scholarly journals An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure

2021 ◽  
Vol 3 ◽  
Author(s):  
Karsta Luettich ◽  
Monita Sharma ◽  
Hasmik Yepiskoposyan ◽  
Damien Breheny ◽  
Frazer J. Lowe
Keyword(s):  
Lung Function ◽  
Mucociliary Clearance ◽  
Adverse Outcome ◽  
Beat Frequency ◽  
Inhalation Exposure ◽  
Ciliary Beat Frequency ◽  
Immune Defense ◽  
Adverse Outcome Pathway ◽  
Functional Components

Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.

scholarly journals Differential effect of anesthetics on mucociliary clearance in vivo in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyle S. Feldman ◽  
Eunwon Kim ◽  
Michael J. Czachowski ◽  
Yijen Wu ◽  
Cecilia W. Lo ◽  
...  
Keyword(s):  
Mucociliary Clearance ◽  
Defense Mechanism ◽  
Ex Vivo ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Wild Type ◽  
Sulfur Colloid ◽  
Ct System

AbstractRespiratory mucociliary clearance (MCC) is a key defense mechanism that functions to entrap and transport inhaled pollutants, particulates, and pathogens away from the lungs. Previous work has identified a number of anesthetics to have cilia depressive effects in vitro. Wild-type C57BL/6 J mice received intra-tracheal installation of 99mTc-Sulfur colloid, and were imaged using a dual-modality SPECT/CT system at 0 and 6 h to measure baseline MCC (n = 8). Mice were challenged for one hour with inhalational 1.5% isoflurane, or intraperitoneal ketamine (100 mg/kg)/xylazine (20 mg/kg), ketamine (0.5 mg/kg)/dexmedetomidine (50 mg/kg), fentanyl (0.2 mg/kg)/1.5% isoflurane, propofol (120 mg/Kg), or fentanyl/midazolam/dexmedetomidine (0.025 mg/kg/2.5 mg/kg/0.25 mg/kg) prior to MCC assessment. The baseline MCC was 6.4%, and was significantly reduced to 3.7% (p = 0.04) and 3.0% (p = 0.01) by ketamine/xylazine and ketamine/dexmedetomidine challenge respectively. Importantly, combinations of drugs containing fentanyl, and propofol in isolation did not significantly depress MCC. Although no change in cilia length or percent ciliation was expected, we tried to correlate ex-vivo tracheal cilia ciliary beat frequency and cilia-generated flow velocities with MCC and found no correlation. Our results indicate that anesthetics containing ketamine (ketamine/xylazine and ketamine/dexmedetomidine) significantly depress MCC, while combinations containing fentanyl (fentanyl/isoflurane, fentanyl/midazolam/dexmedetomidine) and propofol do not. Our method for assessing MCC is reproducible and has utility for studying the effects of other drug combinations.

Mucociliary function in the mouse measured in explanted lung tissue

1995 ◽  
Vol 79 (1) ◽  
pp. 41-46 ◽  
Author(s):  
H. Kurosawa ◽  
C. G. Wang ◽  
R. J. Dandurand ◽  
M. King ◽  
D. H. Eidelman
Keyword(s):  
Lung Tissue ◽  
Mucociliary Clearance ◽  
Beat Frequency ◽  
Processing System ◽  
Ciliary Beat Frequency ◽  
Culture Technique ◽  
Small Airways ◽  
Dose Dependent Fashion ◽  
Large Animals

To develop a method for the study of mucociliary clearance in small-caliber airways, we investigated ciliary function in an in vitro lung tissue culture technique in mice. Lungs were excised from 45 anesthetized mice [weight 30.9 +/- 6.2 (SD) g] and inflated with 2% liquid agarose at 37 degrees C via the trachea. After cooling to 4 degrees C, the lungs were cut into 0.5- to 1.0-mm thick slices and cultured overnight. Ciliary beat frequency (CBF) was measured in airways cut in cross section using a computerized image processing system. In some experiments, charcoal particle transport (PT) in tangentially cut airways was also measured. Airway diameter ranged from 0.3 to 0.8 mm. In this preparation CBF was stable over a 3-h period and unaffected by minor pH changes. Both CBF and PT exhibited a linear dependency on temperature. CBF and PT were significantly correlated with each other. CBF at 37 degrees C (18.7 +/- 2.93 Hz) was almost twofold higher than values at 22 degrees C (9.74 +/- 3.11 Hz). Isoproterenol increased CBF in a dose-dependent fashion (50% effective concentration of 10(-6.75) M); the effect of isoproterenol could be blocked by propranolol. Administration of forskolin (10 microM) also increased both CBF and PT significantly. These findings demonstrate the feasibility of measuring the major aspects of mucociliary clearance in this system. This approach holds promise as a technique suitable to the investigation of both the small airways of humans and other large animals as well as of airways in murine genetic models of respiratory disease.

scholarly journals Application of text mining to develop AOP-based mucus hypersecretion genesets and confirmation with in vitro and clinical samples

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmanuel Minet ◽  
Linsey E. Haswell ◽  
Sarah Corke ◽  
Anisha Banerjee ◽  
Andrew Baxter ◽  
...  
Keyword(s):  
Text Mining ◽  
Lung Function ◽  
Cigarette Smoke ◽  
Clinical Data ◽  
Adverse Outcome ◽  
Clinical Samples ◽  
Adverse Outcome Pathway ◽  
Mucus Hypersecretion ◽  
Lung Biopsies

AbstractMucus hypersecretion contributes to lung function impairment observed in COPD (chronic obstructive pulmonary disease), a tobacco smoking-related disease. A detailed mucus hypersecretion adverse outcome pathway (AOP) has been constructed from literature reviews, experimental and clinical data, mapping key events (KEs) across biological organisational hierarchy leading to an adverse outcome. AOPs can guide the development of biomarkers that are potentially predictive of diseases and support the assessment frameworks of nicotine products including electronic cigarettes. Here, we describe a method employing manual literature curation supported by a focused automated text mining approach to identify genes involved in 5 KEs contributing to decreased lung function observed in tobacco-related COPD. KE genesets were subsequently confirmed by unsupervised clustering against 3 different transcriptomic datasets including (1) in vitro acute cigarette smoke and e-cigarette aerosol exposure, (2) in vitro repeated incubation with IL-13, and (3) lung biopsies from COPD and healthy patients. The 5 KE genesets were demonstrated to be predictive of cigarette smoke exposure and mucus hypersecretion in vitro, and less conclusively predict the COPD status of lung biopsies. In conclusion, using a focused automated text mining and curation approach with experimental and clinical data supports the development of risk assessment strategies utilising AOPs.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

The effects of in vitro cotitine on nasal ciliary beat frequency

1995 ◽  
Vol 20 (5) ◽  
pp. 465-469 ◽  
Author(s):  
A. M. AGIUS ◽  
M. WAKE ◽  
A. L. PAHOR ◽  
A. SMALLMAN
Keyword(s):  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Ciliary Beat

Application of an adverse outcome pathway-based in vitro testing battery for neurotoxicity evaluation

2021 ◽  
Vol 350 ◽  
pp. S51
Author(s):  
K. Koch ◽  
M. Elgamal ◽  
S. Masjosthusmann ◽  
I. Lauria ◽  
R Hartmann ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
In Vitro Testing

Effects of ethanol on in vitro ciliary motility

1988 ◽  
Vol 65 (4) ◽  
pp. 1617-1620 ◽  
Author(s):  
D. R. Maurer ◽  
J. Liebman
Keyword(s):  
Beat Frequency ◽  
Slow Motion ◽  
Ciliary Beat Frequency ◽  
Blood Levels ◽  
Ciliary Beating ◽  
Ciliary Motility ◽  
Social Drinking ◽  
High Concentrations ◽  
Ciliary Beat

Consumption of ethanol can impair lung function and slow total lung clearance. High concentrations of ethanol have been shown to slow or arrest ciliary beating. This study examined the effects of concentrations of alcohol comparable to blood levels achieved from social drinking on ciliary beat frequency. We obtained ciliated cells by brushing the trachea of unanesthetized sheep during fiber-optic bronchoscopy. The cells were suspended in a perfusion chamber and physiological conditions were maintained in vitro. Ciliary beat frequency and synchrony were determined by slow-motion analysis of video images obtained by interference contrast microscopy. Metachronal ciliary coordination was observed in all preparations. The ciliary beat frequency was stimulated at ethanol concentrations from 0.01 up to but not including 0.1%, unchanged at 0.5 and 1%, and slowed at 2%. While confirming inhibition of ciliary motility at very high ethanol levels, we observed no acute impairment of ciliary function at ethanol concentrations comparable to those achieved from social drinking. Indeed, we found an unexpected stimulation of ciliary beating at low levels of ethanol. How this alteration in ciliary beating would affect pulmonary clearance remains unknown at this time.

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