The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus-induced and house dust mite antigen-induced (HDM antigen-induced) chronic asthma. Tlr6-/- mice with fungal- or HDM antigen-induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6-/- versus WT asthmatic mice. Tlr6-/- DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6-/- mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6-/- mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6-/- mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma.     

Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13

The clinical manifestations of allergic asthma are believed to result from a dysregulated, T helper 2 lymphocyte (Th2)-biased response to antigen. Although asthma symptoms can be controlled acutely, there is a need for a therapy that will address the underlying immune dysfunction and provide continuous control of chronic airway inflammation. The Th2-type cytokines, IL-13 and IL-4, have been demonstrated to play a crucial role in asthma pathogenesis and their selective neutralization results in the alleviation of asthmatic symptoms in mouse models. The activity of both of these cytokines can be inhibited by a mutant IL-4 protein, IL-4 receptor antagonist (IL-4RA), and thus, continual IL-4RA therapy might be beneficial in treatment of chronic asthma. To explore the potential utility of long-term gene therapy for the treatment of asthma we used a recombinant adeno-associated virus (AAV) vector to deliver and provide sustained expression of IL-4RA in vivo. We show that AAV-mediated delivery of IL-4RA to the airways of mice reduces airway hyperresponsiveness (AHR) and airway eosinophilia triggered by either IL-13 or IL-4. Furthermore, AAV-delivered IL-4RA, expressed either systemically or in the airways of mice following allergen sensitization, significantly inhibited development of airway eosinophilia and mucus production and reduced the levels of asthma-associated Th2 cytokines and AHR in the experimental mouse model of allergic asthma. Thus, gene therapy can be a potential therapeutic option to treat and control chronic airway inflammation and asthmatic symptoms.     

Airway inflammatory marker]

Since asthma has been recognized as a chronic inflammatory airway disease, inflammatory markers are useful tools to show the degree of allergic airway inflammation. Asthmatic airway is characterized with infiltration of activated Th2 lymphocyte, eosinophils and mast cells/basophils. Eosinophil derived proteins such as ECP, MBP and EDN are important markers indicating eosinophilic inflammation. Histamine and tryptase are the products of mast cell/basophil activation. These markers are detected in sputum, BALF, serum and urine, and increased in asthmatics. In addition to these markers, NO concentration in exhaled air, cytokines such as IL-4, IL-5, chemokines such as RANTES, eotaxin, LTE4, MMP are inflammatory markers to indicate the quality and quantity of asthmatic airway inflammation. Assessment of these markers, therefore, contributes to better control of asthmatic symptoms with appropriate therapy.     

Therapeutic modulation of allergic airways disease with leukotriene receptor antagonists

Although asthma is one of the most common chronic respiratory conditions, it often remains unrecognized and undertreated, while patients are often reluctant to comply with regular inhaled anti-inflammatory and bronchodilator therapy. Allergic rhinitis co-exists with asthma in as many as 40% of patients, and can be regarded as a continuum of the same inflammatory disease process. Corticosteroids are the 'gold standard' first-line treatment for both conditions, and have a significant impact upon underlying inflammation, symptoms and long-term outcome. Cysteinyl leukotrienes are potent airway inflammatory mediators, suggesting that treatment antagonizing their effects could play a role in disease management. In recent years, leukotriene receptor antagonists have provided a further therapeutic option in the management of allergic airways disease. These drugs are orally active, can be administered once daily, and provide a systemic approach to the management of patients with asthma and allergic rhinitis. We review the pharmacology of leukotriene receptor antagonists, their potential role in clinical practice in patients with allergic airways disease, and likely areas for further research.     

DNA/amphiphilic block copolymer nanospheres reduce asthmatic response in a mouse model of allergic asthma

Asthma is a chronic, inflammatory, respiratory disease caused by an abnormal reactivity against allergens. The most promising treatments for asthma are based on specific immunotherapies, but they lack efficiency and can induce deleterious side effects. Among new modalities of immunotherapy currently in development, DNA vaccination presents a promising approach, as it enables targeted immunotherapy in association with reduced allergenicity. We have developed an innovative, DNA-based vaccine against Dermatophagoides farinae 1 allergen (Der f 1), one of the allergens most commonly encountered by asthma patients in Europe. Intramuscular administration of a Der f 1-encoding plasmid formulated with the block copolymer 704 in healthy mice induced a strong humoral and cellular response with a pro-helper T cell type 1 bias. Administration of the same formulation in asthmatic mice, according to an early vaccination protocol, led to a reduction of airway hyperresponsiveness and a significant decrease in the level of inflammatory cytokines in the bronchoalveolar lavage of Der f 1-vaccinated mice.     

A Short Review of Acupuncture and Bronchial Asthma — Western and Traditional Chinese Medicine Concepts

Bronchial asthma, a chronic inflammatory airway disorder characterized by reversible airway obstruction, is traditionally managed by pharmacological intervention. Despite asthma receiving extensive global attention, the mortality rate remains at unacceptable levels. Over reliance on medication and associated adverse drug effects have led to exploration of alternative management modalities. The effects of acupuncture and moxibustion, a branch of traditional Chinese medicine, in the management of asthma have been extensively reported over the last few decades. This review provides a general overview of the Western and Chinese concepts of management of asthmatic symptoms and, in particular, the use of acupuncture in the management of asthma.     

Moving towards a new generation of animal models for asthma and COPD with improved clinical relevance

Asthma and chronic obstructive pulmonary disease (COPD) are complex inflammatory airway diseases characterised by airflow obstruction that remain leading causes of hospitalization and death worldwide. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies for both conditions. In this review, we describe preclinical in vivo models that recapitulate many of the features of asthma and COPD. Specifically, we discuss the pro's and con's of the standard models and highlight recently developed systems designed to more accurately reflect the complexity of both diseases. For instance, clinically relevant allergens (i.e. house dust mite) are now being used to mimic the inflammatory changes and airway remodelling that result after chronic allergen exposures. Additionally, systems are being developed to mimic steroid-resistant and viral exacerbations of allergic inflammation - aspects of asthma where there is an acute need for new therapies. Similarly, COPD models have evolved to align with the improved clinical understanding of the factors contributing to disease progression. This includes using cigarette smoke to model not only airway inflammation and remodelling, but some systemic changes (e.g. hypertension and skeletal muscle alterations) that are thought to influence disease. Further, mouse genetics are being exploited to gain insights into the genetics of COPD susceptibility. The new models of asthma and COPD described herein demonstrate that improved clinical understanding of the diseases and better preclinical models is an iterative process that will hopefully lead to therapies that can effectively manage severe asthma and COPD.     

Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft–enriched, CD63(+) endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.     

Chronic asthmatic bronchitis

The main pathogenetic mechanisms and morphological picture of chronic asthmatic bronchitis are similar to those of bronchial asthma. The only difference is the absence of regular fits of asphyxia. Diagnosis of this disease is based upon the detection of the broncho-obstructive syndrome and verification of its allergic origin. Therapy of chronic asthmatic bronchitis is based on the same principles as that of bronchial asthma.     

ABCs of Asthma

Asthma results from chronic airway inflammation involving a diversity of activated cells including mast cells, eosinophils, T-lymphocytes, neutrophils, macrophages, and epithelial cells. These cells release proinflammatory cytokine mediators that augment and regulate airway inflammation, leading to airway hyperresponsiveness responsible for the chronic asthma symptoms of dyspnea, wheezing, and chest tightness. It is hypothesized, but unproven, that inflammatory effects can lead to irreversible structural and functional airway changes. Early intervention with anti-inflammatory agents mitigates inflammatory changes, reverses airway obstruction, and may possibly prevent progression of airway remodeling. Current asthma guidelines recommend that initial management should be based on pretreatment assessments of asthma severity as determined by measures of clinical and spirometric impairment in individual patients; subsequent adjustments of pharmacotherapy and avoidance recommendations should be performed at regular follow-up visits and guided by frequent assessments of asthma control. Physicians and providers should continually educate asthmatic patients about proper use of asthma controller medications, avoidance of asthma triggers, and self-management of asthma exacerbations.     

Impact of Aspergillus fumigatus in allergic airway diseases

ABSTRACT: For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA), known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF). The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.     

Acute phase reactants in allergic airway disease

Acute phase reactants have been implicated for their involvement as proinflammatory molecules in various inflammatory diseases. However, little is known regarding their role in the allergic airway disease. The aim of the present study was to examine the blood concentrations of three acute-phase proteins, namely C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen in patients with allergic rhinitis and asthma. Three study groups include: non-smoker allergic rhinitis (n = 50), non-smoker asthma (n = 20), and non-allergic, non-smoker healthy control subjects (n = 20). Patients who have had recent upper or lower respiratory tract infection and trauma, any rheumatological illnesses, malignancy or obesity were excluded. Blood samples were obtained from all the patients and control subjects and were analyzed for serum CRP, SAA and plasma fibrinogen. The mean CRP and fibrinogen values in the rhinitis and asthma groups were not significantly different when compared to the control group. However, the mean SAA levels of both groups were found to be significantly higher than those of the control group (p = 0.002 for rhinitis, p = 0.02 for asthma). There was no significant correlation between the FEV(1) values and the levels of the serum markers. This study demonstrates that acute phase reactant SAA rises in patients with allergic rhinitis and patients with asthma. We therefore suggest that SAA may have a role in the inflammatory airway disease.     

Technology evaluation: ISIS-104838, OraSense

OraSense Ltd (a joint venture between Isis Pharmaceuticals Inc and Elan Corp) is developing ISIS-104838, an antisense oligonucleotide specific for TNF alpha mRNA, as an inhibitor of TNF alpha synthesis. The compound is being developed for the potential treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. This antisense oligonucleotide is currently undergoing phase II clinical trials for RA and Crohn's disease.     

Mucosal permeability and smooth muscle function in asthma

The changes in airway structure that occur in asthma are characteristic of a chronic inflammatory process that involves tissue covered by a mucosal surface. This article reviews the inflammatory process and presentation of evidence that structural changes seen in asthmatic airways are a result of this response. The contribution of the airway muscle and epithelium to the abnormal function of asthmatic airways is also reviewed.     

Asthma: 2015 and beyond

Asthma is a multifactorial, chronic inflammatory disease of the airways. The knowledge that asthma is an inflammatory disorder has become a core fundamental in the definition of asthma. Asthma's chief features include a variable degree of air-flow obstruction and bronchial hyper-responsiveness, in addition to the underlying chronic airways inflammation. This underlying chronic airway inflammation substantially contributes to airway hyper-responsiveness, air-flow limitation, respiratory symptoms, and disease chronicity. However, this underlying chronic airway inflammation has implications for the diagnosis, management, and potential prevention of the disease. This review for the respiratory therapy community summarizes these developments as well as providing an update on asthma epidemiology, natural history, cause, and pathogenesis. This paper also provides an overview on appropriate diagnostic and monitoring strategies for asthma, pharmacology, and newer therapies for the future as well as relevant management of acute and ambulatory asthma, and a brief review of educational approaches.     

Airway remodeling in asthma and its influence on clinical pathophysiology

Bronchial asthma has been characterized by chronic and allergic airway inflammation, which induces cytological and histological changes in the airway structure over time. These changes have been called airway remodeling, which includes goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. Airway epithelium in asthma is often occupied with goblet cells, which contain secretory granules. Airway wall thickness increases because of subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells and submucosal glands. Airway remodeling, therefore, can often cause irreversible airflow limitation, an increase of airway hyperresponsiveness and severity of asthma. Recent studies have demonstrated the molecular and cellular mechanisms of goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. Several lines of evidence suggest that airway remodeling has been induced by cytokines and mediators produced in chronic allergic airway inflammation. Thus, early intervention with inhaled corticosteroid may prevent progress of airway remodeling by suppressing allergic airway inflammation.     

Platelet-activating factor: a possible mediator of the dual response to allergen?

Certain allergic asthmatic patients exhibit a dual response in the lung following bronchial challenge with the appropriate allergen. Often this is paralleled by a cutaneous dual response when the antigen is injected intradermally. The mechanisms underlying such phenomena are not established, but some evidence suggests that the late response is a consequence of the early response. Since platelet activation has been observed following antigen challenge in asthmatic subjects, we have studied the ability of platelet activating factor (PAF-acether, AGEPC) to induce cutaneous inflammatory responses in man. In a time course study over 24 hr, PAF-acether produced a biphasic response: an immediate weal and flare reaction, which resolved within 1-2 hr and was followed some 3-6 hr later by a delayed reaction in which erythema associated with hyperalgesia was evident. These observations suggest that PAF-acether should be considered in the context of allergic asthma as a possible mediator of the dual response to allergen.     

Pathogenesis of asthma

The conception of the pathogenesis of a disease is probably as important in determining the selection of therapies as is the evidence provided by outcome studies of their efficacy. The recent evolution in our understanding of the pathogenesis of asthma has nicely paralleled advances in clinical research on new forms of treatment. This evolution has occurred so smoothly that we may not be fully aware how far it has taken us. Airflow obstruction is still regarded as the fundamental cause of the characteristic asthmatic symptoms of shortness of breath, chest tightness, and wheezing, while the factors leading to airflow obstruction are still assumed to include spasm of airway smooth muscle, thickening of the airway wall, and inspissation of viscid plugs of mucus in the airway lumen. What is new is the recognition of asthma as a chronic disease of the lower airways associated with characteristic inflammatory changes (involving lymphocytes, mast cells, and eosinophils), and possibly irreversible "remodeling" of the airways (by deposition of collagen and proteoglycans, proliferation and transformation of resident cells, and infiltration with inflammatory cells). This modern conception of asthma differs dramatically from the former perception of the disease as an episodic illness characterized by disturbance of the contractile function of airway smooth muscle. The new interpretation has important implications not just for the development of future therapies based on the inflammatory mechanisms involved in the pathogenesis of asthma, but also for the ways in which current therapies should be used.     

Effects of Ecklonia cava ethanolic extracts on airway hyperresponsiveness and inflammation in a murine asthma model: role of suppressor of cytokine signaling.

Ecklonia cava (EC) is a brown alga that evidences radical scavenging activity, bactericidal activity, tyrosinase inhibitory activity, and protease inhibitory activity. However, its anti-allergic effects remain poorly understood. In the current study, we attempted to determine whether pretreatment with EC induces a significant inhibition of asthmatic reactions in a mouse asthma model. Mice sensitized and challenged with ovalbumin (OVA) evidenced typical asthmatic reactions, as follows: an increase in the number of eosinophils in bronchoalveolar lavage fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and airway luminal narrowing; the development of airway hyperresponsiveness; the detection of tumor necrosis factor-alpha (TNF-alpha) and Th2 cytokines, including IL-4 and IL-5 in the bronchoalveolar lavage (BAL) fluid; and the detection of allergen-specific immunoglobulin E (IgE) in the serum. However, the administration of EC extract prior to the final airway OVA challenge resulted in a significant inhibition of all asthmatic reactions. We also demonstrated that EC extracts treatment resulted in significant reductions on matrix metalloproteinase-9 (MMP-9) and Suppressor of cytokine signaling-3 (SOCS-3) expression and a reduction in the increased eosinophil peroxidase (EPO) activity. The treatment of animals with EC extracts resulted in a significant reduction in the concentrations of the Th2 cytokine (IL-4 and IL-5) in the airways, without any concomitant increase in the concentration of Th1 cytokines. These findings indicate that EC extracts may prove useful as an adjuvant therapy for allergic airway reactions via the inhibition of the Th2 response. Accordingly, this study may provide evidence that EC extract performs a critical function in the amelioration of the pathogenetic process of asthma in mice.     

An overview of drug therapy for chronic adult asthma.

Asthma involves bronchoconstrictor mechanisms, possible abnormalities of airway smooth muscles and an inflammatory response. Past emphasis on bronchodilator therapy ignored the underlying inflammatory response. Since chronic asthma can eventually lead to irreversible airflow obstruction from uncontrolled inflammation, current drug therapy stresses both inflammation reduction and bronchodilatation. This article discusses the rationale of current pharmacologic management for the adult client with chronic asthma and presents a step-care approach for management of the disease. Inhaled beta-agonists--effective bronchodilators--are the primary drug of choice. Steroids administered via inhalation are the most effective anti-inflammatory agents available. Cromolyn sodium is useful for prophylactic management of asthma. Theophylline, previously the cornerstone of asthma treatment, is now introduced later in the therapeutic plan as an additional bronchodilator. Inhaled anticholinergics may be tried as adjunctive asthma treatment. With careful assessment, intervention and management, health care providers can successfully care for most adult clients with chronic asthma.