Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Substance interaction with the cell membrane leading to lung fibrosis||KeyEvent|
|Frustrated phagocytosis-induced lung cancer||KeyEvent|
Key Event Description
Proinflammatory cells originate in bone marrow and are recruited to the site of infection or injury via circulation following specific proinflammatory mediator (cytokine and chemokine) signalling. Proinflammatory 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. 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 MA et al., 2011). Sensing or recognition of pathogens and harmful substances results in the recruitment of monocytes to lungs (Shi C and Pamer EG, 2011).
Dendritic cells are antigen-presenting cells (APCs) and they stimulate naïve T-cell proliferation. They are found in the airway epithelium, the alveolar septa, pulmonary capillaries and airway spaces. APCs identify, ingest and process an antigen and present the antigen to resident T-cells in the lymph node initiating the immune response (Kopf M et al., 2015).
Macrophages are the components of mononuclear phagocyte system; they phagocytose pathogens, nanoparticles and other cellular debris. Mononuclear phagocytes originate in bone marrow as blood monocytes, which migrate to different tissues where they differentiate into tissue macrophages. At least three types of macrophages exist in lung: bronchial macrophages, interstitial macrophages and alveolar macrophages. They are found in the air space of the alveoli, parenchymal space (interstitial space) between adjacent alveoli. Lung macrophages can be characterised by their expression of surface markers. Activated macrophages release a variety of cytokines, chemokines, and growth factors (Kopf M et al., 2015).
Neutrophils are a type of polymorphonuclear leukocytes that are among the first to be recruited to an injured or inflamed site and play a major role in acute inflammation. They are the fundamental effectors of the host immune system and their basic role is to clear the infection or exogenous agents causing tissue injury. Neutrophils are continuously generated in the bone marrow and can be found in spleen, liver and lung. The lung holds a large reservoir of mature, terminally differentiated neutrophils, which are patrolling within the lung vasculature during steady state conditions (Kolaczkowska E and Kubes P, 2013). Neutrophil recruitment is initiated by the changes in the endothelium surface following stimulation by alarmin, DAMPs or inflammatory mediators released from resident leukocytes when they come in contact with pathogens or injurious external stimuli.
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 allergen induced fibrosis.
Activated immune cells secrete a variety of proinflammatory mediators, the purpose of which is to propagate the immune signalling and response, which when not controlled, lead to chronic inflammation, extensive cellular death and tissue injury.
It is important to note that the stressor-induced MIE, KE1 and KE2 are part of the functional changes that we collectively considered as inflammation, and together, they mark the initiation of acute inflammation phase.
How It Is Measured or Detected
In vivo, recruitment of proinflammatory cells is measured using bronchoalveolar lavage fluid (BALF) cellularity assay.
The airway epithelium is the largest surface that is targeted by inhaled substances including ENMs. The fluid lining the epithelium (BAL fluid) is lavaged and its composition is assessed as marker of lung immune response to the toxic substances or pathogens. BAL is assessed quantitatively for types of infiltrating cells, levels and types of cytokines and chemokines. Thus, BAL fluid 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 regulatory purposes. For ENMs, in vivo BAL assessment is recommended as a mandatory test (discussed in ENV/JM/MONO(2012)40 and also in OECD inhalation TG for ENMs). Temporal changes in the BAL composition can be prognostic of initiation and progression of lung immune disease (Cho W-S et al., 2010).
In vitro, it is difficult to assess the recruitment of proinflammatory cells. Thus, a suit of proinflammatory mediators specific to cell types are assessed using the same techniques mentioned above (qRT-PCR, ELISA, immunohistochemistry) in cell culture models, as indicative of recruitment of cells into the lungs.
Domain of Applicability
- Molly A. Ingersoll, Andrew M. Platt, Stephane Potteaux, and Gwendalyn J. Randolph. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 2011 Oct; 32(10): 470–477.
- Chao Shi and Eric G. Pamer. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10; 11(11): 762–774.
- Manfred Kopf, Christoph Schneider and Samuel P Nobs. The development and function of lung-resident macrophages and dendritic cells. Nature Immunology 16, 36–44 (2015).
- Elzbieta Kolaczkowska and Paul Kubes. Neutrophil recruitment and function in health and inflammation. Nature Reviews Immunology 2013. 13, 159-175.
- Cho W-S, Duffin R, Poland CA, et al. Metal Oxide Nanoparticles Induce Unique Inflammatory Footprints in the Lung: Important Implications for Nanoparticle Testing. Environmental Health Perspectives. 2010;118(12):1699-1706.