Superfund Research Program

Mechanisms of Vanadium Toxicity in the Respiratory System

Release Date: 06/16/1999

Vanadium is a contaminant on about one-quarter of the country's Superfund sites. Because natural sources also release this metal into soil, water, and air, low levels of vanadium are ubiquitous in the environment, and nearly everyone is exposed to minute quantities of it in food, drinking water, and ambient air. However, people living near hazardous waste sites containing vanadium may experience above average exposures, while those working in industries that either process vanadium or burn fossil fuels containing traces of the metal are at an even higher risk for excess exposures.

Vanadium is known to produce adverse health effects, primarily in the respiratory system. Epidemiological studies have shown that exposures to high levels of vanadium through inhalation can result in inflammation of the lungs and other parts of the respiratory tract. Inhalation studies in animal models provide additional evidence that this metal is a respiratory toxicant.

Inflammation in the respiratory system can compromise its functioning, as well as its ability to mount an appropriate defense against airborne microbial pathogens. Highly vulnerable to damage, the respiratory system, especially the sensitive tissue in the lungs, needs to be protected against inhaled substances that can either damage pulmonary immune defenses or increase allergic diseases. Developing a better understanding of the links between vanadium exposure and adverse respiratory effects is a necessary step towards preventing respiratory infections and diseases.

Researchers at Harvard University are investigating how vanadium compounds cause inflammation in the lungs. In initial studies, these researchers demonstrated that three toxicologically significant forms of vanadium -- sodium metavanadate, vanadyl sulfate, and vanadium pentoxide -- were able to cause an inflammatory response when instilled into the lungs of rats. This inflammation was primarily characterized by an influx of neutrophils, a type of white blood cell that is best known for its role in fighting infectious viruses and bacteria.

Subsequent studies focused on understanding the biological mechanisms by which neutrophils are recruited to the lung following vanadium exposure. Knowing that chemokines, a type of signaling molecule, activate and recruit neutrophils in other types of inflammation, the researchers monitored the effects of vanadium on the levels of the two principal neutrophil chemoattractants expressed in the rat, MIP-2 and KC.

What the researchers found is that levels of messenger RNA (mRNA) for MIP-2 and KC were rapidly induced in rats' lungs as early as 1 hour following vanadium exposure and continued to be expressed for 2 days. The rapid production of MIP-2 and KC in the lung prior to the influx of neutrophils suggests these two molecules are important in the initiation of inflammation.

The chemokines were produced and released by alveolar macrophages, another type of white blood cell involved in the body's inflammatory and immune responses. Thus, vanadium-induced inflammation in the lung appears to be initiated by macrophages which, upon encountering vanadium particles, subsequently produce and release chemical messengers directed specifically to neutrophils for their recruitment to the site of exposure.

In recent in vitro experiments, the Harvard researchers have made significant progress in elucidating the events that take place inside alveolar macrophages when they come in contact with vanadium. The researchers investigated two immediate responses of alveolar macrophages to vanadium: the production of reactive oxygen intermediates and the phosphorylation of cellular proteins.

Exposure of alveolar macrophages to increasing concentrations of sodium metavanadate resulted in a dose-dependent increase in production of reactive oxygen intermediates. In addition, metavanadate exposure greatly increased overall tyrosine phosphorylation in these cells. According to the researchers, "these observations demonstrate that in vitro metavanadate exposure regulates two distinct, yet related intracellular signaling pathways important in initiating inflammatory responses in these cells ..." The researchers hypothesize these pathways may lead to increased expression of the gene coding for MIP-2, one of the protein messengers that activates and recruits neutrophils.

This new information is critical to understanding the unique aspects of vanadium-induced inflammatory responses in the lungs. A number of the specific biochemical and cellular steps involved in vanadium toxicity have been elucidated in vitro and in an animal model, findings that will provide important clues to potential modes of action in humans. Ultimately, these results will aid in preventing adverse health effects by vanadium and other closely related airborne contaminants.

For More Information Contact:

John Godleski
665 Huntington Avenue
Boston, Massachusetts 02115
Phone: 617-432-1252
Email: jgodlesk@hsph.harvard.edu

To learn more about this research, please refer to the following sources:

  • Grabowski GM, Paulauskis JD, Godleski J. 1999. Mediating phosphorylation events in the vanadium-induced respiratory burst of alveolar macrophages. Toxicol Appl Pharmacol 156:170-178. PMID:10222309
  • Shi MM, Chong I, Long NC, Love JA, Godleski J, Paulauskis JD. 1998. Functional characterization of recombinant rat macrophage inflammatory protein-1α and mRNA expression in pulmonary inflammation. Inflammation 22:29-43. PMID:9484648
  • Tsai CS, Shi MM, Chong I, Godleski J, Paulauskis JD. 1997. Vanadium-induced expression of macrophage inflammatory protein (MIP)-1α and MIP-2 mRNA in lung macrophages is dependent on macrophage:epithelial interaction. Am J Respir Crit Care Med 155:A960.
  • Pierce LM, Alessandrini F, Godleski J, Paulauskis JD. 1996. Vanadium-induced chemokine mRNA expression and pulmonary inflammation. Toxicol Appl Pharmacol 138(1):1-11. doi:10.1006/taap.1996.9999 PMID:8658498

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