Tag Archives: corticosteroids

Treating Asthma as an Inflammatory Disease: Conclusions

There was a general consensus that a growing body of compelling data suggests that any patient with asthma, including those with intermittent disease, should receive ICS. Such treatment results in reduced numbers of exacerbations; even patients with mild asthma can have severe exacerbations. However, the long-term effects of intermittent asthma are not known, and there are insufficient data to suggest ICS for all patients.
Many inflammatory markers, such as nitric oxide and leukotrienes, were still believed to be research tools rather than good clinical indicators. However, as asthma is a complex, multifactorial disease and the mechanism of asthma in each patient is likely to be different, it may be that no one marker will be practical.
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Treating Asthma as an Inflammatory Disease: Other Antiinflammatory Therapy in Asthma

Treating Asthma as an Inflammatory Disease: Other Antiinflammatory Therapy in AsthmaLTRAs, IgE blockers, and anti-IL-5 are other antiinflammatory agents that are either currently used (LTRAs, IgE blockers) or in clinical development (anti-IL-5) for the treatment of asthma. As these were not specifically discussed, readers are directed to the literature for further information about the effects of these agents on inflamma-tion.
Spirometry is the reference tool for the diagnosis of asthma and is widely applied in the evaluation of airway hyperreactivity as well as the response to therapeutic intervention. Routine pulmonary function testing has been recommended as part of the assessment and monitoring of acute asthma, as physicians tend to underestimate the degree of airway obstruction, particularly on initial assessment. Spirometry can be performed in children as young as 6 years old. Here

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Treating Asthma as an Inflammatory Disease: Information

Cellular effects of corticosteroids include a reduction in inflammatory cells and mediators, such as mast cells, eosinophils, T-cell cytokines, macrophage cytokines, and dendritic cell numbers. They also reduce endothelial cell number and leakage, goblet cell mucus secretion, and the production of cytokines from smooth-muscle cells. Numerous stud-ies have described the effects of ICS on noninvasive measures of airway inflammation, and readers are directed to current literature reviews for further information.
Expression of a smooth-muscle actin in fibroblasts in the early stages of differentiation has been shown to be inhibited by corticosteroid treatment. Constitutive expression of a smooth-muscle actin was low in myofibroblasts at an early stage of differentiation, intermediate in mildly differentiated lung fibroblasts, and complete in fully differentiated lung myofibroblastic cultures.

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Treating Asthma as an Inflammatory Disease: The Role of ICS in Treating Asthma

Treating Asthma as an Inflammatory Disease: The Role of ICS in Treating AsthmaMyofibroblasts are thought to play a central role in remodeling by propagating and amplifying signals from the bronchial epithelium into the deeper layers of the submucosa through release of soluble mediators. Myofibroblasts are classically characterized by the presence of filaments of a smooth-muscle actin. Local fibroblasts are the most likely progenitors of myofibroblasts, although it has been proposed that myofibroblasts are derived from peripheral blood-derived progenitors known as fibrocytes. Airway myofibroblasts and smooth muscle lie in close proximity, and numbers of myofibroblast-like cells are increased in the lamina reticularis of asthmatic patients after allergen challenge. The phenotype of the myofibroblast is intermediate between the fibroblast and the smooth-muscle cell, and it is thought that myofibroblasts might contribute directly to increased smooth-muscle mass. Both fibroblast and myofibroblast numbers have been shown to increase when subjects are challenged with antigen (Fig 3). http://cfm-online-shop.com/

Similarly, airway smooth-muscle cells in culture have been shown to proliferate significantly faster in patients with asthma than those from control subjects (Fig 4), although this has not been shown in vivo. In cartilaginous airways, patients who have died from asthma also have greater total wall, inner wall, outer wall, smooth-muscle, mucus gland, and cartilage areas in their airways than those of patients with and those without asthma dying suddenly of nonrespiratory causes (p < 0.05).
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Treating Asthma as an Inflammatory Disease: Airway Remodeling

A study of the natural history of respiratory allergy enrolled 142 patients with either allergic rhinitis or allergic asthma and observed them for 10 years. In the 99 subjects who completed the study, 50% of patients with asthma also acquired rhinitis and 31.8% of patients with rhinitis also acquired asthma. Positive family history for atopy was found to be associated with evolution of either rhinitis or asthma to rhinitis plus asthma (Table 1; p = 0.01). Treatment of rhinitis has also been shown to reduce emergency visits for asthma.
Regarding treatment options, oral and nasal antihistamines and nasal corticosteroids are commonly used to treat rhinitis, whereas the cornerstone of treatment and “gold standard” for the long-term control of asthma is ICS. Leukotriene receptor antagonists (LTRAs), which are generally used to treat asthma, may be used in patients with asthma who also have concomitant rhinitis. B-Receptor agonists are effective in asthma but are not used in rhinitis. ICS are considered the most potent and consistently effective long-term control medication for asthma. read more

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Treating Asthma as an Inflammatory Disease: Molecular and Cellular Changes With Allergic Asthma

Treating Asthma as an Inflammatory Disease: Molecular and Cellular Changes With Allergic AsthmaIncreased expression of ICAM-1 has been demonstrated on conjunctival and nasal epithelium in patients with asymptomatic allergic rhinitis caused by mites. This study demonstrated that symptom-free patients sensitized and exposed to perennial allergens always have a weak ICAM-1 expression, even when they are symptom free; this is known as the concept of minimal persistent inflammation, which is also present in patients with seasonal allergic rhinitis. A study in allergic patients has shown that ICAM-1 expression on conjunctival epithelium derives from endogenous synthesis. As inflammation determines prognosis in asthma, there is a need to measure it. Bronchial biopsy remains the standard by which to determine inflammation in the airways.”

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Treating Asthma as an Inflammatory Disease: Allergic Asthma

The mast cell is a key player in the early allergic response that typically starts within minutes of exposure to an appropriate antigen. Acute symptoms peak within 10 to 15 min and typically resolve within 60 min of exposure to an adequate dose of antigen, Studies by Brightling et al and Carroll et al indicate that there is microlocalization of mast cells in the airway smooth muscle, suggesting that interactions between mast cells and smooth-muscle cells are critical for the development of the disordered airway function found in asthma. The mast cell surface-bound Ig E (IgE) is cross-linked by the antigen, leading to mast cell activation and release of potent mediators, such as histamine, leukotrienes, prostaglandin D2, bradykinin, and platelet-activating factor. This results in airway smooth-muscle contraction, edema, and enhanced mucous secretions leading to airflow limitation and acute asthma symptoms, such as nasal discharge, sneezing, bronchocon-striction, and skin weal and flare. Typically, an early phase response may induce a 25% reduction in FEV1. A conjunctival allergen challenge study has also shown increased levels of tryptase in the early phase allergic response. read

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Treating Asthma as an Inflammatory Disease

Treating Asthma as an Inflammatory DiseaseAsthma is a chronic inflammatory disorder of the airway involving many different types of cells and cellular elements. The chronic inflammation leads to an increase in airway hyperresponsiveness with recurrent episodes of wheezing, coughing, and shortness of breath. Inflammation is evident, even in patients with intermittent asthma.2 Airflow limitation is widespread, variable, occurs throughout the tracheobronchial tree, and is usually reversible spontaneously or with treatment. However, if poorly controlled, it can be irreversible. Airway remodeling is a long-term consequence of inflammation, but early treatment limits the damage from inflammation, and inhaled corticosteroids (ICS) suppress inflammation. read only

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Structural Changes in Airway Diseases: Conclusions

Various methodologic aspects should, however, be taken into account when studying these effects.
For example, some agents could possibly be more effective at preventing than reversing airway remodeling, and the duration of treatment and doses of the agents should be considered, as well as the type and duration of the disease. Research on gene therapy in lung diseases is currently under scrutiny. Other than CF or a1-antitrypsin deficiency, it is highly unlikely that a single vector will be therapeutic, as multiple genes are implicated in asthma and COPD diseases. Gene therapy has been studied mostly in relation to CF. Vectors and incorporating techniques need to be optimized to prove helpful in treatment of CF patients. Overall, primary prevention of airway disease is likely to be the most effective tool and can be achieved by allergen avoidance, smoking avoidance, control of infections, or prenatal diagnosis. Treatment of other allergic diseases might possibly prevent the development of asthma, especially in allergic rhinitic subjects and in subjects with asymptomatic AHR and has to be further studied.

Although this is still controversial, we have evidence that the airway remodeling process may have untoward consequences in obstructive diseases, in the clinical expression of the disease, in its development, and in the decline in pulmonary function. The common factor underlying all the structural changes in airway diseases is an injury/repair process. In asthma, the damage follows an allergenic or nonal-lergenic Th2 inflammation and mechanical stress. In COPD, the initial trigger is cigarette smoke inducing direct cell toxicity and inflammatory response. An infectious process is both at the origin of the inflammation observed in CF and bronchiectasis patients. More research should be done to identify key changes, effective treatments, and proper interventional timing to counteract these changes. The prevention of the development of asthma, COPD, or other airway diseases through early interventions on structural changes is an exciting avenue. The potential of novel therapeutic agents to reverse or prevent airway remodeling warrants further evaluation.

Structural Changes in Airway Diseases: Antiremodeling Property

Monoclonal antibodies against IL-5 were shown to be effective in reducing the deposition of ECM proteins tenascin, lumican, and procollagen in the basement membrane of patients with mild asthma. In addition, anti-IL-5 reduces blood and sputum eosinophilia. Subepithelial fibrosis prevention has been observed with anti-IL-5 in a mouse model of asthma. These data suggest that these agents may influence remodeling, which might be partly preventable or reversible.
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