Lung inflammation, injury, and proliferative response after repetitive particulate hexavalent chromium exposure.
BACKGROUND
Chronic inflammation is implicated in the development of several human cancers, including lung cancer. Certain particulate hexavalent chromium [Cr(VI)] compounds are well-documented human respiratory carcinogens that release genotoxic soluble chromate and are associated with fibrosis, fibrosarcomas, adenocarcinomas, and squamous cell carcinomas of the lung. Despite this, little is known about the pathologic injury and immune responses after repetitive exposure to particulate chromates.


OBJECTIVE
In this study we investigated the lung injury, inflammation, proliferation, and survival signaling responses after repetitive exposure to particulate chromate.


METHODS
BALB/c mice were repetitively treated with particulate basic zinc chromate or saline using an intranasal exposure regimen. We assessed lungs for Cr(VI)-induced changes by bronchoalveolar lavage, histologic examination, and immunohistochemistry.


RESULTS
Single exposure to Cr(VI) resulted in inflammation of lung tissue that persists for up to 21 days. Repetitive Cr(VI) exposure induced a neutrophilic inflammatory airway response 24 hr after each treatment. Neutrophils were subsequently replaced by increasing numbers of macrophages by 5 days after treatment. Repetitive Cr(VI) exposure induced chronic peribronchial inflammation with alveolar and interstitial pneumonitis dominated by lymphocytes and macrophages. Moreover, chronic toxic mucosal injury was observed and accompanied by increased airway pro-matrix metalloprotease-9. Injury and inflammation correlated with airways becoming immunoreactive for phosphorylation of the survival signaling protein Akt and the proliferation marker Ki-67. We observed a reactive proliferative response in epithelial cells lining airways of chromate-exposed animals.


CONCLUSIONS
These data illustrate that repetitive exposure to particulate chromate induces chronic injury and an inflammatory microenvironment that may promote Cr(VI) carcinogenesis.
Beaver
Laura M
LM
Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC 20037, USA.
Stemmy
Erik J
EJ
Schwartz
Arnold M
AM
Damsker
Jesse M
JM
Constant
Stephanie L
SL
Ceryak
Susan M
SM
Patierno
Steven R
SR
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002857:Chromium / Q000633:toxicity*; D002908:Chronic Disease; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D011014:Pneumonia / Q000139:chemically induced*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D002857:Chromium; C074702:chromium hexavalent ion; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9