An adverse outcome pathway for lung surfactant function inhibition leading to decreased lung function

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.

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

Scientific Reports ◽

10.1038/s41598-021-85345-9 ◽

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.

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The Adverse Outcome Pathway for Oxidative Stress-Mediated EGFR Activation Leading to Decreased Lung Function

Applied In Vitro Toxicology ◽

10.1089/aivt.2016.0032 ◽

2017 ◽

Vol 3 (1) ◽

pp. 99-109 ◽

Cited By ~ 8

Author(s):

Karsta Luettich ◽

Marja Talikka ◽

Frazer J. Lowe ◽

Linsey E. Haswell ◽

Jennifer Park ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Function ◽

Adverse Outcome ◽

Adverse Outcome Pathway ◽

Egfr Activation

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Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development

Current Research in Toxicology ◽

10.1016/j.crtox.2021.07.002 ◽

2021 ◽

Author(s):

Christine M. Palermo ◽

Jennifer E. Foreman ◽

Daniele S. Wikoff ◽

Isabel Lea

Keyword(s):

Reproductive Tract ◽

Adverse Outcome ◽

Male Rat ◽

Adverse Outcome Pathway ◽

Pathway Network

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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 ◽

10.3390/nano11010180 ◽

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.

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The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology ◽

10.1002/wnan.1708 ◽

2021 ◽

Author(s):

Tyler P. Nicholas ◽

William K. Boyes ◽

David K. Scoville ◽

Tomomi W. Workman ◽

Terrance J. Kavanagh ◽

...

Keyword(s):

Respiratory System ◽

Silver Nanoparticle ◽

Adverse Outcome ◽

Adverse Outcome Pathway ◽

Nanoparticle Toxicity ◽

Gene Environment

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Species pattern of phosphatidylinositol from lung surfactant and a comparison of the species pattern of phosphatidylinositol and phosphatidylglycerol synthesized de novo in lung microsomal fractions

Biochemical Journal ◽

10.1042/bj2540067 ◽

1988 ◽

Vol 254 (1) ◽

pp. 67-71 ◽

Cited By ~ 9

Author(s):

B Rüstow ◽

Y Nakagawa ◽

H Rabe ◽

K Waku ◽

D Kunze

Keyword(s):

Lung Function ◽

Molecular Species ◽

De Novo ◽

Lung Surfactant ◽

Minor Component ◽

Main Species ◽

Surfactant Phospholipids ◽

Species Pattern ◽

A Minor

1. Phosphatidylinositol (PI) is a minor component of lung surfactant which may be able to replace the functionally important phosphatidylglycerol (PG) [Beppu, Clements & Goerke (1983) J. Appl. Physiol. 55, 496-502] without disturbing lung function. The dipalmitoyl species is one of the main species for both PI (14.4%) and PG (16.9%). Besides the C16:0--C16:0 species, the C16:0--C18:0, C16:0--C18:1, C16:0--C18:2 and C18:0--C18:1 species showed comparable proportions in the PG and PI fractions. These similarities of the species patterns and the acidic character of both phospholipids could explain why surfactant PG may be replaced by PI. 2. PI and PG were radiolabelled by incubation of microsomal fractions with [14C]glycerol 3-phosphate (Gro3P). For 11 out of 14 molecular species of PI and PG we measured comparable proportions of radioactivity. The radioactivity of these 11 species accounted together for more than 80% of the total. The addition of inositol to the incubation system decreased the incorporation in vitro of Gro3P into PG and CDP-DG (diacylglycerol) of lung microsomes (microsomal fractions), but did not change the distribution of radioactivity among the molecular species of PG. These results supported the idea that both acidic surfactant phospholipids may be synthesized de novo from a common CDP-DG pool in lung microsomes.

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Development of an Adverse Outcome Pathway for the Onset of Hypertension by Oxidative Stress-Mediated Perturbation of Endothelial Nitric Oxide Bioavailability

Applied In Vitro Toxicology ◽

10.1089/aivt.2016.0031 ◽

2017 ◽

Vol 3 (1) ◽

pp. 131-148 ◽

Cited By ~ 7

Author(s):

Frazer J. Lowe ◽

Karsta Luettich ◽

Marja Talikka ◽

Vy Hoang ◽

Linsey E. Haswell ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Adverse Outcome ◽

Adverse Outcome Pathway ◽

Endothelial Nitric Oxide ◽

Nitric Oxide Bioavailability

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

Scientific Reports ◽

10.1038/srep21978 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 33

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.

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