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Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells
Key Event Relationship Overview
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 Do not cite||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
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
Evidence Supporting this KER
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
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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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.
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