Chronic inflammation in asthma: a contest of persistence vs resolution

Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.     

Asthma as a paradigm for autoimmune disease

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanisms in some cases, by looking at the key elements that regulate the immune response in both asthma and autoimmune conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of asthma and autoimmune conditions in the same patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in asthma, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic diseases suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T cell receptor loci have long been considered important candidates for a common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to successful treatment of asthma and autoimmune conditions.     

Epithelium: at the interface of innate and adaptive immune responses

Several diseases of the airways have a strong component of allergic inflammation in their cause, including allergic rhinitis, asthma, polypoid chronic rhinosinusitis, eosinophilic bronchitis, and others. Although the roles played by antigens and pathogens vary, these diseases have in common a pathology that includes marked activation of epithelial cells in the upper airways, the lower airways, or both. Substantial new evidence indicates an important role of epithelial cells as both mediators and regulators of innate immune responses and adaptive immune responses, as well as the transition from innate immunity to adaptive immunity. The purpose of this review is to discuss recent studies that bear on the molecular and cellular mechanisms by which epithelial cells help to shape the responses of dendritic cells, T cells, and B cells and inflammatory cell recruitment in the context of human disease. Evidence will be discussed that suggests that secreted products of epithelial cells and molecules expressed on their cell surfaces can profoundly influence both immunity and inflammation in the airways.     

Is there a difference between chronic airway inflammation in chronic severe asthma and chronic obstructive pulmonary disease?

PURPOSE OF REVIEW: The lack of a universally accepted definition of chronic severe asthma and the continuous changes in the classification of the severity of stable chronic obstructive pulmonary disease in the last 10 years make it difficult to compare the many studies available. The aim of the review is to compare studies on chronic severe asthma that have a control group of patients with mild to moderate persistent asthma and studies on stable chronic obstructive pulmonary disease that have an age-matched control group of smokers with normal lung function (with or without chronic bronchitis). RECENT FINDINGS: Our review of the recent literature in this field seems to indicate that chronic airway inflammation in chronic severe asthma is characterized in most cases, both in central and peripheral airways, by the same pathological features of mild-moderate persistent asthma with an increased number of activated T lymphocytes, particularly CD4 Th2 cells, and sometimes eosinophils and mast cells. The most notable difference of chronic severe asthma compared with mild to moderate disease is the increased number of neutrophils. Chronic airway inflammation in stable chronic obstructive pulmonary disease is characterized, both in central and peripheral airways, by an increased number of T lymphocytes, particularly CD8+, macrophages and neutrophils. Macrophage and neutrophil counts increase with the progression of the severity of the disease. SUMMARY: These differences in chronic airway inflammation support the consensus that asthma and chronic obstructive pulmonary disease are different diseases along all their stages of severity.     

Understanding the pathogenesis of allergic asthma using mouse models.

OBJECTIVE: This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice. DATA SOURCES: MEDLINE searches were conducted with key words asthma, mouse model, and murine. Additional articles were identified from references in articles and book chapters. STUDY SELECTION: Original research papers and review articles from peer-reviewed journals were chosen. RESULTS: Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5. CONCLUSIONS: AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.     

Immunopathogenesis of Allergic Asthma: More Than the Th2 Hypothesis

Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future.     

Host immune responses and possible therapeutic targets for viral respiratory tract infections in susceptible populations: a narrative review

BackgroundRespiratory viruses are associated with significant global morbidity and mortality, as well as socioeconomic factors. Certain conditions and patient groups are more susceptible to develop severe viral respiratory tract infections (RTIs).ObjectivesTo summarise the data on deregulated immune pathways that have been associated with increased susceptibility to severe viral RTIs in certain populations. We also describe the commonalities of the defective immune pathways across these susceptible populations that may represent possible targets for future therapeutic or preventative approaches.SourcesWe conducted free searches in Medline, Scopus, and Google Scholar for studies focusing on potential mechanisms of immune dysfunction that may be associated with severe viral RTIs in susceptible populations with conditions including pregnancy, obesity, diabetes mellitus, hypertension, cardiovascular disease, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and extremes of age. We considered preclinical/animal data, original human studies, and reviews.ContentInnate and adaptive immune responses become quantitatively and qualitatively compromised in aging, obesity, and diabetes mellitus, with the most pronounced changes affecting T cells. Moreover, immune dysregulation by the so-called inflamm-aging results in chronic low-grade inflammation in such conditions. Increased leptin levels affect the immune system particularly in obesity, while leptin dysregulation plays a role in asthma and COPD pathogenesis. Deficient production of interferon (IFN) type I and III in response to rhinovirus contributes to asthma exacerbations. Similar attenuation of IFN production in response to influenza and rhinovirus has been documented in pregnancy. Dampened type I IFN responses have also been found in diet-induced obese mice and in obese individuals.ImplicationsImmunosenescence and chronic low-grade inflammation accompanying aging and a variety of chronic conditions, such as diabetes, obesity, asthma, COPD, chronic renal disease, and hypertension, contribute to the poor outcomes observed following viral respiratory infections. Commonly affected pathways may represent potential future therapeutic targets.     

Immunology and the menstrual cycle

Sex and gender differences in disease prevalence, pathogenesis and modulation have been frequently reported. The menstrual cycle represents the opportunity to study the physiological effect of hormonal fluctuations in vivo on the immune function and chronic disease modulation. Reports on the effect of the cycle on immune cell numbers and activity fluctuations are scarce, but recent publications demonstrate an increasing interest in the subject. The menstrual cycle might affect immune cell numbers and modulate their activity throughout the 4-week cycle, as demonstrated in the case of regulatory T cells. The implications of these fluctuations are particularly relevant in the field of chronic diseases affecting women of reproductive age. In fact, baseline inflammation and immune cell activation in association with other mechanisms, such as regulation of receptor expression, modulation of muscular contraction and behavioral aspects might explain the menstrual-associated fluctuations described in chronic and acute diseases. In the following review the current knowledge about the modulatory effects of the menstrual cycle on both immune cells and systemic diseases, such as autoimmune diseases, asthma, diabetes, cardiac arrhythmia and schizophrenia, is reported. Most of these diseases display worsening of symptoms premenstrually or during menses due to physiologic effects on the target tissue mediated by progesterone and estrogen fluctuations and, thus, display paradigmatic changes potentially relevant to numerous other conditions.     

Immunobiology of TNFSF15 and TNFRSF25

The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn’s disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics.     

Regulation generation: the suppressive functions of human regulatory T cells

Proper regulation of immune homeostasis is necessary to limit inflammation and prevent autoimmune and chronic inflammatory diseases. Many autoimmune diseases, such as psoriasis, are driven by vicious cycles of activated T cells that are unable to be suppressed by regulatory T cells. Effective suppression of auto-reactive T cells by regulatory T cells (Treg) is critical for the prevention of spontaneous autoimmune disease. Psoriatic Treg cells have been observed to a defect in their capacity to regulate, which clearly contributes to psoriasis pathogenesis. A challenge for translational research is the development of novel therapeutic interventions for autoimmune diseases that will result in durable remissions. Understanding the mechanism(s) of dysregulated T cell responses in autoimmune disease will allow for the development of future therapeutic strategies that may be employed to specifically target pathogenic, proinflammatory cells. Several reports have demonstrated a pathogenic role for Thl and Thl7 cells in psoriasis as well as other autoimmune diseases. Similarly, several laboratories have independently demonstrated functional defects in regulatory T cells isolated from patients with numerous divergent autoimmune diseases. One primary challenge of research in autoimmune diseases is therefore to restore the balance between chronic T cell activation and impairment of Treg suppressor mechanisms. To this end, it is critical to develop an understanding of the many suppressive mechanisms employed by Treg cells in hopes of developing more targeted therapeutic strategies for Treg-mediated autoimmune diseases.     

Neurogenic mechanisms in bronchial inflammatory diseases

Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi-directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene-related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD.     

Regulatory T cells and asthma

Airway inflammation in asthma is characterized by activation of T helper type-2 (Th2) T cells, IgE production and eosinophilia. In many cases, this process is related to an inappropriate T cell response to environmental allergens, and other T cell-dependent pathways may also be involved (such as Th17). Regulatory T cells (Tregs) are T cells that suppress potentially harmful immune responses. Two major subsets of Treg are CD25^hi, Foxp3⁺Tregs and IL-10-producing Tregs. There is evidence that the numbers or function of both subsets may be deficient in patients with atopic allergic disease. Recent work has extended these findings into the airway in asthma where Foxp3 expression was reduced and CD25^hi Treg-suppressive function was deficient. In animal models of allergic airways disease, Tregs can suppress established airway inflammation and airway hyperresponsiveness, and protocols to enhance the development, recruitment and function of Tregs have been described. Together with studies of patients and in vitro studies of human T cells, these investigations are defining potential interventions to enhance Treg function in the airway in asthma. Existing therapies including corticosteroids and allergen immunotherapy act on Tregs, in part to increase IL-10 production, while vitamin D3 and long-acting β-agonists enhance IL-10 Treg function. Other possibilities may be enhancement of Treg function via histamine or prostanoid receptors, or by blocking pro-inflammatory pathways that prevent suppression by Tregs (activation of Toll-like receptors, or production of cytokines such as IL-6 and TNF-α). As Tregs can also suppress the potentially beneficial immune response important for controlling infections and cancer, a therapeutic intervention should target allergen- or site-specific regulation.     

Emerging Roles of T Helper Subsets in the Pathogenesis of Asthma

The cardinal features of asthma include pulmonary inflammation and airway hyperresponsiveness (AHR). Classically, asthma, specifically allergic asthma, has been attributed to a hyperactive Th2 cell immune response. However, the Th2 cell-mediated inflammation model has failed to adequately explain many of the clinical and molecular aspects of asthma. In addition, the outcomes of Th2-targeted therapeutic trials have been disappointing. Thus, asthma is now believed to be a complex and heterogeneous disorder, with several molecular mechanisms underlying the airway inflammation and AHR that is associated with asthma. The original classification of Th1 and Th2 pathways has recently been expanded to include additional effector Th cell subsets. These include Th17, Th9 and Treg cells. Emerging data highlight the involvement of these new Th cell subsets in the initiation and augmentation of airway inflammation and asthmatic responses. We now review the roles of these recently classified effector Th cell subsets in asthmatic inflammation and the insights they may provide in addition to the traditional Th2 paradigm. The hope is that a clearer understanding of the inflammatory pathways involved and the mediators of inflammation will yield better targeted therapeutics.     

Regulation of G-protein-coupled signaling pathways in allergic inflammation

Allergic diseases such as asthma are elicited by maladaptive activation of immune cells such as mast cells and lymphocytes by otherwise innocuous allergens. The numerous mediators secreted by such cells promote both acute inflammation and, in many instances, chronic tissue remodeling. Most of these compounds exert their effects on end-organ targets such as epithelial and endothelial cells and airway smooth muscle by activating G-protein-coupled receptors (GPCRs), which are by far the most abundant type of cell surface receptor. Since GPCRs are also the most common target of allergy therapeutics, a better understanding of their intracellular signaling mechanisms is vital to improve the efficacy of such drugs or to develop new targets. In this review, we focus on some of the new regulatory elements that control the duration and amplitude of GPCR signal transduction pathways in immune effector cells and end-organ structural cells affected by allergic inflammation.     

Apoptosis mediated by cytolytic molecules might be responsible for maintenance of psoriatic plaques

Psoriasis is a chronic hyperproliferative skin disease characterized by keratinocyte hyperproliferation and inflammation. It is generally considered as an autoimmune disease mediated by T cells. The precise mechanism of triggering keratinocyte hyperproliferation is as yet unknown. Apoptosis seems to be important in the maintenance of skin cell homeostasis as well as in the pathogenesis of some skin diseases. We hypothesize how apoptosis mediated by cytolytic mechanisms could be involved in initiating and maintenance of psoriatic plaque. Increased keratinocyte hyperproliferation might develop as a consequence of failure to remove self-reactive T cells by apoptosis that in other way cause significant keratinocyte damage. Apoptotic keratinocytes might trigger an injury response program causing regenerative hyperplasia of epidermal keratinocytes. Another possibility is that the failure to eliminate these abnormal keratinocytes could result in the persistence of chronic inflammatory conditions constantly recruiting specific T cells. Increased epidermal thickness in psoriasis could be also explained by imbalance between the expression of pro- and anti-apoptotic proteins. Epidermal keratinocytes have the ability to produce cytolytic molecules, thus they might also have the potential to protect the epidermis from T cell-mediated damage. In conclusion, hyperproliferation of psoriatic keratinocytes might be partly due to changes in the keratinocyte expression of pro- and anti-apoptotic genes, partly to the damaged keratinocytes triggering an inappropriate wound repair response and partly by the failure to eliminate these abnormal keratinocytes resulting in the persistence of chronic inflammation. Each of the proposed mechanisms might be a possible therapeutic target mainly by new immunomodulatory agents.     

The many ways tissue phagocytes respond to dying cells

Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.     

Role of viral infections in asthma and chronic obstructive pulmonary disease

Substantial evidence implicates common respiratory viral infections in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Children who experience recurrent virally induced wheezing episodes during infancy are at greater risk for developing asthma. In addition, respiratory viral infections are a major trigger for acute exacerbations of both asthma and COPD. Despite the importance of viral infections in asthma and COPD, the mechanisms by which viruses predispose to, or cause exacerbations of, these diseases remain poorly understood. It is clear that viral infections lead to enhanced airway inflammation and can cause airways hyperresponsiveness. The epithelial cell is the principal site of viral infection in the airways and plays a central role in viral modulation of airway inflammation via release of a variety of cytokines, chemokines, and growth factors. The mechanisms by which viral infections modulate epithelial function, therefore, is a topic of intense investigation. The epithelium also contributes to the host innate defense response to viral infection by releasing products that are antiviral and/or can lead to increased recruitment of dendritic cells and lymphocytes. Some evidence supports a role for the epithelial cell in specific immunity, although the response of more conventional cells of the immune system to viral infections is likely the dominant factor in this regard. Although current therapies may help combat virally induced disease exacerbations, they are less than ideal. A better understanding of the mechanisms underlying viral modulation of these diseases, therefore, may lead to new therapeutic approaches.     

The role of resistin as a regulator of inflammation: Implications for various human pathologies

Resistin was originally described as an adipocyte-secreted peptide that induced insulin resistance in rodents. Increasing evidence indicates its important regulatory roles in various biological processes, including several inflammatory diseases. Further studies have shown that resistin in humans, in contrast to its production by adipocytes in mice, is synthesized predominantly by mononuclear cells both within and outside adipose tissue. Possible roles for resistin in obesity-related subclinical inflammation, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, rheumatic diseases, malignant tumors, asthma, inflammatory bowel disease, and chronic kidney disease have already been demonstrated. In addition, resistin can modulate several molecular pathways involved in metabolic, inflammatory, and autoimmune diseases. In this review, current knowledge about the functions and pathophysiological implications of resistin in different human pathologies is summarized, although there is a significant lack of firm evidence regarding the specific role resistin plays in the “orchestra” of the numerous mediators of inflammation.     

Dendritic cells in asthma and COPD: opportunities for drug development

The lung contains many subsets of dendritic cells that are distributed in various anatomical compartments. In homeostatic conditions, a fine-tuned balance exists between plasmacytoid and myeloid dendritic cells necessary for maintaining tolerance to inhaled antigen and avoiding overt inflammation. These subsets of DCs also play important roles in establishment of airway inflammation seen in asthma and chronic obstructive pulmonary disease. Based on these new insights on airway DC biology, several approaches that interfere with DC function show potential as new intervention strategies for these ever increasing diseases.     

Asthma and COPD

The two obstructive airway diseases bronchial asthma and chronic obstructive pulmonary disease (COPD) represent major global causes of disability and death, and COPD is estimated to become the third most common cause of death by 2020. The structural and pathophysiologic findings in both diseases appear to be easily differentiated in the extremes of clinical presentation. However, a significant overlap may exist in individual patients regarding features such as airway wall thickening on computer tomography or reversibility and airway hyperresponsiveness in lung function tests. Airway inflammation differs between the two diseases. In bronchial asthma, airway inflammation is characterized in most cases by an increased number of activated T-lymphocytes, particularly CD4+ Th2 cells, and sometimes eosinophils and mast cells. The most notable difference of chronic severe asthma compared with mild to moderate asthma is an increased number of neutrophils. In stable COPD, airway inflammation is characterized by an increased number of T-lymphocytes, particularly CD8+ T cells, macrophages and neutrophils. With the progression of the disease severity, macrophage and neutrophil numbers increase. Although there may be a partial overlap between asthma and COPD in some patients, the differences in functional, structural and pharmacological features clearly demonstrate the consensus that asthma and COPD are different diseases along all their stages of severity.