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Aop: 173

AOP Title

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Increased substance interaction with the resident cell membrane components leading to lung fibrosis

Short name:

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Substance interaction with the cell membrane leading to lung fibrosis

Graphical Representation

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Authors

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Sabina Halappanavar, Monita Sharma, Ulla Vogel, Hakan Wallin, Amy J. Clippinger

Point of Contact

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Evgeniia Kazymova   (email point of contact)

Contributors

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  • Monita Sharma
  • Sabina Halappanavar
  • Evgeniia Kazymova

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.32 Included in OECD Work Plan


This AOP was last modified on January 14, 2018 22:20

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Revision dates for related pages

Page Revision Date/Time
Increased, interaction with the resident cell membrane components January 05, 2018 12:28
Increased, secretion of proinflammatory mediators January 05, 2018 12:33
Increased, recruitment of inflammatory cells January 05, 2018 12:52
Increased, loss of alveolar capillary membrane integrity January 05, 2018 12:59
Increased, activation of T (T) helper (h) type 2 cells January 05, 2018 13:03
Increased, fibroblast proliferation and myofibroblast differentiation January 05, 2018 13:08
Increased, extracellular matrix deposition January 05, 2018 13:14
Interaction with the cell membrane leads to Increased proinflammatory mediators January 05, 2018 13:18
Increased proinflammatory mediators leads to Recruitment of inflammatory cells January 05, 2018 13:18
Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity January 05, 2018 13:19
Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells January 05, 2018 13:19
Activation of Th2 cells leads to Increased cellular proliferation and differentiation January 05, 2018 13:20
Increased cellular proliferation and differentiation leads to Increased extracellular matrix deposition January 05, 2018 13:20
Bleomycin January 01, 2018 16:49
Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres January 01, 2018 17:52

Abstract

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This AOP describes the linkages between the interaction of substances with the cellular membrane components and the lung fibrosis. Lung fibrosis is a dysregulated or an exaggerated tissue repair process. It denotes the presence of scar tissue in the alveolar capillary region of the lung where gas exchange occurs; it can be localised or more diffuse involving bronchi and pleura. The process involves intricate dynamics between several inflammatory and immune response cells, and the microenvironment of the alveolar-capillary membrane consisting of both immune and non-immune cells, and the lung interstitium, in the presence of sustained or repeated toxicant stimuli. Regardless of the type of stimulus, the interaction between the substance and components of the cellular membrane leading to release of danger signals/alarmins marks the first event, which is a molecular initiating event (MIE) in the process of tissue repair. As a consequence, a myriad of proinflammatory mediators are secreted (KE1) that signal the recruitment of proinflammatory cells into the lungs (KE2). The MIE, KE1 and KE2 represent the same functional changes that are collectively known as inflammation, the purpose of which is to clear the invading pathogen or toxic substance. In the presence of continuous stimulus or persistent toxic substances, tissue injury ensues leading to the alveolar capillary membrane integrity loss (KE3) and activation of adaptive immune response. The purpose of the adaptive immune response is to resolve the inflammation and activate healing process which involves activation of the T Helper type 2 cell signalling (KE4), during which anti-inflammatory and pro-repair/fibrotic molecules are secreted. Once the healing process is initiated, fibroblast proliferation and myofibroblast differentiation is induced (KE5) leading to synthesis and deposition of extracellular matrix or collagen (KE6). Exaggerated collagen deposition leads to alveolar septa thickening, decrease in total lung volume and lung fibrosis (Adverse Outcome).

Lung fibrosis can be induced by many substances, microorganisms or by over expression of specific inflammatory mediators such as cytokines and chemokines. This AOP is also applicable to materials such as nanomaterials that induce an inflammatory response as well as possess unique properties that allow for significant chronicity of the response, which takes place deep within the lung, beyond the airways and within the alveoli. Lung fibrosis occurs in humans and the key biological events involved are the same as the ones observed in experimental rodent models. Thus, this AOP provides a detailed mechanistic account of the process of lung fibrosis across species.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1495 Increased, interaction with the resident cell membrane components Interaction with the cell membrane
2 KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
3 KE 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
4 KE 1498 Increased, loss of alveolar capillary membrane integrity Loss of alveolar capillary membrane integrity
5 KE 1499 Increased, activation of T (T) helper (h) type 2 cells Activation of Th2 cells
6 KE 1500 Increased, fibroblast proliferation and myofibroblast differentiation Increased cellular proliferation and differentiation
7 KE 1501 Increased, extracellular matrix deposition Increased extracellular matrix deposition

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Interaction with the cell membrane leads to Increased proinflammatory mediators adjacent High High
Increased proinflammatory mediators leads to Recruitment of inflammatory cells adjacent High High
Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity adjacent High High
Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells adjacent High High
Activation of Th2 cells leads to Increased cellular proliferation and differentiation adjacent High High
Increased cellular proliferation and differentiation leads to Increased extracellular matrix deposition adjacent High High

Network View

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Stressors

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Life Stage Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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