Academic journal article Environmental Health Perspectives

Lung Inflammation, Injury, and Proliferative Response after Repetitive Particulate Hexavalent Chromium Exposure

Academic journal article Environmental Health Perspectives

Lung Inflammation, Injury, and Proliferative Response after Repetitive Particulate Hexavalent Chromium Exposure

Article excerpt

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.

OBJECTIVES: 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(Vl) 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.

KEY WORDS: chromium, hexavalent, inflammation, injury, intranasal, lung, proliferation, repair. Environ Health Perspect 117:1896-1902 (2009). doi:10.1289/ehp.0900715 available via [Online 19 August 2009]


Lung cancer is the leading cause of cancer deaths in both men and women in the United States (American Cancer Society 2008). Worldwide, it has been estimated that 20-30% of males and 5-20% of females of working age have been occupationally exposed to agents that cause lung cancer (World Health Organization 2002). Chronic inflammation has been implicated in the development of a wide array of human cancers, including lung cancer (reviewed by Coussens and Werb 2002). Inflammatory cells and their chemical mediators arc key participants in the generation of a tumor microenvironment that promotes angiogenesis and participates in cancer metastases (Albini and Sporn 2007). Individuals with underlying inflammation in the lung due to chronic infection, asbestos exposure, or development of interstitial lung disease and asthma are at an increased risk lor lung cancer (Santillan et al. 2003; Turner et al. 2007; Yang et al. 2005). Furthermore, a decreased risk of lung cancer has been reported with the use of nonsteroidal antiinflammatory drugs, further suggesting a role of inflammation in lung cancer pathogenesis (Khuder et al. 2005; Van Dyke et al. 2008).

Certain hexavalent chromium [Cr(VI)J compounds are occupational and potential environmental human respiratory carcinogens (International Agency for Research on Cancer (IARC) 1990]. Workers in the chromate production industry have an elevated risk of respiratory diseases, including fibrosis, hyperplasia of the bronchial epithelium, lung fibrosarcomas, adenocarcinomas, and squamous cell carcinomas (reviewed by IARC 1990). Outside of commercial use, Cr(VI) is a component of industrial waste, and atmospheric particulate Cr is generated by combustion of fossil fuels, wearing of brake linings, ferrochrome and cement production, ore refining, refractory processing, welding, and incineration of all types [Agency for Toxic Substances and Disease Registry (ATSDR) 2000; Fishbein 1981]. …

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