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Pulmonary Pharmacology & Therapeutics Apr 2018Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both... (Review)
Review
Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both in the clinic and in the development of new respiratory medicines. This article reviews the main challenge agents that are in use today (methacholine, mannitol, adenosine, allergens, endotoxin) and emphasises the importance of controlling how these agents are administered. There is a danger that the optimal value of these challenge agents may not be realised due to suboptimal inhaled delivery; thus considerations for effective and reproducible challenge delivery are provided. This article seeks to increase awareness of the importance of precise delivery of inhaled agents used to challenge the airways for diagnosis and research, and is intended as a stepping stone towards much-needed standardisation and harmonisation in the administration of inhaled airway challenge agents.
Topics: Administration, Inhalation; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Drug Delivery Systems; Humans; Lung; Lung Diseases, Obstructive; Reproducibility of Results; Tissue Distribution
PubMed: 29331645
DOI: 10.1016/j.pupt.2018.01.004 -
Journal of Investigational Allergology... 2019While the importance of vascular endothelial growth factor (VEGF) in the pathogenesis of several diseases (eg, neoplasms) has been proven, its role in asthma, especially...
BACKGROUND
While the importance of vascular endothelial growth factor (VEGF) in the pathogenesis of several diseases (eg, neoplasms) has been proven, its role in asthma, especially in terms of the potential associations between genetic variants of VEGF and airway remodeling, has received relatively little attention. Objectives: This study aimed to evaluate the possible connection between a genetic factor, ie, the polymorphism del/ins in the VEGF promoter region, and airway remodeling potential in asthmatics with and without irreversible bronchoconstriction.
MATERIAL AND METHODS
The study population comprised 82 patients with asthma (of whom 42 had irreversible bronchoconstriction) and a group of 40 controls. DNA was isolated from peripheral blood leukocytes. Polymerase chain reaction was used to type the VEGF (18-bp deletion/insertion) gene polymorphism at loci -2549 -2567. Other factors (ie, smoking, disease duration) were also taken into consideration.
RESULTS
The del/del genotype was found in 74.39% of patients with asthma (P=.031; OR=2.38), 80.95% of patients with irreversible bronchoconstriction (P=.012; OR=3.48), and 67.5% patients with reversible bronchoconstriction (P=.251; OR=1.70). The proportion of smokers to nonsmokers was higher (P=.032) and disease duration was longer (P=.041) in patients with irreversible bronchoconstriction than in those with reversible bronchoconstriction.
CONCLUSIONS
Our results showed that the risk of irreversible bronchoconstriction in asthmatics was associated with the presence of the del18 genotype at the -2549 -2567 position in the promoter region of the VEGF gene, as were disease duration and other factors such as smoking.
Topics: Adult; Asthma; Bronchoconstriction; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Promoter Regions, Genetic; Vascular Endothelial Growth Factors
PubMed: 30574871
DOI: 10.18176/jiaci.0369 -
American Journal of Physiology. Lung... Jan 2014Lung mastocytosis and antigen-induced bronchoconstriction are common features in allergic asthmatics. It is therefore important that animal models of asthma show similar...
Lung mastocytosis and antigen-induced bronchoconstriction are common features in allergic asthmatics. It is therefore important that animal models of asthma show similar features of mast cell inflammation and reactivity to inhaled allergen. We hypothesized that house dust mite (HDM) would induce mastocytosis in the lung and that inhalation of HDM would trigger bronchoconstriction. Mice were sensitized with intranasal HDM extract, and the acute response to nebulized HDM or the mast cell degranulating compound 48/80 was measured with respiratory input impedance. Using the constant-phase model we calculated Newtonian resistance (Rn) reflecting the conducting airways, tissue dampening (G), and lung elastance (H). Bronchoalveolar lavage fluid was analyzed for mouse mast cell protease-1 (mMCP-1). Lung tissue was analyzed for cytokines, histamine, and α-smooth muscle actin (α-SMA), and histological slides were stained for mast cells. HDM significantly increased Rn but H and G remained unchanged. HDM significantly expanded mast cells compared with control mice; at the same time mMCP-1, α-SMA, Th2 cytokines, and histamine were significantly increased. Compound 48/80 inhalation caused bronchoconstriction and mMCP-1 elevation similarly to HDM inhalation. Bronchoconstriction was eliminated in mast cell-deficient mice. We found that antigen-induced acute bronchoconstriction has a distinct phenotype in mice. HDM sensitization caused lung mastocytosis, and we conclude that inhalation of HDM caused degranulation of mast cells leading to an acute bronchoconstriction without affecting the lung periphery and that mast cell-derived mediators are responsible for the development of the HDM-induced bronchoconstriction in this model.
Topics: Animals; Antigens; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cell Degranulation; Disease Models, Animal; Female; Male; Mast Cells; Mastocytosis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Pyroglyphidae; p-Methoxy-N-methylphenethylamine
PubMed: 24285269
DOI: 10.1152/ajplung.00055.2013 -
Journal of Applied Physiology... Jul 2022Mice are a valuable model for elegant studies of complex, system-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are...
Mice are a valuable model for elegant studies of complex, system-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, nonterminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouse's neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates volume, inspiratory/expiratory time, breaths per minute, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established that our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex- and age-associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine ( < 0.05), increased lung volume, and decreased breathing rate with aging ( < 0.05), and that house dust mite sensitization decreased volume and flow ( < 0.05) while exacerbating the methacholine-induced increase in inspiratory time ( < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice. We describe a low-cost, variable-pressure head-out plethysmography system that can be used to assess lung function in mice. A balloon cuff is inflated around the mouse's neck to prevent air leak, allowing for accurate measurements of lung volume and air flow. Custom software facilitates system calibration, removes movement artifacts, and eases data analysis. The system was validated by measuring tidal breathing, responses to methacholine, and changes associated with house dust mite sensitization, sex, and aging.
Topics: Animals; Bronchoconstriction; Lung; Lung Volume Measurements; Methacholine Chloride; Mice; Plethysmography; Tidal Volume
PubMed: 35608203
DOI: 10.1152/japplphysiol.00835.2021 -
The European Respiratory Journal Nov 2005
Topics: Animals; Bronchi; Bronchial Diseases; Bronchoconstriction; Constriction, Pathologic; Elasticity; Humans; Stress, Mechanical; Swine
PubMed: 16264032
DOI: 10.1183/09031936.05.00099905 -
British Journal of Clinical Pharmacology 19901. Inhaled adenosine and its parent nucleotide, adenosine 5'-monophosphate (AMP) provoke bronchoconstriction in atopic and asthmatic individuals but not in normal... (Review)
Review
1. Inhaled adenosine and its parent nucleotide, adenosine 5'-monophosphate (AMP) provoke bronchoconstriction in atopic and asthmatic individuals but not in normal subjects. 2. In clinical studies, histamine H1-receptor antagonists, cyclo-oxygenase inhibitors and the mast cell 'stabilising' drugs, sodium cromoglycate and nedocromil, protect against the effects of adenosine bronchoprovocation suggesting the involvement of secondary mast cell mediator release. 3. Adenosine and its analogues potentiate histamine and leukotriene release from mast cells activated by other stimuli in vitro, and may also increase net mediator release from mast cells by counteracting the inhibitory effect of circulating adrenaline. 4. Although adenosine fulfils many of the criteria required for a mediator in asthma, its importance is not fully understood, and the mechanisms by which it provokes bronchoconstriction in asthmatic subjects is far from concluded. 5. Two possibilities are that either adenosine acts directly on luminal mast cells to upregulate histamine secretion, or it acts to initiate neuronal reflexes which stimulate histamine release indirectly and possibly activate peptidergic and/or cholinergic pathways.
Topics: Adenosine; Animals; Asthma; Bronchoconstriction; Humans
PubMed: 2268511
DOI: 10.1111/j.1365-2125.1990.tb05474.x -
Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.American Journal of Respiratory and... Oct 2017Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary...
RATIONALE
Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV).
OBJECTIVES
To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma.
METHODS
Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sV) and the remaining lung (sV) were quantified and compared.
MEASUREMENTS AND MAIN RESULTS
In the sV region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sV region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sV subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sV subregions that were hyperoxic under 80% O conditions.
CONCLUSIONS
HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.
Topics: Adult; Asthma; Bronchoconstriction; Female; Humans; Hypoxia; Lung; Male; Positron Emission Tomography Computed Tomography; Pulmonary Circulation; Vasoconstriction; Young Adult
PubMed: 28644040
DOI: 10.1164/rccm.201612-2438OC -
Respiratory Research Sep 2022Respiratory diseases represent a global health burden. Because research on therapeutic strategies of airway diseases is essential, the technique of precision-cut lung...
BACKGROUND
Respiratory diseases represent a global health burden. Because research on therapeutic strategies of airway diseases is essential, the technique of precision-cut lung slices (PCLS) has been developed and widely studied. PCLS are an alternative ex vivo model and have the potential to replace and reduce in vivo animal models. So far, the majority of studies was conducted with short-term cultivated PCLS (≤ 72 h). As there is large interest in research of chronic diseases and chronic toxicity, feasibility of cultivating human PCLS long-term over 2 weeks and recently over 4 weeks was investigated by another research group with successful results. Our aim was to establish a model of long-term cultivated rat PCLS over a period of 29 days.
METHODS
Rat PCLS were cultured for 29 days and analysed regarding viability, histopathology, reactivity and gene expression at different time points during cultivation.
RESULTS
Cultivation of rat PCLS over a 29-day time period was successful with sustained viability. Furthermore, the ability of bronchoconstriction was maintained between 13 and 25 days, depending on the mediator. However, reduced relaxation, altered sensitivity and increased respiratory tone were observed. Regarding transcription, alteration in gene expression pattern of the investigated target genes was ascertained during long-term cultivation with mixed results. Furthermore, the preparation of PCLS seems to influence messenger ribonucleic acid (mRNA) expression of most target genes. Moreover, the addition of fetal bovine serum (FBS) to the culture medium did not improve viability of PCLS. In contrast to medium without FBS, FBS seems to affect measurements and resulted in marked cellular changes of metaplastic and/or regenerative origin.
CONCLUSIONS
Overall, a model of long-term cultivated rat PCLS which stays viable for 29 days and reactive for at least 13 days could be established. Before long-term cultivated PCLS can be used for in-depth study of chronic diseases and chronic toxicity, further investigations have to be made.
Topics: Animals; Bronchoconstriction; Humans; Lung; RNA; RNA, Messenger; Rats; Serum Albumin, Bovine; Tissue Culture Techniques
PubMed: 36127699
DOI: 10.1186/s12931-022-02169-5 -
PloS One 2014Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals....
Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood. In the present study, we used a computational model of bronchoconstriction to study the effects of DI volumes, time intervals between intermittent DIs, relative speed of ASM constriction, and ASM activation on bronchoconstriction and the emergence of ventilation defects (VDefs). Our results showed a synergistic effect between the volume of DIs and the time intervals between them on bronchoconstriction and VDefs. There was a domain of conditions with sufficiently large volumes of DIs and short time intervals between them to prevent VDefs. Among conditions without VDefs, larger volumes of DIs resulted in greater airway dilation. Similarly, the time interval between DIs, during which the activated ASM re-constricts, affected the amplitude of periodic changes in airway radii. Both the relative speed of ASM constriction and ASM activation affected what volume of DIs and what time interval between them could prevent the emergence of VDefs. In conclusion, quantitative characteristics of DIs, such as their volume and time interval between them, affect bronchoconstriction and may contribute to difficulties in asthma. Better understanding of the quantitative aspects of DIs may result in novel or improved therapeutic approaches.
Topics: Bronchoconstriction; Computer Simulation; Humans; Inhalation; Models, Biological; Pulmonary Ventilation
PubMed: 25402457
DOI: 10.1371/journal.pone.0112443 -
The European Respiratory Journal Feb 1997Airway obstruction in asthma and chronic obstructive pulmonary disease (COPD) is often associated with lung hyperinflation. In this review, we examine the mechanisms... (Review)
Review
Airway obstruction in asthma and chronic obstructive pulmonary disease (COPD) is often associated with lung hyperinflation. In this review, we examine the mechanisms that may cause functional residual capacity (FRC), residual volume (RV) and total lung capacity (TLC) to increase during acute and chronic airway obstruction. Normally, FRC at rest is determined by the static characteristics of the lung and chest wall. When airways narrow, FRC may be also be determined by dynamic factors. There are data suggesting that expiratory flow limitation during tidal breathing represents the starting trigger for FRC to increase, in order to allow breathing at higher flows. Indeed, the increase in FRC during induced bronchoconstriction in asthma is closely associated with the occurrence of flow limitation, i.e. the achievement of maximum flow during tidal breathing. Conversely, the decrease in FRC following bronchodilatation in COPD is closely associated with flow limitation disappearing or occurring at lower lung volumes. In normal young people, RV is determined by the static characteristics of the chest wall. During bronchoconstriction RV may also be determined by dynamic factors; therefore, changes in flow or airway calibre at low lung volumes may modulate RV during bronchoconstriction. During acutely induced bronchoconstriction, RV achieved with an expiration from TLC is less than with an expiration from tidal breathing, and this effect appears to be linked to the bronchodilator effect of the deep inhalation. The reasons for the increase in TLC during airway narrowing are not clear, but the duration of the bronchoconstriction by itself may play a role.
Topics: Bronchoconstriction; Forced Expiratory Flow Rates; Functional Residual Capacity; Humans; Lung; Lung Diseases, Obstructive; Residual Volume; Total Lung Capacity
PubMed: 9042651
DOI: 10.1183/09031936.97.10020468