Asthma is characterized by chronic airway inflammation and airway hyperresponsiveness. Deep inspirations affect airway narrowing and may therefore play a role in airway hyperresponsiveness in... Show moreAsthma is characterized by chronic airway inflammation and airway hyperresponsiveness. Deep inspirations affect airway narrowing and may therefore play a role in airway hyperresponsiveness in asthma. The studies described in this thesis were all directed at further elucidating the (patho)physiological mechanism underlying deep inspiration-induced bronchodilation or to restoring this protective mechanism in asthma. We showed that deep inspiration-induced bronchodilation is reduced in asthma and that this reduction is related to increased numbers of CD4+ lymphocytes in the bronchial submucosa and to increased numbers of mast cells in airway smooth muscle bundles in bronchial biopsies. In addition, impaired deep inspiration-induced bronchodilation is related to lower expression of several smooth muscle proteins (calponin, desmin, and MLCK) in bronchial biopsies, whereas lung function and airway hyperresponsiveness wa s related to higher expression of alpha-SM-actin, desmin and elastin. Further, pulmonary congestion had no influence on airway responses to deep inspiration as measured in patients with mitral valve disease. A course of high-dose corticosteroid treatment increased bronchodilation following deep inspiration in patients with asthma, whereas treatment with tiotropium for 21 days had no effect on airway responses to deep inspiration. Positive-pressure inflation of the lungs reduced airway narrowing, even in patients who showed no airway dilation following an active deep inspiration. Show less
Airways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by... Show moreAirways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by responding to the bronchoconstrictive stimuli, which was thought to be the primary role of ASM cells. In this thesis, we have addressed the role of the secretory capacity of ASM cells in the regulation of airway inflammation in asthma. Using cultures, we have shown that ASM cells release various chemokines (eotaxin, eotaxin-3 and IL-8) involved in the recruitment of inflammatory cells in response to Th2 cytokines and the antimicrobial peptide LL-37. Also airway epithelial cells produce various chemokines in response to Th2 cytokines dependent on their status of differentiation. The IL-8 release by ASM cells is inhibited by the steroid budesonide whereas the combination of this steroid with the beta2-agonist formoterol (a combination often used by patients with asthma) did not further enhance the inhibitory effect. This suggests that other therapies should be developed to fully inhibit chemokine release by ASM cells. Our studies have helped to gain more insight into the role of ASM cells in airway inflammation in asthma and have led to further important research questions that remain to be addressed. Show less
Three aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation.... Show moreThree aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation. In chapter 3 is shown that steroids improve airway hyperresponsiveness, sputum eosinophils, and NO. The changes were not related. This suggests that these markers may provide different information when monitoring anti-inflammatory treatment in asthma. In chapter 4 is shown that alpha-2-macroglobulin is an appropriate marker for measuring microvascular leakage in sputum. This "dual induction" model may used when testing the antiexudative effect of drugs. Chapter 5 demonstrated that the annual decline in FEV1 is related with CD8+ cells. This suggests that inflammatory phenotypes in asthma may have prognostic relevance. In chapter 6 is shown that PEF-variability provides information about asthma severity. Therefore, the current guidelines for the treatment of asthma can be improved by including PEF-variability. In chapter 7 is shown that anti-IgE improves PEF, diminishes allergen responses and is paralleled by a reduction in eosinophils in biopsies and sputum and a decline in IgE+ cells. This suggests that the clinical benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE bearing cells. Show less
