Asthma: The Use of Animal Models and Their Translational Utility

Woodrow, Jane; Sheats, M. Katie; Cooper, Bethanie; Bayless, Rosemary

doi:10.3390/cells12071091

Cited by 24 publications

(16 citation statements)

References 287 publications

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“…We used male Hartley guinea pigs weighing 300–450 g bred under standard conditions in our institutional animal facilities (filtered air at 21 °C, 50–70% humidity, and sterilized bed) and fed Harlan ® pellets and sterilized water. The guinea pig is one of the most frequently used experimental models for asthma studies [ 82 ]. Many of the key physiological processes and chemical mediators in the pathogenesis of this disease were first demonstrated in the guinea pig, such as the action of histamine and leukotrienes [ 82 , 83 , 84 , 85 ].…”

Section: Methodsmentioning

confidence: 99%

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx

Montaño,

Carbajal-García,

Casas-Hernández

et al. 2024

Pharmaceuticals

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Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+]i) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca2+ influx. Major channels involved in Ca2+ influx in ASM cells are L-type voltage-dependent Ca2+ channels (L-VDCCs) and nonselective cation channels (NSCCs). Transient receptor potential vanilloid 4 (TRPV4) is an NSCC recently studied in ASM. Mechanical stimuli, such as contraction, can activate TRPV4. We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca2+]i, characterized by a slow onset and a plateau phase. The TRPV4 antagonist (GSK219) decreased channel activity by 94%, whereas the Ca2+-free medium abolished the Ca2+ response induced by GSK101. Moreover, GSK101 caused Na+ influx in tracheal myocytes. GSK219 reduced the Ca2+ peak and the Ca2+ plateau triggered by His or CCh. TRPV4 blockade shifted the concentration–response curve relating to His and CCh to the right in tracheal rings and reduced the maximal contraction. Finally, the activation of TRPV4 in single myocytes increased the Ca2+ refilling of the SR. We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca2+ and Na+, and the opening of L-VDCCs. The entry of Ca2+ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction.

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Section: Methodsmentioning

confidence: 99%

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx

Montaño,

Carbajal-García,

Casas-Hernández

et al. 2024

Pharmaceuticals

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“…Sheep models of asthma performed by immunisation with house dust mite (HDM), as well as some sheep models of COPD carried out inducing emphysema via segmental instillation of lipopolysaccharide (LPS, also known as endotoxin), have been also proposed; however, only a few drugs tested in these models have reached clinical development or final approval in humans to fully understand the predictability of this species to humans, although they have been used in asthma research for a number of years using Ascaris suum as an antigen (Bischof et al, 2003;Hewson et al, 2012;Van Der Velden et al, 2013;Van der Velden & Snibson, 2011;Woodrow et al, 2023).…”

Section: Animal Versus Human Isolated Airwaysmentioning

confidence: 99%

Use of human airway smooth muscle in vitro and ex vivo to investigate drugs for the treatment of chronic obstructive respiratory disorders

Calzetta,

Page,

Matera

et al. 2023

British J Pharmacology

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Isolated airway smooth muscle has been extensively investigated since 1840 to understand the pharmacology of airway diseases. There has been often poor predictability from murine experiments to drugs evaluated in patients with asthma or chronic obstructive pulmonary disease (COPD). However, the use of isolated human airways represents a sensible strategy to optimise the development of innovative molecules for the treatment of respiratory diseases. This review aims to provide updated evidence on the current uses of isolated human airways in validated in vitro methods to investigate drugs in development for the treatment of chronic obstructive respiratory disorders. This review also provides historical notes on the pioneering pharmacological research on isolated human airway tissues, the key differences between human and animal airways, as well as the pivotal differences between human medium bronchi and small airways. Experiments carried out with isolated human bronchial tissues in vitro and ex vivo replicate many of the main anatomical, pathophysiological, mechanical and immunological characteristics of patients with asthma or COPD. In vitro models of asthma and COPD using isolated human airways can provide information that is directly translatable into humans with obstructive lung diseases. Regardless of the technique used to investigate drugs for the treatment of chronic obstructive respiratory disorders (i.e. isolated organ bath systems, videomicroscopy, wire myography), the most limiting factors to produce high‐quality and repeatable data remain closely tied to the manual skills of the researcher conducting experiments and the availability of suitable tissue.

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“…2,5 The molecular underpinnings associated with such inflammatory changes are incompletely understood, and studying these aspects would allow us to better understand the inherent drivers of these processes. Using translational models of mouse asthma, 6 it is possible to study the distribution of inflammation in all segments 7 of the asthma lungs with the ultimate aim to improve patient treatments and evaluate potential therapies.…”

Section: Introductionmentioning

confidence: 99%

Regional variations in allergen‐induced airway inflammation correspond to changes in soluble guanylyl cyclase heme and expression of heme oxygenase‐1

Sumi,

Westcott,

Stuehr

et al. 2024

The FASEB Journal

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Asthma is characterized by airway remodeling and hyperreactivity. Our earlier studies determined that the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cGMP pathway plays a significant role in human lung bronchodilation. However, this bronchodilation is dysfunctional in asthma due to high NO levels, which cause sGC to become heme‐free and desensitized to its natural activator, NO. In order to determine how asthma impacts the various lung segments/lobes, we mapped the inflammatory regions of lungs to determine whether such regions coincided with molecular signatures of sGC dysfunction. We demonstrate using murine models of asthma (OVA and CFA/HDM) that the inflamed segments of these murine lungs can be tracked by upregulated expression of HO1 and these regions in turn overlap with regions of heme‐free sGC as evidenced by a decreased sGC‐α1β1 heterodimer and an increased response to heme‐independent sGC activator, BAY 60‐2770, relative to naïve uninflamed regions. We also find that NO generated from iNOS upregulation in the inflamed segments has a higher impact on developing heme‐free sGC as increasing iNOS activity correlates linearly with elevated heme‐independent sGC activation. This excess NO works by affecting the epithelial lung hemoglobin (Hb) to become heme‐free in asthma, thereby causing the Hb to lose its NO scavenging function and exposing the underlying smooth muscle sGC to excess NO, which in turn becomes heme‐free. Recognition of these specific lung segments enhances our understanding of the inflamed lungs in asthma with the ultimate aim to evaluate potential therapies and suggest that regional and not global inflammation impacts lung function in asthma.

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Asthma: The Use of Animal Models and Their Translational Utility

Cited by 24 publications

References 287 publications

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx

Use of human airway smooth muscle in vitro and ex vivo to investigate drugs for the treatment of chronic obstructive respiratory disorders

Regional variations in allergen‐induced airway inflammation correspond to changes in soluble guanylyl cyclase heme and expression of heme oxygenase‐1

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