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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

10. Bakan ND, Ozkan G, Camsari G, Gur A, Bayram M, Acikmese B,

Cetinkaya E. Silicosis in denim sandblasters. Chest (In press)
11. Centers for Disease Control and Prevention. Silicosis mortality, prevention, and control-United States, 19682002. MMWR Morb Mortal
Wkly Rep 2005;54:401405.
12. Maxfield R, Alo C, Reilly MJ, Rosenman K, Kalinowski D, Stanbury
M, Valiante DJ, Jones B, Randolph S, Socie E, et al. Surveillance

VOL 184

2011

for silicosis, 1993Illinois, Michigan, New Jersey, North Carolina,

Ohio, Texas, and Wisconsin. MMWR CDC Surveill Summ 1997;46:
1328.

Copyright 2011 by the American Thoracic Society

DOI: 10.1164/rccm.201108-1440ED

Vitamin D and Asthma: Another Dimension

In this issue of the Journal, Gupta and colleagues (pp. 13421349)
add to the ever-enlarging body of literature reporting associations between vitamin D status (as reflected by serum 25(OH)D
concentrations) and measures of asthma severity and control
(1). In a well-characterized clinical cohort of children with either moderate or severe (treatment-resistant) asthma, they investigated associations between serum 25(OH)D and lung
function, asthma control, exacerbations, and medication history.
As might be expected in light of prior reports, the investigators
found an inverse relationship between 25(OH)D and asthma
severity, exacerbations, and inhaled glucocorticoid requirement,
and a positive relationship between 25(OH)D and both lung
function and asthma control. These findings validate, using data
obtained directly from patients with severe asthma, other
reports in which vitamin D status is associated with asthma
severity in children (24). The authors take their findings a step
further, however, by also providing us with data regarding vitamin D and aspects of airway pathology.
Per established protocol, fiberoptic bronchoscopy was performed during the clinical evaluation of a subset of the children
with severe asthma. Using endobronchial biopsy specimens from
these patients, the investigators were able to quantify measures
of tissue inflammation and airway remodeling in the context of
vitamin D status. While there was not a relationship between 25
(OH)D and tissue eosinophils, neutrophils, or mast cells, there
was a significant and inverse correlation between 25(OH)D and
the volume fraction of airway smooth muscle (ASM), independent of differences in myocyte proliferation. This increase in
ASM volume associated with lower vitamin D levels was observed independent of other pathological findings of airway
remodeling. While the authors point out the limitations of their
dataset, and while there are challenges inherent in disentangling
the confounding roles of variables such as environment, race/
ethnicity, atopy, and concurrent treatment in a study of this size
and design, these observations open another dimension in clinical investigation of the vitamin Dasthma association.
Much of the existing literature in pediatric asthma has focused
on vitamin D either as a potential modulator of immune function, for example by reducing exacerbation risk (5), or as a modifier of sensitivity to glucocorticoids (4). But there have also
been reports that reduced serum 25(OH)D is unfavorably associated with measures of airflow, bronchodilator responsiveness,
and airway hyperresponsiveness, and the findings in this manuscript suggest that these observations are mediated in part by
changes in ASM structure and/or function. In some of the
reported clinical studies, vitamin Dassociated alterations in
lung function occur in the absence of concurrent increases in
markers of atopy or airway inflammation, for example, total
IgE, skin prick test reactivity, or circulating eosinophils (3).
Thus, although current concepts regarding airway remodeling
would suggest that increases in ASM cell growth, proliferation,
or migration occur in the setting of ongoing tissue inflammation
and in step with other changes such as subepithelial fibrosis,
basement membrane thickening, and angiogenesis (6), the

clinical literature in this area would suggest that the decoupling

of ASM volume from inflammation reported herein may not be
entirely unexpected. Indeed, the authors speculate that their data
provide in vivo validation of in vitro experiments indicating that
vitamin D has direct inhibitory effects on airway smooth muscle
proliferation, independent of any effects on airway inflammation
(7, 8). Although much remains to be clarified regarding the
mechanisms by which vitamin D alters ASM in vivo, given that
this work was conducted in a pediatric population, it is interesting
to view these data in light of the recent report of Zosky and
colleagues, in which physiologic and histologic assessments in
mice demonstrated a link between vitamin D deficiency and developmental alterations in lung structure and function (9).
A number of mechanisms could underpin the inverse relationship between vitamin D levels and ASM hypertrophy described in this study at the molecular level. The vitamin D
receptor (VDR), a nuclear receptor whose cognate ligand is vitamin D, may repress the activity of prohypertrophic signaling
pathways that are active in the asthmatic airway. Supporting this
notion, vitamin D prevents the induction of asmooth muscle
actin expression in renal myofibroblasts by TGF (10), which has
been implicated in promoting both ASM hypertrophy and myofibroblast activation in asthma. Vitamin D also plays a critical
role in calcium homeostasis and signaling in many tissues, raising the possibility that vitamin D may limit prohypertrophic
signaling associated with excessive airway hyperresponsiveness.
Intriguingly, in cultured ASM, VDR represses RCAN1 expression, a calcineurin inhibitor that regulates cardiac hypertrophy
(11, 12), and additional studies are needed to determine
whether the effects of vitamin D in other contractile cell types
are applicable to ASM biology in asthma.
This study also raises the possibility that the VDR engages in
molecular crosstalk with glucocorticoid signaling in ASM. Although a causal effect of vitamin D deficiency in promoting
ASM hypertrophy could lead to a secondary steroid-resistant
phenotype, it is also possible that vitamin D signaling modulates the activity of the glucocorticoid receptor in airway
smooth muscle at the molecular level. Indeed, in peripheral
blood mononuclear cells, the activation of MKP-1 by glucocorticoids is enhanced by vitamin D (13). In converse, the glucocorticoid receptor is known to cooperatively induce targets of
vitamin D signaling in bone and kidney cells, and also induces
the expression of the VDR itself (14). Moreover, VDR and the
glucocorticoid receptor utilize overlapping transcriptional
co-regulators such as GRIP1 and steroid-activating factor 1,
providing another mechanism for combinatorial crosstalk.
The molecular intersection of VDR and glucocorticoid receptor signaling in ASM remains to be fully determined. It will be
of particular interest to determine whether these signaling
pathways converge to repress ASM hypertrophy independently from antiinflammatory effects, as is suggested by the
findings in this study.
Together, these data suggest that the effects of reduced vitamin D on ASM may occur independently of airway inflammation

Editorials

1325

and may provide a explanation for the reductions in lung function observed with reduced serum 25(OH)D, both in asthma and
in populations without asthma (15). Until the various hypotheses raised by this work are refined and tested further, we are left
concluding that vitamin D status is an easily measurable and
correctable clinical state that might have direct bearing on important clinical parameters such as lung function, bronchodilator responsiveness, and airway hyperresponsiveness, in part via
effects on ASM. The inclusion of appropriate surrogate clinical
outcomes and translational mechanistic aims into ongoing and
future clinical vitamin D supplementation trials in asthma is an
opportunity to determine if this is the case.
Author Disclosures are available with the text of this article at www.atsjournals.org.

Anthony N. Gerber M.D., Ph.D.

E. Rand Sutherland M.D., M.P.H.
Department of Medicine
National Jewish Health
Denver, Colorado
and
Department of Medicine
University of Colorado School of Medicine
Denver, Colorado
References
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Saglani S. Relationship between serum vitamin D, disease severity,
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Med 2011;184:13421349.
2. Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM,
Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, et al. Serum
vitamin D levels and markers of severity of childhood asthma in Costa
Rica. Am J Respir Crit Care Med 2009;179:765771.
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Zeiger RS, Weiss ST, Litonjua AA. Serum vitamin D levels and severe asthma exacerbations in the childhood asthma management
program study. J Allergy Clin Immunol 2010;126:5258.
4. Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY.
Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 2010;
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5. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D

supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 2011;127:
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6. Panettieri RA Jr. Asthma persistence versus progression: does airway
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structure. Am J Respir Crit Care Med 2011;183:13361343.
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inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int 2005;68:15001510.
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Bassel-Duby R, Williams RS, Olson EN. Dual roles of modulatory
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Copyright 2011 by the American Thoracic Society

DOI: 10.1164/rccm.201109-1737ED

Ambient Particulate Air Pollution, Environmental

Tobacco Smoking, and Childhood Asthma: Interactions
and Biological Mechanisms
The World Health Organization (WHO) estimates that 24% of
the global burden of disease is caused by environmental factors
that can be averted (1). Understanding the role of the environment in asthma is a natural ambition in the overall search to
understand environmental burdens: In an individual expressing
the asthmatic phenotype, worsening of asthma control is logically related to environmental agents, and the airways are directly exposed to environmental challenges. As much as 44% of
the asthma disease burden has been attributed to mitigable
environmental risk factors, as opposed to genetic/familial factors or risk factors such as outdoor exposure to pollens (deemed
not modifiable) (1).
Childhood asthma is exacerbated by environmental agents,
many of which are modifiable, including allergens from dust
mites, cockroaches, and other animal and fungal sources; indoor
exposure to dampness; indoor smoke from solid fuels; secondhand smoke (SHS); and ambient air pollution (14). On a typical

day children may be exposed to a number of different environmental agents at home, in daycare centers and schools, and
outdoors. Most research conducted thus far has focused on
the investigation of isolated risk factors. Little is known about
the effects on children of concurrent exposures to multiple risk
factors, and whether they interact with each other to potentiate
adverse effects on asthma or whether one factor might produce
an effect that reduces the effect of another.
In this issue of the Journal, Rabinovitch and colleagues
(pp. 13501357) report novel results from a repeated-measures
study of children aged 6 to 15 years that begins to address this
gap (5). Rather than focusing on individual asthma triggers in
isolation, these investigators used an in-depth panel study of
a relatively small group of children with asthma to evaluate
the interactive effects of SHS and particulate matter air pollution, two common established environmental risk factors,
on disease severity. In particular, they focused on how SHS