Mechanistic Explanation of Chrome Carcinogenicity - What about other agents?

Toxicology and Applied PharmacologyVolume 235, Issue 1, 15 February 2009, Pages 47-56

Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium

Laura M. Beavera, b, Erik J. Stemmyb, c, Stephanie L. Constantb, c, Arnold Schwartzd, Laura G. Littleg, Jason P. Gigleyc, Gina Chuna, b, Kent D. Sugdeng, Susan M. Ceryaka, b, e, f and Steven R. Patiernoa, b, f, ,
aDepartment of Pharmacology and Physiology, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
bInstitute of Biomedical Sciences, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
cDepartment of Microbiology, Immunology and Tropical Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
dDepartment of Pathology, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
eDepartment of Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
fGW Cancer Institute, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA
gThe University of Montana, Department of Chemistry, 32 Campus Drive, Missoula, MT 59812, USA

Abstract
Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens that release genotoxic soluble chromate, and are associated with fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. We postulate that inflammatory processes and mediators may contribute to the etiology of Cr(VI) carcinogenesis, however the immediate (0–24 h) pathologic injury and immune responses after exposure to particulate chromates have not been adequately investigated. Our aim was to determine the nature of the lung injury, inflammatory response, and survival signaling responses following intranasal exposure of BALB/c mice to particulate basic zinc chromate. Factors associated with lung injury, inflammation and survival signaling were measured in airway lavage fluid and in lung tissue. A single chromate exposure induced an acute immune response in the lung, characterized by a rapid and significant increase in IL-6 and GRO-α levels, an influx of neutrophils, and a decline in macrophages in lung airways. Histological examination of lung tissue in animals challenged with a single chromate exposure revealed an increase in bronchiolar cell apoptosis and mucosal injury. Furthermore, chromate exposure induced injury and inflammation that progressed to alveolar and interstitial pneumonitis. Finally, a single Cr(VI) challenge resulted in a rapid and persistent increase in the number of airways immunoreactive for phosphorylation of the survival signaling protein Akt, on serine 473. These data illustrate that chromate induces both survival signaling and an inflammatory response in the lung, which we postulate may contribute to early oncogenesis.

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BrooklynDodger(s) Comment: This study provides some single dose results for a known human carcinogen in the target organ. Chromate ion appears the active agent. Should all agents which impact survival signaling, apoptosis, be considered carcinogens? At least, would this biological response trigger further study? The Dodger(s) wonder about ferric oxide, which is also an oxidizer.