European Journal of Pharmacology (v.533, #1-3)

Preface by G. Folkerts (1).

Corticosteroids: The drugs to beat by Peter J. Barnes (2-14).
Corticosteroids are the most effective anti-inflammatory therapy for asthma and other chronic inflammatory and immune diseases. Recently new insights have been gained into the molecular mechanisms whereby corticosteroids suppress inflammation. Inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-κB and activator protein-1. These transcription factors bind to and activate coactivator molecules, which acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex. Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase, which inhibits MAP kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side effects. In some patients with steroid-resistant asthma there are abnormalities in GR signalling pathways. In chronic obstructive pulmonary disease (COPD) patients and asthmatic patients who smoke HDAC2 is markedly impaired as a result of oxidative and nitrative stress so that inflammation is resistant to the anti-inflammatory effects of corticosteroids. Corticosteroids are likely to remain the mainstay of asthma therapy and new therapeutic strategies may reverse the corticosteroid insensitivity in COPD and severe asthma.
Keywords: Glucocorticoid receptor; Transcription factor; Histone deacetylase; Histone acetyltransferase; Nuclear factor-κB; Inflammation; Asthma; COPD (chronic obstructive pulmonary disease); Corticosteroid resistance;

β2-adrenoceptor agonists are the first-line treatment of asthma and chronic obstructive pulmonary disease (COPD), in which a short-acting β2-adrenoceptor agonist is used as required for relief of bronchoconstriction. A long-acting β2-adrenoceptor agonist may be added to an inhaled corticosteroid as step 3 in the management of chronic asthma. Long-acting β2-adrenoceptor agonists may also be added in treatment of COPD. This review examines the beneficial and detrimental effects of β2-adrenoceptor agonists. The beneficial effects of β2-adrenoceptor agonists are mainly derived from their bronchodilator activity which relieves the bronchiolar narrowing and improves air flow. The potential anti-inflammatory actions of stabilizing mast cell degranulation and release of inflammatory and bronchoconstrictor mediators, is considered. Other potential beneficial responses include improvements in mucociliary clearance and inhibition of extravasation of plasma proteins that is involved in oedema formation in asthma. The side effects of β2-adrenoceptor agonists are primarily related to β2-adrenoceptor-mediated responses at sites outside the airways. Of major concern has been the development of tolerance and this is discussed in relation to incidence of increased morbidity and mortality to asthma over the past three decades. A clinical aspect of β2-adrenoceptor pharmacology in recent years has been the recognition of genetic polymorphism of the receptor and how this affects responses to and tolerance to β2-adrenoceptor agonists. A controversial feature of β2-adrenoceptor agonists is their stereoisomerism and whether the inactive (S)-isomer of salbutamol had detrimental actions in the commercially used racemate. The consensus is that despite these adverse properties, β2-adrenoceptor agonist remains the most useful pharmacological agents in the management of asthma and COPD.
Keywords: β-adrenoceptor; Airway; Bronchodilatation; Mucociliary clearance; Inflammation; Stereoisomerism; Genetic polymorphism;

The combination of inhaled corticosteroids and long-acting β2-adrenoceptor agonists is increasingly used as maintenance therapy in patients with moderate to severe asthma or chronic obstructive pulmonary disease (COPD). The main effect of inhaled corticosteroids is thought to be mediated through suppression of airway inflammation, while long-acting β2-adrenoceptor agonists are thought to work by inducing bronchodilation. However, there is emerging data to indicate that these two classes of drugs interact positively with each other, leading to added or perhaps synergistic benefits for patients. Corticosteroids enhance the expression of β2-adrenoceptor, thus providing protection against desensitization and development of tolerance to β2-adrenoceptor agonists, which may occur with prolonged use of these medications. Long-acting β2-adrenoceptor agonists, on the other hand, may amplify the anti-inflammatory effects of corticosteroids by accelerating nuclear translocation of the glucocorticoid receptor complex, and enhancing transcription and expression of steroid-inducible genes in pro-inflammatory cells. In clinical trials, corticosteroids in combination with long-acting β2-adrenoceptor agonists reduce exacerbation rates, and improve lung function and health status of patients with moderate to severe asthma or COPD beyond that achieved by individual component therapy. Their effects on mortality are unknown. There is a large clinical trial currently underway, which will provide mortality data by the year 2006. On balance, clinical evidence supports the use of combination therapy in moderate to severe asthma and COPD.
Keywords: Glucocorticoid; Adrenergic beta-agonist; COPD; Asthma;

Anticholinergic agents in asthma and COPD by Nicholas J. Gross (36-39).
Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4–8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1–2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients.
Keywords: Muscarinic receptor; Antimuscarinic agent; COPD (Chronic Obstructive Pulmonary disease); Asthma; Ipratropium; Tiotropium;

Twenty five years after the structure elucidation of slow reacting substance of anaphylaxis, antileukotrienes are established as a new therapeutic modality in asthma. The chapter reviews the biochemistry and pharmacology of leukotrienes and antileukotrienes with particular focus on the different usage of antileukotrienes for treatment of asthma and rhinitis in Europe and the US. Further research needs and new areas for leukotriene involvement in respiratory diseases are also discussed.
Keywords: Asthma; Allergic rhinitis; Leukotriene; Glucocorticosteroid; Bronchoprovocation;

Control by cholinergic mechanisms by Kurt Racké; Uwe R. Juergens; Sonja Matthiesen (57-68).
In the respiratory tract acetylcholine is neurotransmitter in ganglia and postganglionic parasympathetic nerves, but in addition is paracrine mediator released from various non-neuronal cells. Almost every cell type present in the respiratory tract expresses nicotinic and muscarinic receptors and therefore appears to be a target for acetylcholine. The present review describes the mechanisms of synthesis and release of acetylcholine from neuronal and non-neuronal cells and the differential control mechanisms. The different cholinoceptors, multiple nicotinic and muscarinic receptors and their signalling are outlined and their involvement in the modulation of the function of various target cells, smooth muscles, nerves, surface epithelial, secretory cells, fibroblasts and inflammatory cells is discussed in detail.
Keywords: Acetylcholine; Airway; Muscarinic receptor; Nicotinic receptor; Airway smooth muscle;

Histamine receptors are hot in immunopharmacology by Cezmi A. Akdis; F. Estelle R. Simons (69-76).
In addition to its well-characterized effects in the acute allergic inflammatory responses, histamine has been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and other functions leading to chronic inflammation. Histamine also regulates dendritic cells, T cells and B cells, as well as related antibody isotype responses. In addition, acting through its receptor 2, histamine positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The diverse effects of histamine on immune regulation appear to be due to differential expression and regulation of 4 types of histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors for histamine is highly decisive for the biological effects of histamine and drugs that target histamine receptors. This article highlights recent discoveries in histamine immunobiology and discusses their relevance in allergic inflammation.
Keywords: Histamine; T cell; B cell; Histamine receptor; Inflammation; Allergy; Asthma;

Adenosine in the airways: Implications and applications by Lucia Spicuzza; Giuseppe Di Maria; Riccardo Polosa (77-88).
Adenosine in a signaling nucleoside eliciting many physiological responses. Elevated levels of adenosine have been found in bronchoalveolar lavage, blood and exhaled breath condensate of patients with asthma a condition characterized by chronic airway inflammation. In addition, inhaled adenosine-5′-monophosphate induces bronchoconstriction in asthmatics but not in normal subjects. Studies on animals and humans have shown that bronchoconstriction is most likely due to the release of inflammatory mediators from mast cells. However a number of evidences suggest that adenosine modulates the function of many other cells involved in airway inflammation such as neutrophils, eosinophils, lymphocytes and macrophages. Although this clear pro-inflammatory role in the airways, adenosine may activate also protective mechanisms particularly against lung injury. For many years this dual role of adenosine in the respiratory system has represented an enigma, and only recently it has become clear that biological functions of adenosine are mediated by four distinct subtypes of receptors (A1, A2A, A2B, and A3) and that biological responses are determined by the different pattern of receptors distribution in specific cells. Therefore, pharmacological modulation of adenosine receptors, particularly A2B, may represent a novel therapeutic approach for inflammatory diseases. Moreover, as bronchial response to adenosine strictly reflects airway inflammation in asthma, bronchial challenge with adenosine is considered a valuable clinical tool to monitor airway inflammation, to follow the response to anti-inflammatory treatments and to help in the diagnostic discrimination between asthma and chronic obstructive lung disease.
Keywords: Adenosine; Asthma; AMP; Mast cells; Airway inflammation;

Prostanoids as pharmacological targets in COPD and asthma by Stéphanie Rolin; Bernard Masereel; Jean-Michel Dogné (89-100).
COPD (Chronic Obstructive Pulmonary Disease) and bronchial asthma are two severe lung diseases which represent a major problem of world public health. Leukotrienes and prostanoids play an important role in the pathogenesis of pulmonary diseases. Prostanoids: prostaglandins (PGs) and thromboxane A2 (TXA2), the cyclooxygenase metabolites of arachidonic acid are implicated in the inflammatory cascade that occurs in asthmatic airways. Recently, the roles played by isoprostanes or prostaglandin-like compounds nonenzymatically generated via peroxidation of membrane phospholipids by reactive oxygen species, in particular F2-isoprostanes, in pulmonary pathophysiology have been highlighted. This article aims to provide an overview of the role of prostanoids and isoprostanes in the pathogenesis of COPD and asthma and to discuss the pharmacological strategies developed in prevention and/or treatment of these pathologies.
Keywords: Asthma; Chronic obstructive pulmonary disease; Prostanoid; Isoprostanes;

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARγ regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Synthetic PPARγ agonists have been developed, such as the thiazolidinediones rosiglitazone and pioglitazone. These act as insulin sensitizers and are used in the treatment of type 2 diabetes. Recently however, PPARγ ligands have been implicated as regulators of cellular inflammatory and immune responses. They are thought to exert anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes. Several studies have demonstrated that PPARγ ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the airways. This review will outline the anti-inflammatory effects of synthetic and endogenous PPARγ ligands and discuss their potential therapeutic effects in animal models of inflammatory airway disease.
Keywords: PPARγ; Airway; Inflammation; Asthma;

Phosphodiesterases hydrolyse intracellular cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into inactive 5′ monophosphates, and exist as 11 families. They are found in a variety of inflammatory and structural cells. Inhibitors of PDEs allow the elevation of cAMP and cGMP which lead to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation or of immune responses. PDE4 inhibitors specifically prevent the hydrolysis of cAMP, and PDE4 isozymes are present in inflammatory cells. Selective PDE4 inhibitors have broad spectrum anti-inflammatory effects such as inhibition of cell trafficking, cytokine and chemokine release from inflammatory cells, such as neutrophils, eosinophils, macrophages and T cells. The second generation PDE4 inhibitors, cilomilast and roflumilast, have reached clinical trial stage and have some demonstrable beneficial effects in asthma and chronic obstructive pulmonary disease (COPD). The effectiveness of these PDE4 inhibitors may be limited by their clinical potency using doses that have minimal effects on nausea and vomiting. Topical administration of PDE4 inhibitors may provide a wider effective to side-effect profile. Development of inhibitors of other PDE classes, combined with PDE4 inhibition, may be another way forward. PDE5 is an inactivator of cGMP and may have beneficial effects on hypoxic pulmonary hypertension and vascular remodelling. PDE3 and PDE7 are other cAMP specific inactivators of cAMP. PDE7 is involved in T cell activation and a dual PDE4–PDE7 inhibitor may be more effective in asthma and COPD. A dual PDE3–PDE4 compound may provide more bronchodilator and bronchoprotective effect in addition to the beneficial PDE4 effects.
Keywords: Phosphodiesterase; Phosphodiesterase inhibitor; Asthma; Chronic obstructive pulmonary disease; Cilomilast; Roflumilast; Rolipram;

RETRACTED: Kinase inhibitors and airway inflammation by Ian M. Adcock; K. Fan Chung; Gaetano Caramori; Kazuhiro Ito (118-132).
Apologies are offered to readers of the journal that this was not detected during the submission process.

In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different structural cells. These activities are mandatory for many physiological processes including development, wound healing and cell trafficking. Deregulation of proteolytic–antiproteolytic network and inappropriate secretion of various MMPs by stimulated structural or inflammatory cells is thought to take part to pathophysiology of numerous lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis and lung cancer. Cytokines and growth factors are involved in these inflammatory processes and some of those mediators interact directly with MMPs and TIMPs leading either to a regulation of their expression or changes in their biological activities by proteolytic cleavage. In turn, cytokines and growth factors modulate secretion of MMPs establishing a complex network of reciprocal interactions. Every MMP seem to play a rather specific role and some variations of their expression are observed in different lung diseases. The precise role of these enzymes and their inhibitors is now studied in depth as they could represent relevant therapeutic targets for many diseases. Indeed, MMP inhibition can lead either to a decrease of the intensity of a pathological process or, in the contrary for some of them, to an increase of disease severity. In this review, we focus on the role played by MMPs and TIMPs in asthma and we provide an overview of their potential roles in COPD, lung fibrosis and lung cancer, with a special emphasis on loops including MMPs and cytokines and growth factors relevant in these diseases.
Keywords: Matrix metalloproteinase; Tissue inhibitor of MMP; Asthma; Cytokine; Growth factors;

The broken balance in aspirin hypersensitivity by Andrzej Szczeklik; Marek Sanak (145-155).
Aspirin was introduced into medicine over a century ago and has become the most popular drug in the world. Although the first hypersensitivity reaction was described soon after aspirin had been marketed, only recently a phenomenon of cysteinyl leukotriene overproduction brought new insights on a balance between pro- and anti-inflammatory mediators derived from arachidonic acid. We describe the most common clinical presentations of aspirin hypersensitivity, i.e. aspirin-induced asthma, rhinosinusitis and aspirin-induced urticaria. We also present their biochemical background. Despite relatively high incidence of these reactions, aspirin hypersensitivity remains underdiagnosed worldwide.Acute reactions of aspirin hypersensitivity are elicited via cyclooxygenase inhibition by non-steroid anti-inflammatory drugs. Coxibs, selective inhibitors of cyclooxygenase-2 isoenzyme, do not precipitate symptoms in susceptible patients. Though hypersensitivity correlates with cyclooxygenase-1 inhibition, diminished tissue expression was described only for cyclooxygenase-2.Aspirin-induced asthma and aspirin-induced urticaria, in a substantial part of the patients, are driven by a release of mediators from activated mast cells. These cells in physiological conditions are under inhibitory control of prostaglandin E2. The origin of aspirin hypersensitivity remains unknown, but accumulating data from genetic studies strongly suggest that environmental factor, possibly a common viral infection, can trigger the disease in susceptible subjects.
Keywords: Aspirin hypersensitivity; Cyclooxygenase; Non-steroid anti-inflammatory drug; Cysteinyl leukotriene; Lipoxin;

Protease-activated receptor2 (PAR2) is a subtype of G protein-coupled receptor that is widely expressed within the respiratory tract. Stimulation of PAR2 by proteases such as trypsin and tryptase, or by small peptidic activators induces a complex array of effects within the airways. One such PAR2-mediated effect by basal airway epithelial cells is the generation of prostaglandin E2. Prostaglandin E2 produces a raft of anti-inflammatory effects within the airways, principally through the activation of the prostanoid EP2 and EP3 receptor subtypes. This article reviews the PAR2-prostaglandin E2-prostanoid EP receptor axis and discusses approaches through which its activation may provide beneficial effects in respiratory disease.
Keywords: Protease-activated receptor; Prostaglandin E2; Prostanoid receptor; Respiratory tract;

Extending the understanding of sensory neuropeptides by Katelijne O. De Swert; Guy F. Joos (171-181).
The tachykinins substance P and neurokinin A are present in human airways, in sensory nerves and immune cells. Tachykinins can be recovered from the airways after inhalation of ozone, cigarette smoke or allergen. They interact in the airways with tachykinin NK1, NK2 and NK3 receptors to cause bronchoconstriction, plasma protein extravasation, and mucus secretion and to attract and activate immune cells. In preclinical studies they have been implicated in the pathophysiology of asthma and chronic obstructive pulmonary disease, including allergen- and cigarette smoke induced airway inflammation and bronchial hyperresponsiveness and mucus secretion. Dual NK1/NK2 or triple NK1/NK2/NK3 tachykinin receptor antagonists offer therapeutic potential in airway diseases such as asthma and chronic obstructive pulmonary disease.
Keywords: Tachykinin; Substance P; Neurokinin A; Asthma; Chronic obstructive pulmonary disease; Airway inflammation;

Chronic inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD) are major contributors to the global burden of disease. Although inflammatory cells play the central role in the pathogenesis of the diseases, recent observations indicate that also resident respiratory cells represent important targets for pulmonary drug development. Especially targeting airway neuromediators offers a possible mechanism by which respiratory diseases may be treated in the future. Among numerous peptide mediators such as tachykinins, calcitonin gene-related peptide, neurotrophins or opioids, vasoactive intestinal polypeptide (VIP) is one of the most abundant molecules found in the respiratory tract. In human airways, it influences many respiratory functions via the receptors VPAC1, VPAC2 and PAC1. VIP-expressing nerve fibers are present in the tracheobronchial smooth muscle layer, submucosal glands and in the walls of pulmonary and bronchial arteries and veins. Next to its strong bronchodilator effects, VIP potently relaxes pulmonary vessels, and plays a pivotal role in the mediation of immune mechanisms. A therapy utilizing the respiratory effects of VIP would offer potential benefits in the treatment of obstructive and inflammatory diseases and long acting VIP-based synthetic non-peptide compounds may represent a novel target for drug development.
Keywords: VIP; Cytokine; Lung; Tachykinin;

Nerve growth factor: The central hub in the development of allergic asthma? by Christina Nassenstein; Olaf Schulte-Herbrüggen; Harald Renz; Armin Braun (195-206).
Neurotrophins like nerve growth factor (NGF), originally described as nerve growth factors in neuronal development, have been implicated in many physiological processes in the last years. They are now regarded as important factors involved in the resolution of pathological conditions. NGF has profound effects on inflammation, repair and remodeling of tissues. However, in the lung these beneficial effects can transact into disease promoting actions, e.g., in allergic inflammation or respiratory syncytial virus (RSV) infection. Overproduction of NGF then enhances inflammation, and promotes (neuronal) airway hyperreactivity and neurogenic inflammation. We hypothesize that NGF overexpression in certain vulnerable time windows during infancy could be a major risk factor for the development of asthma symptoms.
Keywords: Nerve growth factor; Nerve growth factor receptor; Asthma; Airway hyperreactivity; Airway inflammation; Neurogenic inflammation;

The transient receptor potential vanilloid 1: Role in airway inflammation and disease by Pierangelo Geppetti; Serena Materazzi; Paola Nicoletti (207-214).
The transient receptor potential vanilloid 1 (TRPV1) is an excitatory cation channel, rather selectively expressed in a subpopulation of nociceptive, primary sensory neurons that promote neurogenic inflammation via neuropeptide release. TRPV1 is activated by noxious temperature, low extracellular pH and diverse lipid derivatives, and is uniquely sensitive to vanilloid molecules, including capsaicin. TRPV1 expression and sensitivity is highly regulated by diverse G protein-coupled and tyrosine kinase receptors. Other exogenous or endogenous chemical agents, including reactive oxygen species, ethanol and hydrogen sulphide sensitize/activate TRPV1. In the airways, TRPV1 agonists cause cough, bronchoconstriction, microvascular leakage, hyperreactivity and hypersecretion. Patients with asthma and chronic obstructive pulmonary disease are more sensitive to the tussive effect of TRPV1 agonists and TRPV1 activation may contribute to respiratory symptoms caused by acidic media present in the airways during asthma exacerbation, gastroesophageal reflux induced asthma or in other conditions. TRPV1 antagonists may be useful in the treatment of these diseases.
Keywords: Transient receptor potential vanilloid 1; Cough; Asthma exacerbation; Acidic media;

Peptide and non-peptide bradykinin receptor antagonists: Role in allergic airway disease by William M. Abraham; Mario Scuri; Stephen G. Farmer (215-221).
Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.
Keywords: Kinin; Airway inflammation; Animal model; Asthma; Therapy;

Oxidant and antioxidant balance in the airways and airway diseases by Irfan Rahman; Saibal K Biswas; Aruna Kode (222-239).
Although oxygen is a prerequisite to life, at concentrations beyond the physiological limits it may be hazardous to the cells. Since the lungs are directly exposed to very high amounts of oxygen, it is imperative for the organ to possess defences against possible oxidative challenge. The lungs are therefore endowed with an armamentarium of a battery of endogenous agents called antioxidants. The antioxidant species help the lungs ward off the deleterious consequences of a wide variety of oxidants/reactive oxygen species such as superoxide anion, hydroxyl radical, hypohalite radical, hydrogen peroxide and reactive nitrogen species such as nitric oxide, peroxynitrite, nitrite produced endogenously and sometimes accessed through exposure to the environment. The major non-enzymatic antioxidants of the lungs are glutathione, vitamins C and E, beta-carotene, uric acid and the enzymatic antioxidants are superoxide dismutases, catalase and peroxidases. These antioxidants are the first lines of defence against the oxidants and usually act at a gross level. Recent insights into cellular redox chemistry have revealed the presence of certain specialized proteins such as peroxiredoxins, thioredoxins, glutaredoxins, heme oxygenases and reductases, which are involved in cellular adaptation and protection against an oxidative assault. These molecules usually exert their action at a more subtle level of cellular signaling processes. Aberrations in oxidant: antioxidant balance can lead to a variety of airway diseases, such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis which is the topic of discussion in this review.
Keywords: Oxidants; Antioxidants; Lungs; Glutathione; Superoxide dismutase; Thioredoxin;

Reactive nitrogen species in the respiratory tract by Fabio L.M. Ricciardolo; Antonino Di Stefano; Federica Sabatini; Gert Folkerts (240-252).
Endogenous Nitric Oxide (NO) plays a key role in the physiological regulation of airway functions. In response to various stimuli activated inflammatory cells (e.g., eosinophils and neutrophils) generate oxidants (“oxidative stress”) which in conjunction with exaggerated enzymatic release of NO and augmented NO metabolites produce the formation of strong oxidizing reactive nitrogen species, such as peroxynitrite, in various airway diseases including asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis and acute respiratory distress syndrome (ARDS). Reactive nitrogen species provoke amplification of inflammatory processes in the airways and lung parenchyma causing DNA damage, inhibition of mitochondrial respiration, protein dysfunction and cell damage (“nitrosative stress”). These effects alter respiratory homeostasis (such as bronchomotor tone and pulmonary surfactant activity) and the long-term persistence of “nitrosative stress” may contribute to the progressive deterioration of pulmonary functions leading to respiratory failure.Recent studies showing that protein nitration can be dynamic and reversible (“denitration mechanisms”) open new horizons in the treatment of chronic respiratory diseases affected by the deleterious actions of “nitrosative stress”.
Keywords: Nitric oxide; Oxidant; Peroxynitrite; Nitrosative stress; Asthma; COPD (Chronic Obstructive Pulmonary Diseases);

The arginine–arginase balance in asthma and lung inflammation by Nives Zimmermann; Marc E. Rothenberg (253-262).
Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research underscoring the need for new scientific inquiry. Using global microarray analysis, we have recently uncovered that asthmatic responses involve metabolism of arginine by arginase. We found that the cationic amino acid transporter (CAT)2, arginase I, and arginase II were particularly prominent among the allergen-induced gene transcripts. These genes are key regulators of critical processes associated with asthma including airway tone, cell hyperplasia and collagen deposition, respectively. Furthermore, systemic arginine levels and arginine metabolism via nitric oxide synthase (NOS) can have profound effect on lung inflammation. This review focuses on the current body of knowledge on l-arginine metabolism in asthma and lung inflammation.
Keywords: Arginine; Arginase; Asthma; Allergy; Lung;

Nitric oxide (NO) is present in the exhaled breath of humans and other mammalian species. It is generated in the lower airways by enzymes of the nitric oxide synthase (NOS) family, although nonenzymatic synthesis and consumptive processes may also influence levels of NO in exhaled breath. The biological properties of NO in the airways are multiple, complex, and bidirectional. Under physiological conditions, NO appears to play a homeostatic bronchoprotective role. However, its proinflammatory properties could also potentially cause tissue injury and contribute to airway dysfunction in disease states such as asthma and chronic obstructive pulmonary disease (COPD). This article will review the physiological and pathophysiological roles of NO in the airways, discuss the rationale for the use of drugs that modulate NO pathways – nitric oxide synthase inhibitors and NO donors – to treat inflammatory airway diseases, and attempt to predict the likely therapeutic benefit of such agents.
Keywords: Asthma; Chronic obstructive pulmonary disease; Nitric oxide;

A closer look at chemokines and their role in asthmatic responses by Joost J. Smit; Nicholas W. Lukacs (277-288).
Inflammatory cell recruitment is a hallmark phenomenon of all inflammatory diseases, including allergic asthma. In allergy and asthma, recruitment of inflammatory cells such as T cells, dendritic cells, mast cells, eosinophils and neutrophils, is mediated via a number of chemokines and their receptors. Not only are chemokines involved in recruitment of these cells, they also play a role in activation and differentiation of inflammatory cells, among others, by selectively activating Th1 or Th2 cells or by effects on epithelial or endothelial cells. Binding of chemokines with their receptors has been demonstrated to be highly promiscuous and the subsequent activation pattern on effector cells is very heterogeneous, which has lead to confusion and has complicated research in this field. Nonetheless, chemokines and their receptors are important potential therapeutical targets in allergy and asthma because of their central role in cell recruitment and activation during inflammation.
Keywords: Allergy; Asthma; Chemokines; Chemokine receptor;

Agents against cytokine synthesis or receptors by Toshiyuki Yamagata; Masakazu Ichinose (289-301).
Various cytokines play a critical role in pathophysiology of chronic inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The increasing evidence of the involvement of these cytokines in the development of airway inflammation raises the possibility that these cytokines may become the novel promising therapeutic targets. Studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. Although blocking antibody against IL-5 markedly reduces the infiltration of eosinophils in peripheral blood and airway, it does not seem to be effective in symptomatic asthma, while blocking IL-13 might be more effective. On the contrary, anti-inflammatory cytokines themselves such as IL-10, IL-12, IL-18, IL-23 and interferon-γ may have a therapeutic potential. Inhibition of TNF-α may also be useful in severe asthma or COPD. Many chemokines are also involved in the inflammatory response of asthma and COPD through the recruitment of inflammatory cells. Several small molecule inhibitors of chemokine receptors are now in development for the treatment of asthma and COPD. Antibodies that block IL-8 reduce neutrophilic inflammation. Chemokine CC3 receptor antagonists, which block eosinophil chemotaxis, are now in clinical development for asthma therapy. As many cytokines are involved in the pathophysiology of inflammatory lung diseases, inhibitory agents of the synthesis of multiple cytokines may be more useful tools. Several such agents are now in clinical development.
Keywords: Asthma; Chronic obstructive pulmonary disease; Cytokine; Chemokine; Chemokine receptor;

IgE molecules play a crucial role in allergic respiratory diseases and may cause chronic airway inflammation in asthma through activation of effector cells via high-affinity (FcεRI) or low-affinity (FcεRII) IgE receptors. Since the discovery of IgE antibodies our understanding of the mechanisms of allergy has improved to such an extent that we can differentiate allergic/atopic from intrinsic respiratory diseases.Therapeutic anti-IgE antibodies, able to reduce free IgE levels and to block the binding of IgE to FcεRI without crosslinking IgE and triggering degranulation of IgE-sensitized cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (omalizumab) binds IgE at the same site as these antibodies bind FcεRI and FcεRII. Consequently, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the FcεR1 receptor already masks the anti-IgE epitope.Studies in patients with atopic asthma showed that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted effective in reducing asthma-related symptoms, decreasing corticosteroid use and improving quality of life of asthmatic patients. Recent studies show the benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled by optimal pharmacological therapy. The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases such as allergic rhinitis, a favorable safety profile and a convenient dosing frequency.
Keywords: Allergic asthma; Anti-IgE-antibody; Allergic respiratory diseases; Monoclonal antibody anti-IgE; Omalizumab;

Toll-like receptors—novel targets in allergic airway disease (probiotics, friends and relatives) by Wojciech Feleszko; Joanna Jaworska; Eckard Hamelmann (308-318).
Experimental and epidemiological studies enabled to hypothesize that stimulation of the immune system by selected microbial products may prevent or treat allergic diseases. According to recent advances in molecular immunology, this stimulation acts via group of conserved receptors present on antigen presenting cells, known as toll-like receptors (TLRs). These receptors play an essential role in antigen presentation and latter development of immune response into pro-allergic (Th2), cellular (Th1) or regulatory (Tr1) responses. Since toll-like receptors govern decisive points in immune regulation, an extensive research focuses on agents interfering with their immunomodulatory activities. In this report, we review information on the potential use of microbial products in allergy prevention and therapy, which are believed to target toll-like receptor network. Current toll-like receptor-based approaches, as well as potential use of lipopolysaccharide (and derivates), oligonucleotides, mycobacteria, bacterial extracts, and probiotics are discussed herein.
Keywords: Allergy; Asthma; Bacterial extract; CpG motif; Hygiene hypothesis; Lipopolysaccharide; Mycobacteria; Probiotics; T helper cell; Toll-like receptors; T regulatory cells;

Free immunoglobulin light chains as target in the treatment of chronic inflammatory diseases by Maurice van der Heijden; Aletta Kraneveld; Frank Redegeld (319-326).
Immunoglobulin free light chains were long considered irrelevant bystander products of immunoglobulin synthesis by B lymphocytes. To date, different studies suggest that free light chains may have important functional activities. For instance, it has been shown that immunoglobulin free light chains can elicit mast cell-driven hypersensitivity responses leading to asthma and contact sensitivity. Free light chains also show other biologic actions such as anti-angiogenic and proteolytic activities or can be used as specific targeting vehicles. Levels of free light chain levels in body fluids increase markedly in diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we will focus on the unexpected biological activities of immunoglobulin free light chains with special attention to its possible role in the induction of chronic inflammatory diseases.
Keywords: Asthma; Immunoglobulin free light chain; Hypersensitivity; Mast cell; Multiple sclerosis; Rheumatoid arthritis;

Stem cell factor and its receptor c-Kit as targets for inflammatory diseases by Laurent Reber; Carla A. Da Silva; Nelly Frossard (327-340).
Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-γ, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases.
Keywords: SCF (stem cell factor); Kit; Inflammation; Mast cell; Eosinophil; Asthma;

Nanomedicine for respiratory diseases by Ulrich Pison; Tobias Welte; Michael Giersig; David A. Groneberg (341-350).
Nanotechnology provides new materials in the nanometer range with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanomaterial such as nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. Thus, applied nanotechnology to medical problems – nanomedicine – can offer new concepts that are reviewed.The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used as transporter in vivo. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based “molecular” imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology there is potential for nanoparticles and -systems to become useful tools as therapeutic and diagnostic tools in the near future.
Keywords: Nanotechnology; Nanomaterial; Nanoparticle; Nanocarrier; Quantum dot; Respiratory medicine;

Author Index (351-352).

Keyword Index (353-357).