Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

Mays, Tamer Y. El; Choudhury, Parichita; Leigh, Richard; Koumoundouros, Emmanuel; Velden, Joanne Van der; Shrestha, Grishma; Pieron, Cora; Dennis, John; Green, Francis Hy; Snibson, Kenneth J.

doi:10.1186/s12931-014-0098-x

Cited by 12 publications

(11 citation statements)

References 56 publications

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“…Large-animal models can, however, play an important role in filling this need. Indeed, the physiological and immunological similarities between sheep and human lungs ( 60 , 61 ) have contributed to the widespread use of sheep as translational models for human lung research ( 26 , 27 ), including for asthma ( 62 – 65 ), the delivery of drugs via the upper respiratory tract ( 66 – 68 ), emphysema ( 69 – 71 ), pulmonary hypertension ( 72 – 74 ), physical lung injury ( 75 – 78 ), lung infection ( 28 , 79 – 81 ), respiratory distress syndromes ( 82 – 85 ), asbestosis ( 86 – 88 ), and lung cancer ( 89 , 90 ).…”

Section: Discussionmentioning

confidence: 99%

Variability of the Sheep Lung Microbiota

Glendinning

Wright

Pollock

et al. 2016

Appl Environ Microbiol

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Sequencing technologies have recently facilitated the characterization of bacterial communities present in lungs during health and disease. However, there is currently a dearth of information concerning the variability of such data in health both between and within subjects. This study seeks to examine such variability using healthy adult sheep as our model system. Protected specimen brush samples were collected from three spatially disparate segmental bronchi of six adult sheep (age, 20 months) on three occasions (day 0, 1 month, and 3 months). To further explore the spatial variability of the microbiotas, more-extensive brushing samples (n = 16) and a throat swab were taken from a separate sheep. The V2 and V3 hypervariable regions of the bacterial 16S rRNA genes were amplified and sequenced via Illumina MiSeq. DNA sequences were analyzed using the mothur software package. Quantitative PCR was performed to quantify total bacterial DNA. Some sheep lungs contained dramatically different bacterial communities at different sampling sites, whereas in others, airway microbiotas appeared similar across the lung. In our spatial variability study, we observed clustering related to the depth within the lung from which samples were taken. Lung depth refers to increasing distance from the glottis, progressing in a caudal direction. We conclude that both host influence and local factors have impacts on the composition of the sheep lung microbiota.IMPORTANCE Until recently, it was assumed that the lungs were a sterile environment which was colonized by microbes only during disease. However, recent studies using sequencing technologies have found that there is a small population of bacteria which exists in the lung during health, referred to as the “lung microbiota.” In this study, we characterize the variability of the lung microbiotas of healthy sheep. Sheep not only are economically important animals but also are often used as large animal models of human respiratory disease. We conclude that, while host influence does play a role in dictating the types of microbes which colonize the airways, it is clear that local factors also play an important role in this regard. Understanding the nature and influence of these factors will be key to understanding the variability in, and functional relevance of, the lung microbiota.

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Section: Discussionmentioning

confidence: 99%

Variability of the Sheep Lung Microbiota

Glendinning

Wright

Pollock

et al. 2016

Appl Environ Microbiol

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“…For this study, a sample size of 16 subjects was estimated to be able to detect a treatment difference of at least a 14% change in FEV 1 with a 95% confidence interval with a power of over 90% in a two-sided test, assuming that the variability observed would be like the response to S1226 in the sheep allergen challenge model [ 15 ]. The sheep model used airway resistance as a model of airway caliber.…”

Section: Methodsmentioning

confidence: 99%

“…They involve pH and epithelial-dependent mechanisms [ 13 ] and do not require adrenergic [ 14 ] or cholinergic pathways [ 12 ]. The combination of CO 2 with perflubron in preclinical studies produced a synergistic effect, providing rapid and sustained bronchodilation [ 13 – 15 ]. S1226 showed rapid opening of airways in sheep sensitized and challenged with house dust mites and rats sensitized and challenged with ovalbumin.…”

Section: Introductionmentioning

confidence: 99%

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A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

Swystun

Green

Dennis³

et al. 2018

Trials

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BackgroundThis study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model.MethodsThis was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge.ResultsNo significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo.ConclusionsS1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated.Trial registrationClinicalTrials.gov, NCT02334553. Registered on 12 November 2014.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2720-6) contains supplementary material, which is available to authorized users.

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“…Sheep have been widely used in biomedical research to model a number of human pathologies including asthma (68,69), osteoporosis (70), sepsis (71) and acute lung injury (ALI) (72)(73)(74), as they also share many physiological similarities with humans (75)(76)(77).…”

Section: Intrinsic Pathway Extrinsic Pathwaymentioning

confidence: 99%

Validation of acute traumatic coagulopathy in an ovine model of trauma and haemorrhage

Zyl¹

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This thesis describes an ovine model of complex trauma and haemorrhage that demonstrates coagulation changes using both traditional plasma based assays and point of care viscoelastic assays that are consistent with current definitions of ATC. The degree of coagulopathy was correlated with the degree of shock as quantified by arterial lactate.Coagulopathy was also associated with activation of the protein C pathway and shedding of the endothelial glycocalyx. Fibrinolysis did not make a significant contribution to the coagulopathy observed and there was no evidence of altered platelet function in this model.ii

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Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

Cited by 12 publications

References 56 publications

Variability of the Sheep Lung Microbiota

Variability of the Sheep Lung Microbiota

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

Validation of acute traumatic coagulopathy in an ovine model of trauma and haemorrhage

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