Chronic inflammation and asthma (original) (raw)
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A new mechanism regulating the initiation of allergic airway inflammation
2007
Background: The earliest immune events induced by allergens are poorly understood, yet are likely essential to understanding how allergic inflammation is established. Objective: We sought to describe the earliest signaling events activated by allergen and determine their significance to allergic inflammation. Methods: A fungal-associated allergenic proteinase (FAP) or ovalbumin was administered once intranasally to wild-type mice to determine their ability to induce allergy-associated genes and initiate allergic lung inflammation. Mice deficient in recombinase activating gene 1, C3a, the C3a anaphylatoxin receptor, and MyD88 were challenged similarly to understand the requirement of these molecules and T and B cells for allergic inflammation. Adoptive T-cell transfer experiments were further performed to determine whether signal transducer and activator of transcription 6 (STAT6) was required for cell recruitment and allergic inflammation. Results: FAP, but not ovalbumin, induced eosinophilic airway inflammation and lung IL-4 production in the absence of adaptive immune cells after the transcriptional induction of allergy-specific airway chemokines. Allergen-mediated chemokine secretion and innate allergic lung inflammation occurred in the absence of STAT6, recombinase activating gene 1, C3a, C3a anaphylatoxin receptor, Toll-like receptor 4, and MyD88 but required intact proteinase activity. Furthermore, FAP induced recruitment of T H 2 cells and eosinophils to lungs independently of STAT6, which was previously thought to be required for T H 2 cell homing. Conclusion: FAP induces allergic lung inflammation through a previously unrecognized innate immune signaling mechanism. Clinical implications: These findings reveal a new paradigm for understanding how allergic inflammation begins and suggest novel possibilities for the prevention and treatment of allergic diseases, such as asthma. (J Allergy Clin Immunol 2007;120:334-42.)
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2004
Background Asthma is associated with recruitment of eosinophils, accumulation of chronic inflammatory cells in the airway walls, subepithelial fibrosis and other structural changes of airway wall remodelling. The role of ongoing exposure to allergens in their pathogenesis remains unclear. Objective To examine whether changes of inflammation and remodelling were reversible following cessation of antigenic challenge in a mouse model of chronic asthma. Methods BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged by inhalation of a low mass concentration of antigen for 8 weeks, leading to development of acute-on-chronic airway inflammation, subepithelial fibrosis and other changes of airway wall remodelling. Epithelial injury was assessed by immunohistochemistry, while inflammation and remodelling were quantified by appropriate histomorphometric techniques. Regression of lesions was assessed in animals examined at 1, 2 and 4 weeks after exposure to OVA ceased. Results We did not find evidence of airway epithelial injury in this model of low-level chronic inhalational exposure to antigen. Persistence of the recruitment of eosinophils and chronic inflammatory cells in the airway walls was dependent on continuing antigenic challenge, as was persistence of mucous cell hyperplasia/metaplasia. Subepithelial fibrosis and epithelial hypertrophy exhibited delayed reversibility following cessation of exposure to antigen, possibly related to matrixassociated accumulation of transforming growth factor-b 1 . Conclusion In chronic asthma, low-level antigenic challenge may be required to maintain the inflammatory response in the airway wall, but airway remodelling may persist in its absence.
Journal of Occupational Medicine and Toxicology, 2008
Over the last decade mouse models of experimental asthma proved to be a valuable tool for the investigation of mechanisms that underlie acute allergic airway inflammation and development of airway hyperresponsiveness, two of the hallmarks of human asthma. Nevertheless, these acute models fail to reflect the aspects of this chronic disease because they do not represent any signs of chronicity and airway remodelling as it is defined by subepithelial fibrosis, goblet cell hyperplasia and airway smooth muscle cell hypertrophy. Recent mouse models were successful in overcoming these limitations by using chronic allergen-challenges. These new models of chronic experimental asthma now proved as a novel tool to examine the complex interaction of infiltrating inflammatory cells and structural cells such as fibroblasts and smooth muscle cells that ultimately leads to airway remodelling and stable airflow limitation. Recent studies clearly demonstrated that T helper 2 (TH2) cells and their typical cytokines play a critical role not only in airway inflammation but also in the development of airway remodelling. Since the transcription factor GATA-3 is essential for TH2 cell development and the production of several TH2 type cytokines this intracellular molecule represents a new promising target for therapeutic intervention in asthma that might even effect airway remodelling.
Inflammatory cells in asthma: Mechanisms and implications for therapy
Journal of Allergy and Clinical Immunology, 2003
Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD + (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells. (J Allergy Clin Immunol 2003;111:S5-17.)
New insights into the pathogenesis of asthma
Journal of Clinical Investigation, 2003
Asthma is a disease whose ability to cause episodic symptomatology has been appreciated since antiquity. Although the fine points of the definition can be debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized reversible obstruction of airflow and to define reversibility as a greater than 12% increase in the patient's forced expiratory volume in 1 second (FEV 1 ) that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as methacholine and histamine or specific antigens, is the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of recurrent wheeze, cough, or shortness of breath, reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating airway hyperresponsiveness. It has long been assumed that patients with asthma experience intermittent attacks and have relatively normal lung function during intervening periods. More recent studies have demonstrated that asthma can cause progressive lung impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.
Inflammation in allergic asthma: Initiating events, immunological response and risk factors
Respirology, 2004
Inflammation in allergic asthma: Initiating events, immunological response and risk factors FERREIRA MAR. Respirology 2004; 9 : 16-24 Abstract: Allergic asthma affects 155 million people worldwide. Currently, it is a disease that can be controlled by diverse therapeutic approaches but that cannot be cured. This means that asthma is one of the most expensive diseases for healthcare systems in developed countries. Efficient prevention strategies are therefore greatly needed to reduce both individual morbidity and national economic burdens. This requires a detailed knowledge of the immunological and physiological mechanisms involved in asthma. This review synthesizes current understanding about the immunobiology of IgE-mediated asthma. It discusses the initiating events, the main immunological and inflammatory processes, and addresses the importance of risk factors in the development and maintenance of allergic diseases. Finally, it integrates these concepts in a theoretical causal model for atopic asthma.
New Aspects in the Immunopathology of Severe Asthma
Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry, 2009
Severe asthma afflicts only a small portion of the population of asthmatics; however, due to the severity of the disease, treatment of these patients generates disproportionately high costs, which account for as much as spent for treatment of all other asthmatics. This issue gains even more importance since currently available medications are often not sufficient to treat or even dampen the inflammatory response in the airways of severe asthmatics. Whereas mild-to-moderate asthma is characterized by reversibility of airway obstruction, severe asthma frequently includes a degree of fixed airflow limitation and corticosteroid refractoriness. In contrast to mild-to-moderate asthma, the inflammatory response in the airways appears to be much more complex including neutrophils as the dominating leukocyte subpopulation. A plethora of neutrophilderived mediators and enzymes appears to perpetuate or aggravate the inflammatory response and its pathophysiologic consequences by forming several positive feedback loops. Although neutrophil infiltration into the airways is a common feature of acute asthma exacerbations, these cells are observed in the airways of severe asthmatics in the absence of bacterial infections. Since the identification of T helper 17 (TH17) cells in airway infiltrates of severe asthmatics, TH17 cells are also implicated in the immunopathology of the disease. By secreting interleukin 17A TH17 cells are able to induce the airway epithelial cell production of IL-8, the most potent chemoattractant for neutrophils. However, understanding the role of these cells within the context of the immunopathology of severe asthma is just in the fledging stages. This review aims at summarizing the actual knowledge on the immunopathologic mechanisms underlying this disease.
New Insights into Asthma Pathogenesis
Allergy & Clinical Immunology International - Journal of the World Allergy Organization, 2004
Although Th-2-mediated inflammation is a key therapeutic target in asthma, its relationship to altered structure and functions of the airways is largely unknown. In addition to inflammation, asthma is a disorder involving the airway epithelium that is more vulnerable to environmental injury and responds to this by impaired healing. This establishes a chronic wound scenario that is capable of sustaining chronic inflammation as well as remodeling. This response occurs as a consequence of activation of the epithelial-mesenchymal unit, involving reciprocal activities of growth factors belonging to the fibroblast growth factor, epidermal growth factor, and transforming growth factor- families. The observation that structural changes in the airways in children at or before the onset of asthma occurs irrespective of inflammation might suggest that premodeling is required before Th-2 inflammatory responses can be sustained. Once established, altered function of constitutive airway cells, including fibroblasts, smooth muscle, nerves, and the epithelium, provides an abnormal microenvironment in which to generate a separate set of signals that underpin the acute/subacute inflammation characteristic of asthma exacerbations, triggered by viruses, pollutants, and allergens.
Inflammatory cells in asthma: Mechanisms and implications for therapy. Discussion
The Journal of Allergy and Clinical Immunology, 2003
Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD + (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells. (J Allergy Clin Immunol 2003;111:S5-17.)