Asthma & Airway Hyperresponsiveness
Asthma is a complex disease, whose principal characteristics include reversible airflow obstruction, airway hyperresponsiveness, airway inflammation, mucus hypersecretion and airway remodeling. The disease has reached epidemic proportions worldwide and typically starts early on in life. Asthma can be both chronic and heterogeneous and is often associated with allergies to airborne antigens.
ACCURATE CHALLENGES, DETAILED MEASUREMENTS
Assessing airway responsiveness in response to aerosol challenges is the most frequently reported outcome for asthma research. When equipped with an integrated nebulizer, the flexiVent can be used to both deliver aerosol challenges to a subject’s lungs and follow the developing bronchoconstriction through automated data collection. Using proprietary algorithms, the system can calculate and display an estimate of the dose delivered to the subject’s airway opening. Detailed dose-response curves demonstrating airway hyperresponsiveness are computed and graphed in real-time.
Partitioning the response to describe the contribution from the central airways and tissue mechanics offers additional insight into the disease. It allows researchers to study pathophysiological mechanisms related to airway hyperresponsiveness in mice.
REFERENCES
- Forced expiration measurements in mouse models of obstructive and restrictive lung diseases.- Devos, Fien C., et al. Respiratory Research 18.1 (2017): 123.
- Evaluation of respiratory system mechanics in mice using the forced oscillation technique. – McGovern et al. J Vis Exp., 75: E50172, 2013.
- Assessment of airway hyperresponsiveness in mouse models of allergic lung disease using detailed measurements of respiratory mechanics. – Hartney et al. Methods Mol Biol., 1032: 205, 2013.
- IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways. – Kearley et al. Am J Respir Crit Care Med., 183: 865, 2011.
- Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma. – North et al. Respir Res., 12: 19, 2011.
STANDARDIZED PROCESSES
Disease models are often generated by exposing subjects to aerosols of allergens using acute or chronic protocols in order to establish relevant asthma phenotypes. The inExpose has been specifically designed to allow for repetitive precise dosage concentration delivery by controlling air flow rates and aerosol generation devices. This is done through automated exposure profiles, which also help to reduce user error and minimize outcome variations among subjects, study, and research groups. The inExpose operates under various configurations and protocols to ensure that the subjects receive repeated yet consistent exposure environments throughout experimentation.
COMPROMISE BETWEEN ACCURACY AND INVASIVENESS
In respiratory research, the most specific and precise measurements come at the cost of increased invasiveness. This has been described as the phenotyping uncertainty principle (PUP). For example, while the forced oscillation technique employed by the flexiVent system scores the highest in terms of measurement, accuracy, and precision, it lies the furthest from the subject’s natural state on an invasiveness continuum. On the other hand, as subjects are closer and closer to their natural state when using various plethysmography techniques, measurement specificity and precision register lower and lower on an accuracy continuum.
Various plethysmography techniques exist to measure lung function in preclinical studies: unrestrained whole body plethysmography (WBP), double chamber plethysmography (DCP), or head-out plethysmography (HOP). While each lung function measurement technique has value, the choice of the technique to be used should be weighed against the research objective and be based on a clear understanding of the technique, the outcomes, and the related liabilities. Measurements using plethysmography systems are done in conscious subjects where various external factors significantly impact the outcomes obtained.
CLASSICAL PHARMACOLOGY
The airway smooth muscle plays an undeniable role in asthma. The excessive amount of contraction it can generate as well as the enhanced sensitivity have been associated with key characteristics of asthma, namely bronchoconstriction and airway hyperresponsiveness. Studying its intrinsic ability to contact or relax in an isolated tissue bath where external influences can be removed can offer complimentary data to in vivo lung function measurements. This technique is a classic pharmacological tool that can be applied to various types of contractile tissues from different species.
REFERENCES
- Airway smooth muscle in the pathophysiology and treatment of asthma. – Doeing et al. J Appl Physiol., 114:834-843, 2013.
- Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro. – Xue et al. J Appl Physiol., 104:610-615, 2008.
- Increased mechanical strain imposed on murine lungs during ventilation in vivo depresses airway responsiveness and activation of protein kinase Akt. – Xue et al. J Appl Physiol., 114:1506-1510, 2013.
- Measurement of smooth muscle function in the isolated tissue bath-applications to pharmacology research. – Jespersen et al. J Vis Exp., 95:e52324, doi:10.3791/52324, 2015.