PCLS: Unraveling the Intricacies of Asthma Research
In the quest for better treatment options, precision cut lung slices (PCLS) have emerged as a cutting-edge tool in preclinical asthma research
George Scott is a Principal Scientist at Regeneron in the department of Immune and inflammatory diseases, for which he has been a member for 10 years. During that time, he has worked on many programs that have advanced to the clinic for indications ranging from allergy to autoimmunity. He is a member of a group that is primarily involved in studying allergy and Type 2 disease. To that end, he has been involved in preclinical work for dupilumab for asthma and itepkimab. His group uses models of lung inflammation such as house dust mite and cigarette exposure along with lung function test to evaluate functional endpoints for clinal candidate molecules. The work he will present will be from recent publication in Cytokines highlighting some of the preclinical work they have done with dupilumab where lung function was a critical endpoint in understanding efficacy and dosing.
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 disease severity and progression. It allows researchers to study pathophysiological mechanisms related to airway hyperresponsiveness in mice. Learn how a leading preclinical asthma researcher uses the flexiVent for their research in this interview!
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.
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.
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. Using the physioLens with PCLS allows for airways to be individually characterized for bronchoconstriction. Details about the size, shape and location of the airways are all acquired. External influences are removed, allowing for direction understanding of bronchoconstriction. This technique is an emerging pharmacological tool.
In the quest for better treatment options, precision cut lung slices (PCLS) have emerged as a cutting-edge tool in preclinical asthma research
Mast cells are crucial players in the body’s defense mechanisms, orchestrating immune responses and contributing to the maintenance of homeostasis. However, when mast cells undergo excessive proliferation or activation, it can lead to chronic inflammatory disorders such as asthma.
Dual vaccination against IL-4 and IL-13 using kinoids (a conjugate vaccine) is one of the therapeutic strategies suggested to neutralize the response induced by this type 2 inflammation. In recent studies by Conde et al 2021, House Dust Mite (HDM)-treated mice, which exhibit key characteristics of human chronic asthma, were used to test prophylactic and therapeutic dual vaccination efficiency in this allergic mouse model.
Assessment of airway hyperresponsiveness (AHR) is considered the gold standard in experimental asthma models. In their recent publication, Dr. Steele and colleagues’ objective was to shed light on the immunopathogenic role of CX3CL1/Fractalkine because of its elevated levels in fungal-sensitized asthmatics.
Asthma – From Mouse To Man “The assessment of lung function endpoints used in preclinical drug testing may hold the key to translation of drug
Due to the wide variety of strains available and ease of procurement and care, the mouse dominates in vivo pre-clinical research. Although a robust model, important divergences from human physiology makes
Dr. Venkatachalem’s lab focuses on lung diseases such as asthma, chronic obstructive pulmonary disease, LAM, & pulmonary hypertension. This group is leading the research on elucidating the role of sex steroids in lung diseases like asthma.
Still researching your asthma animal model? Learn more about which animal is the most popular asthma animal model, the advantages and disadvantages of each, what goes into a successful model, the sensitization and challenge phases, and much more.
The Halayko lab focuses on the
pathogenesis of bronchial asthma and is at the forefront of preclinical asthma research. We sat down with Dr. Halayko to learn more about his work and get his thoughts on the current state and future of asthma research.
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