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Event: 1499

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased, activation of T (T) helper (h) type 2 cells

Short name

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Activation of Th2 cells

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Biological Context

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Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Substance interaction with the pulmonary cell membrane leading to pulmonary fibrosis	KeyEvent	Cataia Ives (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Naïve CD4+ T cells differentiate into four types of T helper (Th) cells – Th1, Th2, Th17 and inducible regulatory T cells following exposure to infectious agents. The differentiation process begins when antigen presenting cells (APCs) come in contact with toxic substances and is mainly driven by cytokines that make up the microenvironment. For example, increased concentrations of Interleukin (IL)-12 secreted by APCs in the environment may be biased towards Th1 type and increased IL-6 or IL-4 in the environment may commit to Th2 type differentiation. Th1 cytokines, Interferon gamma (IFN-γ) and IL-12 induce inflammation, aid in clearance of toxic substances, induce tissue damage and control the fibrotic responses. IFN-γ has suppressive effects on the production of extracellular matrix proteins including collagen and fibronectin. The Th2 response suppresses Th1 mediated response, which results in decreased Th1 cell-mediated tissue damage but at the same time contributing to the persistence of toxic substances leading to perpetuation of tissue damage, triggering uncontrolled healing response. The major sources of Th2 cytokines are Th2 cells themselves; however, mast cells, macrophages, epithelial cells and activated fibroblasts have shown to produce IL-4, IL-13 and IL-10 upon appropriate stimulation. Th2 cytokines IL-4 and IL-13 regulate wound healing.

Literature evidence for its perturbation in the context of pulmonary fibrosis:

For fibroplasia or fibrosis, the type of CD4+ T cell response that develops is crucial. Studies conducted in mice that do not express Th2 cytokines IL-4, IL-5 and IL-13 show complete attenuation of fibrosis despite the highly active Th1 response. Th2 cytokines IL-4 and IL-13 are elevated in fibrotic lungs; IL-13 activates Transforming growth factor beta 1 (TGF-β1) and initiates fibroblast proliferation and differentiation in lung fibrosis (Lee et al., 2001). Overexpression of IL-13 induces sub-epithelial airway fibrosis in mice in the absence of any other external pro-inflammatory or pro-fibrotic stimulus (Zhu et al., 1999). Both multi-walled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes induce elevated expression of IL-4 and IL-13 in bronchoalveolar lavage fluid (BALF) of mouse lungs (Park et al., 2011), and increased levels of IL-25 and IL- 33 in BALF and mouse lungs exposed to MWCNTs (Dong and Ma, 2018). In a rare human study, increased levels IL-4 and IL-5 were observed in the sputum of humans exposed to MWCNTs at an occupational setting (Fatkhutdinova et al., 2016). Overexpression of IL-10 increases IL-4 and IL-13 production and lung fibrosis following exposure to silica (Barbarin et al., 2005). Alveolar macrophages from asbestosis patients (a form of lung fibrosis) exhibit M2 phenotype (He et al., 2013). Ex vivo culture of alveolar macrophages obtained from BALF of patients suffering from idiopathic pulmonary fibrosis with collagen type I showed enhanced levels of M2 macrophage markers C-C motif chemokine ligand (CCL)-18, CCL-2 and CD204 (Stahl et al., 2013). Th2 response associated expression of IL-33 cytokine enhances polarisation of M2 macrophages and inducing M2-mediated expression of IL-13 and TGF-β1 in mice (Dong and Ma, 2018). Cigarette smoke induces expression of genes associated with M2 sub-phenotypes, which is further enhanced in smokers presenting with chronic obstructive pulmonary disease (Shaykhiev et al., 2009).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Targeted enzyme-linked immunosorbent assays (ELISA) or real-time quantitative polymerase chain reaction (qRT-PCR) (routinely used and recommended):

The ELISA and qRT-PCR are routinely used to assess the levels of protein and mRNA of several Th1 and Th2 cytokines including IL-4, IL-5, IL- 13, IL-10, IL-12, IFN-γ. In addition, the levels of TGF-β is also assessed, expression of which is increased following induction of IL-13 synthesis. The other genes of relevance to Th2 response and eventual pro-fibrotic response include Arginine (Arg)-1 and Arg-2. BALF supernatant collected from lungs of animals exposed to toxic substances or human patients is used. Tissue homogenates or cell pellets can also be used. Expression of these genes and proteins can be assessed in in vitro cell cultures exposed to pro-fibrotic stimulus. Apart from assaying single protein or gene at a time, cytokine bead arrays or cytokine PCR arrays can be used to detect a whole panel of Th1 and/or Th2 cytokines using a multiplex method. This method is quantitative and especially advantageous when the sample amount available for testing is scarce. The details of ELISA and qRT-PCR are described under Event 1495. The details of BALF sample collection is described under Event 1497.

Domain of Applicability

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References

List of the literature that was cited for this KE description. More help

1. Barbarin V, Xing Z, Delos M, Lison D, Huaux F. Pulmonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles. Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L841-8. doi: 10.1152/ajplung.00329.2004.

2. Dong J, Ma Q. Type 2 Immune Mechanisms in Carbon Nanotube-Induced Lung Fibrosis. Front Immunol. 2018 May 22;9:1120. doi: 10.3389/fimmu.2018.01120.

3. Fatkhutdinova LM, Khaliullin TO, Vasil'yeva OL, Zalyalov RR, Mustafin IG, Kisin ER, Birch ME, Yanamala N, Shvedova AA. Fibrosis biomarkers in workers exposed to MWCNTs. Toxicol Appl Pharmacol. 2016 May 15;299:125-31. doi: 10.1016/j.taap.2016.02.016.

4. He C, Ryan AJ, Murthy S, Carter AB. Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages. J Biol Chem. 2013 Jul 12;288(28):20745-57. doi: 10.1074/jbc.M112.410720.

5. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001 Sep 17;194(6):809-21. doi: 10.1084/jem.194.6.809.

6. Park EJ, Roh J, Kim SN, Kang MS, Han YA, Kim Y, Hong JT, Choi K. A single intratracheal instillation of single-walled carbon nanotubes induced early lung fibrosis and subchronic tissue damage in mice. Arch Toxicol. 2011 Sep;85(9):1121-31. doi: 10.1007/s00204-011-0655-8.

7. Shaykhiev R, Krause A, Salit J, Strulovici-Barel Y, Harvey BG, O'Connor TP, Crystal RG. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol. 2009 Aug 15;183(4):2867-83. doi: 10.4049/jimmunol.0900473.

8. Stahl M, Schupp J, Jäger B, Schmid M, Zissel G, Müller-Quernheim J, Prasse A. Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation. PLoS One. 2013 Nov 20;8(11):e81382. doi: 10.1371/journal.pone.0081382.

9. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999 Mar;103(6):779-88. doi: 10.1172/JCI5909.