Aop:144

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AOP Title

Lysosomal damage leading to liver inflammation
Short name: NM-induced liver inflammation

Authors

Kirsten Gerloff

Brigitte Landesmann°

Karin Aschberger°

Gladys Ouedraogo*


°F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM

Directorate F – Health, Consumers and Reference Materials

Joint Research Centre, European Commission

  • L’Oreal Research & Innovation, France


Kirsten-Britta.Gerloff(at)yahoo.de

Brigitte.Landesmann(at)ec.europa.eu

Karin.Aschberger(at)ec.europa.eu

GOUEDRAOGO(at)rd.loreal.com

Status

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This AOP page was last modified on 12/11/2016.

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Abstract

Hepatotoxicity is known to be an important endpoint of regulatory concern; especially in drug development it has been one of the most frequent reasons for pharmacovigilance safety reports and withdrawal of drugs from the market. Liver inflammation can be both the relevant endpoint itself, or it occurs during development of liver fibrosis, for example, upon repeated exposure. The current AOP links lysosomal disruption to liver inflammation. Lysosomal damage can be caused by multiple initiators: examples are the detergent O-methyl-serine dodecylamide hydrochloride (MSDH), alpha-tocopheryl succinate, naphthazarine [1] [2], 3-aminopropanal [2], the antimalarial agent artesunate (ART) [3] and also nanomaterials (NMs) [4]. Lysosomal rupture by NMs has been described as one of the main causes for their potential to induce cellular damage, which is subsequently linked to an increase of reactive oxygen species (ROS), mitochondrial damage and induction of the inflammatory cascade. Liver inflammation is therefore a local outcome following translocation of NMs to the liver. Uptake and disruption of the lysosome is not a classical MIE, as no "molecular" but rather mechanical processes are involved. However, it is the initiating event for the described AOP.

Background (optional)

Hepatic inflammation accompanies the majority of acute and chronic liver disorders, as it can stimulate the development of fibrotic or cirrhotic responses if it remains unresolved (Brenner et al., 2013). The use and possible application areas of NMs 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. Due to the fast increasing amount of newly developed NMs it won't be possible in the future to test their toxicity on a case by case basis, as is often still done today. Some of the major contributors to regular (nano)particle exposure are poorly soluble metal oxide particles such as TiO2 or the amorphous SiO2, both commonly used in cosmetics, pharmaceutical products or foods [5][6].

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[7][8][9]. 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[10][11], an increase in inflammatory markers such as pro-inflammatory cytokines and/or infiltration of inflammatory cells[8][12][13], an increase of markers for oxidative stress[14][15], apoptosis, necrosis and also fibrosis[16][17]. Liver damage and inflammation have also been reported for other metal oxide particles such as SiO2[18][19] via various application routes such as intraperitoneal injection or oral administration. 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, but also the size of the NM, plays an important role whether these reach the liver, and to which extent they're accumulated[20].

Recent studies underpinned the importance of the lysosomal NM uptake with respect to a NM-induced mechanism of toxicity. Once a NM is taken up by a cell, its transport into the acidic milieu of the lysosome can enhance the solubility of a NM, or the material remains in its initial nano form. Both situations can induce toxicity, causing lysosomal swelling, followed by lysosomal damage and the release of pro-apoptotic proteins, consequently inducing inflammation[21][22][23]. It is known that particles of low solubility and toxicity, such as TiO2, may cause inflammation in proportion to their specific surface area[24][25] and, as more recently described, their zeta potential[23], which describes the electric potential between the surface of a NM (or associated groups thereon) and the suspension medium. Disruption of the lysosome can then trigger an inflammation cascade in the target organ. The particle-driven inflammatory response is associated with tissue damage, remodelling and mutagenesis and is referred to as secondary particle toxicity following the exhaustion of antioxidant and DNA damage repair capacities[26][27][28].

But not only NMs cause lysosomal damage: chemicals and proteins like certain xenobiotics, LLOMe (L-Leucyl-L-leucine methyl ester) or glutamate are known inducers of lysosomal rupture, and Reactive Oxygen Species (ROS) such as H2O2 can amplify this effect[29]. The amount of lysosomal enzymes that are released into the cytosol regulates the cell death pathway which is initiated by lysosomal damage: it plays a vital role in the induction of apoptosis, whereas massive lysosomal rupture leads to necrosis[30]. Lysosomes are known to trigger mitochondrial mediated apoptosis by the release of cathepsins into the cytosol[29]. At the same time however, lysosomes themselves are a source of ROS, which can lead to damage of the mitochondrial membrane[21][31]. Zhu and colleagues found that TiO2 induced cell death in a Bak/Bax independent manner, however acting via the lysosomes[32], supporting the importance to consider the pathway involving ROS, while at the same time, mitochondria were found to be indispensable for cell death initiated by lysosomal destabilization[33].

Overall, the connection between lysosomal and mitochondrial damage with inflammation, and more specifically liver inflammation, is well known, regardless if triggered by chemicals, proteins or NMs (reviewed in[34][35]) and it is directly connected to multiple other adverse outcomes such as fibrosis. Therefore, due to its high importance it is described extensively in the current AOP.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Lysosome, Disruption Strong

Key Events

Event Support for Essentiality
Oxidative Stress, Increase Moderate
Mitochondrial dysfunction, N/A Strong
Cell injury/death, N/A Strong
Cytokine, Release Strong
Inflammatory cells, Infiltration Strong

Adverse Outcome

Adverse Outcome
Liver, Inflammation

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Oxidative Stress, Increase Directly Leads to Mitochondrial dysfunction, N/A Strong Weak
Mitochondrial dysfunction, N/A Directly Leads to Cell injury/death, N/A Strong Weak
Cell injury/death, N/A Directly Leads to Cytokine, Release Strong Weak
Lysosome, Disruption Directly Leads to Oxidative Stress, Increase Moderate Weak
Lysosome, Disruption Directly Leads to Mitochondrial dysfunction, N/A Strong Weak
Cytokine, Release Directly Leads to Inflammatory cells, Infiltration Strong Moderate
Inflammatory cells, Infiltration Directly Leads to Liver, Inflammation Strong

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Life Stage Applicability

Life Stage Evidence Links
all life stages Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Weak NCBI

Sex Applicability

Sex Evidence Links
Unspecific

Graphical Representation

AOP-144.jpg

Overall Assessment of the AOP

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. Lysosomal damage can occur in almost all cell types and all organs. This is shown by several mechanistic studies that used immune or brain cells[36][21][37][38], thus underlining the broad applicability of the MIE/early KE. Therefore, to current knowledge, this AOP is not limited to a specific life stage.


Taxonomic Applicability

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, where a specific knock-down could be performed. Examples include

mouse: [1] [2][39][40][36]

human: [2][38][4][40][3][41]

Only some studies analysed specific aspects of the AOP in rat models, for example [42][43]


Sex Applicability

As described above, the AOP is widely applicable, therefore no specific sex applicability is known at this point.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Depending on the considered trigger, lysosomal disruption can be either the MIE or already an early KE. In the present AOP, it has been identified as the relevant (M)IE, as the lysosomal uptake of NMs can result in simple storage of the material, or in damage to the lysosomal membrane, which is the MIE of the described AOP. This is dependent on the NM's properties, as has been described above. Briefly, the acidic milieu within the lysosome can further enhance solubility of a (soluble) NM, or it remains in its initial nano form. Both situations can induce toxicity, causing lysosomal swelling, followed by lysosomal disruption and the release of pro-apoptotic proteins [21][23]. Particles of low solubility and toxicity, such as TiO2, may cause inflammation in proportion to their specific surface area[44][45] and their zeta potential[23].

Subsequent to lysosomal disruption, secretion or ROS can be initiated, which then leads to damage to the mitochondrion. As the main role of lysosomes is the degradation of macromolecules, they are filled with more than 50 acid hydrolases to serve this purpose[46]. Amongst these are cathepsins that are released into the cytosol once lysosomal membrane permeabilisation (LMP) occurs. The major substrate of cathepsins are Bid, Bcl-2 and Bax. This initiates the subsequent activation of caspase-9 and 3/7, leading to mitochondrial membrane permeabilisation (MMP) and mitochondria-induced apoptosis[29]. Both pathways of initiating MMP are essential in this AOP. The role of ROS is a complex one: increased ROS lead to the induction of MMP, while MMP again leads to the secretion of ROS, thus initiating a vicious cycle. Overall, the vital role of MMP in LMP-induced cell death was underpinned by work of Boya and colleagues: by using the quinolone antibiotics ciprofloxacin (CPX) or norfloxacin (NFX) (with or without UV light) which are known inducers of LMP, treatment of cells resulted in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. However, inhibition of the lysosomal accumulation of CPX or NFX suppressed their capacity to induce LMP and to kill cells. Moreover, using Bax/Bak double deficient cells, MMP and subsequent cell death were completely abolished, showing that mitochondria are indispensable for cell death initiated by lysosomal destabilization[47].

Therefore, cell death is described as the subsequent KE to mitochondrial dysfunction, which can lead to the induction of the apoptotic pathway. Apoptosis is a complex process that regulates whether cell death leads to the development of inflammation or quiet removal of a damaged cell, for example during development or normal tissue turnover. This most likely depends on the severity of the effect[48]. Dying hepatocytes can release intracellular molecules known as damage-associated molecular patterns (DAMPs), which, if persistent, can induce the so-called sterile inflammation. This occurs in the absence of pathogens and is a key factor for the development of (liver) inflammation [49][50]. Mitochondrial DNA (mtDNA) and mitochondria-derived formyl peptides are examples of mitochondria-derived DAMPs which bind to pattern recognition receptors (PPRs) such as toll-like receptors (TLRs). TLRs are found expressed in most liver cells, including hepatocytes, Kupffer cells (KCs) or hepatic stellate cells (HPCs) [49].

Activation of apoptosis leads to the induction of a variety of cytokines such as macrophage inflammatory protein-2 (MIP-2)/IL-8, KC, IL-6, MCP-1/CCL2 and sICAM-1, which is described as the next KE. When apoptosis was blocked by inhibition of caspase-3, the chemokine-induction was significantly reduced. [51][52].

An increase in cytokine release is inevitably linked to subsequent infiltration of inflammatory cells, KE number 5. Specifically neutrophils (PMNs) are recruited towards a chemotactic gradient. This could even be quantified by using chemotaxis assays, which allow for determining relevant chemokine concentrations in order to trigger neutrophil migration [53]. The neutrophilic cytosol contains granules that are filled with a variety of proteins, such as defensins, bactericidal-permeability-increasing protein, proteases (e.g. elastase, cathepsins), and myeloperoxidase (MPO) that consumes hydrogen peroxide (H2O2) and generates hypochlorous acid (HOCl), the most bactericidal oxidant that is produced by PMN [54][55]. Activation of PMNs leads to the production of a variety of pro-inflammatory cytokines, e.g. IL-1ß, IL-6, IL-12 and IL-23, which can further aggravate the resulting inflammation[56].

The outcome of infiltration of neutrophils and other immune cells leads to the development and establishment of inflammation. It could be shown that depletion of neutrophils by using the neutrophil depleting antibody NIMP-R14 directly resulted in a drastic reduction of the resulting liver inflammation[57]. A general proof of the importance of infiltrated neutrophils is the fact that liver inflammation is usually clinically confirmed by analysis of histological features, marked by the influx of neutrophils (which can be stained by using Haematoxylin and eosin) [58].

Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.


MIE to Oxidative stress when lysosomal damage is reduced by neutralizing the lysosomal pH with NH4Cl, ROS-induction is strongly decreased Wang et al., 2016 Direct evidence was found by inhibiting lysosomal damage and applying time-resolved experiments.
A decrease of lysosomal ROS by treatment of cells with lysosomal inhibitors delayed the mitochondrial ROS burst and thus cell toxicity. Kubota et al., 2010
ROS production as a consequence of LMP was found after 3 h, and clear reduction of antioxidant enzymes took place from 6 h following exposure, prior to alteration of the MMP Gosh et al., 2011
Using positively charged polystyrene nanoparticles (PS-NH2) as initiators, the authors performed a time-resolved experiment where lysosomal damage was found as the first adverse effect, followed by an increase in reactive oxygen species and subsequent loss in mitochondrial membrane potential. They could show that KEup occurred at earlier time points (3-6 hours) than KEdown (starting after 8 hours). Wang et al., 2013
Oxidative stress to Mitochondrial dysfunction Oxidative stress induction (by using t-butylhydroperoxide TBH) directly affects the opening of the mitochondrial permeability transition pore Halestrap et al., 1997 Inhibition of the ROS source could delay mitochondrial damage, and treatment with an antioxidant could partly inhibit the effect on the mitochondrion.
Opening of the mitochondrial permeability transition pore was found to lead to an increase in the mitochondrial membrane potential, which could be partly inhibited by addition of the antioxidant GSH Hüser et al., 1998
Cell treatment with a lysosomal inhibitor was found to delay the production of ROS that act on mitochondria, thus mitochondria-related cell death was delayed Kubota et al., 2010
Superoxide-radical-triggered increase in Ca2+ uptake to the mitochondrion was found to precede loss of mitochondrial membrane potential, which was independent of other oxidants and mitochondrially derived ROS, as determined by using respective inhibitors. This work shows the specific effects of external and not mitochondrially derived ROS on mitochondrial damage Madesh et al., 2005
MIE to Mitochondrial dysfunction Inhibition of cathepsin B decreased subsequent tBid translocation and downstream caspase 3 activation. Gao et al., 2014 Time-resolved experiments and the use of specific inhibitors confirmed this KER.
Inactivated cathepsin D or the cathepsin D inhibitor pepstatin A prevented the release of cytochrome c, caspase activation and induction of apoptosis. Roberg et al., 1999; 2002
By using high content imaging to show the occurrence of LMP and MMP at different concentrations in a variety of different cell lines, it could be shown that the IC50/EC50 values for the induction of lysosomal damage were lower than those for mitochondrial damage in all tested cells Anguissola et al., 2014
Cathepsin B release occurred before caspace c release (1 vs 6-15h); Lysotracker positive stain was present already after 1 hour, whereas MMP staining was positive only after 6 hours and later. Boya et al., 2003
Mitochondrial dysfuntion to Cell death By using high content imaging to show the occurrence of MMP and cell death markers at different concentrations in a variety of different cell lines, it could be shown that the IC50/EC50 values for the induction of MMP were lower than those for most markers of cell death in all tested cells Anguissola et al., 2014 Inhibition of the MMP can prevent the onset of apoptosis; MMP is induced at lower concentrations, prior to cell death
When applying an apoptotic trigger, stabilisation of the MMP can directly inhibit the onset of apoptosis Marchetti et al., 1996: Mitochondrial Permeability Transition Is a Central Coordinating Event of Apoptosis
Cell death to Cytokine release A high fat diet increases the amount of plasma mtDNA levels, which were shown to induce TLR9, accompanied by the induction of TNF-a. TLR9 knock-out mice were shown to show less severe symptoms for developing liver inflammation when put on a high fat diet compared to control mice Garcia-Martinez et al., 2016 mitochondria-derived DAMPs bind to pattern recognition receptors such as toll-like receptors, which directly upregulates cytokines, as did the induction of the apoptotic pathway. Inhibition of apoptosis prevented upregulation of cytokines.
Induction of apoptosis by using an anti-Fas antibody was found to lead to upregulation and secretion of KC and MIP-2 in liver tissue, while inhibition of caspase-3 significantly reduced chemokine-induction Faouzi et al., 2001
Cytokine release to Infiltration of inflammatory cells Neutralisation of chemokines leads to abrogating an inflammatory response to Fas-induced hepatic inflammation. Faouzi et al., 2001 Useful chemotaxis-assays are available that make use of isolated immune cells ex vivo and allow for quantification of this KER. Those results give an indication on concentrations necessary for cell migration, but need to be carefully considered with regards to direct transferability to the in vivo situation. Moreover, not only IL-8 is responsible for the recruitment of neutrophils, but also other chemokines can contribute to attraction of inflammatory cells. However, additional proof for this KER is provided by the neutralization of chemokines, which prevented a further onset of inflammation.
Quantification of neutrophil migration in dependence of IL-8 concentration showed a biphasic exhibition of migration, with an optimum random neutrophil motility at 3 nM of IL-8 Lin et al., 2004
Addition of 200ng/ml anti-Fas antibody to HeLa cells resulted in the secretion of about 0.7ng/ml IL-8 into the supernatant. The same study showed that supernatants of cells treated with 250ng/ml anti-Fas induced the strongest infiltration of neutrophils (which was almost abolished when the supernatants were treated with an anti-IL-8 antibody). This infiltration was strongly decreased upon dilution of the supernatants. Thus, this allows for a rough quantification of the IL-8 concentrations that are needed for potent chemoattraction of neutrophils Cullen et al., 2013
Infiltration of inflammatory cells to Liver inflammation Neutrophil infiltration and subsequent liver inflammation and are drastically attenuated in IL-1R1 deficient mice or by using a neutralizing antibody, and also in the absence of IL-17RA signalling. The same study demonstrated that increased IL-17A was mainly expressed by CD4+ T cells, but also by neutrophils themselves, in the damaged liver, showing that these cells are critical for the further recruitment of circulating immune cells into the tissue. Depletion of neutrophils (by using the neutrophil depleting antibody NIMP-R14) directly resulted in a drastic reduction of the inflammation Tan et al., 2013 Inhibition of messengers for the infiltration of inflammatory cells leads to a strong reduction of these. Furthermore, direct inhibition of neutrophils prevents the onset of liver inflammation.
A general proof of the importance of infiltrated neutrophils is the fact that liver inflammation is usually clinically confirmed by analysis of histological features, marked by the influx of neutrophils (which can be stained by using Haematoxylin and eosin) Huebscher 2006

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.


Overall, quantitative understanding of the individual KERs is low. A lot is based on established knowledge, particularly late KERs that describe cytokine upregulation and immune cell infiltration during the onset of inflammation. Mostly, this knowledge is supported by experiments using inhibitors, specific activators or neutralising substances (such as antibodies).

The KER from the MIE to KE1 (Oxidative stress) is based on findings where the lysosomal response was inhibited or reduced; a subsequent induction of ROS could be decreased and further outcomes (such as effects on the mitochondrion) delayed. Temporal concordance was described (LMP was followed by production of ROS, which was followed by alterations of the MMP); however, quantitative understanding is still low.

It is well-established that Oxidative stress leads to Mitochondrial Dysfunction, although also for this KER, quantitative understanding is low. Inhibition of the ROS source could delay mitochondrial damage, and treatment with an antioxidant could partly inhibit the effect on the mitochondrion. A direct effect of oxidative stress on the opening of the mitochondrial permeability transition pore has been found already in 1997, which was described to lead to an increase in the mitochondrial membrane potential.

The KER from the MIE to Mitochondrial dysfunction is based on findings in time-resolved experiments and the use of specific inhibitors which confirmed this KER. The prominent role of cathepsins, which are secreted from a compromised lysosome, was repeatedly underpinned. Also here, quantitative understanding is still low.

Mitochondrial dysfuntion leads to Cell death by, for example, induction of apoptosis. Stabilising the MMP prior to applying an apoptotic trigger can prevent the onset of apoptosis. MMP is induced at lower concentrations, prior to cell death. However, quantitative understanding is low.

Studies on the role of Cell death inducing to Cytokine release found that mitochondria-derived DAMPs bind to pattern recognition receptors such as toll-like receptors, which directly upregulates cytokines, as did the induction of the apoptotic pathway. Inhibition of apoptosis prevented upregulation of cytokines.

The KER from Cytokine release to Infiltration of inflammatory cells can be described quantitatively, as useful chemotaxis-assays are available that make use of isolated immune cells ex vivo. Those results give an indication on concentrations necessary for cell migration, but need to be carefully considered with regards to direct transferability to the in vivo situation. Moreover, not only IL-8 is responsible for the recruitment of neutrophils, but also other chemokines can contribute to attraction of inflammatory cells. However, additional proof for this KER is provided by the neutralization of chemokines, which prevented a further onset of inflammation.

A general proof of the importance of Infiltration of inflammatory cells in the development of Liver inflammation is found by the fact that liver inflammation is usually clinically confirmed by analysis of histological features, marked by the influx of neutrophils. Inhibition of messengers for the infiltration of inflammatory cells leads to a strong reduction of these. Furthermore, direct inhibition of neutrophils prevents the onset of liver inflammation.

Considerations for Potential Applications of the AOP (optional)

References

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