Cobalt-Induced Lung Injury and Hypoxia-Inducible Factor 1α Free

We read with great interest the in vivo study by Saini et al. (2010) characterizing cobalt-induced acute lung injury, which depends on hyoxia-inducible factor (HIF)1α. Their study apparently showed that HIF1α modulates the dominance of effector leukocytes in the inflamed lung (neutrophils vs. eosinophils) employing a genetic approach. However, we have some comments.

At first, in Abstract, Saini et al. (2010) stated that cobalt-exposed control mice showed neutrophilic inflammation with the induction of Th₁ cytokines. However, in their results, the lung interferon-γ level was not increased in these mice. On the other hand, although interleukin (IL)-2 was elevated by cobalt in both genotypes of mice, this cytokine shows a biphasic role in Th₁/Th₂ immunity. Rather, cobalt-treated control mice exhibited an early increase in the levels of tumor necrosis factor-α and IL-6, which is likely to be due to macrophage activation. Overall, it does not seem that cobalt exposure allowed the control lung to proceed to the Th₁ milieu.

Second, in Introduction and Discussion, they referred to the clinical entity “cobalt asthma” or “asthma-like phenotype.” However, in their study, Saini et al. (2010) examined neither lung function (airway responsiveness) nor airway smooth muscle cell characterization, particularly in HIF1α^Δ/^Δ mice. Mast cell–mediated bronchoconstriction may be investigated in cobalt-inhaled mice in the future since HIF1α is implicated in mast cell activation (Sumbayev et al., 2009). As for the pathophysiology noted in the cobalt-exposed HIF1α^Δ/^Δ mice in their study, it would be better to select the term “Th₂-biased eosinophilic airway inflammation.”

Third, it should be interesting to clarify the correlation between HIF1α and other nuclear factors related to the Th₁/Th₂ response, such as T-bet and GATA-3 with or without allergic traits. To date, HIF1α reportedly positively regulates the allergic pathophysiology in vivo (Guo et al., 2009; Lee et al., 2007). However, it is possible that HIF1α plays a role in the activation of Th-related signaling dependent on the cell and/or tissue types, inflammatory stimuli, etc.

Finally, regarding metal-exposed lung eosinophilia, we experienced a similar phenomenon in our in vivo study in which the acute inhalation of concentrated ambient particles (CAPs) collected in an urban city caused an increase in the number of eosinophils recovered in bronchoalveolar lavage fluids in the presence of lipopolysaccharide (LPS) compared with inhaled control air (Inoue, Hirano, Kobayashi, Takano, in preparation). LPS can biphasically lead to the Th₁/Th₂ condition. Furthermore, CAPs contain various metals including cobalt; accordingly, considering the study by Saini et al. (2010), this CAP-provoked lung eosinophilia related to LPS observed in our study might be caused, at least in part, by hard metals such as cobalt, probably through imbalance of the HIF pathway. Further investigation is needed to clarify this point.

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