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Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity
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 Do not cite||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
Acute lung injury followed by normal repair of the ACM results in rapid resolution of the tissue injury and restoration of tissue integrity and function. The irreversible loss of alveolar membrane integrity occurs when 1) acute inflammation is not able to get rid of the toxic substance or invading pathogen (this happens following exposure to a toxic substance that is persistent or when the host is repeatedly exposed to the substance over a long period of time, 2) acute inflammation, originally incited to protect the host from external stimuli and to maintain normal homeostasis, by itself damages the host, resulting in tissue injury, and 3) the host fails to initiate a resolution response, which is essential to override the self-perpetuating inflammation response (Nathan, 2002). Loss of type-1 epithelial cells and endothelial cells, the collapse of alveolar structures and fusion of basement membranes, and persistent proliferation of type II alveolar epithelial cells on a damaged ECM, mark this phase (Strieter and Mehrad, 2009). The lung tissues from patients diagnosed with idiopathic pulmonary fibrosis show ultrastructural damage to the ACM with type-1 pneumocyte and endothelial cell injury (Strieter and Mehrad, 2009). In rodents treated with bleomycin, the damaged ACM resembles that seen in the fibrotic human lung (Grande et al., 1998).
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility of this KER is high. There is a mechanistic relationship between an increase in pro-inflammatory cells and mediators, and damage to the ACM (Bhalla et al., 2009; Ward 2003; Zemans et al., 2009).
Exposure to high doses of insoluble nanomaterials can impair the macrophage-mediated clearance process, initiating chronicity of inflammation characterized by cytokine release, ROS synthesis and the tissue damage cascade (Palecanda and Kobzik, 2001) and subsequently leading to tissue injury. For example, exposure to crystalline silica generates oxidative stress, increased release of pro-inflammatory cytokines (e.g. TNF-α, IL-1, IL-6), activation of transcription factors (e.g. NF-κB, AP-1), and other cell signalling pathways including MAP and ERK kinase (Hubbard et al., 2001; Hubbard et al., 2002; Fubini and Hubbard 2003). In silicosis, TNF-α is suggested to play a critical role in the observed pathogenicity (Castranova et al., 2004), which in turn, is dependent on activation of NF-κB and ROS synthesis (Shi et al.,1998; Cassel et al.,2008; Kawasaki et al., 2015). It has been proposed that IPF is a disorder of elevated oxidative stress, with the existence of an oxidant-antioxidant imbalance in distal alveolar air spaces (MacNee, 2001). Several studies have reported that anti-oxidant treatment attenuates the bleomycin-induced oxidative burden and subsequent pulmonary fibrosis (Wang et al., 2002; Serrano-Mollar et al., 2003; Punithavathi, et al., 2000).
Mice deficient in Nalp3 showed reduced inflammation, lower cytokine production and dampened fibrotic response following exposure to asbestos or silica (Dostert et al., 2008). SWCNT exposure induces alveolar macrophage activation, enhanced oxidative stress, increased and persistent expression of pro-inflammatory mediators associated with chronic inflammation and severe granuloma formation in mice (Chou et al., 2008). Bleomycin treatment induces increased lung weight, epithelial cell death, inflammation, increased hydroxyproline content, collagen accumulation and fibrotic lesions in mice, all of which were elevated in mice deficient in Nrf2 (Cho et al., 2004). MWCNT-induced fibrotic response is the result of interplay between oxidative stress and inflammation, which determines the severity of the fibrotic pathology. Mice lacking Nrf2 (the nuclear factor erythroid 2-related factor 2), that is associated with mounting anti-oxidant defense against oxidative stress, exhibit exuberant fibrotic responses to MWCNT (Dong and Ma, 2016).
Uncertainties and Inconsistencies
Although there is enough evidence to suggest a role for persistent inflammation and oxidative stress in ACM integrity loss, a direct relationship is hard to establish as studies involving inhibition of early pro-inflammatory cellular influx alter other immune cell types, thereby altering the end outcome.
Known modulating factors
One publication examined the timescale of KE induction with relation to this KER, in the context of AOP 173. Mo et al., 2019 found that KE2 (Event 1497) (1 and 3 days post-exposure) precedes KE3 (Event 1498) (3 and 7 days post-exposure) in mice exposed to 50 μg per mouse of nickel nanoparticles by intratracheal instillation.
In vitro/in vivo/population study
KE1 (Event 1496)
KE2 (Event 1497)
KE3 (Event 1498)
KE6 (Event 1501)
Mo Y et al., 2019
Mice C57BL/6, 50 mg per mouse intratracheal instillation
1- and 3-days post-exposure
1 and 3 days
LDH activity, oxidative stress protein content
3- and 7-days post-exposure
42 days post-exposure
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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- Castranova, V. (2004). Signaling Pathways Controlling The Production Of Inflammatory Mediators in Response To Crystalline Silica Exposure: Role Of Reactive Oxygen/Nitrogen Species. Free Radical Biology and Medicine, 37(7), pp.916-925.
- Chaudhary, N., Schnapp, A. and Park, J. (2006). Pharmacologic Differentiation of Inflammation and Fibrosis in the Rat Bleomycin Model. American Journal of Respiratory and Critical Care Medicine, 173(7), pp.769-776.
- Cho, H., Reddy, S., Yamamoto, M. and Kleeberger, S. (2004). The transcription factor NRF2 protects against pulmonary fibrosis. The FASEB Journal, 18(11), pp.1258-1260.
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- Kim H et al. Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses. Arch Toxicol. 2015, 90(3): 617-32.
- Kim, S., Lee, J., Yang, H., Cho, J., Kwon, S., Kim, Y., Her, J., Cho, K., Song, C. and Lee, K. (2010). Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice. Toxicological Research, 26(3), pp.217-222.
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- Punithavathi, D., Venkatesan, N. and Babu, M. (2000). Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. British Journal of Pharmacology, 131(2), pp.169-172.
- Sapoznikov A et al. Early disruption of the alveolar-capillary barrier in a ricin-induced ARDS mouse model: neutrophil-dependent and -independent impairment of junction proteins. Am J Physiol Lung Cell Mol Physiol, 2019, 316(1): L255-L268.
- Sellamuthu R et al. Molecular mechanisms of pulmonary response progression in crystalline silica exposed rats. Inhalation toxicology, 2017, 29(2): 53-64.
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- Strieter, R. and Mehrad, B. (2009). New Mechanisms of Pulmonary Fibrosis. Chest, 136(5), pp.1364-1370.
- Umbright, C., Sellamuthu, R., Roberts, J. R., Young, S. H., Richardson, D., Schwegler-Berry, D., McKinney, W., Chen, B., Gu, J. K., Kashon, M., & Joseph, P. (2017). Pulmonary toxicity and global gene expression changes in response to sub-chronic inhalation exposure to crystalline silica in rats. Journal of toxicology and environmental health. Part A, 80(23-24), 1349–1368.
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- Ward P. A. (2003). Acute lung injury: how the lung inflammatory response works. The European respiratory journal. Supplement, 44, 22s–23s.
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- Zeidler-Erdely, P. C., Battelli, L. A., Stone, S., Chen, B. T., Frazer, D. G., Young, S. H., Erdely, A., Kashon, M. L., Andrews, R., & Antonini, J. M. (2011). Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice. Inhalation toxicology, 23(2), 112–120.
- Zemans, R. L., Colgan, S. P., & Downey, G. P. (2009). Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. American journal of respiratory cell and molecular biology, 40(5), 519–535.