The Relevance of Animal Models for Aerosol Studies

Phalen, Robert F.; Oldham, Michael J.; Wolff, Ronald K.

doi:10.1089/jamp.2007.0673

Cited by 58 publications

(27 citation statements)

References 65 publications

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“…Mice have lower number of cilia, fewer Clara cells and restriction of submucosal glands to the trachea resulting in a different filtering of inhaled particles compared to man [101]. This can have an impact on the distribution of inhaled particles throughout the respiratory tract [139,140]. Mice furthermore do not have a cough reflex and many mediators such as histamine and tachykinins have different pharmacological effects in humans, which complicates mechanistic analysis of the effects of inhaled pollutants on bronchial hyperresponsiveness [101,138].…”

Section: Relevance Of Data From Murine Research: Pro/con Of Mouse Modelsmentioning

confidence: 99%

“…iiiii) Finally, also anatomical and developmental differences can be important. Differences in pulmonary lobulation and bronchial branching (six airway generations in mice versus 23 airway generations in humans), which are already present during the embryonic stage of lung development, can affect particle distribution [139]. In this view, the anatomical location of specific pathological mechanisms induced by particles, such as remodeling, might be different in mice compared to man.…”

Section: Relevance Of Data From Murine Research: Pro/con Of Mouse Modelsmentioning

confidence: 99%

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Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

et al. 2010

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Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed.

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Section: Relevance Of Data From Murine Research: Pro/con Of Mouse Modelsmentioning

confidence: 99%

Section: Relevance Of Data From Murine Research: Pro/con Of Mouse Modelsmentioning

confidence: 99%

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

et al. 2010

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“…and pulmonary administration of both CMS and colistin, albeit to separate groups of animals; i.e., it was not a crossover study. It is important that significant differences in the anatomical structure of the rodent (monopodial) and human (dichotomous) respiratory systems (21,22) may lead to differences in drug disposition within the lungs and in absorption into the systemic circulation. Clinically relevant delivery systems cannot be easily replicated in rodents, which may cause differences in drug disposition (23).…”

mentioning

confidence: 99%

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Landersdorfer

Nguyen

Lieu

et al. 2017

Antimicrob Agents Chemother

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Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.

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“…Nebulisers developed speci fi cally for delivery of aerosols to animals such as the "AeroProbe" from Trudell Medical and the "Microsprayer" from Penncentury are examples of devices used for particle delivery directly to the mucosal surfaces of the respiratory tract. These devices overcome the dif fi cult nature of the mouse breathing pattern and anatomy [ 109 ] and allow dose-response studies to be conducted.…”

Section: Aerosolised Formulationsmentioning

confidence: 99%

Mucosal Delivery of RNAi Therapeutics

González

Nielsen

Thomsen

et al. 2012

Advances in Delivery Science and Technology

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The effectiveness of RNA interference-based drugs is dependent on accumulation at the target site in therapeutically relevant amounts. Local administration to the mucosal surfaces lining the respiratory, gastrointestinal and genitourinary tracts allows access into diseased areas without the necessity to overcome serum nuclease degradation, rapid renal and hepatic clearance and non-speci fi c tissue accumulation associated with systemic delivery. This work describes RNAi therapeutics focused on pulmonary, oral, rectal and intravaginal routes of administration. Mucosal barrier components including site variations and delivery considerations are addressed in order to design an effective mucosal delivery strategy.

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The Relevance of Animal Models for Aerosol Studies

Cited by 58 publications

References 65 publications

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Mucosal Delivery of RNAi Therapeutics

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