Loss of Hypoxia-Inducible Factor 2 Alpha in the Lung Alveolar Epithelium of Mice Leads to Enhanced Eosinophilic Inflammation in Cobalt-Induced Lung Injury

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 HIF1 contrib utes to cobalt toxicity in vitro, loss of HIF1 in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1 and HIF2 show unique tissue expression profiles, and HIF2 is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2 activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2 in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2(/)) were exposed to cobalt (60 g/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2 leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2(/) mice, suggesting a role for epithelial HIF2 in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2(/) and control mice were compared. In summary, our data suggest that although loss of HIF2 does not afford protection from cobalt-induced lung inflammation, epithelial HIF2 signaling does play an important role in modulating the inflammatory and repair response in the lung.