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NIOSH Respiratory Diseases Research Program

Evidence Package for the National Academies' Review 2006-2007

NIOSH Programs > Respiratory Diseases > Evidence Package > 3. Interstitial Lung Diseases > 3.2 Silica-Induced Respiratory Diseases

3.2f) Oxidant Injury is a Critical Mechanism for Interstitial Lung Disease

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Issue

Epidemiology studies indicate that the potency of airborne silica can vary among different workplaces using different industrial processes. Mechanistic information is critical to resolve this issue. Such information would be useful for risk assessment and setting of standards as well as for developing prevention strategies. A recent hypothesis indicates that the pathogenic potency of a particle depends in part on its ability to generate reactive species on its surface and/or its ability to stimulate production of reactive oxygen and nitrogen species from phagocytic cells. When oxidant generation is excessive and prolonged, anti-oxidant protective systems fail and oxidant damage occurs, initiating pulmonary disease.

Approach

In response to the growing scientific literature supporting the link between oxidant injury and pathogenesis, RDRP scientists began informal interactions and discussions beginning in the mid-1980s with a West Virginia University researcher with expertise in use of electron spin resonance spectroscopy to measure radicals generated by chemical reactions. As a result, RDRP scientists were among the first to measure the generation of reactive oxygen species from alveolar macrophages in response to particle exposure, such as silica using chemiluminescence as a sensitive assay system. In addition, RDRP scientists and their collaborator were among the first to demonstrate the generation of radicals on the surface of silica upon grinding.

Based on these early findings, an oxidant injury group was organized in RDRP. It consisted of scientists with expertise in molecular biology, chemistry, cell biology, and pathology. In 1996, this became an oxidant injury team with newly recruited multi-disciplinary scientists.

RDRP developed an electron spin resonance facility. Instrumentation in this facility allows the measurement of radical generation (quantification and identification of radical species) by silica, by cells or tissues slices exposed to silica, or in the lung of a living mouse in real time following silica exposure. RDRP scientists developed techniques to measure the production of reactive oxygen species (superoxide anion and hydrogen peroxide) and reactive nitrogen species (nitric oxide and peroxynitrite) from lung cells either in vitro or ex vivo. RDRP scientists developed techniques to monitor oxidant stress resulting from silica exposure in vivo by measuring lipid peroxidation, antioxidant depletion, exhaled NO, nitrotryrosine residues, and oxidant-induced DNA damage.

These activities led to several major findings: silica exposure in lung cells generates oxidative species, and in alveolar macrophages or polymorphonuclear leukocytes leads to the production of superoxide anion and hydrogen peroxide. Silica dusts often contain trace iron, and when hydrogen peroxide, produced by phagocytes, interacts with surface iron on silica, highly potent hydroxyl radicals are generated.

Silica exposure in the rat lung in vivo causes iNOS induction and the production of nitric oxide by alveolar macrophages and alveolar type II epithelial cells. This elevated nitric oxide can react with the silica-induced superoxide to form peroxynitrite, which can damage surrounding lung tissue forming nitrotyrosine residues (16, A3-76).

RDRP scientists demonstrated that silica-induced oxidants can activate signaling pathways controlling transcription factor activation and the production of inflammatory cytokines and chemokines as well as fibrogenic factors and growth factors. Thus, oxidant stress is linked with the initiation and progression silica-induced lung disease (17, 18, A3-77, A3-78).

RDRP scientists employed oxidant species scavengers and antioxidants to demonstrate the role of reactive oxygen species in silica-induced lung disease. Studies employing iNOS knockout mice demonstrate that nitric oxide plays a role in initiation and progression of silicosis (19, A3-79). It is hoped that elucidation of the mechanistic role of oxidative species in silicosis and silica-induced cancer may result in biomarkers of early disease and effective treatment to prevent disease progression.

Outputs and Transfers

Four key peer-reviewed publications from this research are mentioned and referenced above.

Numerous abstracts and presentations at scientific conferences and publications in peer-reviewed journals resulted from projects on silica and, in addition, RDRP sponsored or co-sponsored three conferences on oxidant injury:

  • Oxygen Radicals and Lung Injury, Morgantown, West Virginia, August 1993
  • Oxygen/Nitrogen Radicals and Cell Injury, Durham, North Carolina, October 1997
  • Oxygen/Nitrogen Radicals: Cell Injury and Disease, Morgantown, West Virginia, June 2002

These conferences brought together international experts to evaluate the state-of-science regarding the role of oxidant stress in disease and the use of antioxidants as preventative treatments.

RDRP scientists co-edited four books on oxidant production and oxidant injury (A3-80).

Intermediate Outcomes

RDRP helped improve recognition of silica-induced oxidant injury by the scientific community and regulatory agencies as a critical mechanism for the initiation and progression of interstitial lung disease. Through its research on mineral-dust induced oxidant injury, RDRP played a role in driving future research and providing a mechanistic framework for hazard identification and risk assessment.

Oxidant stress was identified as “the best developed paradigm for nanoparticle toxicity” by Nel et al. in a 2006 paper published in Science,74 in which RDRP’s work is prominently cited (A3-81).

The portion of RDRP that is concerned with oxidant injury was reviewed by an extramural panel of scientists/customers/stakeholders in 2001. RDRP outputs in this area were found to be highly cited (RDRP papers from the Oxidant Injury Program had a greater citation rate than those from the top universities in the U.S.) and viewed by the panel as influencing the direction of science in lung disease and the development of polices by regulatory agencies (A3-82).

The IARC Monograph on the “Evaluation of the Carcinogenic Risk of Chemicals to Humans, Silica, Some Silicates, Coal Dust and Para-aramid Fibers” (1997) noted oxidant stress as an important factor in silica-induced lung disease and cited RDRP’s work.73

RDRP expertise developed initially in the scientific arena of oxidant injury caused by inhaled agents is also being applied to agents other than silica. Examples include:

  • Environmental Protection Agency (EPA) directed the International Life Sciences Institute (ILSI) to form an international panel of 13 experts to develop a short-term screening strategy to evaluate fiber toxicity.75 This panel noted the importance of free-radical generation in a screening strategy and cited RDRP’s work (A3-83). An RDRP scientist also served on this panel.
  • EPA directed ILSI to form an international panel of 14 experts to develop a screening in strategy for the toxicity of nanomaterials.76 This panel also noted the importance of free-radical generation in a screening strategy. RDRP work was cited and two RDRP scientists served on this panel (A3-84).

What’s Ahead

RDRP’s goal in the area of oxidant injury for the future is to provide mechanistic information for hazard identification and risk assessment. Research efforts focused on the determination of the role of oxidant stress in occupational disease will be in the development of inhibitors, therapeutic interventions, and delivery systems for treatment of pulmonary disease. A plan to patent a treatment or delivery system is in progress. We will also continue to disseminate information by sponsorship and organization of scientific conferences on the role of oxidant stress in disease (specifically three conferences are planned, one on metals, one on nanotechnology, and one on oxidant injury).

Intermediate Goal and Objectives Moving Forward

RDRP’s intermediate goal is to prevent and reduce silica-induced respiratory diseases.  The objectives are to:

  • Provide information needed to inform OSHA in its anticipated review of the silica standard, including information about differential toxicity of freshly fractured silica
  • Reduce silica exposures by increasing substitution and by developing and disseminating guidance for dust control in at-risk industries and occupations
  • Continue surveillance activities on silicosis, especially in specific occupations at risk
  • Provide mechanistic data on dose- and time-dependence of silica-induced lung cancer
  • Provide mechanistic data concerning the role of a novel gene (mdig) in silica-induced lung cancer
  • Develop new tools for early detection of silica-induced respiratory diseases including standards for use of digital radiography in surveillance for silicosis and a biomarker to detect early development of the disease process.

74. Nel A, Xia T, Madler L, Li N [2006]. Toxic potential of materials at the nanolevel. Science 311:622-627.

75. Testing of fibrous particles: Short-term assays and strategies. Inhal Toxicol 17: 497-537.

76. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy [2006]. Particle Fibre Toxicol.

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