Asthma hyperresponsive airways

No longer is asthma considered a condition with isolated, acute episodes of bronchospasm. Rather, asthma is now understood to be a chronic inflammatory disorder of the airways—that is, inflammation makes the airways chronically sensitive. When these hyperresponsive airways are irritated, airflow is limited, and attacks of coughing, wheezing, chest tightness, and breathing difficulty occur. 

Asthma may be exacerbated by work involving exercise or exposure to cold, dusts, or irritants, to which hyperresponsive airways react. For example, people with asthma react with airway narrowing to sulphur dioxide at concentrations below the recommended occupational standards [1]. Such individuals have a prior history of asthma, no latent interval of symptom-free exposure, and symptoms are improved by avoiding heavy exposure to the provoking agent, and by appropriate drug therapy. 

Asthma is an extremely complex condition characterized by variable and reversible airways obstmction combiaed with nonspecific bronchial hypersensitivity (1 3). The cause of asthma, which is not always readily diagnosed (4), remains unknown. Days, if not weeks, ate needed to document the spontaneous reversal of the airways obstmction ia some patients. Asthmatics experience both an immediate hypersensitivity response and a delayed late-phase reaction, each mediated by a different pathway. Chronic asthma has come to be viewed as an inflammatory disease (5). The late-phase reaction plays a key role ia iaduciag and maintaining the inflammatory state which ia turn is thought to iaduce the bronchial hyperresponsiveness (6). The airways obstmction results from both contraction of airways smooth muscle and excessive bronchial edema. Edema, a characteristic of inflammatory states, is accompanied, ia this case, by the formation of a viscous mucus which can completely block the small airways. 

Theophylline s predominant mode of action appears to be bronchocHlation. However, it has also been shown that prophylactic acHriinistration of theophylline provides some protection from asthma attacks and suppresses the late-phase response (67,68). Some researchers beHeve that at therapeutic semm concentrations theophylline may inhibit the development of airway inflammation (69). There are conflicting reports on the effect of theophylline on allergen-induced bronchial hyperresponsiveness some clinical stucHes report a reduction in hyper-responsiveness, others do not (69,70). Theophylline clearly does not reverse the general bronchial hyperresponsiveness over the course of long-term therapy (71). Because of the relationship between... 

The activation of mast cells by allergen initiates the asthma symptoms within minutes after allergen contact, the early allergic response (EAR), within horns the late allergic response (LAR), and within years and after rqDeated asthma episodes, chronic airway inflammation, airway remodeling, and airway hyperresponsiveness. 

Bronchial Asthma. Figure 2 Mechanisms of bronchial hyperresponsiveness. Toxic products from eosinophils [cationic peptides, reactive oxygen species (ROS)] cause epithelial injury. Nerve endings become easily accessible to mediators from mast cells, eosinophils [eosinophil-derived neurotoxin (EDN)], and neutrophils, and to airborne toxicants such as S02. Activation of nerve endings stimulates effector cells like mucosal glands and airway smooth muscle either directly or by cholinergic reflexes. 

Asthma is a complex respiratory disorder that involves mast cell degranulation, mucous secretions, and smooth muscle hypertrophy and hyperresponsiveness. Smooth muscle hyperresponsiveness has suggested some defect in the regulation of smooth muscle contractility. Therefore, a number of studies concerning asthma have centered on whether alterations in the regulation of smooth muscle contraction (Figure 4) are responsible for hyperactivity in asthmatic airway smooth muscle. 

AS, Chung KF, Sturton G, Wong SIT, McKenzie AN Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 2007 120 1324-1331. 

Other therapeutic uses of cannabinoid agonists have been reported. The potential of cannabinoids as a treatment for asthma is supported experimentally. A CBi agonist, (i )-methanandamide (21), inhibited nerve growth factor (NGF)-induced airway hyperresponsiveness in vivo [251]. The antipruritic effect of cannabinoids has been reported, the action being mediated by both CBi and CB2 pathways [252]. Treatment with cannabis extract improved urinary tract symptoms of multiple sclerosis patients significantly in an open-label pilot study [253]. 

Asthma is characterized by inflammation, airway hyperresponsiveness (AHR), and airway obstruction. Inhaled antigens... 

Airway hyperresponsiveness is defined as the exaggerated ability of the airways to narrow in response to a variety of stimuli. Although AHR exists in patients without asthma, it is a characteristic feature of asthma and appears to be directly related to airway inflammation and the severity of asthma.1,3 Treatment of airway inflammation with inhaled corticosteroids attenuates AHR in asthma but does not eliminate it.1 Clinically, AHR manifests as increased variability of airway function. Although not commonly used to diagnose asthma, AHR can be evaluated clinically using a methacholine or histamine bronchoprovocation test. 

Ying S, Robinson DS, Meng Q, et al. Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsive-... 

The desired outcome in the pharmacological treatment of asthma is to prevent or relieve the reversible airway obstruction and airway hyperresponsiveness caused by the inflammatory process. Therefore, categories of medications include bronchodilators and anti-inflammatory drugs. 

The National Asthma Education and Prevention Program (NAEPP) defines asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. In susceptible individuals, inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are usually associated with airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an increase in bronchial hyperresponsiveness (BHR) to a variety of stimuli. 

Kim YS.KoHM, Kang Nl.etal Mast cells play a key role in the development of late airway hyperresponsiveness through TNF-oi in a murine model of asthma. Eur J Immunol 2007 37 1107-1115. 

Bryce PJ, Geha R, Oettgen HC Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma. J Allergy Clin Immunol 2003 112 149-158. 

Inhaled corticosteroids mediate a variety of immunological actions and are commonly used in the treatment of allergic asthma [28]. However, not all patients respond well to this treatment and some are steroid-resistant. In a recent study, Tantisira et al. [29] described a new genetic non-synonymous variation in TBX21 that encodes for the transcription factor T-bet (T-box expressed in T cells) associated with significant improvement of the airway hyperresponsiveness in children affected by allergic asthma [30]. Noteworthy, the... 

Finotto S, Glimcher L T cell directives for transcriptional regulation in asthma. Springer Semin Immunopathol 2004 25 281-294. Finotto S, De Sanctis GT, Lehr HA, et al Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J Exp Med 2001 193 1247-1260. 

CTLA41g inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Thl/Th2 subsets in a murine model of asthma. Am J Respir Cell Mol Biol 1998 18 453-462. 

Kim SH, Bae JS, Suh CH, Nahm DH, Holloway JW, Park HS. (2005) Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA-intolerant asthma a positive association with airway hyperresponsiveness. Allergy. 60, 760-765. 

Antagonists at the A3 receptor would prevent periodic exacerbations of asthma and lead over the longer term to a reduction in airways inflammation and bronchial hyperresponsiveness. 

The antibodies to IL-4 inhibit allergen-induced airway hyperresponsiveness (AHR), globlet cell metaplasia and pulmonary eosinophilia in animal models. Inhibition of IL-4 by soluble IL-4 receptor (SIL-4R, Nuvance) has proven to be very promising in treating asthma. Clinical trials with recombinant SIL-4R administered by a single weekly dose of 3 mg via nebulization have been effective in controlling the symptoms of moderate persistent asthma. 

Cromones such as cromolyn sodium (Intal, Nasal-crom) and nedocromil sodium (Tilade) can help prevent bronchospasm in people with asthma. These drugs are not bronchodilators and will not reverse bronchoconstriction during an asthmatic attack. Hence, these agents must be taken prior to the onset of bronchoconstriction, and they must typically be administered prophylactically to prevent asthma attacks that are initiated by specific, well-defined activities (e.g., exercise, exposure to a friend s pet, pollen).107 Likewise, the regular use of these drugs several times each day for several months may decrease airway hyperresponsiveness so that the incidence of asthmatic attacks decreases.102,113... 

There is evidence that both occupational and environmental exposures to chemicals (both proteins and haptens) can result in the induction or exacerbation of respiratory allergies (Table 19.6). Of particular concern is the induction of allergic asthma. In sensitized asthmatic individuals the antigen challenge generally causes a type I (IgE-mediated) immediate hypersensitivity response with release of mediators responsible for bronchoconstriction. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hypersecretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is not mediated by IgE. 

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