Differential ability of transition metals to induce pulmonary inflammation.

Transition metals are components of airborne particles and have been implicated in adverse health effects. The relative inflammatory potential of these metals is usually inferred from separate studies that focus on only one or a few individual metals. Comparisons of relative potency among several metals from these separate studies can be difficult. In one comprehensive study, we measured the pulmonary effects of equimolar doses of six metals in soluble form. Our purpose was to compare inflammatory potential and pulmonary toxicity among individual transition metals. Rats received saline, 0.1 or 1.0 micromol/kg of vanadium, nickel, iron(II), copper, manganese, or zinc as sulfates. Bronchoalveolar lavage (BAL) was performed at 0, 4, 16, or 48 h postinstillation. All treatments except V showed increased lactate dehydrogenase activity in BAL fluid; Cu- and Ni-exposed animals had the highest levels. Protein levels in BAL fluid were more than five times higher in Cu-exposed animals compared to other metal treatments at 16 and 48 h. At the 0.1 micromol/kg dose, only Cu induced significant neutrophilia at 16 and 48 h. For the 1.0 micromol/kg dose, all metals tested induced significant neutrophilia, with mean neutrophil numbers for Cu and Mn significantly higher compared to the other metals. At 48 h, neutrophil numbers were still elevated in all metal exposures. Only Mn caused substantial eosinophilia. At the 1.0 micromol/kg dose, only Cu induced macrophage inflammatory protein-2 (MIP-2) mRNA at 4 h. By 48 h, induction of MIP-2 mRNA was observed for all metal exposures except Cu, which subsequently returned to baseline levels. On an equimolar basis, Cu was the most proinflammatory metal, followed by Mn and Ni, while V, Fe(II), and Zn induced similar levels of inflammation. Overall, there were many similarities in the pulmonary responses of the metals we tested. However, we also observed divergent, metal-specific responses. These differential responses suggest that metals induce pulmonary inflammation by differing pathways or combinations of signals.

The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates.

Epidemiologic and occupational studies indicate adverse health effects due to inhalation of particulate air pollutants, but precise biologic mechanisms responsible have yet to be fully established. The tracheobronchial epithelium forms the body's first physiologic barrier to such airborne pollutants, where ciliary movement functions to remove the offending substances caught in the overlying mucus layer. Resident and infiltrating phagocytic cells also function in this removal process. In this paper, we examine the role of reactive oxygen and nitrogen species (ROS/RNS) in the response of airway epithelium to particulates. Some particulates themselves can generate ROS, as can the epithelial cells, in response to appropriate stimulation. In addition, resident macrophages in the airways and the alveolar spaces can release ROS/RNS after phagocytosis of inhaled particles. These macrophages also release large amounts of tumor necrosis factor alpha (TNF-alpha), a cytokine that can generate responses within the airway epithelium dependent upon intracellular generation of ROS/RNS. As a result, signal transduction pathways are set in motion that may contribute to inflammation and other pathobiology in the airway. Such effects include increased expression of intercellular adhesion molecule 1, interleukin-6, cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase, cytosolic phospholipase A2, and hypersecretion of mucus. Ultimately, ROS/RNS may play a role in the global response of the airway epithelium to particulate pollutants via activation of kinases and transcription factors common to many response genes. Thus, defense mechanisms involved in responding to offending particulates may result in a complex cascade of events that can contribute to airway pathology.