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Activation of Th2 cells leads to Increased cellular proliferation and differentiation
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||High||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
The wound healing process involves an inflammatory phase, during which the damage tissue/wound is provisionally filled with extracellular matrix (ECM). This phase is characterised by secretion of cytokines/chemokines, growth factors and recruitment of inflammatory cells, fibroblasts and endothelial cells. The activated T helper (Th)1/Th2 response and increased pool of specific cytokines and growth factors such as Interleukin (IL)-1β, IL-6, IL-13, and Transforming growth factor beta (TGF-β), induce fibroblast proliferation. Th type 2 (Th2) cells can directly stimulate fibroblasts to synthesise collagen with IL-1 and IL-13. Th2 cytokines IL-13 and IL-4, known to mediate the fibrosis process induce phenotypic transition of human fibroblasts (Hashimoto S, 2001). IL-13 is shown to inhibit Matrix metalloproteinases (MMP)-mediated matrix degradation resulting in excessive collagen deposition by downregulating the synthesis and expression of matrix degrading MMPs. IL-13 is also suggested to induce TGF-β1 in macrophages and its absence results in reduced TGF-β1 expression and decrease in collagen deposition (Fichtner-Feigl et al., 2006). These cytokines are suggested to initiate polarisation of macrophages to the alternative phenotype (M2). Th2 cells that synthesise IL-4 and IL-13 induce synthesis of Arginase (Arg)-1 in M2 macrophages. The Arg-1 pathway stimulates synthesis of proline for collagen synthesis required for fibrosis (Barron and Wynn, 2011).
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility for this KER is high. There is a widely understood functional relationship between Th2 response related mediators, and their ability to induce proliferation and differentiation of fibroblasts (Shao et al., 2008; Wynn, 2004; Wynn, 2012).
Uncertainties and Inconsistencies
Due to multifarious functions of several cytokines involved in the process of inflammation and repair, the timing of when a pathway is intervened in an experiment is important in the assessment of the KER studies. For example, exposure to pro-fibrotic bleomycin stimulates IL-4 production during the acute inflammatory phase, which is suggested to limit the recruitment of T lymphocytes and production of damaging cytokines such as Tumor necrosis factor alpha (TNF-α), IFN-γ, and nitric oxide, playing a tissue protective role. However, production of IL- 4 during the chronic phase of tissue repair and healing, favors fibrosis manifestation. Treatment of IL4 -/- mice with low doses of bleomycin induced fewer fibrotic lesions compared to IL-4 +/+ mice. However, treatment of high doses of bleomycin induced more lethality in IL-4 -/- mice compared to the wild type mice (Huaux et al., 2003). Moreover, the KEs represented in AOP 173 can function in parallel in a positive feedback loop, perpetuating and magnifying the response at each stage. The resulting microenvironment may contain the same molecules in different proportions exhibiting different functions. Thus, the complexity of the process and the functional heterogeneity of the molecular players involved, makes it nearly impossible to establish KERs using a targeted deletion of one single gene or a pathway in a study, which is how most of the studies are designed.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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