Involvement in Asthma

Asthma has been traditionally viewed as a chronic inflammatory condition characterized by airway infiltration by activated mast cells and eosinophils, orchestrated by specific Th2-type T lymphocytes (24). However, neutrophils have recently been implicated in more severe forms of asthma, and it is also increasingly evident that the bronchial epithelium, endothelium, fibroblasts, and the extracellular matrix play a dynamic role in the airway inflammation of asthma (Fig. 2). 

Studies support the view that CD4+ (Th2) and cytotoxic CD8+ (Tc) T cells are a major source of Th2-type cytokines in the airways in asthma (29-32). Co-localization studies of BAL and bronchial biopsy samples from both atopic and nonatopic asthmatics confirm that T cells are the predominant cells encoding mRNA for IL-3, IL-4, IL-5, IL-10, and GM-CSF. T cells are considered to play an important role in regulating IgE synthesis in asthma. This is mediated by the increased T-cell production of IL and IL-13 and the accentuated expression of the accessory molecule CD40L on activated T cells in asthma, which binds to its ligand on B cell after B cell-T cell physical contact, delivering essen- 

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Therapeutic studies have demonstrated a role for T cells in asthma airway inflammation. Prednisolone treatment in corticosteroid-sensitive asthmatics (CSA) results in improved lung function, reduced airway hyperresponsiveness (AHR), accompanied by a reduction in eosinophil counts, and a reduction in the numbers of CD4+ T cells expressing mRNA encoding IL-3, D -S, and granulocyte macrophage-colony stimulating factor (GM-CSF) but not IL-2, IL-4, or IFNy 

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The biochemistry of cytokine and chemokine involvement in asthma is complex (216,217). Future studies will distinguish the relative importance of these systems to asthma. The involvement of the cytokine pathway in asthma, however, has been confirmed by the linkage of a locus for an enzyme in this pathway, dipeptidyl peptidase (DPPIO), located on chromosome 2ql4-32. 

MA Fath, X Wu, RE Hileman, RJ Linhardt, MA Kashem, RM Nelson, CD Wright, WM Abraham. Interaction of secretary leukocyte protease inhibitor with heparin inhibits protease involved in asthma. J Biol Chem 273 13563— 13569, 1998. 

Another potential advantage of extra-fine corticosteroid aerosols is their apparently greater accessibility to peripheral airways (< mm in diameter) which appear to be poorly penetrated by conventional CFC-based aerosols. Recent data indicate that airway inflammation is present in both large and small airways, as well as alveolar tissue, and that airway wall remodeling occurs in small airways. The clinical significance of small airways involvement in asthma, its contribution to fatal asthma or to the accelerated rate of decline in lung function with age that occurs in asthma, and the consequences of treating the small airways component... 

The p2-adrenergic receptor gene mutations have, therefore, been associated with a wide spectrum of respiratory phenotypes that include altered drug responses and bronchial hyperreactivity disease. The [l2-adrcncrgic receptor polymorphisms probably represent only a few of the genetic variables involved in asthma pathophysiology [157,165]. There may be potential to use these variants more widely to personalize diagnosis and treatment options. 

The biochemistry of cytokine and chemokine involvement in asthma is complex, however. While the cytokine pathway is likely to be involved in asthma, the role of specific chemokine receptor variants in disease is still a subject of active investigation. In fact, GWAS studies suggest a modest role for two chemokine genes other than CCR5-CCL18 and CXCL12 [316],... 

The fact that compounds in the PCA test, e.g., bufrolln and doxantrazole have been less than promising in clinical trials of asthma, has shed doubt on the capacity of this test to predict clinical efficacy. Longer treatment times may be necessary to achieve clinical benefit with this class of compounds or perhaps there are as yet ill-defined pathologic mechanisms involved in asthma that are unaccounted for in experimental models. 

Chemokine and Inflammatory Bowel Diseases 121 Table 6.5 Chemokine receptors and their ligands demonstrated to be involved in asthma. 

Many specific mediator receptors are involved in asthma but they are so abundant that specific antagonists for these receptors have little effect, with an exception for cysteinyl leukotriene-1 (cys-LTj) receptors which are distributed predominantly on airway smooth muscle and (to a lesser extent) on macrophages. Their numbers are small, however, and this may explain why antileukotrienes like montelukast and zafirlukast, which prevent predominantly leukotriene-induced bronchoconstriction, are less effective than P2-agonists. 

Because of the emotional involvement in asthma as an etiologic factor and the fear elicited by the dyspnea, the very act of placing the hands on the patient will have beneficial effects and serve to calm him as you treat. This alone can be a significant therapeutic factor. 

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