Airway hyperresponsiveness induced by cationic proteins in vivo: site of action (original) (raw)
Related papers
Exaggerated airway narrowing in mice treated with intratracheal cationic protein
Journal of Applied Physiology, 2006
Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways (Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019–2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-l-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we...
Deep Inhalation Prevents the Respiratory Elastance Response to Methacholine In Rats
Pediatric …, 2006
The bronchodilator effect of deep inhalation (DI) may be assessed from the time course of respiratory system resistance (Rrs) and reactance (Xrs) measured by the forced oscillation technique at a single frequency. The aim of the study was to assess the effect of DI in the closed chest rat. Under anesthesia and mechanical ventilation, seven Brown Norway rats were given regular DI (BN-di) and six underwent continuous tidal ventilation (BN) throughout an otherwise similar methacholine (Mch) challenge protocol. Rrs and Xrs were monitored at 20 Hz and apparent respiratory system elastance (Ers) was computed from Xrs. After Mch nebulization, there was a significant increase in Rrs and Ers compared with saline. Ers, but not Rrs, decreased after the DI and BN-di were found to have lower Ers than BN. Thus, DI significantly alters Ers and its response to Mch. Computer simulations suggested reversal of increased viscoelasticity and/or inhomogeneous behavior by the DI in that model.
Journal of Clinical Investigation, 1994
We have previously reported that human eosinophil granule major basic protein and synthetic cationic proteins such as poly-L-arginine and poly-L-lysine, can increase airway responsiveness in vivo. In the present study, we have investigated whether activation of sensory C-fibers is important in this phenomenon. Dose-response curves to methacholine were constructed before and 1 h after intratracheal instillation of poly-L-lysine in anaesthetized spontaneously breathing rats, and the concentration of methacholine required to induce a doubling in total lung resistance was calculated. Poly-L-lysine induced a fivefold increase in airway responsiveness, which was inhibited by neonatal capsaicin treatment and potentiated by phosphoramidon (100 jtg/ml). Furthermore, pretreatment with either CP, 96-345, or RP-67580 two selective NK-1 receptor antagonists inhibited poly-L-lysine-induced airway hyperresponsiveness and plasma protein extravasation. In vitro, cationic proteins stimulated the release of calcitonin gene-related peptidelike immunoreactivity from perfused slices of the main bronchi. Our results demonstrate that cationic proteins can activate sensory C-fibers in the airways, an effect which is important in the subsequent development of airway hyperresponsiveness and plasma protein extravasation. Cationic proteins may therefore function as a link between inflammatory cell accumulation and sensory nerve activation. (J.
Journal of Applied Physiology, 2006
Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC50): 22.9 ± 5.7 mg/ml for A/J vs. 3.3 ± 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC30 0.22 ± 0.08 mg/ml for A/J vs. 0.03 ± 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerat...
Smooth Muscle in the Maintenance of Increased Airway Resistance Elicited by Methacholine in Humans
American Journal of Respiratory and Critical Care Medicine, 2014
Rationale: Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). Objectives: To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. Methods: On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H 2 O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. Measurements and Main Results: The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, 236.2 6 11.8 vs. 14.4 6 13.2%; 12 min post-DI, 239.5 6 9.8 vs. 15.2 6 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. Conclusions: The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.
Methacholine responsiveness of proximal and distal airways of monkeys and rats using videomicrometry
Journal of applied physiology (Bethesda, Md. : 1985), 2002
Rat and monkey are species that are used in models of human airway hyperresponsiveness. However, the wall structures of rat and monkey airways are different from each other, with that of the monkey more closely resembling that of humans. We hypothesized that differences in wall structure would explain differences in airway responsiveness. Using videomicrometry, we measured airway luminal area in lung slices to compare proximal and distal airway responsiveness to methacholine in the rat and monkey. The airway type was then histologically identified. Proximal airways of the young rat and monkey were equally responsive to methacholine. In contrast, respiratory bronchioles of monkeys were less responsive than were their proximal bronchi, whereas the distal bronchioles of rats were more responsive than their proximal bronchioles. Both proximal and distal airways of younger monkeys were more responsive than those of older monkeys. Airway heterogeneity in young monkeys was greatest with re...
Effects of ventilation, humidity and temperature on airway responsiveness to methacholine in rats
European Respiratory Journal, 2002
Exercise-induced bronchoconstriction is associated with heat and water loss from the airways. It is not known whether these conditions can influence the response to bronchoactive agonists. The effects of different degrees of alveolar ventilation on the pulmonary response to methacholine and the role of humidity and temperature in this response were evaluated. Wistar rats were anaesthetized, tracheostomized and mechanically ventilated. Increasing doses of methacholine were infused intravenously and respiratory system resistance (Rrs) and elastance (Ers) were measured. The rats were ventilated with dry air at 13uC, dry air at 37uC, humid air at 13uC and humid air at 37uC. These four groups were further divided into three subgroups with a respiratory frequency adjusted to reach a carbon dioxide tension in arterial blood of 30, 40 and 50 mmHg. Temperature, humidity and level of alveolar ventilation did not influence the position of the dose/response curve to methacholine. However, the maximal changes in Ers were significantly lower in the rats ventilated with humid air. In addition, maximal changes in Ers were significantly higher in the rats with lower alveolar ventilation. These differences were not observed for maximal values of Rrs. The pulmonary response to methacholine in normal rats is significantly affected by the humidity of inspired air and the level of alveolar ventilation. This influence is more intense in the small airways and/or distal airspaces. This suggests that exercise or hyperventilation can change the behaviour of airway smooth muscle.
AJP: Lung Cellular and Molecular Physiology, 2007
We investigated the effect the loss of the CAT-2 gene (CAT-2−/−) has on lung resistance (RL) and tracheal isometric tension. The RL of CAT-2−/− mice at a maximal dose of acetylcholine (ACh) was decreased by 33.66% ( P = 0.05, n = 8) compared with that of C57BL/6 (B6) mice. The isometric tension of tracheal rings from CAT-2−/− mice showed a significant decrease in carbachol (CCh)-induced force generation (33.01%, P < 0.05, n = 8) compared with controls. The isoproterenol- or the sodium nitroprusside-induced relaxation was not affected in tracheal rings from CAT-2−/− mice. The activity of iNOS and arginase in lung tissue lysates of CAT-2−/− mice was indistinguishable from that of B6 mice. Furthermore, the expression of phospholipase-Cβ (PLC-β) and phosphatidylinositol-( 4 )-phosphate-5-kinase-γ (PIP-5K-γ) was examined in the lung tissue of CAT-2−/− and B6 mice. The expression of PIP-5K-γ but not PLC-β was significantly reduced in CAT-2−/− compared with B6 mice. The reduced airway s...
Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans
2003
Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (V m40) and partial (V p40) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (RL), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). RL and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, V m40, and V p40, but insignificantly affected lung volumes, elastic recoil, RL, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of V m40 to V p40. In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen. lung elastic recoil; pulmonary resistance; dynamic elastance; methacholine challenge; deep inhalation Original submission in response to a special call for papers on "Airway Hyperresponsiveness: From Molecules to Bedside."