Professor and Associate Head, Cell Biology and Anatomy

Deputy Director, Southwest Environmental Health Science Center
Ph.D., West Virginia University

e-mail address: lantz@email.arizona.edu

Exposure to environmental toxicants alters lung structure and function and leads to impairment of the pulmonary defense mechanisms in the lung. Current investigations are examining the effects of arsenic exposure, tobacco smoke and uranium exposure. Exposure to environmental air pollutants may severely affect lung growth and development. The effects of arsenic or uranium exposure on embryonic rat lung development are being examined by maternal drinking water exposures. Pregnant females have been exposed to 500 ppb as arsenic or to various doses of uranium from conception until embryonic day 18. Lungs have been removed and analyzed for metal-induced alterations in gene expression using subtractive hybridization techniques and microarray analysis. Ongoing analysis has identified several extracellular matrix genes that have been altered by the exposures. In addition, genes involved in vascular development also appear to be targets. Alterations in gene expression are currently being correlated with alterations in structure and lung function. In addition, alterations in protein levels and sites of expression are being determined using Western blots and immunohistochemistry.

Using whole animal exposures, we are also continuing to investigate the interactions of arsenic and cigarette smoke exposure in the lung. Previously, we have seen that inhalation of arsenic and cigarette smoke act synergistically to cause oxidative stress in the lung. At the doses examined, neither arsenic nor cigarette smoke alone lead to any significant changes. However, together the exposures resulted in increased DNA oxidation after 28 days of exposure. We are continuing these experiments by examining the effects of cigarette smoke exposure and exposure to arsenic in the drinking water. Lungs and other tissues are being collected from animals exposed for up to 8 weeks. Analysis will include alterations in gene expression.

In addition, we are currently investigating the effects of acute smoke on expression and activity of the anti-inflammatory cytokine, interleukin-10 (IL-10). We have been able to show that after exposure to complex smoke levels of IL-10 in induced sputum collected from firefighters was reduced. Because exposure to complex smoke will lead to increased oxidative stress, we are investigating the role of radical production on the biological activity of the IL-10. We have found that in in vitro systems, IL-10 activity can actually be enhanced when the cytokine is exposed to peroxynitrite. Using an MS proteomics approach, we have identified the molecular modifications that occur on the IL-10 protein to be methione sulfoxides. We will attempt to determine if these alterations also occur in in vivo situations.

Finally, because of our interest in the role of inflammation in lung injury, we are currently evaluating the anti-inflammatory activity of compounds isolated from three plants that have been extensively used in Indian medicine. These include turmeric, ginger and boswellia. We have been able to demonstrate that extracts from these plants are able to inhibit inflammatory mediator production in a dose dependent manner. Potential sites of action are being investigated.

Lantz, R. Clark, Ranulfo Lemus, Robert W. Lange and Meryl H. Karol. Rapid reduction of intracellular glutathione in human bronchial epithelial cells exposed to occupational levels of toluene diisocyanate. Toxicol. Sci. 60:348-355, 2001.

Wijeweera, Jayanthika B., A. Jay Gandolfi, Alan Parrish and R. Clark Lantz. Sodium arsenite enhances AP-1 and NFkB DNA binding and induces stress protein expression in precision-cut rat lung slices. Toxicol. Sci. 61:238-294, 2001.

Burgess, Jefferey L., Christopher J. Nanson, Richard Gerkin, Mark L. Witten, Tracy A. Hysong and R. Clark Lantz. Rapid decline in sputum IL-10 concentration following occupational smoke exposure. Inhalation Toxicol. 14:133-140, 2002

Freels, Jon L., Dan K. Nelson, Jeffrey C. Hoyt, Michael Habib, Hiroki Numanami, R. Clark Lantz and Richard A. Robbins. Enhanced activity of IL-10 after nitration in reducing IL-1 production by stimulated peripheral blood mononuclear cells. J. Immunol. 169:4568-71, 2002.

Hays, Allison, R., Clark Lantz and Mark L. Witten. Correlation between in vivo and in vitro pulmonary responses to jet propulsion fuel 8 using precision-cut lung slices and a dynamic organ culture system. Toxicol. Pathol. 31:200-207, 2003

Lantz, R. Clark, Jason Orozco and Matthew S. Bogdanffy. Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol. Sci. 75:423-431, 2003.

Lantz, R. Clark, Guan Jie Chen, Aniko M. Solyom, Shivanand D. Jolad and Barbara N. Timmermann. The effect of turmeric extracts on inflammatory mediator production. Phytomedicine (in press)