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° F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM
Directorate F – Health, Consumers and Reference Materials
Joint Research Centre, European Commission
Point of Contact
Marina Kuburic (email point of contact)
- Brigitte Landesmann
- Marina Kuburic
- Kirsten Gerloff
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development||1.47||Included in OECD Work Plan|
This AOP was last modified on April 30, 2019 12:58
|N/A, Mitochondrial dysfunction 1||March 12, 2018 11:19|
|N/A, Cell injury/death||December 05, 2018 08:26|
|Endocytotic lysosomal uptake||December 05, 2018 08:00|
|Disruption, Lysosome||November 12, 2018 08:23|
|Increased Pro-inflammatory mediators||August 02, 2018 02:47|
|Leukocyte recruitment/activation||December 01, 2017 09:33|
|Activation, Stellate cells||December 05, 2018 08:28|
|Accumulation, Collagen||December 05, 2018 08:28|
|N/A, Liver fibrosis||December 05, 2018 08:29|
|endocytosis leads to Disruption, Lysosome||November 12, 2018 10:41|
|Disruption, Lysosome leads to N/A, Mitochondrial dysfunction 1||November 12, 2018 10:47|
|N/A, Mitochondrial dysfunction 1 leads to N/A, Cell injury/death||November 29, 2016 20:08|
|N/A, Cell injury/death leads to Increased pro-inflammatory mediators||November 12, 2018 10:52|
|Increased pro-inflammatory mediators leads to Leukocyte recruitment/activation||November 12, 2018 10:55|
|Leukocyte recruitment/activation leads to Activation, Stellate cells||November 12, 2018 10:58|
|Activation, Stellate cells leads to Accumulation, Collagen||December 05, 2018 08:51|
|Accumulation, Collagen leads to N/A, Liver fibrosis||December 05, 2018 08:52|
|nanoparticles||December 21, 2016 09:40|
|ROS||December 21, 2016 09:40|
|o-methyl-serine dodecylamide hydrochloride (MSDH)||December 21, 2016 09:43|
|3-aminopropanal||December 21, 2016 09:44|
|artesunate||December 21, 2016 09:44|
|Chloroquine bis(phosphate)||December 04, 2018 04:25|
|Norfloxacin||December 04, 2018 04:26|
|Ciprofloxacin||December 04, 2018 04:26|
Hepatotoxicity is known to be an important endpoint of regulatory concern; it has been one of the frequent reasons for pharmacovigilance safety reports and human health risk assessments. Liver fibrosis in particular is a health problem resulting from chronic or repeated-dose chemical exposure and it is considered as an adverse outcome of regulatory interest. Liver fibrosis is a long and complex process involving various hepatic cell types, molecular mediators, receptors and signalling pathways. It occurs as a result of imbalance between collagen deposition and destruction, but also changes in the extracellular matrix composition (ECM). Due to this complexity appropriate cell model is currently unavailable.
The current AOP links endocytic lysosomal uptake and the formation of liver fibrosis. The molecular initiating event (MIE) is endocytic lysosomal uptake of chemical, leading to lysosomal disruption, the first key event (KE). Lysosomal disruption induces mitochondrial dysfunction, which leads to cell injury and both apoptosis and necrosis. Lysosomal disruption, mitochondrial dysfunction and cell injury/death present KEs on the cellular level. Cell death releases damage-associated molecular patterns (DAMPs) which lead to increased inflammatory mediators presence, the next KE along the path. Inflammatory mediators attract and activate leukocytes, which present the next KE. Activated leukocytes through molecular mediators activate hepatic stellate cells, which increases α-SMA in them. This KE increases amount of collagen I and III, which causes its accumulation. Collagen accumulation presents KE at the tissue level and leads to adverse outcome (AO) - liver fibrosis, which changes normal functioning of the whole organ. There is also important on-going process present throughout the pathway, which is connected with different KEs- oxidative stress. It is not classified as individual KE, but described in KEs and KERs related to it.
The value of this AOP is that it might support chemical risk assessment by identifying upstream biomarkers for adverse outcome, even though the adequate cell model is not available. This systematic organization of existed knowledge, but also of present uncertainties can facilitate regulatory processes, but also indicate the need for the new testing methods.
The AOP endocytic lysosomal uptake to liver fibrosis has high biological plausibility, supported with empirical evidence. However, quantitative data and temporal sequences between KEs are currently lacking and further efforts are necessary in their provision.
Liver fibrosis is currently an important health problem potentially leading in its progressive form to cirrhosis and as such present a significant economic burden (Lim and Kim, 2008). The only therapy for chronic liver failure is liver transplantation, with 5.500 liver transplantations in Europe on a yearly basis, costing up to €100.000 the first year (Safadi and Friedman, 2002). There are constant research attempts for new therapeutic strategies, but so far without success. AOP concept presents an alternative approach which organizing mechanistic toxicological knowledge can lead to prevention of liver fibrosis.
The use and possible applications of nanomaterials (NMs) are in constant increase, for example in food, food-related products or cosmetics. Therefore, the safety of NMs systemically taken up in the body needs to be ensured. The liver is known to be one of the main target organs for ingested NMs, but inhaled particles can also reach the liver upon clearance from the lung (Johnston et al., 2010; Cui et al., 2011; Geraets et al., 2012). In vivo experiments on gavaged or injected (intraperitoneal or intravenously) TiO2 suggest a wide range of adverse effects on the liver: an increase in general serum markers for liver damage such as Alanine Aminotransferase or Aspartate Aminotransferase (Liu et al., 2009; Duan et al., 2010), an increase in inflammatory markers such as pro-inflammatory cytokines and/or infiltration of inflammatory cells (Ma et al., 2009; Cui et al., 2011; Kermanizadeh, 2012), an increase of markers for oxidative stress (Liu et al., 2010; Soliman et al., 2013), apoptosis, necrosis and also fibrosis (Chen et al., 2009; Alarifi et al., 2013). Oral NM administration appeared to induce overall milder adverse effects than systemic administration, most likely due to the typically limited absorption of NMs in the GI tract. Thus, it is important to keep in mind that the route of exposure and the size of the NM, play important role whether these reach the liver, and to which extent they're accumulated (Kermanizadeh, 2014).
Once a chemical is taken up by a cell, it is transported into the lysosome. In the lysosome, acidic environment can enhance the solubility of a NM, or it remains in initial nano form. Both situations can induce toxicity, causing lysosomal swelling, followed by lysosomal damage and the release of pro-apoptotic proteins (Wang et al., 2013; Cho et al., 2011; Cho et al., 2012). But not only NMs cause lysosomal damage: fluoroquinolones (Ouedraogo et al., 2000), lysosomotropic detergents such as o-methyl-serine dodecylamide hydrochloride (Villamil Giraldo et al., 2016), artesunate (Yang et al., 2014), chloroquine (Ashoor et al., 2013) can do the same, and Reactive Oxygen Species (ROS) such as H2O2 can amplify this effect (Repnik et al., 2012). The amount of lysosomal enzymes released into the cytosol regulates the cell death pathway: controlled increased permeability of lysosomal membrane, caused by limited level of stress, plays a vital role in the induction of apoptosis, whereas massive lysosomal rupture, caused by high stress levels, leads to necrosis (Bursch, 2001; Guicciardi et al., 2004). Lysosomes are known to trigger mitochondrial mediated cell death by the release of cathepsins into the cytosol (Repnik et al., 2012). At the same time however, lysosomes themselves are a source of ROS, which can lead to damage of the mitochondrial membrane (Wang et al., 2013; Kubota et al., 2010). Cell death further on leads to inflammation (Faouzi et al., 2001), which activates hepatic stellate cells and induce them to secrete collagen (Casini et al., 1997). It is established that collagen accumulation is a prestage of liver fibrosis (Bataller and Brenner, 2005; Lee and Friedman, 2011).
Overall, the connection between lysosomal and mitochondrial damage with liver inflammation and further on with fibrosis, is well known, regardless if triggered by chemicals, proteins or NMs (reviewed in Malhi and Gores, 2008; Kong et al., 2014). Therefore, due to its high importance it is described extensively in the current AOP.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1539||Endocytotic lysosomal uptake||endocytosis|
|2||KE||898||Disruption, Lysosome||Disruption, Lysosome|
|3||KE||177||N/A, Mitochondrial dysfunction 1||N/A, Mitochondrial dysfunction 1|
|4||KE||55||N/A, Cell injury/death||N/A, Cell injury/death|
|5||KE||1493||Increased Pro-inflammatory mediators||Increased pro-inflammatory mediators|
|6||KE||1494||Leukocyte recruitment/activation||Leukocyte recruitment/activation|
|7||KE||265||Activation, Stellate cells||Activation, Stellate cells|
|8||KE||68||Accumulation, Collagen||Accumulation, Collagen|
|9||AO||344||N/A, Liver fibrosis||N/A, Liver fibrosis|
Relationships Between Two Key Events
(Including MIEs and AOs)
|endocytosis leads to Disruption, Lysosome||adjacent||High|
|Disruption, Lysosome leads to N/A, Mitochondrial dysfunction 1||adjacent||High|
|N/A, Mitochondrial dysfunction 1 leads to N/A, Cell injury/death||adjacent||Moderate||Low|
|N/A, Cell injury/death leads to Increased pro-inflammatory mediators||adjacent||High|
|Increased pro-inflammatory mediators leads to Leukocyte recruitment/activation||adjacent||High|
|Leukocyte recruitment/activation leads to Activation, Stellate cells||adjacent||High|
|Activation, Stellate cells leads to Accumulation, Collagen||adjacent||High|
|Accumulation, Collagen leads to N/A, Liver fibrosis||adjacent||High|
|o-methyl-serine dodecylamide hydrochloride (MSDH)|
Life Stage Applicability
|Not Otherwise Specified|
Overall Assessment of the AOP
Assessment of the Weight-of-Evidence supporting the AOP
Concordance of dose-response relationships
The present AOP is a purely qualitative description of the pathway. The present literature does not provide quantitative information on dose-response relationships.
Temporal concordance among the key events and adverse outcome
There is empirical evidence to support that a change in KEup leads to a change in the respective KEdown, leading to the AO.
Strength, consistency, and specificity of association of adverse outcome and initiating event
There is strong empirical evidence on the link between MIE and AO that has been described.
Biological plausibility, coherence, and consistency of the experimental evidence
There is high biological plausibility in the description of the AOP and its components. The available data describing the AOP are logic, coherent and consistent with current biological knowledge.
Uncertainties, inconsistencies and data gaps
The present AOP description is plausible, but entirely qualitative, and the addition of quantitative data on dose-response relationship and temporal scale would improve its applicability. Also, though there is strong empirical evidence supporting this AOP, at certain KERs we found some inconsistencies that need to be further investigated. Existing uncertainties and inconsistencies are stated in each KER description, but here we will describe the most important ones.
Repnik and colleagues detected that after exposure to LLOMe, cathepsins remain in lysosomes and are being degraded there which is in contradiction with most of the previous studies (Repnik et al., 2017). There is strong empirical evidence that incubation of cathepsin B with mitochondria and cytosolic factors increase mitochondrial permeabilization, but in some studies pharmacological inhibition of cathepsins or knockout of genes coding for cathepsins failed to prevent mitochondrial membrane permeabilizatio and cell death, suggesting that other lysosomal proteases might be responsible for Bid cleavage (Reiners et al., 2002; Boya et al., 2003).
The histochemical analysis of hippocampus of rats treated with domoic acid for 15 days has revealed no presence of apoptotic bodies and no Fluoro-Jade B positive cells (Schwarz et al., 2014).
The inflammatory role of HMGB-1 is still not completely clear. There are many studies that confirm its pro-inflammatory activity, but in some experiments highly purified HMGB-1 had little pro-inflammatory activity (Rouhiainen et al., 2007), while in another injection of recombinant HMGB-1 into infarcted heart muscle in vivo stimulated regeneration and repair (Limana et al., 2005).
Lloyd and colleagues found that several chemokines can stimulate the adherence of peripheral blood lymphocytes to ICAM-1 coated slides (Loyd et al., 1996). However, by using a parallel plate flow chamber, other study failed to observe such an effect (Carr et al., 1996).
Domain of Applicability
Life Stage Applicability
The described AOP is a general mechanism, that furthermore can be considered as not being limited to only the liver as the target organ. Also, to current knowledge, this AOP is not limited to a specific life stage.
Most of the work performed to elaborate parts of this AOP was done using murine or human cells and cell lines, human blood samples or tissues, or mouse models. Examples include
mouse: Narumi et al., 1992; Fahy et al., 2001; Kagedal et al., 2001; Faouzi et al., 2001; Werneburg et al., 2002; Chen et al., 2007; Seki et al., 2007; Leung et al., 2008; Dalton et al., 2009; Lee et al., 2009 Gäbele et al., 2009; Nan et al., 2013; Pradere et al., 2013; McHedlidze et al., 2014; Chang et al., 2014;
rat: Rockey et al., 1992;George et al., 1999; Reeves et al., 2000; Luckey and Petersen, 2001; Duffield et al., 2005; Imamura et al., 2005; Natajaran et al., 2006; Liedtke et al., 2011; Li et al., 2012; Jung et al., 2015
human: Bleul et al., 1996; Miyamoto et al., 2000; Andersson et al., 2000; Yamada et al., 2001; Scaffidi et al., 2002; Safadi and Friedman, 2002; Boya et al., 2003; Cirman et al., 2004; Bataller and Brenner, 2005; Bell et al., 2006; Rockey and Friedman, 2006; Friedman, 2008; Lim and Kim, 2008; Winklhofer and Haass, 2010; Clarke et al., 2010; Hamacher-Brady et al., 2011; Santibañez et al., 2011; Lee and Friedman, 2011; Wang et al., 2013; Loos et al., 2014; Decaris et al., 2015; Sun et al., 2015;
As described above, the AOP is widely applicable, therefore no specific sex applicability is known at this point.
Essentiality of the Key Events
The essentiality of almost all of the KEs in this AOP was rated high as there is much experimental evidence that the blocking of one KE prevents the next downstream KE and therefore the whole AOP. The essentiality of KE Mitochondrial dysfunction was rated as moderate, as there are two pathways to apoptosis (the next downstream KE), intrinsic and extrinsic, and only intrinsic pathway includes mitochondrial dysfunction (reviewed in Elmore, 2007).
Some of the evidence for the essentiality of KEs is listed below.
Exposure of cells to ammonium chloride prior to exposure to sphingosine resulted in formation of NH3, which entered into lysosomes and became protonated and increased the pH of the organelle. This exposure prevented the accumulation of sphingosine in the lysosome and provided protection against its lysosomolytic and apoptosis-inducing effects (Kagedal et al., 2001).
Inhibition of lysosomal membrane permeabilization (LMP) with Baf A1 – that inhibits lysosomal vacuolar H+ ATP-ase, prevented mitochondrial membrane permeabilization (MMP) - the next downstream KE, while inhibition of MMP in Bax/Bak double knocks out cells didn't prevent LMP (Boya et al., 2003).
Faouzi and colleagues showed that the inhibition of apoptosis causes inhibition of the inflammatory response (Faouzi et al., 2001), while other study showed that an inhibitor of apoptosis is blocking the release of HMGB-1 mediator specifically (Bell et al., 2006).
A human CXC chemokine antagonist, growth-related oncogene GROα(8-73), inhibited calcium mobilization induced by MIP-2, and the pretreatment of mice with this antagonist inhibited, in a dose-dependent manner, the influx of neutrophils induced by MIP-2, TNF-α, LPS and IL-1β (McColl and Clark-Lewis, 1999).
There is strong evidence that the blockade of TGF-β alone is sufficient to completely block experimental fibrogenesis in liver (reviewed in Gressner et al., 2002). The activation of HSCs can be partially blocked by anti-TGF-β antibodies (Zimmermann et al., 2010) and blocked by overexpression of Smad7, a natural antagonist of TGF-β signalling (Dooley et al., 2003). Macrophage depletion led to a significant reduction in the number of HSCs (Duffield et al., 2005).
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Support for essentiality of KEs
MIE Endocytic lysosomal uptake
Essentiality of the MIE is high.
Exposure of cells to NH3 prevented the accumulation of sphingosine, known lysosomotropic agent, in the lysosomes and provided protection against its lysosomolytic and apoptosic effects (Kagedal et al., 2001).
KE1 Lysosomal disruption
Essentiality of the KE1 is high.
Inhibition of LMP prevented MMP, the next downstream KE, and the entire pathway (Boya et al., 2003). The treatment of the cells with cathepsins inhibitors decreased MMP and prevented apoptosis (Roberg et al., 1999; Kagedal et al., 2001).
KE2 Mitochondrial dysfunction
Essentiality of the KE2 is moderate.
There are two apoptotic pathways, intrinsic and extrinsic, and only intrinsic pathway includes mitochondrial dysfunction (reviewed in Elmore, 2007).
KE3 Cell death/injury
Essentiality of the KE3 is high.
The inhibition of apoptosis causes blockage of release of inflammatory mediators and inhibition of the inflammatory response (Faouzi et al., 2001; Bell et al., 2006).
KE4 Increased inflammatory mediators
Essentiality of the KE4 is high.
Chemokine antagonist can prevent influx of neutrophils (McColl and Clark-Lewis, 1999).
KE5 Leukocyte recruitment/ activation
Essentiality of the KE5 is high.
Macrophage depletion leads to a significant reduction in the number of HSCs, the next downstream KE (Duffield et al., 2005). After bile duct ligation, Kupffer cell–depleted mice showed almost complete suppression of HSC activation and fibrosis (Seki et al., 2007).
KE6 HSC activation
Essentiality of the KE6 is high.
Experimental inhibition of HSC activation prevents fibrosis (Friedman, 2002; Anan et al., 2006; Kisseleva and Brenner, 2008; Son et al., 2009).
KE7 Collagen accumulation
Essentiality of the KE7 is high.
Continuing imbalance between the deposition and degradation of ECM is a pre-requisite of liver fibrosis (Lee and Friedman, 2011).
AO Liver fibrosis
It is generally accepted that any chronic and repeated liver injury can result in myofibroblast activation, leading to hepatic fibrosis and cirrhosis (Jaeschke, 2002; Lee William, 2003; Ramachandran and Kakar, 2009).
Support for Biological Plausibility of KERs
Biological plausibility of the KER between MIE and KE1 is high.
Trapping of lysosomotropic agents accumulates substances inside of the lysosomes, increases volume of these organelles, and big lysosomes are more prone to rupture (Ono et al., 2003).
Biological plausibility of the KER between KE1 and KE2 is high.
In the last decade there is a growing body of evidences about the strong functional link between lysosomes and mitochondria that play an important role in physiology and pathology. The evidences also showed link between lysosomal and mitochondrial damage, and that lysosomal damage precedes mitochondrial injury (e.g. Droga-Mazovec et al., 2008; Ghosh et al., 2011).
Biological plausibility of the KER between KE2 and KE3 is high.
There is functional mechanistic understanding supporting this relationship between KE2 and KE3, involving ROS formation, ATP depletion and apoptogenic factors (Richter et al., 1996; Leist et al., 1997; Nicotera et al., 1998; Brenner and Mak, 2009; Lu et al., 2014; Zhou et al., 2015).
Biological plasubility of the KER between KE3 and KE4 is high.
The dead cells can secrete inflammatory mediators that trigger infiltration of immune cells. However, if this becomes chronic it has the potential to enhance tissue damage and ultimately induce fibrosis (Jaeschke, 2002; Cullen et al., 2013).
Biological plausibility of the KER between KE4 and KE5 is high.
There is much evidence that application of chemokines attract leukocytes to specific site in different species (Beck et al., 1997; Lee et al., 2000; Fahy et al., 2001; Nikiforou et al., 2016).
Biological plausibility of the KER between KE5 and KE6 is high.
The recruitment of immune cells from the circulation into the injured tissue is the key mechanism during fibrogenesis in the liver (Heymann and Tacke, 2016).
Biological plausibility of the KER between KE6 and KE7 is high.
The functional relationship between stellate cells activation and collagen accumulation is consistent with established biological knowledge (Milani et al., 1994; Benyon and Arthur; 2001; Safadi and Friedman, 2002; Kershenobich Stalnikowitz and Weisssbrod , 2003; Bataller and Brenner, 2005; Kolios et al., 2006; ; Guo and Friedman, 2007; Li, Jing-Ting et al., 2008; López-Novoa and Nieto, 2009; Lee und Friedman 2011).
Biological plausibility of the KER between KE7 and AO is high.
By definition, liver fibrosis is the excessive accumulation of ECM proteins that are produced by HSCs. The KER between this KE and the AO is undisputed (Poynard et al., 1997; Bataller and Brenner, 2005; Rockey and Friedman, 2006; Brancatelli et al., 2009; Lee and Friedman, 2011).
Empirical Support for KERs
Empirical support of the KER between MIE and KE1 is high.
Even the accumulation of substances that are physiologically present in lysosomes, such as pro-cathepsins, can lead towards lysosomal dysfunction (Jung et al., 2015). Sphingosine is a lysosomotropic agent that accumulates within the lysosomes, where it permeabilizes the membrane via a detergent mechanism and provokes release of lysosomal enzymes (Kagedal et al., 2001). NM captured in lysosomes can cause lysosomal swelling, disruption and the release of pro-apoptotic proteins (Cho et al., 2011; Cho et al., 2012; Wang et al., 2013).
Empirical support of the KER between KE1 and KE2 is high.
LMP is detected couple of hours earlier than MMP, after exposure to ciprofloxacine, norfloxacine and hydroxychloroquine, and cells with MMP are sub-ensmeple of the group of cells with LMP (Boya et al., 2003).
When isolated mitochondria are incubated with purified cathepsin B in the presence of cytolic extracts, a release of cytochrome c from mitochondria is detected (Guicciardi et al., 2000). The microinjection of cathepsin D to the cell causes cytochrome c release, caspases activation and apoptosis (Roberg et al., 2002).
Bid protein needs to be cleaved in order to cause cytochrome c release (Luo et al., 1998; Gross et al., 1999; Stoka et al., 2001).
Incubation of Bax with isolated mitochondria resulted in cytochrome c release while Bcl-xl inhibits this release (Jurgensmeier et al., 1998).
Empirical support of the KER between KE2 and KE3 is moderate.
Mice injected intraperitoneally with DomA have shown increase of the TUNEL positive cells in the hippocampus, decreased indicators of mitochondria function and elevated ROS levels (Lu et al., 2012, Wu et al., 2012). The incidence of downstream KE (cell death) is higher than the incidence of downstream KE (mitochondrial dysfunction).
In vitro studies (Giordano et al., 2007; 2009) suggest that both KEs are affected by the same dose of DomA and that the incidence of KE down (cell death) is higher than the incidence of KE up (mitochondrial dysfunction), with KE up happening earlier than KE down.
Empirical support of the KER between KE3 and KE4 is high.
During the apoptosis of Jurkat cells treated with various agents, HMGB-1 was released into the media (Bell et al., 2006), which was found to activate leukocytes and stimulate the production of pro-inflammatory mediators in vitro (Li et al., 2004; Zimmermann et al., 2004). ATP can also stimulate the production of pro-inflammatory cytokines from macrophages (Ferrari et al., 1997; Ferrari et al., 2006).
Neutralization or genetic deficiency of IL-1 inhibited inflammation responses to injected dead cells (Chen et al., 2007; Kono et al., 2010). Injection into mice of a variety of other dead cell types that genetically lack both IL-1α and IL- 1β stimulated an inflammatory response that was equivalent to that of wildtype necrotic cells (Kono et al., 2010). This implicates that IL-1 that is driving the sterile inflammatory response in many cases is not coming directly from the dead cell but is produced by cells in the host upon recognition of cell death.
Empirical support of the KER between KE4 and KE5 is high.
The exposure of mice to FliCind strain S. Typhimurium triggered a significant neutrophil influx in the spleen of wild-type mice, but not of Il1b−/−Il18−/− mice (Jorgensen et al., 2016).
It was shown that exposure of cells to IL-1β, TNF-α, and IFN-γ resulted in the induction of RANTES mRNA and protein (Ortiz et al., 1996; Miyamoto et al., 2000). Intradermal injection of RANTES induces a potent T-lymphocyte and eosinophils recruitment (Fahy et al., 2001; Beck et al., 1997). Intradermal administration of MIP-1a resulted in accumulation of monocytes, lymphocytes, eosinophils and recruitment of neutrophils (Lee et al., 2000).
The number of white blood cells, monocytes, and neutrophils was increased in cord blood after 6 days of IL-1α exposure (Nikiforou et al., 2016).
Empirical support of the KER between KE5 and KE6 is moderate.
Karlmark et al., 2009 found that intrahepatic CD11bF4/80 monocyte-derived cells and liver resident macrophages produce TGF-β1 and thereby directly activate HSCs. It was proven that the treatment of cultured hepatic cells with TGF-β1 increased type I pro-collagen mRNA levels (Czaja et al., 1989).
Empirical support of the KER between KE6 and KE7 is moderate.
It is difficult to stimulate sufficient collagen production and its incorporation into a pericellular matrix in vitro. Because of that analytical methods have focused on measurement of pro-collagen secreted into culture medium or measurement of α-smooth muscle actin (α-SMA) expression, a marker of fibroblast activation. In primary culture, HSCs from normal liver begin to express α-SMA coincident with culture-induced activation (Rockey et al., 1992; Chen and Raghunath, 2009).
Empirical support of the KER between KE7 and AO is high.
There is a smooth transition from collagen accumulation to liver fibrosis without a definite threshold with plenty in vivo evidence (Poynard et al., 1997; Bataller and Brenner, 2005; Rockey and Friedman, 2006; Brancatelli et al., 2009; Lee and Friedman, 2011).
Quantitative understanding of the AOP is low, as there is lack of quantitative data on dose-responce relationship. Further research efforts should be made in this direction to improve the quantitative understanding of the present AOP.
Considerations for Potential Applications of the AOP (optional)
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