Loss of hypoxia-inducible factor 2 alpha in the lung alveolar epithelium of mice leads to enhanced eosinophilic inflammation in cobalt-induced lung injury.

Abstract

Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2α(Δ/Δ)) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.

• Authors: Steven P Proper, Yogesh Saini, Krista K Greenwood, Lori A Bramble, Nathaniel J Downing, Jack R Harkema, John J Lapres
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 137 Issue 2 Pg. 447-57 (Feb 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 24218148 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Cytokines
• endothelial PAS domain-containing protein 1
• Cobalt
• cobaltous chloride
• Doxycycline

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (deficiency, genetics)
• Bronchoalveolar Lavage Fluid (cytology)
• Cobalt (toxicity)
• Cytokines (genetics, immunology)
• Disease Models, Animal
• Doxycycline (pharmacology)
• Gene Expression Profiling
• Immunohistochemistry
• Lung Injury (chemically induced, complications, immunology, pathology)
• Mice
• Mice, Knockout
• Pulmonary Alveoli (drug effects, immunology, pathology)
• Pulmonary Eosinophilia (chemically induced, etiology, immunology, pathology)
• Respiratory Mucosa (drug effects, immunology, pathology)