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Event: 1498

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Loss of alveolar capillary membrane integrity

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Loss of alveolar capillary membrane integrity

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Substance interaction with the lung cell membrane leading to lung fibrosis KeyEvent Sabina Halappanavar (send email) Under development: Not open for comment. Do not cite EAGMST Under Review
Lung surfactant function inhibition leading to impaired lung function KeyEvent Jorid Birkelund Sørli (send email) Under development: Not open for comment. Do not cite Under Development


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
human Homo sapiens Not Specified NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult High

Sex Applicability

No help message More help
Term Evidence
Male High
Female Not Specified

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Loss of alveolar capillary membrane integrity

The alveolar-capillary membrane (ACM) is the gas exchange surface of the lungs that is only ~0.3µm thick and is the largest surface area within the lung that separates the interior of the body from the environment. It is comprised of the microvascular endothelium, interstitium, and alveolar epithelium. As a consequence of its anatomical position, and the large surface area, it is the first point of contact for any inhaled pathogen, particles or toxic substances. Thus, ACM is subjected to injury constantly and rapidly repaired following the external insults without formation of fibrosis or scar tissue. The extent of ACM injury or how rapidly its integrity is restored is a pivotal determinant of whether the lung restores its normal functioning following an injury or is replaced by fibrotic lesion or scar tissue (Fakuda et al., 1987; Shwarz et al., 2001). Significant loss of endothelium and epithelium of the ACM results in loss of the barrier and membrane integrity. Increased membrane permeability leading to efflux of protein-rich fluid into the peribronchovascular interstitium and the distal airspaces of the lung, disruption of normal fluid transport via downregulated Na channels or malfunctioning Na+/K+ATPase pumps, loss of surfactant production, increased expression of epithelial or endothelial cell markers such as intercellular adhesion molecule-1 (ICAM-1) or decreased expression of surfactant D are few of the markers of decreasing lung compliance arising from the lost integrity of ACM (Johnson and Matthay, 2010).

KE3 associative event 1 - Chronic inflammation

In the presence of continuous stimulus (e.g., presence of biopersistent toxic fibres such as asbestos, MWCNTs) or following repeated stimulus (e.g., repeated exposure to silica or coal dust), the ensuing cell injury fuels the inflammatory mechanisms leading to accumulation of immune cells, prolonged inflammation and aggravated tissue damage. This sustained and perpetuated immunological response is termed as chronic inflammation. During this phase, active inflammation, tissue injury and destruction, and tissue repair processes proceed in tandem. Thus, the causative substance must contain unique physico-chemical properties that grant the material biopersistance in the pulmonary environment or the pulmonary system has to be repeatedly exposed to the same substance that perpetuates the tissue injury leading to loss of ACM. Although, increases in number of neutrophils are observed during chronic inflammation, mononuclear phagocytes (circulating monocytes, tissue macrophages) and lymphoid cells mark this phase. The macrophages, components of mononuclear phagocyte system, are the predominant cells in chronic inflammation. Activated macrophages release a variety of cytokines, chemokines, growth factors, which when uncontrolled, lead to extensive tissue injury, cellular death and necrosis, the other characteristics of chronic inflammation, leading to ACM loss. The other types of inflammatory cells found in chronic inflammation include eosinophils in allergen induced lung fibrosis, lymphocytes and epithelial cells.

KE3 associative event 2 - Oxidative stress  

Superoxide anion (O2-) and the hydroxyl radical (OH) are the common ROS found in the biological systems that are unstable due to unpaired electrons. As such, all tissues including lung have efficient antioxidant system to counteract the ROS induced oxidation. The antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase act directly to inactivate ROS and associated reactions. In addition, phase II detoxifying enzymes, including glutathione-S-transferase, NADPH quinone oxidoreductase and glutamate-cysteine ligase catalytic act as indirect antioxidant enzymes. However, when the balance between oxidant and antioxidants is tipped towards oxidants, oxidative stress occurs. ROS, when interacted with biomolecules, initiate their oxidation. During the process, proteins, DNA and lipids are oxidized. Oxidative stress modulates the cellular signalling processes and contributes to oxidative stress-induced tissue injury. It also plays a role in the tissue injury caused by inflammatory processes in lungs. The infiltrating neutrophils and macrophages generate superoxide anion which is converted to hydrogen peroxide by superoxide dismutase enzyme. OH is formed by a secondary reaction in the presence of Fe2+. ROS can also be produced by NADPH oxidase present in phagocytes. The other enzyme that contributes to ROS synthesis during inflammatory processes is the myeloperoxidase from neutrophils.  In a self-perpetuating loop, inflammatory cells generate oxidative stress leading to increased airspace epithelial permeability, increased cell death and increased expression of pro-inflammatory genes, all of which lead to secretion of inflammatory cytokines/chemokines leading to prolonged and chronic inflammation.

Evidence for its perturbation

Bleomycin exposure causes alveolar barrier dysfunction (Miyoshi et al., 2013). Cigarette smoke impairs tight junction proteins and leads to altered permeability of the epithelial barrier (Schamberger et al., 2014). Exposure to pro-fibrotic drug bleomycin destroys structural architecture of the tight junctions, increases permeability, epithelial death and loss of specialised repair proteins such as claudins. Thoracic radiation and bleomycin-induced lung injury results in decreased expression of E-cadherin and Aquaporin-5 expression (Almeida et al., 2013; Gabazza et al., 2004).

Epithelium and basement membrane injury is a prerequisite for the development of fibrotic lesion (Brody et al., 1981). Repeated exposure to or biopersistent toxic substances, pathogens or lung irritants initiate non-resolving inflammation and ACM injury (Costabel et al., 2012). Chronic inflammation mediated by overexpression of cytokines such as IL-1 (Kolb et al., 2001), TNFa (Sime et al., 1998), T-helper type 2 cytokine IL-13 or exposure to specific proteinases initiate ACM injury, significant loss of the epithelium and endothelium of the ACM resulting in loss of the barrier. In patients diagnosed with idiopathic pulmonary fibrosis, both type 1 pneumocyte and endothelial cell injury with the ACM barrier loss is observed.

Bleomycin and silica exposure generate persistent inflammation and lung damage (Thrall, 1995; Chau, 2005). Exposure to SWCNTs induces persistent inflammation, granuloma and diffuse intestinal fibrosis in mice after pharyngeal aspiration (Shevedova, 2005). MWCNTs act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer, 2013). Inhaled particles induce chronic inflammation (Hamilton, 2008; Thakur, 2008; Ernst, 2002). Increased numbers of alveolar macrophages, neutrophils and eosinophils are observed in the BALF of patients suffering from IPF and chronic inflammation is associated with decreased survival (Parra, 2007; Schwartz 1991; Yasuoka, 1985).

The BALF of patients diagnosed with interstitial diseases contains increased levels of 8-isoprostane (Psathakis, 2006) and carbonyl-modified proteins (Lenz, 1996), markers of oxidative modification of lipids and proteins. In vivo, increased ROS levels in rodents (Ghio, 1998) and enzymatic production of nitric oxide in rat alveolar macrophages is observed after asbestos exposure (Quinlan, 1998). Some nanoparticles induce oxidative stress that contributes to cellular toxicity (Shi, 2012). NADPH oxidase derived ROS is a critical determinant of the pulmonary response to SWCNTs in mice (Shvedova, 2008). Oxidative lipidomics analysis of the lungs of CNT-exposed mice showed, phospholipid oxidation (Tyurina, 2011). ROS synthesis is suggested to be important for inflammosome activation involving NLR-related protein 3 complex, activated caspase-1 and IL-1b, which is observed following exposure to a variety of pro-fibrotic stimuli including, asbestos and crystalline silica (Dostert, 2008; Cassel, 2008) and long needle-like CNTs. In the case of asbestos, frustrated phagocytosis triggered ROS synthesis leads to inflammosome activation, which is associated with asbestos induced pathology (Dostert, 2008).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Proteinosis, BAL fluid protein content

The compromised ACM integrity in vivo can be measured by measuring total protein or total albumin content in the BAL fluid derived from experimental animals exposed to lung toxicants or in human patients suffering from lung fibrosis. In addition to albumin, the total urea in BAL fluid is also a good indicator of the ACM integrity loss (Schmekel et al., 1992).

Cel type considerations

ACM loss is a tissue level event. In vitro, assays with human cells are desired; however, the use of cells derived from experimental animals including alveolar macrophages, dendritic cells, epithelial cells, and neutrophils are routinely used. Primary cells are preferred over immortalised cell types that are in culture for a long period of time. In vitro, studies often assess the altered expression of pro-inflammatory mediators, increased ROS synthesis or oxidative stress and cytotoxicity events, an interplay between these three biological events occurring following exposure to stressors, is suggested to induce cell injury, which  is reflective of tissue injury or loss of ACM (Halappanavar, 2019) in vivo.

Cytotoxicity assessment

Cellular viability or cytotoxicity assays are the most commonly used endpoints to assess the leaky or compromised cell membrane. The most commonly employed method is the trypan blue exclusion assay – a dye exclusion assay where cells with intact membrane do not permit entry of the dye into cells and thus remain clear, whereas the dye diffuses into cells with damaged membrane turning them to blue colour. Other high throughput assays that use fluorescent DNA stains such as ethidium bromide or propidium iodide can also be used and cells that have incorporated the dye can be scored using flow cytometry.

LDH release assay is a very sensitive cytotoxicity assay that measures the amount of LDH released in the media following membrane injury. The assay is based on measuring the reduction of NAD and conversion of a tetrazolium dye that is measured at a wavelength of 490 nm.

The Calcein AM assay depends on the hydrolysis of calcein AM ( a non-fluorescent hydrophobic compound that permeates live cells by simple diffusion) by non-specific intracellular esterases resulting in production of calcein, a hydrophilic and strongly fluorescent compound that is readily released into the cell culture media by the damaged cells.

Although the above mentioned assays work for almost all chemicals, insoluble substances such as NMs can confound the assay by inhibiting the enzyme activity or interfering with the absorbance reading. Thus, care must be taken to include appropriate controls in the assays.

Transepithelial/transendothelial electrical resistance (TEER)

TEER is an accepted quantitative technique that measures the integrity of tight junctions in cell culture models of endothelial and epithelial cell monolayers. They are based on measuring ohmic resistance or measuring impedance across a wide range of frequencies.

The other methods include targeted RT-PCR or ELISA assays for tight junction proteins, cell adhesion molecules and inflammatory mediators such as IFNg, IL-10, and IL-13.   

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help
  1. Almeida, C., Nagarajan, D., Tian, J., Leal, S., Wheeler, K., Munley, M., Blackstock, W. and Zhao, W. (2013). The Role of Alveolar Epithelium in Radiation-Induced Lung Injury. PLoS ONE, 8(1), p.e53628.
  2. Beamer, C., Girtsman, T., Seaver, B., Finsaas, K., Migliaccio, C., Perry, V., Rottman, J., Smith, D. and Holian, A. (2012). IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology, 7(6), pp.1070-1081.
  3. Brody, A., Soler, P., Basset, F., Haschek, W. and Witschi, H. (1981). Epithelial-Mesenchymal Associations of Cells in Human Pulmonary Fibrosis and in BHT-Oxygen-Induced Fibrosis in Mice. Experimental Lung Research, 2(3), pp.207-220.
  4. Cassel, S., Eisenbarth, S., Iyer, S., Sadler, J., Colegio, O., Tephly, L., Carter, A., Rothman, P., Flavell, R. and Sutterwala, F. (2008). The Nalp3 inflammasome is essential for the development of silicosis. Proceedings of the National Academy of Sciences, 105(26), pp.9035-9040.
  5. Chua, F., Gauldie, J. and Laurent, G. (2005). Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 33(1), pp.9-13.
  6. Costabel, U., Bonella, F. and Guzman, J. (2012). Chronic Hypersensitivity Pneumonitis. Clinics in Chest Medicine, 33(1), pp.151-163.
  7. Dostert, C., Petrilli, V., Van Bruggen, R., Steele, C., Mossman, B. and Tschopp, J. (2008). Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica. Science, 320(5876), pp.674-677.
  8. Ernst, H., Rittinghausen, S., Bartsch, W., Creutzenberg, O., Dasenbrock, C., Görlitz, B., Hecht, M., Kairies, U., Muhle, H., Müller, M., Heinrich, U. and Pott, F. (2002). Pulmonary inflammation in rats after intratracheal instillation of quartz, amorphous SiO2, carbon black, and coal dust and the influence of poly-2-vinylpyridine-N-oxide (PVNO). Experimental and Toxicologic Pathology, 54(2), pp.109-126.
  9. Gabazza, E., Kasper, M., Ohta, K., Keane, M., D'Alessandro-Gabazza, C., Fujimoto, H., Nishii, Y., Nakahara, H., Takagi, T., Menon, A., Adachi, Y., Suzuki, K. and Taguchi, O. (2004). Decreased expression of aquaporin-5 in bleomycin-induced lung fibrosis in the mouse. Pathology International, 54(10), pp.774-780.
  10. Ghio, A., Kadiiska, M., Xiang, Q. and Mason, R. (1998). In Vivo Evidence of Free Radical Formation After Asbestos Instillation. Free Radical Biology and Medicine, 24(1), pp.11-17.
  11. Hamilton, R., Thakur, S. and Holian, A. (2008). Silica binding and toxicity in alveolar macrophages. Free Radical Biology and Medicine, 44(7), pp.1246-1258.
  12. He, C., Murthy, S., McCormick, M., Spitz, D., Ryan, A. and Carter, A. (2011). Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation. Journal of Biological Chemistry, 286(17), pp.15597-15607.
  13. Johnson, E. and Matthay, M. (2010). Acute Lung Injury: Epidemiology, Pathogenesis, and Treatment. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 23(4), pp.243-252.
  14. Kolb, M., Margetts, P., Anthony, D., Pitossi, F. and Gauldie, J. (2001). Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. Journal of Clinical Investigation, 107(12), pp.1529-1536.
  15. Kulkarni, T., de Andrade, J., Zhou, Y., Luckhardt, T. and Thannickal, V. (2016). Alveolar epithelial disintegrity in pulmonary fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 311(2), pp.L185-L191.
  16. Lenz, A., Costabel, U. and Maier, K. (1996). Oxidized BAL fluid proteins in patients with interstitial lung diseases. European Respiratory Journal, 9(2), pp.307-312.
  17. Miyoshi, K., Yanagi, S., Kawahara, K., Nishio, M., Tsubouchi, H., Imazu, Y., Koshida, R., Matsumoto, N., Taguchi, A., Yamashita, S., Suzuki, A. and Nakazato, M. (2013). Epithelial Pten Controls Acute Lung Injury and Fibrosis by Regulating Alveolar Epithelial Cell Integrity. American Journal of Respiratory and Critical Care Medicine, 187(3), pp.262-275.
  18. Parra, E., Kairalla, R., Ribeiro de Carvalho, C., Eher, E. and Capelozzi, V. (2006). Inflammatory Cell Phenotyping of the Pulmonary Interstitium in Idiopathic Interstitial Pneumonia. Respiration, 74(2), pp.159-169.
  19. Psathakis, K., Mermigkis, D., Papatheodorou, G., Loukides, S., Panagou, P., Polychronopoulos, V., Siafakas, N. and Bouros, D. (2006). Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. European Journal of Clinical Investigation, 36(5), pp.362-367.
  20. Quinlan, T., BeruBe, K., Hacker, M., Taatjes, D., Timblin, C., Goldberg, J., Kimberley, P., O’Shaughnessy, P., Hemenway, D., Torino, J., Jimenez, L. and Mossman, B. (1998). Mechanisms of Asbestos-induced Nitric Oxide Production by Rat Alveolar Macrophages in Inhalation and in vitro Models. Free Radical Biology and Medicine, 24(5), pp.778-788.
  21. Schamberger, A., Mise, N., Jia, J., Genoyer, E., Yildirim, A., Meiners, S. and Eickelberg, O. (2014). Cigarette Smoke–Induced Disruption of Bronchial Epithelial Tight Junctions Is Prevented by Transforming Growth Factor-β. American Journal of Respiratory Cell and Molecular Biology, 50(6), pp.1040-1052.
  22. Schmekel, B., Bos, J., Khan, A., Wohlfart, B., Lachmann, B. and Wollmer, P. (1992). Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers. Thorax, 47(8), pp.603-608.
  23. Schwartz, D., Helmers, R., Dayton, C., Merchant, R. and Hunninghake, G. (1991). Determinants of bronchoalveolar lavage cellularity in idiopathic pulmonary fibrosis. Journal of Applied Physiology, 71(5), pp.1688-1693.
  24. Schwarz, M. (2001). Acute lung injury: cellular mechanisms and derangements. Paediatric Respiratory Reviews, 2(1), pp.3-9.
  25. Shi, J., Karlsson, H., Johansson, K., Gogvadze, V., Xiao, L., Li, J., Burks, T., Garcia-Bennett, A., Uheida, A., Muhammed, M., Mathur, S., Morgenstern, R., Kagan, V. and Fadeel, B. (2012). Microsomal Glutathione Transferase 1 Protects Against Toxicity Induced by Silica Nanoparticles but Not by Zinc Oxide Nanoparticles. ACS Nano, 6(3), pp.1925-1938.
  26. Shvedova, A., Kisin, E., Mercer, R., Murray, A., Johnson, V., Potapovich, A., Tyurina, Y., Gorelik, O., Arepalli, S., Schwegler-Berry, D., Hubbs, A., Antonini, J., Evans, D., Ku, B., Ramsey, D., Maynard, A., Kagan, V., Castranova, V. and Baron, P. (2005). Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology, 289(5), pp.L698-L708.
  27. Shvedova, A., Kisin, E., Murray, A., Kommineni, C., Castranova, V., Fadeel, B. and Kagan, V. (2008). Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes. Toxicology and Applied Pharmacology, 231(2), pp.235-240.
  28. Sime, P., Marr, R., Gauldie, D., Xing, Z., Hewlett, B., Graham, F. and Gauldie, J. (1998). Transfer of Tumor Necrosis Factor-α to Rat Lung Induces Severe Pulmonary Inflammation and Patchy Interstitial Fibrogenesis with Induction of Transforming Growth Factor-β1 and Myofibroblasts. The American Journal of Pathology, 153(3), pp.825-832.
  29. Thakur, S., Hamilton, R. and Holian, A. (2008). Role of Scavenger Receptor A Family in Lung Inflammation from Exposure to Environmental Particles. Journal of Immunotoxicology, 5(2), pp.151-157.
  30. Tyurina, Y., Kisin, E., Murray, A., Tyurin, V., Kapralova, V., Sparvero, L., Amoscato, A., Samhan-Arias, A., Swedin, L., Lahesmaa, R., Fadeel, B., Shvedova, A. and Kagan, V. (2011). Global Phospholipidomics Analysis Reveals Selective Pulmonary Peroxidation Profiles upon Inhalation of Single-Walled Carbon Nanotubes. ACS Nano, 5(9), pp.7342-7353.
  31. YASUOKA, S., NAKAYAMA, T., KAWANO, T., OGUSHI, F., DOI, H., HAYASHI, H. and TSUBURA, E. (1985). Comparison of cell profiles on bronchial and bronchoalveolar lavage fluids between normal subjects and patient with idiopathic pulmonary fibrosis. The Tohoku Journal of Experimental Medicine, 146(1), pp.33-45.