Enhanced responses to varying concentrations of bronchoconst
Enhanced responses to varying concentrations of bronchoconstrictors, such as MCh, and airway obstruction are characteristic of ecopipam and common to other clinical states, including chronic obstructive pulmonary disease, lung transplantation, and infection- or chemical agent-induced airway inflammation (Kuhn et al., 2000). Accordingly, there is evidence that mechanical modulation of airway smooth muscle tone and airway narrowing are at least as important as inflammatory contractile mediators in the pathogenesis of airway hyperresponsiveness (Brusasco and Pellegrino, 2003). A study using transgenic mice expressing IL-6 or IL-11 showed similar emphysema-like airspace enlargements, nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis and structural alterations; these types of changes in respiratory airways can have important effects on airway physiology and reactivity (Kuhn et al., 2000). Thus, in the present study, the airway responsiveness to MCh challenge (100mg/mL) was measured, and, at the 0.6U elastase dose, Raw and G were found to be significantly decreased in the closed thorax condition compared with the values of the corresponding control groups. When the thorax was open, Raw was similar between elastase doses, but G was significantly higher for the 0.3U elastase dose. These data suggest that an intact thorax is necessary to regulate the resistance and parenchymal tethering of the respiratory system. Furthermore, MCh diffusion is dependent on lumen-alveolar-capillary area, which can significantly affect the time course of airway narrowing (Bates et al., 2012). Mucus secretion can contribute to this reduction in resistance during the later stages of COPD (Lange et al., 1990). Additionally, we suggest that the responsiveness to MCh was lower in elastase-induced emphysema because of significant increases in the collapsed and hyperinflated areas; these areas may distort the nearby parenchyma and decrease the area (from the air space to the respiratory epithelium and muscle) through which MCh can diffuse. In this case, the lung becomes more heterogeneous without expected parenchymal tethering when MCh is aerosolised. These changes may lead to regions that are either more sensitive to, or that receive more, MCh and become extremely constricted or even atelectatic, while adjacent regions may be hyperinflated (Nagase et al., 1994). Furthermore, reduced myosin and cellular signalling pathways, like oxidative stress, myostatin, and others may be factors involved in the loss of integrity of muscle mass in the diaphragms of mice with elastase-induced emphysema (Fermoselle et al., 2011); thus, the activity of the diaphragm and other muscles is limited, and these muscles cannot produce the active force required for effective bronchoconstriction. Hysteresivity, a measure of the ratio of the energy dissipated per cycle to the stored energy (Ludwig and Dallaire, 1994), is calculated as the ratio of elastance to resistance. Modification of the collagen-elastin fibre network might be the main determinant in the increase in hysteresivity (Rocco et al., 2003). In this study, hysteresivity responsiveness was higher in the elastase-induced emphysema group, indicating a loss of accumulated energy due to altered lung configuration, which caused heterogeneity. Muscarinic receptor antagonists, which are currently widely used as bronchodilators in the treatment of COPD, may have beneficial anti-inflammatory and anti-remodelling effects. Muscarinic receptor regulation of airway smooth muscle tone is enhanced in asthma and COPD by two major mechanisms: first, increased expression and enhanced function of signalling molecules that are essential for muscarinic receptor-mediated airway smooth muscle contraction; and second, exaggerated release of neuronal acetylcholine due to neuronal mechanisms associated with inflammation (Kolahian and Gosens, 2012). Moreover, the actual mechanisms of airway inflammation and remodelling may involve the non-neuronal cholinergic system (Meurs et al., 2013). In COPD, cholinergic tonus is increased (Meurs et al., 2013), and the possibility that aerosolised MCh, even with the short-term administration (10s aerosolisation time and recording over 3min), contributes to and increments the inflammatory response cannot be excluded. In vitro studies have shown that activated muscarinic M1 receptors induce leukotriene B4 release from bovine bronchial epithelial cells, which, in turn, stimulates the chemotactic activity of eosinophils, neutrophils, and monocytes (Koyama et al., 1998). Antagonists of muscarinic receptors and β2-adrenoceptors may have cooperative effects on asthma and COPD in airway smooth muscle (Meurs et al., 2013). This information has provided new perspectives on therapy for airway remodelling and lung function decline in chronic disease.