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Key Event Title
Increased, recruitment of inflammatory cells
|Level of Biological Organization|
Key Event Components
|inflammatory response||inflammatory cell||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Substance interaction with the pulmonary cell membrane leading to pulmonary fibrosis||KeyEvent||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
|Frustrated phagocytosis-induced lung cancer||KeyEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Dysregulated fibrinolysis/bradykinin leading to hyperinflammation||KeyEvent||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Frustrated phagocytosis leads to malignant mesothelioma||KeyEvent||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
|TLR9 activation leading to Multi Organ Failure and ARDS||KeyEvent||Cataia Ives (send email)||Under development: Not open for comment. Do not cite|
|Interaction with lung cells leads to lung cancer||KeyEvent||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
|Cytopathic SARS-CoV-2 leads to hyperinflammation||KeyEvent||Allie Always (send email)||Under development: Not open for comment. Do not cite|
|ERa inactivation leads to increased fat mass and insulin resistance.||KeyEvent||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
|All life stages||High|
Key Event Description
Pro-inflammatory cells originate in bone marrow and are recruited to the site of infection or injury via circulation following specific pro-inflammatory mediator (cytokine and chemokine) signalling. Pro-inflammatory cells are recruited to lungs to clear the invading pathogen or the toxic substance. Monocytes (dendritic cells, macrophages, and neutrophils) are subsets of circulating white blood cells that are involved in the immune responses to pathogen or toxicant stimuli (Kolaczkowska and Kubes, 2013; Kopf et al., 2015). They are derived from the bone marrow. They can differentiate into different macrophage types and dendritic cells. They can be categorised based on their size, the type of cell surface receptors and their ability to differentiate following external or internal stimulus such as increased expression of cytokines. Monocytes participate in tissue healing, clearance of toxic substance or pathogens, and in the initiation of adaptive immunity. Recruited monocytes can also influence pathogenesis (Ingersoll et al., 2011). Sensing or recognition of pathogens and harmful substances results in the recruitment of monocytes to lungs (Shi and Pamer, 2011). Activated immune cells secrete a variety of pro-inflammatory mediators, the purpose of which is to propagate the immune signalling and response, which when not controlled, leads to chronic inflammation, cell death and tissue injury. Thus, Event 1496 and Event 1497 act in a positive feedback loop mechanism and propagate the proinflammatory environment.
Literature evidence for its perturbation:
Macrophages accumulate in bronchoalveolar fluid (BALF) post-exposure to bleomycin (Phan et al., 1980; Smith et al., 1995). Nanomaterial (NM)-induced inflammation is predominantly neutrophilic (Poulsen et al., 2015; Rahman L et al., 2017a; Rahman et al., 2017b; Shvedova et al., 2005). An increased number of neutrophils (Reynolds et al., 1977) is observed in the BALF of patients with idiopathic pulmonary fibrosis. Eosinophils are a type of white blood cells and a type of granulocytes (contain granules and enzymes) that are recruited following exposure to allergens, during allergic reactions such as asthma or during fibrosis (Reynolds et al., 1977). Multi-walled carbon nanotubes (MWCNTs) induce increased eosinophil count in lungs (Købler C et al., 2015). MWCNTs act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer et al., 2013).
It is important to note that the stressor-induced Event 1495, Event 1496, and Event 1497 are part of the functional changes that we collectively consider as inflammation, and together, they mark the initiation of acute inflammatory phase. Event 1495 and Event 1496 occur at the cellular level. Event 1497 occurs at the tissue level.
How It Is Measured or Detected
In vivo, recruitment of pro-inflammatory cells is measured using BALF cellularity assay. The fluid lining the lung epithelium is lavaged (BALF) and its composition is assessed as marker of lung immune response to the toxic substances or pathogens. BALF is assessed quantitatively for types of infiltrating cells, levels and types of cytokines and chemokines. Thus, BALF assessment can aid in developing dose-response of a substance, to rank a substances’ potency and to set up no effect level of exposure for the regulatory decision making. For NMs, in vivo BALF assessment is recommended as a mandatory test (discussed in ENV/JM/MONO(2012)40 and also in OECD inhalation test guideline for NMs). Temporal changes in the BALF composition can be prognostic of initiation and progression of lung immune disease (Cho et al., 2010).
In vitro, it is difficult to assess the recruitment of pro-inflammatory cells. Thus, a suit of pro-inflammatory mediators specific to cell types are assessed using the same techniques mentioned above (Real-time reverse transcription-polymerase chain reaction [qRT-PCR], Enzyme-linked immunosorbent assays [ELISA], immunohistochemistry) in cell culture models, as indicative of recruitment of cells into the lungs. Alternatively, the use of precision cut lung slices can allow for limited assessment of recruitment of tissue resident inflammatory cells, based on the repertoire of cells remaining in the specific slice following harvesting. This method was used to show that there is a histological increase in inflammatory foci following treatment with bleomycin and MWCNTs (Rahman et al., 2020). Finally, more complicated microfluidic lung-on-a-chip devices can be used to assess the migration of select immune cells and fibroblasts toward a simulated epithelium following treatment with a pro-fibrotic compound (He et al., 2017). However, this method is limited to two cell types, and it lacks the reservoirs of immune cells present in the body in vivo.
Domain of Applicability
Human, mouse, rat
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