Cobalt-Induced Lung Injury and Hypoxia-Inducible Factor 1α
Ken-ichiro Inoue
1
2
Masako Kiyono
1
2
Yuka Sone
1
2
Hirohisa Takano
0
1
0
National Institute for Environmental Studies
,
Tsukuba 305-8506
,
Japan
1
Guo
,
J., Lu, W., Shimoda, L. A., Semenza, G. L., and Georas, S. N. (2009).
Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1- alpha-deficient mice. Int. Arch.
Allergy Immunol. 149, 98-102. Lee, K. S., Kim, S. R., Park, H. S., Park, S. J., Min, K. H., Lee, K. Y., Choe, Y. H., Hong, S. H., Han, H. J., Lee, Y. R.
, et al. (2007). A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha. Exp. Biol. Med.
39, 756-768. Saini, Y., Greenwood, K. K., Merrill, C., Kim, K. Y., Patial, S., Parameswaran, N., Harkema, J. R., and LaPres, J. J. (2010).
Acute cobalt- induced lung injury and the role of hypoxia-inducible factor 1alpha in modulating inflammation. Toxicol. Sci.
116, 673-681. Sumbayev, V. V., Nicholas, S. A., Streatfield, C. L., and Gibbs, B. F. (2009). Involvement of hypoxia-inducible factor-1 HiF(1alpha) in IgE-mediated primary human basophil responses. Eur. J. Immunol. 39, 3511-3519
2
Department of Public Health and Molecular Toxicology, School of Pharmacy, Kitasato University
,
Tokyo 108-8641
,
Japan
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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)1a. Their study
apparently showed that HIF1a 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
cobaltexposed control mice showed neutrophilic inflammation with
the induction of Th1 cytokines. However, in their results, the
lung interferon-c 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-a 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 HIF1aD/D mice.
Mast cellmediated bronchoconstriction may be investigated in
cobalt-inhaled mice in the future since HIF1a is implicated in
mast cell activation (Sumbayev et al., 2009). As for the
pathophysiology noted in the cobalt-exposed HIF1aD/D 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 HIF1a and other nuclear factors related to the Th1/Th2
response, such as T-bet and GATA-3 with or without allergic
traits. To date, HIF1a reportedly positively regulates the
allergic pathophysiology in vivo (Guo et al., 2009; Lee et al.,
2007). However, it is possible that HIF1a 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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