Defining and unpacking the core concepts of pharmacology education.

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.

Identifying the core concepts of pharmacology education.

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.

Embedding responsible conduct in learning and research into an Australian undergraduate curriculum.

Responsible conduct in learning and research (RCLR) was progressively introduced into the pharmacology curriculum for undergraduate science students at The University of Western Australia. In the second year of this undergraduate curriculum, a lecture introduces students to issues such as the use of animals in teaching and responsible conduct of research. Third year student groups deliver presentations on topics including scientific integrity and the use of human subjects in research. Academic and research staff attending these presentations provide feedback and participate in discussions. Students enrolled in an optional capstone Honours year complete an online course on the responsible conduct of research and participate in an interactive movie. Once RCLR became established in the curriculum, a survey of Likert-scaled and open-ended questions examined student and staff perceptions. Data were expressed as Approval (% of responses represented by Strongly Agree and Agree). RCLR was found to be relevant to the study of pharmacology (69-100% Approval), important for one's future career (62-100% Approval), and stimulated further interest in this area (32-75% Approval). Free entry comments demonstrated the value of RCLR and constructive suggestions for improvement have now been incorporated. RCLR modules were found to be a valuable addition to the pharmacology undergraduate curriculum. This approach may be used to incorporate ethics into any science undergraduate curriculum, with the use of discipline-specific topics. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):53-59, 2017.

Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.

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.

The mechanism of deep inspiration-induced bronchoprotection: evidence from a mouse model.

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.

Effects of simulated tidal and deep breathing on immature airway contraction to acetylcholine and nerve stimulation.

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 0.5x, 2x and 4x 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.

Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary 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.

The impact of respiratory syncytial virus infection on endothelin receptor function and release in sheep bronchial explants.

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 microM) 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 microM) and dexamethasone (1 microM) 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.

The single mediator approach to asthma therapy: is it so unreasonable?

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.

Impact of parainfluenza-3 virus infection on endothelin receptor density and function in guinea pig airways.

We examined the impact of parainfluenza-3 (P-3) respiratory tract viral infection on the density and function of endothelin (ET) receptor subtypes (ET(A) and ET(B)) in guinea pig tracheal smooth muscle. Total specific binding of [(125)I]ET-1 and the relative proportions of ET(A) and ET(B) binding sites for this ligand were assessed at day 0 (control) and at 2, 4, 8 and 16 days post-inoculation. At day 0, the proportions of ET(A) and ET(B) binding sites were 30% and 70% respectively. Total specific binding was significantly reduced at day 4 post-inoculation (32% reduction, n=8-12, P<0.05) and was largely due to a corresponding fall in ET(B) receptor density at this time point (38% reduction, n=8-12, P<0.05). The density of ET(A) receptors also fell significantly at day 8 post-inoculation (33% reduction, n=6-12, P<0.05). By day 16 post-inoculation, the densities of ET(A) and ET(B) receptors had recovered to control values. The ratio of ET(A):ET(B) receptor subtypes did not alter with P-3 infection. While P-3 infection reduced the density of tracheal smooth muscle ET(A) and ET(B) receptors, the contractile sensitivity and maximum response to carbachol and ET-1 was not altered in tissue from day 4 post-inoculation compared with the control. There seems to be a significant functional reserve for both receptor subtypes in this species that buffers the impact of P-3 infection on airway smooth muscle responsiveness to ET-1.

Enhanced ET(A) receptor-mediated contractile function is associated with reduced ET(A) receptor density in sheep bronchial explants maintained in culture.

We are interested in developing an airway explant culture system using sheep bronchi in which to establish respiratory viral infection and from which tissue can be used for functional, biochemical and immunohistochemical studies involving the endothelins (ETs). Freshly harvested sheep bronchial airway smooth muscle contains a homogeneous population of the ET(A) receptor. However, the potency of ET-1 and maximum contractile response of sheep bronchial explants to ET-1 increased with time in culture, despite these parameters remaining constant for carbachol in explants maintained for up to 48 h. The possibility that this was caused by changes in ET receptor density was assessed using light microscopic quantitative autoradiography. In view of the increased responsiveness to ET-1 in cultured explants, it was surprising to demonstrate a significant decrease in total ET receptor (59+/-6% compared with the initial value, n=4-5; P<0.01) and ET(A) receptor (51+/-2% compared with the initial value, n=4-5, P<0.01) density in sheep bronchial explants after 48 h. No ET(B) receptors were detected. Thus, the culture of sheep bronchial explants was associated with an increase in ET(A) receptor-mediated contractile function that was accompanied by a decrease in ET(A) receptor density. In addition, the structural integrity of the ciliated epithelium was preserved using this culture protocol, a feature that is critical to successful respiratory viral infection. The significant changes in ET receptor density and function in these bronchial explants must be carefully considered when assessing any effects of respiratory viral infection in this model.