Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium.
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-alpha 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.
Beaver
Laura M
LM
Department of Pharmacology and Physiology, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, USA.
Stemmy
Erik J
EJ
Constant
Stephanie L
SL
Schwartz
Arnold
A
Little
Laura G
LG
Gigley
Jason P
JP
Chun
Gina
G
Sugden
Kent D
KD
Ceryak
Susan M
SM
Patierno
Steven R
SR
D000281:Administration, Intranasal; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D014408:Biomarkers, Tumor / Q000633:toxicity; D002857:Chromium / Q000008:administration & dosage* / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced*; D019570:Inhalation Exposure; D008171:Lung Diseases / Q000139:chemically induced*; D051379:Mice; D008807:Mice, Inbred BALB C; D010316:Particle Size; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D000393:Air Pollutants; D014408:Biomarkers, Tumor; D002857:Chromium; C074702:chromium hexavalent ion; D051057:Proto-Oncogene Proteins c-akt