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Relationship: 1705


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis adjacent Moderate Low Sabina Halappanavar (send email) Under development: Not open for comment. Do not cite WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

During the tissue injury-mediated immune response, naïve CD4+ T helper (Th) cells differentiate into two major functional subsets: Th1 and Th2 type. Both Th1 and Th2 secrete distinct cytokines that promote proliferation and differentiation of their respective T cell population and inhibit proliferation and differentiation of the opposing subset. Th2 cytokines including pro-inflammatory and fibrotic mediators such as GATA binding protein 3 (GATA-3), Interleukin (IL)-13 and Arginase (Arg)-1 are increased in lung-irradiation induced fibrosis (Brush et al., 2007; Han et al., 2011; Wynn, 2004). Th2 immune response is implicated in allergen-mediated lung fibrosis. Meta-analysis of gene expression data collected from lungs of mice exposed to various fibrogenic substances including multi-walled carbon nanotubes (MWCNTs), showed that the expression and function of Th2 response associated genes and pathways are altered in fibrotic lungs (Nikota et al., 2016). Exposure of mice lacking Signal transducer and activator of transcription 6 (STAT6) to MWCNTs resulted in abrogated expression of Th2 genes and reduced lung fibrosis (Nikota et al., 2017). IL-4, the archetypal Th2 cytokine is a pro-fibrotic cytokine and is elevated in idiopathic pulmonary fibrosis (IPF) and lung fibrosis. Overexpression of pro-fibrotic Th2 cytokine IL-13 results in sub-epithelial fibrosis with eosinophilic inflammation (Wilson and Wynn, 2009). In silica-induced pulmonary fibrosis in mice, T regulatory lymphocytes are recruited to the lungs where they increase expression of Platelet-derived growth factor (PDGF) and Transforming growth factor beta (TGF-β) (Maggi et al., 2005). Chemokines associated with the Th2 response in airway epithelial cells include C-C motif chemokine ligand (CCL)1, CCL17, CCL20, and CCL22 (Lekkerkerker et al., 2012).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plasubility of this KER is high as there is a mechanistic relationship between alveolar capillary membrane (ACM) injury (tissue damage), and the induction of a Th2 response (responsible for wound healing) (Gieseck et al., 2018; Wynn, 2004).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Exogenous delivery of TNF-α to mouse lungs with established fibrosis, reduced the fibrotic burden. Exogenous treatment with TNF-α slowed the M2 macrophage polarisation. TNF-α deficient mice showed prolonged pro-fibrotic response and M2 polarisation following bleomycin treatment (Redente et al., 2014).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help
  1. Brush J, Lipnick SL, Phillips T, Sitko J, McDonald JT, McBride WH. Molecular mechanisms of late normal tissue injury. Semin Radiat Oncol. 2007 Apr;17(2):121-30. doi: 10.1016/j.semradonc.2006.11.008.

  2. Caldwell CC, Chen Y, Goetzmann HS, Hao Y, Borchers MT, Hassett DJ, Young LR, Mavrodi D, Thomashow L, Lau GW. Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. Am J Pathol. 2009 Dec;175(6):2473-88. doi: 10.2353/ajpath.2009.090166.

  3. Chang X, Zhu A, Liu F, Zou L, Su L, Li S, Sun Y. Role of NF-κB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO. Environ Toxicol. 2017 Apr;32(4):1354-1362. doi: 10.1002/tox.22329. 

  4. Gieseck RL 3rd, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018 Jan;18(1):62-76. doi: 10.1038/nri.2017.90.

  5. Haczku A, Cao Y, Vass G, Kierstein S, Nath P, Atochina-Vasserman EN, Scanlon ST, Li L, Griswold DE, Chung KF, Poulain FR, Hawgood S, Beers MF, Crouch EC. IL-4 and IL-13 form a negative feedback circuit with surfactant protein-D in the allergic airway response. J Immunol. 2006 Mar 15;176(6):3557-65. doi: 10.4049/jimmunol.176.6.3557. 

  6. Han G, Zhang H, Xie CH, Zhou YF. Th2-like immune response in radiation-induced lung fibrosis. Oncol Rep. 2011 Aug;26(2):383-8. doi: 10.3892/or.2011.1300.

  7. Jackson JA, Friberg IM, Little S, Bradley JE. Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies? Immunology. 2009 Jan;126(1):18-27. doi: 10.1111/j.1365-2567.2008.03010.x.

  8. Kikuchi N, Ishii Y, Morishima Y, Yageta Y, Haraguchi N, Itoh K, Yamamoto M, Hizawa N. Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance. Respir Res. 2010 Mar 18;11(1):31. doi: 10.1186/1465-9921-11-31. 

  9. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest. 2001 Jun;107(12):1529-36. doi: 10.1172/JCI12568.

  10. Lekkerkerker AN, Aarbiou J, van Es T, Janssen RA. Cellular players in lung fibrosis. Curr Pharm Des. 2012;18(27):4093-102. doi: 10.2174/138161212802430396. 

  11. Li J, Zhao L, Zhang Y, Li W, Duan X, Chen J, Guo Y, Yang S, Sun G, Li B. Imbalanced immune responses involving inflammatory molecules and immune-related pathways in the lung of acute and subchronic arsenic-exposed mice. Environ Res. 2017 Nov;159:381-393. doi: 10.1016/j.envres.2017.08.036.

  12. Maggi E, Cosmi L, Liotta F, Romagnani P, Romagnani S, Annunziato F. Thymic regulatory T cells. Autoimmun Rev. 2005 Nov;4(8):579-86. doi: 10.1016/j.autrev.2005.04.010. 

  13. Miyazaki Y, Araki K, Vesin C, Garcia I, Kapanci Y, Whitsett JA, Piguet PF, Vassalli P. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J Clin Invest. 1995 Jul;96(1):250-9. doi: 10.1172/JCI118029.

  14. Nikota J, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Meta-analysis of transcriptomic responses as a means to identify pulmonary disease outcomes for engineered nanomaterials. Part Fibre Toxicol. 2016 May 11;13(1):25. doi: 10.1186/s12989-016-0137-5.

  15. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0.

  16. Ortiz LA, Lasky J, Hamilton RF Jr, Holian A, Hoyle GW, Banks W, Peschon JJ, Brody AR, Lungarella G, Friedman M. Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp Lung Res. 1998 Nov-Dec;24(6):721-43. doi: 10.3109/01902149809099592.

  17. Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989 Sep 1;170(3):655-63. doi: 10.1084/jem.170.3.655.

  18. Redente EF, Keith RC, Janssen W, Henson PM, Ortiz LA, Downey GP, Bratton DL, Riches DW. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol. 2014 Apr;50(4):825-37. doi: 10.1165/rcmb.2013-0386OC. 

  19. Venosa A, Malaviya R, Choi H, Gow AJ, Laskin JD, Laskin DL. Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis. Am J Respir Cell Mol Biol. 2016 Mar;54(3):436-46. doi: 10.1165/rcmb.2015-0120OC. 

  20. Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009 Mar;2(2):103-21. doi: 10.1038/mi.2008.85.

  21. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004 Aug;4(8):583-94. doi: 10.1038/nri1412. 

  22. Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994 Jul;145(1):114-25.