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.

Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia

“…Myeloid cell HIF-1α has been shown to be instrumental in inflammation through myeloid cell development, phagocytosis, and antimicrobial production ( 46 – 48 ). In addition to HIF-1α regulation of inflammation, HIF-2α can regulate macrophage function in tumor models, eosinophil function in the lung, and IL-6 secretion from endothelial cells ( 49 – 51 ). Therefore, it is possible that another cell-specific HIF-1α or HIF-2α could be responsible for regulating cytokine secretion in response to K. pneumoniae infection.…”

Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice

“…Previous studies used 10 mM cobalt chloride (CoCl 2 ) in 25 μL volume to treat mice by oropharyngeal aspiration for 5 days on, 2 days off, and another 5 days on. This cobalt concentration corresponds to 60 μg daily exposure per mouse [ 55 , 56 ]. The doses of metal nanoparticles we used in our in vivo model (50 μg per mouse) is much lower than the doses used in a previous study with cobalt oxide nanoparticle (Nano-CoO) exposure [ 57 ].…”

Role Of Hif2α Oxygen Sensing Pathway In Bronchial Epithelial Club Cell Proliferation

“…Finally, recent studies also suggest the ability of HIF2α to initiate anti-inflammatory pathways. Indeed, HIF2α gene inactivation exacerbates pulmonary eosinophilic inflammation upon cobalt chloride-induced lung injury 26 . Therefore, it could be considered firstly that potentiation of HIF2α could attenuate lung dysfunction in COPD by counteracting associated oxidative stress, cell damage and inflammation, and secondly a possible contribution of HIF2α -induced Club cell proliferation.…”

“…Nevertheless, a recent study has shown that lower HIF2α levels are associated with multiple severity phenotypes of chronic obstructive pulmonary disease (COPD) in humans, and emphysema severity-associated genes in mice 25 . Along this line, it was recently found that loss of the HIF2α isoform in airway cells leads to enhanced airway inflammation upon lung injury 26 . In the present study, we have identified Club (Clara) bronchial epithelial cells, previously involved in the maintenance and protection of bronchial epithelium, as a novel cell type that displays a remarkable proliferative potential upon in vivo exposure to hypoxia.…”