Current Drug Targets – Inflammation & Allergy, Vol. 4, No. 4, 2005
Contents
Granulocyte
Toxicity in the Lung
Guest
Editor: Hannu Kankaanranta
Editorial
Pp.413-413
Hannu Kankaanranta
Neutrophils and Eosinophils: Clinical Implications of
their Appearance, Presence and Disappearance in Asthma and COPD Pp.415-423
A.P. Watt, B.C. Schock
and M. Ennis
Transepithelial Migration, Necrosis and Apoptosis as
Silent and Pro- Inflammatory Fates of Airway Granulocytes Pp.425-431
Jonas Erjefalt
Pharmacological Regulation of Human Eosinophil Apoptosis Pp.433-445
Hannu Kankaanranta,
Eeva Moilanen and Xianzhi Zhang
Regulation of Neutrophil Apoptosis and Removal of
Apoptotic Cells Pp.447-454
Annemieke Walker,
Carol Ward, Emma L. Taylor, Ian Dransfield, Simon P. Hart, Christopher Haslett
and Adriano G. Rossi
Anti-Inflammatory Mechanisms of Glucocorticoids Targeting
Granulocytes Pp.455-463
Gaetano Caramori and
Ian Adcock
Production and Degradation of Oxygen Metabolites During
Inflammatory States in the Human Lung Pp.465-470
Vuokko L. Kinnula
Nitric Oxide Production and Signaling in Inflammation Pp.471-479
Riku Korhonen, Aleksi
Lahti, Hannu Kankaanranta and Eeva Moilanen
Control of Eosinophil Toxicity in the Lung Pp.481-486
G.M. Walsh, M. Al-Rabia,
M.G. Blaylock, D.W. Sexton, C.J.A. Duncan and A. Lawrie
Role of Oxygen Radicals in
Inflammation and Allergy
Guest Editors: Masahiko Kato
/ Hirokazu Kimura
Editorial
Pp.487-487
Masahiko Kato, Hirokazu
Kimura
Toxicity and Roles of Reactive Oxygen Species Pp.489-495
H. Kimura, T. Sawada,
S. Oshima, K. Kozawa, T. Ishioka and M. Kato
Oxygen Radicals in Inflammation and Allergy Related to
Viral Infections Pp.497-501
M. Kato, Y. Hayashi
and H. Kimura
Inflammatory Cells and Oxygen Radicals Pp.503-504
Makoto Nagata
Role of Oxygen Radicals on Bronchial Asthma Pp.505-509
Takao Fujisawa
Oxidative Stress-Related Molecules as a Therapeutic
Target for Inflammatory and Allergic Diseases Pp.511-515
Y. Naito, H. Takano
and T. Yoshikawa
Oxidative Stress in Allergic and Inflammatory Skin
Diseases Pp.517-519
Yoshimichi Okayama
Abstracts
[Back to top] Editorial
Hannu Kankaanranta
The role of the eosinophil in the pathogenesis of asthma was recently questioned by studies with anti-cytokine therapies that reduced the number of circulating eosinophils dramatically, but failed to affect the clinical measures of asthma. Although of ultimate importance to this field, those findings led to a dramatic halt in the development programs for anti-eosinophil based therapies for asthma and allergy. However, more recent studies showed that a decrease in peripheral blood eosinophil count does not lead to clearance of eosinophils or their granule products from the lungs of patients with asthma. Rather than casting doubt to the role of eosinophil in asthma, recent evidence further strengthens the role of eosinophil both as an effector cell and in orchestrating the immunological events central to asthma.
It appears that not only the eosinophil, but also the neutrophil may play a role in the pathogenesis of moderate to severe asthma. Neutrophils are considered to be important effectors in the pathogenesis of COPD. However, recent evidence implicates a role for eosinophils also in COPD, especially during the COPD exacerbations. Now we are living a time of reappraisal of the importance of granulocytes, both the eosinophil and the neutrophil, in the pathogenesis of asthma and COPD. Thus it is time to critically evaluate the recent advances in eosinophil and neutrophil biology and their clinical correlates and to evaluate the avenues for future drug development to limit the toxicity of granulocytes in the lung.
Eosinophils and neutrophils are both terminally differentiated granulocytes, which are able to produce several proinflammatory mediators and reactive oxygen species. Increase in nitric oxide production by inducible nitric oxide synthase has been shown to occur in asthma. Thus, in addition to their own production of reactive oxygen (ROS) and/or nitrogen species (RNS), granulocytes are exposed to reactive oxygen and nitrogen metabolites produced by other cells or tobacco smoke in the lung. Thus, it is important to understand the signalling related to ROS/RNS and regulation of their production as well as means to protect from their effects.
The numbers of eosinophils and neutrophils in the lung are regulated by several factors, namely the balance of recruitment and migration of granulocytes to the lung and removal of granulocytes from the lung. Identification of eosinophil cytolysis in asthmatic airways, leading to the release of toxic eosinophil contents and/or free eosinophil granules to the surrounding tissues serves as a background why we should seek for the mechanisms and ways how to clear the lung from eosinophils and/or neutrophils. Thus several groups focus on finding the mechanisms how granulocyte apoptosis is controlled and seek potential drug targets to selectively remove eosinophils and /or neutrophils from the asthmatic or allergic airways to reduce their toxicity. To achieve these goals, we also need to learn how the currently used anti-inflammatory medication, especially the glucocorticoids, affect granulocytes and what is the contribution of eosinophils and neutrophils to the clinical presentation of asthma and COPD.
I hope that this special theme issue on “Control of granulocyte toxicity in the lung” will provide the reader with an update on the current knowledge in controlling eosinophil and neutrophil toxicity in the lung. Finally, I would like to thank all the authors, who represent some of the most prominent groups in this field, for contributing to this Hot Topic issue.
[Back to top] Neutrophils and Eosinophils: Clinical Implications of
their Appearance, Presence and Disappearance in Asthma and COPD
A.P. Watt, B.C. Schock
and M. Ennis
Asthma and chronic obstructive pulmonary disease (COPD) are common chronic disorders. Traditionally, asthma has been associated with an eosinophilic inflammation and COPD with neutrophilic inflammation. In this review we will highlight the maturation, recruitment, activation, action and apoptosis of these cells. In addition we will focus on the evidence for their presence in disease and suggest potential new therapeutic interventions.
[Back
to top] Transepithelial Migration, Necrosis and Apoptosis as Silent and Pro-
Inflammatory Fates of Airway Granulocytes
Jonas Erjefalt
In inflammatory airway diseases, granulocytes such as eosinophils and neutrophils infiltrate the tissue where they are thought to exert pathogenic activities. To avoid a catastrophic accumulation of activated granulocytes, their recruitment must be balanced by efficient cell clearance mechanisms. In this regard, the focus has been on elimination through apoptosis and subsequent engulfment of apoptotic cells by phagocytes. However, novel data suggest that in the airways, powerful non-apoptotic mechanisms are also critically involved in cell clearance. One such mechanism is transepithelial migration into the airway lumen where the mucociliary escalator executes the final elimination. The physiological clearance of tissue granulocytes is normally silent, but can under certain situations shift to become a pro-inflammatory event. For example, apoptotic cells that escape phagocytosis, disintegrate in a pro-inflammatory process called secondary necrosis. In other situations, granulocytes are triggered to undergo an active and violent cytolytic death. This delicate balance in vivo, between silent and violent properties of granulocyte demise, complicates the design of pro-apoptotic pharmacological interventions. On the other hand, this insight may also open possibilities to new exciting treatment strategies. In this context, promoting transepithelial migration, prevention of secondary necrosis, and boosting the macrophage phagocytic system appear as exciting treatment avenues.
[Back to top] Pharmacological Regulation of Human Eosinophil Apoptosis
Hannu Kankaanranta,
Eeva Moilanen and Xianzhi Zhang
Eosinophilic inflammation of the airways is a key characteristic of asthma. The balance between eosinophil recruitment into the lung and their removal from the lungs determines the number of eosinophils in the airways. Apoptosis or programmed cell death is of importance in the removal of eosinophils from the lungs. In asthma, eosinophil apoptosis is delayed. Glucocorticoids enhance eosinophil apoptosis, whereas b2-agonists may delay apoptosis in eosinophils. Detailed knowledge on the mechanisms that regulate this process gives an opportunity to develop specific asthma therapies targeting the eosinophil. This review aims to focus on the signalling leading to or preventing apoptosis in human eosinophils as well as reviews the current evidence on the regulation of eosinophil apoptosis and/or survival in allergic diseases.
[Back to top] Regulation
of Neutrophil Apoptosis and Removal of Apoptotic Cells
Annemieke Walker,
Carol Ward, Emma L. Taylor, Ian Dransfield, Simon P. Hart, Christopher Haslett
and Adriano G. Rossi
The accumulation of neutrophils during inflammation is essential for the destruction and removal of invading microorganisms. However, for resolution of inflammation to occur, neutrophils must also be removed from the inflammatory site since these cells are capable of releasing tissue toxic molecules. Neutrophil removal has been shown to occur via apoptosis and phagocyte clearance of apoptotic cells. Therefore, manipulation of these processes is likely to be a key therapeutic strategy in the management of inflammatory disease. In this review, we examine mediators of neutrophil survival and apoptosis and the signalling pathways that regulate the balance between life and death in these cells.
[Back to top] Anti-Inflammatory
Mechanisms of Glucocorticoids Targeting Granulocytes
Gaetano Caramori and Ian Adcock
Asthmatic inflammation involves the recruitment and activation of inflammatory cells, and changes in the structural cells of the lung and asthma are characterized by an increased expression of components of the inflammatory cascade including cytokines, chemokines, growth factors, enzymes, receptors and adhesion molecules. The increased expression of these proteins seen in asthma is generally the result of enhanced gene transcription, since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. There is clear evidence that neutrophils, long thought of as being transcriptionally inert, can respond to stimuli to induce inflammatory genes. Glucocorticoids are very effective in controlling the inflammation seen in asthmatic airways. Beyond their recognized actions on eosinophil and neutrophil apoptosis, glucocorticoids have profound effects on the chemotaxis, activation and release of mediators from granulocytes (eosinophils, neutrophils and basophils). Few mechanistic studies are available in these cells, but it appears that in granulocytes, glucocorticoids target the same signaling pathways, such as nuclear factor-kB (NF-kB) and activator protein-1 (AP-1), that are important in other cells. We summarize these known mechanisms at the end of this review.
[Back to top] Production
and Degradation of Oxygen Metabolites During Inflammatory States in the Human
Lung
Vuokko L. Kinnula
Lung represents a tissue that encounters a high oxidant burden but is also endowed with efficient protection against oxygen and reactive oxygen species (ROS). The oxidant stress experienced by the lung is enhanced by exogenous oxidant producing toxins most importantly pollutants and cigarette smoke, as well as by increased oxidant production during lung inflammation. The major oxidant generating enzymes present in human lung include NADPH oxidase, myeloperoxidase, eosinophil peroxidase and nitric oxide synthases, all of which are induced during inflammatory states. The antioxidant machinery of human lung against ROS is more versatile than often assumed. In addition to metal binding proteins, mucus components and small molecular weight antioxidants and vitamins, lung tissue possesses a highly cell specific and compartmentalized defense system containing several antioxidant enzymes with variable locations, inducibilities and kinetics. Inflammatory states like asthma, chronic obstructive lung disease (COPD) and parenchymal lung disorders have been shown to lead to serious disturbances in the oxidant/antioxidant balance of the lung with consequent oxidant mediated cell injury. Novel synthetic antioxidant mimetics may have the potential to slow or terminate the progression of lung diseases associated with free radicals.
[Back to top] Nitric
Oxide Production and Signaling in Inflammation
Riku Korhonen, Aleksi Lahti, Hannu Kankaanranta and Eeva Moilanen
Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. It possesses cytotoxic properties that are aimed against pathogenic microbes, but it can also have damaging effects on host tissues. NO reacts with soluble guanylate cyclase to form cyclic guanosine monophosphate (cGMP), which mediates many of the effects of NO. NO can also interact with molecular oxygen and superoxide anion to produce reactive nitrogen species that can modify various cellular functions. These indirect effects of NO have a significant role in inflammation, where NO is produced in high amounts by inducible nitric oxide synthase (iNOS) and reactive oxygen species are synthesized by activated inflammatory cells. The present review deals with NO production and signaling in inflammation, especially in relation to human neutrophils and eosinophils.
[Back to top] Control
of Eosinophil Toxicity in the Lung
G.M. Walsh, M. Al-Rabia, M.G. Blaylock, D.W. Sexton, C.J.A. Duncan and A. Lawrie
The inappropriate accumulation of eosinophils and the subsequent release of their potent pro-inflammatory mediator arsenal are thought to be important contributors to the pathogenesis of asthma and other allergic diseases. It is also becoming apparent that eosinophils may play a role in the orchestrations of immune responses in the asthmatic lung. There is therefore much interest in the development of strategies to limit or prevent eosinophil-induced toxicity. The mechanisms by which eosinophils accumulate in the peribronchial tissues of the lung are complex and include enhanced differentiation and release from the bone marrow, selective adhesion and transendothelial migration, directed movement in response to specific chemotactic mediators and finally prolonged survival as a consequence of delayed apoptosis. Thus it can be appreciated that there are many points at which the toxicity of eosinophils can be limited or even prevented. Important areas for potential advances in glucocorticoid (GC) development include efforts to dissociate their anti-inflammatory effects from unwanted side effects. Other areas include the development of humanised monoclonal antibodies against IL-4, IL-13 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for eosinophil accumulation in the asthmatic lung. Several avenues of research are currently underway in an attempt to define mechanisms by which proinflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. This review will discuss both the potential and shortcomings of these diverse approaches to limit eosinophil toxicity in the asthmatic lung.
[Back to top] Editorial
Masahiko Kato, Hirokazu Kimura
The recent developments in research on oxygen radicals have resulted in various new approaches for the treatment of allergic and inflammatory diseases. The aim of this issue is to provide timely reviews on the role of oxygen radicals in inflammation and allergy, with a special focus on the design and synthesis of new therapeutic agents and approaches. The inaugural issue contains reviews spanning several areas of interests.
The first review "Toxicity and Roles of Reactive Oxygen Radicals" by Dr. H. Kimura (Gunma Prefectural Institute of Public Health and Environmental Sciences) describes an overview of the basic properties, toxicity, and roles of oxygen radicals.
The next review "Oxygen Radicals in Inflammation and Allergy Related to Viral Infections" by myself (M. Kato, Department of Allergy and Immunology, Gunma Children’s Medical Center) describes the roles of oxygen radicals in allergic inflammations such as bronchial asthma induced by viral infection, specifically with respiratory syncytial virus (RSV). RSV infection enhances eosinophilic inflammation in asthma.
At the sites of inflammation, multiple inflammatory cells, including eosinophils, neutrophils, and macrophages, are capable of releasing oxygen radicals. The third review "Inflammatory Cells and Oxygen Radicals" by Dr. M. Nagata (Department of Respiratory Medicine, Saitama Medical School) states that oxygen radicals can promote an adhesive interaction between inflammatory and endothelial cells, which could culminate in the manifestations of inflammatory diseases such as asthma.
The fourth review "Role of Oxygen Radicals on Bronchial Asthma" by Dr. T. Fujisawa (Mie National Hospital, Mie, Japan) describes an elegant technique to measure oxygen radicals and the footprints of oxidant stress in patients with asthma and investigates the possible involvement of oxygen radicals in individual pathophysiology. He has further discussed that therapeutic interventions that reduce oxidant stress and enhance antioxidant defense may be useful in the treatment of asthma.
The fifth review "Oxidative Stress-Related Molecules as Therapeutic Targets for Inflammatory and Allergic Diseases" by Dr. Y. Naito (Molecular Gastroenterology and Hepatology and Inflammation and Immunology, Graduates School of Kyoto Prefectural University of Medicine) provides interesting information on the recent advances in the prevention of allergic or nonallergic inflammation.
Atopic dermatitis is a chronic inflammatory skin condition that occurs in childhood and often predates more serious allergic conditions. The final (sixth) review "Oxidative Stress in Allergic and Inflammatory Skin Diseases" by Dr. Y. Okayama (Research Unit for Allergy Transcriptome, Research Center for Allergy & Immunology, RIKEN Yokohama Institute) reports on the involvement of oxygen radicals in the pathogenesis of allergic and inflammatory skin diseases such as atopic dermatitis, urticaria, and psoriasis.
Finally, to the authors who have contributed to this issue, we would like to thank the Editor-in-Chief Dr. C. K. Lau and members of the Editorial Advisory Board who have reviewed the articles. We would also like to thank Bentham Science Publishers for their assistance.
[Back to top] Toxicity
and Roles of Reactive Oxygen Species
H. Kimura, T. Sawada, S. Oshima, K. Kozawa, T. Ishioka and M. Kato
The history of studies in biology regarding reactive oxygen species (ROS) is approximately 40 years. During the initial 30 years, it appeared that these studies were mainly focused on the toxicity or microbicidal-related agents of ROS. However, recent studies have identified another action regarding oxidative signaling, other than toxicity of ROS. Basically, it is suggested that ROS are reactive, and degenerate to biomacromolecules such as DNA and proteins, leading to deterioration of cellular functions as an oxidative stress. On the other hand, recent studies have shown that ROS act as oxidative signaling in cells, resulting in various gene expressions. For example, NADPH oxidase, a major source of superoxide radicals (O2-), expresses in various tissues such as leukocytes and cardiovascular systems, and ROS derived from the enzyme play important roles in cell proliferation, differentiation, and cell death. In this review, we have focused on and described the basic properties, toxicity, and roles of ROS.
[Back to top] Oxygen
Radicals in Inflammation and Allergy Related to Viral Infections
M. Kato, Y. Hayashi and H. Kimura
Oxygen radicals including superoxide anion (O2-) and nitric oxide (NO) are involved in a variety of inflammatory diseases induced by viral infection. In this review, we focus on the role of oxygen radicals in allergic inflammation such as bronchial asthma induced by viral infection--specifically, with respiratory syncytial virus (RSV). This infection in early childhood is a risk factor for development of wheezing, significant decreases in pulmonary function, and increases in airway reactivity. RSV infection also exacerbates recurrent wheezing attacks in patients with established asthma.
Recently, we have demonstrated that RSV enhanced superoxide production by human eosinophils stimulated with a lipid mediator such as platelet-activating factor. This response depends on a b2 integrin, aMb2, which is critical for eosinophil effector functions. Our results suggest that eosinophils and their products promote RSV-induced airway inflammation in asthma. Close delineation of the mechanism by which RSV enhances eosinophilic inflammation in asthma should yield clues to more effective therapy.
[Back to top] Inflammatory
Cells and Oxygen Radicals
Makoto Nagata
At sites of inflammation, multiple inflammatory cells including eosinophils, neutrophils, and macrophages are capable of generating reactive oxygen species (ROS), which can contribute to development of various diseases. In case of allergic inflammation, for example, the lung cells obtained by bronchoalveolar lavage (BAL) following antigen challenge generates superoxide anion at nanomolar concentrations. Eosinophils obtained from BAL following a segmental allergen challenge generate more superoxide anion than eosinophils obtained from the peripheral circulation. Such ROS may contribute not only to tissue injury but also to inflammatory reactions. For example, hydrogen peroxide can stimulate both neutrophil and eosinophil adhesion as an autocrine or paracrine mediator via the upregulation of b2 integrin. Furthermore, ROS may alter morphological or functional properties of endothelial cells, including permeability and adhesion molecule expression. Thus, ROS can promote adhesive interaction between inflammatory and endothelial cells, which could culminate in manifestations of inflammatory diseases such as bronchial asthma.
[Back to top]
Role of Oxygen Radicals on Bronchial Asthma
Takao Fujisawa
Bronchial asthma is an inflammatory disorder characterized by recruitment and activation of various inflammatory cells including eosinophils and T cells in the airway mucosa. Oxygen radicals are produced by inflammatory cells in the airways and/or inhaled directly from environmental air. There is ample evidence that oxygen radical production is increased in asthma and is closely related to the pathogenesis and that exogenous oxidants such as cigarette smoke and ozone directly cause asthma exacerbation. The mechanism by which oxygen radicals cause asthma pathology is oxidation or nitration of proteins, lipids, or DNA to cause dysfunction of these molecules. In addition, physiological antioxidant system, which is equipped to protect host from detrimental oxidants, is impaired in asthma, possibly because of inflammation. Thus, the imbalance between oxidant and antioxidant that is called oxidant stress is critical in asthma pathogenesis. Elegant technique to measure oxygen radicals and the footprints of oxidant stress in patients with asthma have been developed and give an important clue to evaluate possible involvement of oxygen radicals in individual pathophysiology. Therapeutic interventions that reduce oxidant stress and enhance antioxidant defense may be useful in the treatment of asthma.
[Back to top]
Oxidative Stress-Related Molecules as a Therapeutic Target for Inflammatory and
Allergic Diseases
Y. Naito, H. Takano and T. Yoshikawa
There is a growing body of evidence that oxidative stress mediated by reactive oxygen species plays an important role in the pathogenesis of various kinds of allergic and non-allergic inflammation. These data suggest that blocking reactive oxygen species should be useful for amelioration of allergic or non-allergic inflammation in the respiratory and intestinal tracts. In addition, the modulation of oxidative stress-related molecules, such as inducible nitric oxide synthase and redox-sensitive transcriptional factors, may be useful for the regulation of these inflammatory responses. In this review, we have summarized the recent advances in the prevention of allergic or non-allergic inflammation, especially the diesel exhaust particle-induced respiratory allergic response and dextran sulfate sodium-induced intestinal inflammation in rodents.
[Back to top] Oxidative Stress in Allergic and Inflammatory Skin
Diseases
Yoshimichi Okayama
The skin is exposed to endogenous and environmental pro-oxidant agents, leading to the harmful generation of reactive oxygen species (ROS). The resulting oxidative stress damages proteins, lipids, and DNA. An imbalance between ROS and antioxidants can lead to an elevated oxidative stress level. Some evidence indicates that allergic and inflammatory skin diseases like atopic dermatitis, urticaria and psoriasis are mediated by oxidative stress. For example, monocytes from patients with atopic dermatitis are primed to generate ROS in response to zymosan, a Toll-like receptor 2 (TLR2) ligand, suggesting that Staphylococcus aureus may damage lesional skin of the disease by production of ROS. Mast cells generate mainly intracellular ROS following the aggregation of FceRI; these ROS may act as secondary messengers in the induction of several biological responses. The present review summarizes the involvement of ROS in the pathogenesis of allergic and inflammatory skin diseases.