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Relationship: 1702
Title
Interaction with the lung cell membrane leads to Increased proinflammatory mediators
Upstream event
Downstream event
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 lung resident cell membrane components leading to lung fibrosis | adjacent | Moderate | Moderate | Sabina Halappanavar (send email) | Under development: Not open for comment. Do not cite | EAGMST Under Review |
Interaction with lung resident cell membrane components leads to lung cancer | adjacent | Moderate | Moderate | Penny Nymark (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Innate immune response is the first line of defence in any organism against invading infectious pathogens and toxic substances. It involves tissue triggered startle response to cellular stress and is described by a complex set of interactions between the toxic stimuli, soluble macromolecules and cells (reviewed in Nathan, 2002). The process culminates in a functional change defined as inflammation, purpose of which is to resolve infection and promote healing. In lungs, the interaction of toxic substances with resident cells results in cellular stress, death or necrosis leading to release of intracellular components such as alarmins (DAMPs, IL-1a, HMGB1). Released alarmins (danger sensors) bind cell surface receptors such as Interleukin 1 Receptor 1 (IL-1R1), Toll Like Receptors (TLRs) or others leading to activation of innate immune response signalling.
For example, binding of IL-1a to IL-1R1 can release Nuclear Factor (NF)-κb resulting in its translocation to nucleus and transactivation of pro-inflammatory genes including cytokines, growth factors and acute phase genes. The signalling also stimulates secretion of a variety of pro-inflammatory mediators. Overexpression of IL-1a in cells induces increased secretion of pro-inflammatory mediators. Products of necrotic cells are shown to stimulate the immune system in an IL-1R1-dependent manner (Chen et al., 2007).
The secreted alarmins activate resident cells pre-stationed in the tissues such as mast cells or macrophages leading to propagation of the already initiated immune response by releasing more eicosanoids, cytokines, chemokines and other pro-inflammatory mediators. Thus, secreted mediators signal the recruitment of neutrophils, which are the first cell types to be recruited in acute inflammatory conditions. Neutrophil influx in sterile inflammation is driven mainly by IL-1a (Rider P, 2011). IL-1 mediated signalling regulates neutrophil influx in silica-induced acute lung inflammation (Horning V, 2008). IL1 signalling also mediates neutrophil influx in other tissues and organs including liver and peritoneum. Other types of cells including macrophages, eosinophils, lymphocytes are also recruited in a signal-specific manner. Recruitment of leukocytesinduces critical cytokines associated with the Th2 immune response, including TNF-α, IL-1β, and IL-13.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility of this relationship is high. There is a mechanistic relationship between the MIE (Event 1495) and KE1 (Event 1496) which has been evidenced in a number of both in vitro and in vivo model systems in response to stressors such as, asbestos, silica, bleomycin, carbon nanotubes, and metal oxide nanoparticles (Behzadi et al., 2017; Denholm & Phan 1990; Mossman & Churg 1998).
Increased expression of IL-1a or IL-1b following lung exposure to MWCNTs, bleomycin, micro silica particles, silica crystals, and polyhexamethyleneguanidine phosphate has been shown to be associated with neutrophil influx in rodents (Hornung et al., 2008; Girtsman et al., 2014; Gasse et al., 2007; Nikota et al., 2017; Suwara et al., 2013; Rabolli et al., 2014). Inhibition of IL-1 function by knocking out the expression of IL-1R1 using IL-1R1 KO mice or via treatment with IL-1a or IL-1b neutralising antibodies results in complete abrogation of lung neutrophilic influx following exposure to MWCNTs (Nikota et al, 2017), cigarette smoke (Halappanavar et al., 2013), silica crystals (Rabolli et al., 2014) and bleomycin (Gasse et al., 2017). In transgenic mice lacking IL1R1, Myd88 signalling or the IL-33 receptor St2, early inflammatory responses are suppressed following silica or bleomycin treatment (Dong, et al., 2014; Gasse et al., 2017).
Empirical Evidence
Empirical support for this KER is moderate. There are limited in vitro studies, which show a temporal and dose-dependent relationship between these two events, using the upregulation of specific surface receptors as a proxy for direct membrane interaction (Chan et al., 2018; Denholm & Phan, 1990; Roy et al., 2014). There are also studies that provide general support for the idea that an interaction with the lung resident cell membrane components leads to increased, secretion of pro-inflammatory and pro-fibrotic mediators (Table 1).
Dose-Response Evidence:
There are a few studies which provide evidence for a dose-response relationship in this KER. An in vitro study demonstrated a concentration-response relationship, in which silica exposure induced increases in pro-inflammatory cytokines through scavenger receptors in cultured bone marrow-derived murine mast cells. Cells were exposed to 6.25, 12.5, 25 or 50 mg/cm2 SiO2 for 24 h. Scavenger receptor MSR2 expression increased over time at 50 mg/cm2 and in a concentration dependant relationship. Moreover, TNF-a, IL-13 and MCP-1 increased in a concentration-dependent manner (Brown et al., 2007). This provides indications that at higher concentrations of the stressor, the interaction with the lung resident cell membrane components (Event 1495) leads to an increased secretion of pro-inflammatory mediators (Event 1496).
Temporal Evidence:
In vitro and in vivo studies have demonstrated temporal concordance of the KEs.
Toll-like receptor 4 signal pathway was evaluated in differentiated macrophages exposed to silica at 2.5 mg/cm2. After 16 and 24 h, the mRNA expression level of TLR4 increased. Moreover, the protein expression level of TLR-4 and related MyD88/TIRAP pathway increased at 24 h. Release of IL-1b, IL-6, IL-10, and TNF-a was induced by silica exposure at 24 h. Pre-treatment with TAK-242, an inhibitor of TLR4 signaling, suppressed the release of the cytokines (Chan et al., 2018).
Macrophages exposed to ZnO nanoparticles at 2.5 mg/mL for 24 h increased the expression level of TLR6 and MyD88, TRAF, and IRAK. At 24 h, they also observed an increase in the mRNA and protein levels of the pro-inflammatory cytokines IL-1b, IL-6, and TNF-a. These results demonstrated that ZnO nanoparticles induced pro-inflammatory mediators by TLR stimulation and MAPKs activation (Roy et al., 2014).
The pro-inflammatory IL-1b induced granulocyte migration and can be produced as a result of cellular detection of PAMPs. Mice exposed to 2.5 mg/mouse of silica by instillation showed an increase of mRNA expression of pro-IL-1b in BALF at 6, 12, and 24 h post-exposure in a time-dependent manner. At early time points (1 h, 3 h, 6 h), there was an increase in the release of an alarmin (IL-1a) which indicates that the alarmin was released due to cell damage leading to cytokine production and an inflammatory reaction. Moreover, at 24 h, the levels of mature IL-1b and neutrophil accumulation in BALF increased. Neutralization or deletion of IL-1a reduced the observed responses (Rabolli et al., 2014).
Epithelial damage can lead to the release of alarmins. In this stead, conditioned media from primary human bronchial epithelial cells (PBECs) exposed to thapsigargin was able to induce a pro-inflammatory response in primary human lung fibroblasts. PBECs were exposed to thapsigargin 20 mM for 2 h. After that, the cell culture medium was replaced, and cells were incubated for 24 h. At this time, the medium was recovered and used to culture lung fibroblast for 5 h. This conditioned media from epithelial cells damage contains the alarmin IL-1a, which induced increased gene expression of IL-6, IL-8, MCP-1, and GMC-CSF in fibroblasts. These responses were reduced with anti-IL-1a treatment (Suwara et al., 2014).
Heijink et al. 2015 conducted a similar strategy to identify the relationship between DAMPs and pro-inflammatory mediator release after exposure to cigarette smoke (CS). Neutrophils treated with CS bubbled for 1 min, released high levels of HMGB1 as a consequence of necrotic cell death. The cell-free supernatant, which contains HMGB1, was used to culture human bronchial epithelial cells, and after 24 h it promoted the production of CXCL 8 by lung epithelial cells. Pharmacological inhibitors, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC) and RAGE antagonist peptide (RAP), reduced the effect of CXC8L release.
HMGB1 and HSP-70 can be released by damaged hepatocytes. In a study, mice were treated with acetaminophen 350 mg/Kg for 3 and 6 h. At these time points, the liver perfusate was obtained and an increase in HSP-70 and HMGB1 protein levels was observed. RAW 264.7 cells treated with the liver perfusate exhibited increased mRNA expression levels of MCP-1 and IL-1b (Brittany et al. 2010).
Female mice were intratracheally administered with bleomycin at 5 mg/kg to represent idiopathic pulmonary fibrosis. IL-33, a molecule that can act as a DAMP, increased in lungs after 3 and 7 days of treatment. In serum, at 7-, 14- and 28-days post-exposure, IL-4 and IL-13 increased. It was concluded that IL-33/ST2 signaling pathway is involved in pulmonary fibrosis by bleomycin (Xu et al., 2016).
Uncertainties and Inconsistencies
Attenuation or complete abrogation of KE1 (Event 1496) and KE2 (Event 1497) following inflammogenic stimuli is observed in rodents lacking functional IL-1R1 or other cell surface receptors that engage innate immune response upon stimulation. However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNT was suppressed at 24 hr in mice deficient in IL1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving DAMPs is fundamental for survival, which may necessitate activation of compensatory signaling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response.
Quantitative Understanding of the Linkage
A majority of the in vivo studies are conducted with only one dose and thus, it is difficult to derive quantitative dose-response relationships based on the existing data. However, it is clear from the studies referenced above that greater concentrations or doses of pro-fibrotic substances results in higher release of alarmins, and consequently, higher pro- inflammatory signalling. The above studies also demonstrate strong temporal relationships between the individual KEs.
Response-response Relationship
One study has demonstrated a response-response relationship for this KER.
Human intervertebral disc cells were treated with 0, 0.5, 1, or 2 mg/ml of recombinant HMGB1 for 24 h. Protein levels were determined in cell medium supernatant by ELISA. HMGB1 stimulates the expression of IL-6 and MMP-1 in a response-response relationship. A strong correlation was observed by Spearman’s rank correlation coefficient between HMGB1 treatment and IL-6 or MMP-1 levels (Shah et al., 2018).
Other reports have studied both KEs, but they do not indicate if the response-response relationship was linear or not (coefficient or correlation is not shown) (Fukuda et al. 2017; Kim et al., 2020, Piazza et al., 2013; Yang et al., 2012; Chakraborty et al., 2017).
Time-scale
Some studies have described how long after a change in the MIE (Event 1495; interaction substance and components), KE1 (Event 1496;pro-inflammatory mediators are secreted) is impacted (Table 3.).
Table 3. Time-scale related studies relevant to the MIE (Event 1495) - KE1 (Event 1496) relationship.
Reference |
In vitro/in vivo/population study |
Design |
MIE (Event 1495) |
KE1 (Event 1496) |
Timepoint |
Timepoint |
|||
Xu et al., 2016 |
In vivo |
40 Female Kunming strain mice Bleomycin was intratracheally administered 5 mg/Kg. Days post-exposure |
IL-33 3, 7 days |
IL-4, IL-13 7, 14, and 28 days |
Roy et al., 2014 |
In vitro |
Primary mice macrophages exposed to 2.5 mg/ml ZnO for 24 hrs. |
Increased TLR6 expression 0.5, 3, 6, 12, and 24 h |
Increased IL-6, TNF-a 24 h |
Rabollli et al., 2014 |
In vivo |
Female C57BL/6 mice Exposed to silica 2.5 mg/mouse by instillation |
Increased the release of IL-1 a 1, 3, and 6 h |
Increased mRNA expression of pro IL-1b 6, 12, and 24 h |
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Pancreatic cancer cells stimulated with S100A8 and S100A9 released pro-inflammatory cytokines IL-8, TNF-a, and FGF. Cancer cell-derived conditioned media and the individual cytokines (TNF-a and TGF-b) induced the protein expression of S100A8 and S100A9 in HL-60 monocytic cell line and primary human monocytes (Nedjadi et al. 2018).
Domain of Applicability
References
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