Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic ...sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pharmacology education currently lacks a research‐based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual ...learning. The Core Concepts in Pharmacology Expert Group (CC‐PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory—a valid and reliable tool to assess learner attainment of concepts. In the current study, CC‐PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug–response. First, a one‐sentence definition was developed for each core concept. Next, sub‐concepts were established for each core concept. These twenty core concepts, along with their respective definitions and sub‐concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning.
The second stage of development of core concepts of pharmacology education; defining each concept, and unpacking the concept by articulation of sub‐concepts.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a ...curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion‐based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology.
Over 50 pharmacology educators from Australia and New Zealand worked together to identify the core concepts of pharmacology education. The figure shows the 19 concepts identified and the process taken to produce this list
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
In healthy individuals, deep inspirations (DIs) taken prior to a bronchial challenge reduce the bronchoconstrictor response, which is termed "bronchoprotection". The mechanism(s) of DI-induced ...bronchoprotection is unclear. The forced oscillation technique was used to assess the effect of prior DI on subsequent bronchoconstriction to methacholine (MCh) in BALB/c mice. We assessed likely mechanisms for the bronchoprotective effects of DI including reduced airway narrowing (from changes in airway resistance) and/or closure (changes in tissue elastance) and enhanced bronchodilation to a subsequent DI (% reversal in airway narrowing). DI prior to MCh challenge: 1) did not reduce but instead enhanced airway narrowing (p<0.05); 2) increased ventilation heterogeneity (p<0.05); 3) enhanced the subsequent bronchodilatory response to DI (p<0.05); and 4) reduced tissue elastance (p<0.05), suggesting opening of closed airways or alveoli units. Our findings suggest that DI prior to MCh challenge may elicit a series of changes, some of which are beneficial to respiratory function (enhanced bronchodilation), while others place greater load on the system (enhanced bronchoconstriction and ventilation heterogeneity). It is proposed that the relative magnitudes of these opposing physiological and mechanical effects will determine the net effect on respiratory function in health and disease.
Asthma is a complex inflammatory disease of the airways involving reversible bronchoconstriction. Chronic obstructive pulmonary disease is typified by inflammation and airflow limitation that has an ...irreversible component. There is now substantial evidence that Rho kinase is involved in many of the pathways that contribute to the pathologies associated with these respiratory diseases including bronchoconstriction, airway inflammation, airway remodelling, neuromodulation and exacerbations due to respiratory tract viral infection. Indeed the Rho kinase inhibitor Y-27632 causes bronchodilatation and reduces pulmonary eosinophilia trafficking and airways hyperresponsiveness. Furthermore, accumulating evidence suggests that inhibition of Rho kinase could have a major beneficial impact on symptoms and disease progression in asthma and COPD by modulating several other systems and processes. Thus, the Rho kinase pathway may indeed be a worthwhile therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease.
ABSTRACT
Background and objective: In adults, respiratory movements, such as tidal and deep breaths, reduce airway smooth muscle force and cause bronchodilation. Evidence suggests that these ...beneficial effects of oscillatory strain do not occur in children, possibly because of reduced coupling of the airways to lung tissue or maturational differences in the intrinsic response of the airways to oscillatory strain.
Methods: The bronchodilator effects of oscillatory strain were compared in isolated airway segments from immature (3–4 weeks and 8–10 weeks old) and mature (18–20 weeks old) pigs. The lumen of fluid‐filled bronchi was volume‐oscillated to simulate tidal breaths and 0.5×, 2× and 4× tidal volumes. Contractions to acetylcholine and electrical field stimulation were recorded from the lumen pressure and were compared under oscillating and static conditions. Airway stiffness was determined from the amplitude of the lumen pressure cycles and the volume of oscillation.
Results: Volume oscillation reduced contractions to acetylcholine and electrical field stimulation in an amplitude‐dependent manner and the percentage reduction was the same for the different stimuli across all age groups. There was no difference in the relaxed dynamic stiffness of airways from the different age groups.
Conclusions: The intrinsic response of the airway wall to equivalent dynamic strain did not differ in airways from pigs of different ages. These findings suggest that mechanisms external to the airway wall may produce age‐related differences in the response to lung inflation during development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Asthma involves a complex syndrome of respiratory pathologies that ultimately results in bronchial obstruction and reduced lung ventilatory capacity. Inflammation of the respiratory tract underlies ...this disease and can be linked to the production and release of multiple mediators of bronchoconstriction and airway wall restructuring and obstruction. Disease triggers vary between patients and include allergens, exercise, inhaled irritants and virus infections. Disease severity can also be highly variable from patient to patient. All of this indicates a heterogeneous disease phenomenon. Bronchodilator drugs that induce rapid symptom relief are just one component of conventional asthma therapy. The use of controller agents, such as anti-inflammatory glucocorticoids, constitutes the other important treatment option. The question is whether a key mediator is released in asthma that can be targeted by either single or multiple therapeutic agents to halt or reverse this complex mix of disease processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We investigated the impact of respiratory syncytial virus (RSV) infection, an important asthma precipitant, on endothelin receptor function and release in sheep bronchial explants. RSV infection was ...confirmed using polymerase chain reaction and immunohistochemistry. Since sheep airway smooth muscle contains only endothelin-A receptors, sarafotoxin (Stx) S6c did not cause airway contraction. In contrast, sarafotoxin S6c (300 nM) caused contraction in RSV-infected bronchial explants (8 ± 3% carbachol Emax). However, we could not detect airway smooth muscle endothelin-B receptors in explants using autoradiography. RSV infection per se did not alter the release of immunoreactive endothelin from sheep bronchial explants (control = 11.6 ± 0.9 pg versus RSV = 12.1 ± 0.9 pg). Interestingly, dexamethasone (1 μM) alone increased endothelin release in both control (17.9 ± 2.0 pg) and RSV-infected tissue (18.3 ± 3.1 pg). The combined presence of protease-activated receptor-2 (PAR-2) ligand (100 μM) and dexamethasone (1 μM) also increased endothelin release from control tissue (17.3 ± 1.4 pg), but endothelin release was suppressed by PAR-2 ligand in RSV-infected tissue (10.3 ± 0.8 pg), probably because PAR-2 expression was increased by RSV. In summary, the novel expression of endothelin-B receptors triggered by RSV might be relevant to RSV-associated asthma. Furthermore, activation of airway PAR-2 may be protective in asthma where endothelin levels are elevated in part via endothelin release suppression.
Background: Laboratory practicals are under scrutiny with concerns that they fall short of genuine enhancement of learning and the perceived cost- and resource-saving benefits associated with ...computer simulations. Further, students are more discerning and require that all teaching activities optimise their learning. Consequently it is essential to ascertain students' expectations of hands-on practicals and which features are perceived to facilitate learning to guide curriculum refresh.Methods: Paper-based surveys of second and third year pharmacology students were used to obtain information about student expectations of what they would gain from these laboratory practicals, which facets enhanced and which detracted from their enjoyment of these activities, and which key elements augmented their learning. Approval for this project was obtained from the University of Western Australia Human Ethics Committee (RA/4/1/9046). Results: One hundred and fourteen second-year students and 100 third-year students completed the survey. Approximately two-thirds of the second-year students were 19 years of age, with women slightly outnumbering men (57% vs 42%, respectively). By contrast, about two-thirds of the 3rd year students were 20 years of age, with the gender profile reversed (56% men; 44% women). Both cohorts overwhelmingly agreed that staff preparedness and interest (96% agreement) as well as well-organised practicals (94% agreement) were essential to their learning. Third-year students (82%) were much more likely than second-year students (61%) to value practicals as a means of revising and reinforcing core content. Neither group expressed any substantial concern regarding any equipment problems, that protocols were recipe-based or that there was little opportunity to design their own practicals, although in each instance, the third-year students were slightly more concerned (2nd year: 25% agreement that the issue detracted from enjoyment, 16% and 10% respectively; 3rd year: 37% agreement, 14% and 15%, respectively).Conclusion: There was near-unanimous agreement from students that engaged and engaging staff conducting well-organised practical activities enhanced their learning. Students were largely tolerant of problems that might arise during these practicals and activities that might seem repetitive, particularly when core concepts from lecture material were reinforced. Design and implementation of learning opportunities should take into account students expectations and learning needs.
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