Current Molecular Medicine - Volume 8, Issue 5, 2008

Airway inflammation is a hallmark of chronic airway diseases, including bronchial asthma and COPD. In the last two decades there has been a significant increase in the incidence and prevalence of allergy and asthma worldwide. The airway epithelium remains under constant exposure to environmental factors including viruses, bacteria, allergens, and toxic inhalants. Many inflammatory cells and mediators, which are released in the airways upon allergen exposure and injury to the airway epithelium, act in synergistic or antagonistic manner to induce immune response or immune tolerance. This Special Issue of the Current Molecular Medicine brings together state-of-the-art contributions of the top-notch scientists in the field of airway diseases that ensure an authoritative text. There has been tremendous increase in our knowledge on the molecular pathogenesis of airway diseases. Therefore, it is rather impossible to include each and every aspect of airway diseases. None-the-less, every effort has been made to present up-to-date information with critical evaluation and future directions on the role of key inflammatory cells and mediators in airway diseases. On the cover page, I have tried to schematically depict the molecular pathogenesis of airway inflammation and asthma. I sincerely thank Dr. Anirban Maitra, the Editor-in-Chief of the Current Molecular Medicine, for providing me the opportunity to organize this special issue. This issue would not have been completed without amazing patience, and excellent cooperation and support of the wonderful staff members of the Current Molecular Medicine, especially Ms. Samina Khan, the Senior Manager Publications, Bentham Science Publishers Ltd. I would also like to express my sincere gratitude to both authors and reviewers, for their efforts in preparing and ensuring the high scientific quality of the papers in this special issue.

GATA-3 is a transcription factor that is specifically expressed in T helper 2 (Th2) cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes. In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. In human T lymphocytes GATA-3 is normally localized to the cytoplasm, but on activation by antigen-presenting cells via the T cell receptor (CD3) and co-stimulatory receptor CD28 GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-α. Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by competing for nuclear entry via importin-α and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1. GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained. Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.

Eicosanoids are diverse mediators of inflammation that derive from a single cell membrane phospholipid- associated precursor, arachidonic acid. This precursor is metabolized to several groups of lipid mediators, including (but not limited to) prostaglandins, leukotrienes, and lipoxins, in a tightly regulated, coordinated, cell- and context-specific manner. Each mediator serves regulatory and homeostatic functions in the onset and resolution of inflammation, immune responses, and tissue repair. The cloning of biosynthetic enzymes and G protein-coupled receptors for each of these mediators, the development of transgenic mice deficient in these molecules, and the availability of selective antagonists have permitted studies that have rapidly expanded our understanding of the scope of biologic functions for these mediators, with potential ramifications for the pathogenesis and treatment of human asthma. This review summarizes these findings and reviews the data from both mouse and human studies pertinent to the pathobiologic role of each mediator.

Asthma is characterized by the presence of increased numbers of inflammatory cells in the airway in particular eosinophils and Th2 lymphocytes. In addition to the presence of inflammatory cells, the airways of patients with asthma exhibit varying levels of structural changes termed airway remodeling. These structural changes include subepithelial fibrosis, smooth muscle hypertrophy/hyperplasia, epithelial cell mucus metaplasia, and increased angiogenesis. This review focuses on the potential role of the eosinophil in promoting features of airway remodeling including fibrosis and neovascularization in chronic asthma. Eosinophils may potentially contribute to airway remodeling through release of eosinophil derived mediators such as TGFβ which act directly upon target fibroblasts to promote fibrosis. In addition to the potential importance of the eosinophil to remodeling in asthma, eosinophilic esophagitis (EE) is another eosinophil associated disease that is associated with increased levels of esophageal eosinophils, increased levels of TGFβ expression, and increased levels of fibrosis, suggesting that a similar mechanism of remodeling may contribute to both of these eosinophil associated diseases. However, remodeling in both asthma and EE is likely complex involving both eosinophil dependent and eosinophil independent pathways. Further studies in both humans and animal models will help to increase our knowledge of the contribution of the eosinophil to remodeling in asthma as well as EE.

The generation of an allergic immune response requires at least two signals for complete activation of T cells. Costimulatory molecules are integral to the second signal. In this review, we analyze the costimulatory molecule signaling lymphocytic activation molecule (SLAM) and other recently described SLAM family members. We highlight recent findings that position SLAM as critical for allergic inflammation and its role in modulation of cytokine secretion. Furthermore, a possible role of SLAM as a link between the adaptive and innate immune response is also discussed. Understanding the role of costimulatory molecules, including SLAM and SLAM family members, may elucidate mechanisms involved in the allergic immune response, and suggest potential therapeutic opportunities.

Prostaglandin D2 (PGD2) is a major prostanoid produced mainly by mast cells in allergic diseases, including bronchial asthma. However, its role in the pathogenesis of asthma remains unclear. PGD2-induced vasodilatation and increased permeability are well-known classical effects that may facilitate transendothelial migration of inflammatory cells, such as eosinophils, mast cells, lymphocytes, and monocytes in allergic inflammation. These effects are initiated via a PGD2 receptor, D prostanoid receptor (DP), and are referred to as DP-mediated vasodilation-extravasation. Recently, novel functions of DP have been identified. Furthermore, a novel and different receptor of PGD2, CRTH2, has been discovered. To date, DP and CRTH2 have been shown to be major PGD2-related receptors that have pivotal roles in mediating allergic diseases by effects such as directly regulating the migration of inflammatory cells and controlling the production of cytokines and lipid mediators. Available evidence suggests that CRTH2 and DP may collaborate in allergic inflammation. This review focuses on the novel roles of DP and CRTH2 in the initiation and maintenance of allergy.

Redox balance is particularly important in the airways because they are the first points of contact with environmental pollutants such as ozone, particles, and cigarette smoke, as well as pathogens such as bacteria and viruses. However, an imbalance between toxicant-induced reactive oxygen (ROS) and nitrogen (RNS) species and the antioxidant defense system leads to oxidative stress, which has been implicated in the development and/or perpetuation of airway diseases, including malignancy. Various antioxidant enzymes and proteins are critical to maintaining the reducing environment of the cell and preventing the damage to various biomolecules that is elicited by ROS/RNS. Emerging evidence indicates that transcriptional activation of the antioxidant response element (ARE) plays a crucial role in modulating oxidative stress and providing cytoprotection against prooxidant stimuli. This review focuses on the regulation and functional roles of key effectors that bind to the ARE and differentially (up- or down-) regulate gene expression in lung tissue/cell types in response to respiratory toxicants. It also provides a perspective on whether boosting ARE-mediated gene expression with dietary plants and synthetic plant products will offer a better therapeutic strategy for mitigating oxidative stress and respiratory pathogenesis.

Interleukin (IL)-4 and IL-13 share many biological activities. To some extent, this is because they both signal via a shared receptor, IL-4Rα. Ligation of IL-4Rα results in activation of Signal Transducer and Activator of Transcription factor 6 (STAT6) and Insulin Receptor Substrate (IRS) molecules. In T- and B-cells, IL- 4Rα signaling contributes to cell-mediated and humoral aspects of allergic inflammation. It has recently become clear that IL-4 and IL-13 produced in inflamed tissues activate signaling in normally resident cells of the airway. The purpose of this review is to critically evaluate the contributions of IL-4- and IL-13-induced tissue responses, especially those mediated by STAT6, to some of the pathologic features of asthma including eosinophilic inflammation, airway hyperresponsiveness, subepithelial fibrosis and excessive mucus production. We also review the functions of some recently identified IL-4- and/or IL-13-induced mediators that provide some detail on molecular mechanisms and suggest an important contribution to host defense.

Dendritic cells are crucial in determining the functional outcome of allergen encounter in the lung. Antigen presentation by myeloid DCs leads to Th2 sensitization typical of allergic disease, whereas antigen presentation by plasmacytoid DCs serves to dampen inflammation. It is increasingly clear that DCs have an antigen presenting function beyond sensitisation. DCs therefore constitute a novel target for the development of anti-allergic therapy aimed at the origin of the inflammatory cascade. A careful study of DC biology and of the receptors expressed by lung DCs has provided a framework for the discovery of novel anti-allergic compounds.

Chloride channels are involved in many different physiological processes such as cell migration, proliferation and apoptosis. The importance of the CLC family of chloride channels in these cellular functions has been recognized only recently. Infiltration of inflammatory cells, such as eosinophils, T cells, mast cells and neutrophils, is a hallmark of allergy and asthma. Indeed, chronic asthma is associated with widespread damage to the bronchial epithelium, due to excessive apoptosis, and with defective epithelial repair. However, the relationship between the immune cells of allergic airway diseases and chloride channels has not been clearly elucidated. In this review, characteristics of CLC channels are mainly discussed based on their function and presence in different immune cells in airway diseases. Not only are chloride channels involved in the recruitment of immune cells, they also play a role in the activation of these cells. Thus, understanding the role of CLC channels in the immune cells would provide unique insights to the pathophysiologic process of chronic asthma and the means to prevent or reverse the disease.

Mucous cell metaplasia (MCM), defined by the appearance of mucous cells in airways where mucous cells were not present, is a consistent pathologic characteristic in the peripheral airways of bronchial asthma. Under mild inflammatory conditions MCM occurs as a result of pre-existing airway epithelial cells (AECs) starting to express mucin genes and differentiating into mucous cells. Under extensive inflammatory responses, AECs proliferate, and the development of MCM involves the differentiation of pre-existing and proliferating cells into mucous cells. Epithelial cell numbers per mm basal lamina are increased by approximately 30%. IL-13 is the central cytokine that is responsible for MCM in asthma through GABA-R- and STAT6- mediated mechanisms involving the calcium-activated chloride channel CLCA. IL-13 is also responsible for the proliferation of AECs by causing cells to produce TGFα that acts on the epidermal growth factor (EGF) receptor. Normally, resolution of MCM involves two distinct mechanisms. 1) Some of the metaplastic mucous cells stop the synthesis of mucus and dedifferentiate into Clara or serous cells to reconstitute the epithelium. 2) When proliferation of epithelial cells had occurred, approximately 30% of metaplastic cells are eliminated during the resolution process. Thus, a safe approach to reducing IL-13-induced MCM would involve blocking mucous synthesis and storage, blocking secretion of stored mucus, and eliminating hyperplastic mucous cells. Understanding the molecular mechanisms of each of these processes is necessary for developing effective therapies for reducing mucous hypersecretion in asthma and leading to a repaired epithelium.

Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung has the capacity to mediate many aspects of the pathophysiology of such diseases including asthma and chronic obstructive pulmonary disease (COPD). Until recently, the CD4+ lymphocyte component of these inflammatory influxes was thought to consist of Th1 or Th2 type cells, however a third group of cells termed Th17 have been identified. These cells follow a distinct differentiation profile requiring TGFβ and IL-6 leading to the expression of the Th17 selective transcription factor, RORγt. Differentiation of these cells is restricted by Th1 and Th2 cytokines including IFNγ and IL-4 which attenuate Th17 cell differentiation. The presence of Th17 cells in the airway has yet to be confirmed, yet IL-17 is expressed in both asthma and COPD. Many of the inflammatory effects of Th17 cells are attributed to the expression of this cytokine. For example, IL-17 upregulates the expression of a number of CXCR2 chemokines including CXCL1, CXCL6 and CXCL8 together with neutrophil survival factors GM-CSF and G-CSF from the airway epithelium. This would suggest that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma and COPD. In addition, IL-17 can act synergistically with viral infection or other inflammatory mediators including TNF-α to potentiate these responses. Confirmation of the presence of Th17 cells in the airways in disease warrants further investigation since these cells would present a novel therapeutic opportunity to reduce neutrophilic inflammation in the lung.

Asthma, chronic obstructive pulmonary disorder (COPD), and cystic fibrosis (CF), chronic diseases of the airways, are characterized by symptoms such as inflammation of the lung tissue, mucus hypersecretion, constriction of the airways, and excessive fibrosis of airway tissue. Transforming growth factor (TGF)-β, a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of these chronic airway diseases, especially with respect to airway remodeling. Eosinophils can be activated by and are a major source of TGF-β in asthma. The action of TGF-β also shows associations with other cell types, such as T cells and neutrophils, which are involved in the pathogenesis of asthma. TGF-β can perpetuate the pathogenesis of COPD and CF, as well, through its induction of inflammation via release from and action on different cells. The intracellular signaling induced by TGF-β in various cell types has been elucidated and may point to mechanisms of action by TGF-β on different structural or immune cells in these airway diseases. Some possible treatments, especially that prevent the deleterious airway changes induced by the action of either eosinophils or TGF-β in asthma, have been investigated. TGF-β-induced signaling pathways, especially those in different cell types in asthma, COPD, or CF, may provide potential therapeutic targets for the treatment of some of the most devastating airway diseases.

IL-10 can be considered an important agent in the resolution of inflammation. Originally named “cytokine synthesis inhibitory factor” for its ability to inhibit IFN-γ and IL-2 production in Th2 cells, it is secreted by monocytes, macrophages, mast cells, T and B lymphocytes, and dendritic cells (DCs). IL-10 production and release by monocytic cells in response to allergic challenge is upregulated by TNF-α, and by negative feedback regulation of itself. However, it is also secreted by T regulatory cells (Tregs), under the control of IL- 2. Importantly in the context of asthma, IL-10 inhibits eosinophilia, by suppression of IL-5 and GM-CSF, by direct effects on eosinophil apoptosis, and effects on cell proliferation through down-regulation of IL-1. A number of its cytokine suppressive characteristics are now thought to occur through its upregulation of suppressor of cytokine signaling (SOCS)-3. IL-10 is also a suppressor of nitric oxide (NO) production, which may have ramifications for its role in airway inflammatory diseases. Initial clinical trials have demonstrated relative safety and few clinically adverse events at doses of recombinant human IL-10 below 50 μg/kg, with mixed success in treatment of patients with inflammatory bowel disease and psoriasis. However, both steroid therapy and allergen specific immunotherapy are known to elevate endogenous IL-10 levels, which may account for their efficacy, suggesting that further study of IL-10 as a target for treatment of airway inflammatory diseases such as asthma and COPD is warranted.