients. PGD2 levels became depressed only in ATA, while AIA subjects demonstrated highlyvariable response. Interestingly, a generalized activation of phospholipases, manifested by increase in BAL fluid arachidonic acid levels was observed in AIA alone.

Two speakers addressed the issue of the cellular source of cys LTs. Tak Lee (London, UK) in collaboration with Michael Schmitz (Davos, Switzelland) performed airway mucosal blopsies in AIA individuals. Their results indicate that AIA patients have an increased number of mast cells and eosinophils compared to aspirin tolerant asthmatics. Since these cells are abundant sources of cys LTs, they might be responsible, suggested the authors, for the enhanced LTs production seen in this condition. Interestingly, there was no difference between AIA and ATA groups with relation to COX 1 and COX 2 expression in the bronchial biopsy samples. Tony Sampson (Southampton, UK) confirmed the finding of exaggerated eosinophilia, but reported that AIA bronchial mucosa had a trend to lower counts of tryptase positive mast cells compared to AIA. In his study, performed in collaboration with Cracow and Harvard University (K.F. Austen) groups, he observed a 4 fold higher count of cells positive for IL 5 in AIA, while staining for IL 3 and GM CSF was not different between the groups. In both groups the mean proportion of eosinophils expressing 5 LO or FLAP was high, while the mean proportion of mast cells expressing 5 LO or FLAP was low. This seems to suggest that chronic eosinophilia is the driving force behind cys LTs overproduction in the AIA lung.

In a pharmacological study with the potent cys LTs receptor antagonis, MK0679, Barbro Dahlén (Stockholm, Sweden) demonstrated that this compound caused a significant protection against the airway obstruction induced by inhalation of Iysine aspirin. She measured in urine a PGD2 metabolite, 9a110 PGF2a. In basal state, the metabolite's urinary levels, contrary to LTE4, were not elevated in AIA patients. They raised, however, following aspirin challenge, perhaps due to release of PGD2 from mast cells. In 1988 Sebastiano Bianco (Milano, Italy) reported on the protective effects of inhaled frusemide against various bronchoconstrictor stimuli in asthma. At the Symposium, he discussed the mechanism of the beneficial effect of inhaled loop diuretics, and suggested that it may depend on release of bronchoprotective prostaglandin, e.g. PGE2. This possibility could be of indirect relevance to AIA, since inhaled PGE2 was recently demonstrated, independently by Milano's and Cracow's groups, to offer remarkable protection against aspirin precipitated attacks of asthma.

Clinical course, diagnosis and management of AIA

The last day of the Symposium, devoted to clinical aspects of AIA, started with tribute paid to Dr Max Samter (Chicago, IL, USA), present in the audience, who made important contributions to our understanding of AIA. Then Eva NizanLowska (Cracow, Poland) presented on behalf of AIANE investigators, preliminary assessment of the clinical results, registered in the specially developed database. So far, data on 313 aspirin sensitive asthmatics treated by 15 centers in 9 European countries were received by the Coordinating Center. This constitutes the largest collection of AIA patients in the world. There were 217 women and 96 men; the predominance of women being observed in all countries. The mean age of patients was 48 years. In majority of them, the first symptoms of aspirin intolerance appeared in the third or fourth decade of life. The characteristic clinical course was described. Of all patients, 70% had evident abnormalities on CT scan of paranasal sinuses, 80% had to be treated with corticosteroids. Evaluation of the rich clinical data has just begun. In Japan, said Susumu Suetsugu (Nagoya), AIA is relatively common clinical syndrome, affecting 10% of adult asthmatic population. Japanese Society for study of AIA was founded in 1979; it wants to strengthen the link with AIANE. Provocation challenges are becoming popular, and noramidopyrine inhalation testing is the most common procedure employed in Japan.

Chronic inflammatory process in the nose, leading to nasal polyposis, is an integral component of AIA clinical picture. Niels Mygind (Copenhagen, Denmark) discussed histology of nasal polyps and features of the immune inflammation, characterized by prominent infiltration with CD4+ cells, increased formation of cytokines in the epithelial cells and upregulation of VCAM 1 in endothelial cells. Treatment of nasal polyps consists of intranasal steroids, systemic steroids and polypectomy alone or in combination. In recalcitrant cases an ethmoidectomy and continuous prednisolone therapy is indicated. Cesar Picado (Barcelona, Spain) assessed the diagnostic value of acoustic rhinomanometry, a method measuring acoustic reflections from the nasal cavity of a sound pulse. Change in nasal volume due to congestion precipitated by 25 mg L lysine aspirin instilled into each nostrils, were measured. This method of moderate sensitivity can be useful in studying AIA patients with severe bronchial obstruction in whom neither oral nor inhaled challenge can be performed.

In a significant proportion of the patients with AIA discrete signs of autoimmunity were recently reportedby the Cracow's group. These findings were supported by Michel Joseph, who with his colleagues in Lille, France, identified serum autoantibodies against a major 55 kD antigen present in endothelial cells and platelets. These autoantibodies were detected in 70 % of patients with AIA. Autoimmune symptoms only occasionally prompt the patients to seek medical attention, either because they are of weak intensity or because they are overshadowed by major problems of asthma. Donald Stevenson, during discussion of this presentation, remarked that severe asthmatics are under strong corticotherapy which may confine autoimmune symptoms below detectable levels. Three presentations addressed specific therapeutic aspects of AIA. Is it possible to treat the underlying inflammation in AIA using the same drug that precipitates respiratory reactions? The answer is yes, and the word is: desensitization. Recent results presented by Donald Stevenson (La Jolla, CA, USA) point to efficacy of aspirin desensitization followed by chronic aspirin administration. This approach decreased the intensity of sinusitis, need for polypectomies/sinus surgery and hospitalization. At the same time the smell returned and steroids dose could be reduced. The influence of steroids on the leukotriene synthesis was rewieved by Philippe Godard (Montpellier, France). The results of his in vitro studies, using blood neutrophils and monocytes, led him to the conclusion that glucocorticosteroids act, at least, on three different levels: they lower the phospholipid bioavailability, they inhibit PLA2 and 5 LO. These experimental studies were then extended to the clinical setting in which an expert system, developed in Montpellier, has been succesfully used. In a cohort of severe asthmatic patients, treated for at least a year with a high dose of inhaled and oral steroids, blockade of arachidonic acid cascade was far from being complete, and LTE4 was still released into urine. Perhaps, the use of anti leukotriene compounds might improve the insight into these complex interactions.

Leukotriene receptor antagonists and leukotriene biosynthesis inhibitors have been shown to attenuate the airway obstruction induced by challenge with: allergen, exercise, dry cold air, PAF and aspirin. Anti leukotriene compounds might find a place in chronic treatment of AIA, said Sven Erik Dahlén (Stockholm, Sweden). After reviewing various classes of these compounds, he presented the results of the Stockholm Cracow crossover, double blind study in which 40 AIA patients (20 Swedes, 20 Poles) received two 6 week treatments with Zileuton, a 5 LO inhibitor, or placebo. It is noteworthy that 95% of the patients were on chronic corticotherapy. Zileuton caused both acute and chronic improvement in pulmonary function, reduction in ß agonist use, return of the sensation of smell, and decrease in the bronchial hyperresponsiveness to histamine, possibly reflecting inhibition of the inflammatory process. The improvements observed in this first study were particularly encouraging, since at the dose level used, the 5 LO inhibitor caused only partial reduction of leukotriene biosynthesis, measured as urinary excretion of LTE4.

Wealth of new data and prolific ideas presented at the Symposium stirred a great deal of vivid discussion. These were diligently coordinated by chairpersons of the sessions, Drs: M. Balazy (Valhalla, NY), S. Chyrek Borowska (Bialystok), W. Droszcz (Warsaw), R. Dworski (Nashville, TN), S. Hurd (Washington, DC), M. Kowalski (Lodz), P. Kuna (T odz), J. Malolepszy (WrocIaw), J. Musial (Cracow), W. Pierzchala (Katowice), T. Plusa (Warsaw), E. Rogala (Zabrze), B. Romanski (Bydgoszcz), K Roszkowski (Warsaw). M. Schmitz Schumann (Davos), K. Sladek (Cracow), M. Taniguchi (Nagoya), J. Zielinski (Warsaw).

The discussions lasted till late evenings, in the lovely medieval and Renaissance districts of Cracow. And there was more to the Symposium! Space does not permit to review 67 poster presentations, coming from as distant places as Australia and India to as close as Belarus. We might refer to them in the forthcoming issues of our Newsletter.

The proceedings of the Symposium will be published as the book in the prestigious series Lung Biology in Health and Disease, executive editor: Dr Claude Lenfant, NIH, USA.

The organizers gratefully acknowledge the financial support of AIANE, the State Research Council of Poland, and the pharmaceutical companies: Abbott, Astra, GlaxoWellcome and Merck.

Eva Nizankowska, Grayna Bochenek and Andrew Szczeklik
AlANE's Coordinating Center

Remarques, conseils et suggestions sont les bienvenus; ils seront publiés dans le courrier des lecteurs. Ecrivez/Write to Professeur Philippe Godard ou à la liste de diffusion/Asmanet Forum Asma-L

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