Open Journal of Respiratory Diseases, 2013, 3, 44-51 Published Online May 2013 (
Vitamin A, Vitamin E, Lutein and β-Carotene in Lung
Tissues from Subjects with Chronic Obstructive
Pulmonary Disease and Emphysema
Michael W. Schäffer, Somdutta Sinha Roy, Shyamali Mukherjee, Salil K. Das*
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, USA
Email: *
Received March 2, 2013; revised April 3, 2013; accepted April 10, 2013
Copyright © 2013 Michael W. Schäffer et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Vitamin A (VA) and its active metabolites play an essential role in lung airway function. Patients with moderate to se-
vere chronic obstructive pulmonary disease (COPD) have a lower serum retinol concentration, and improvement of
their 1-second Forced Expiratory Volume (FEV1) is achieved with VA supplementation. In order to test our hypothesis
that the VA signaling pathway is compromised in COPD, we obtained 20 lung samples from COPD patients differing in
the degree of emphysema as judged by their FEV% values. All were smokers or were exposed to secondhand smoke.
Levels of VA (retinol/retinyl ester), tocopherols and carotenoids (lutein, beta-carotene) in these samples were deter-
mined using HPLC. Additional analytes beside VA were included for their known roles as antioxidants and modulators
of VA-action. VA levels (retinol/retinyl ester) decreased significantly with the increase in severity of emphysema.
Among other analytes, α-tocopherol levels fell by 25.8% in the severe emphysema group in comparison to the mild
emphysema group, and lutein levels similarly decreased in severe compared to moderate emphysema groups. However,
beta-carotene levels remained unchanged. Thus there is a significant linear correlation between lung VA-levels and the
severity of emphysema. There was also a significant reduction in the levels of α-, δ-tocopherol and lutein in the severe
emphysema group of COPD patients who either smoked or were exposed to smoke.
Keywords: COPD; β-Carotene; Emphysema; Lutein; Vitamin A; Vitamin E; HPLC
1. Introduction
Chronic bronchitis and emphysema present two types of
COPD. Presently, COPD is the fourth leading killer of
adults in the US and likely to be the third leading cause
of death by 2020 [1]. Approximately 12 million adults
are diagnosed with COPD, 120,000 die from it each year,
and an additional 12 million adults may have undiagnosed
COPD [2]. As an added problem, smokers with COPD
have a higher risk of lung cancer [3].
Previous studies suggested a link between a local res-
piratory vitamin A deficiency and the severity of COPD
[4]. The Second National Health and Nutrition Examina-
tion Survey [5] documented that a smoker’s risk of de-
veloping COPD is dose-dependently decreased by the
intake of vitamin A. Vitamin A and its active metabolite
all-trans retinoic acid (Tretinoin, ATRA) are important
for growth and differentiation of many tissues/organs,
including lung [6,7]. Further, retinoid signaling elements,
such as receptors and binding proteins have been de-
scribed in the adult lung [7]. Numerous findings suggest
that ATRA may protect against emphysema [8,9]. Re-
cently, several studies have shown that ATRA is effec-
tive in promoting alveolization in papain-induced em-
physema in dogs [10] and elastase-induced emphysema
in adult rats [11].
We previously reported that exposure of guinea pigs to
cigarette smoke caused an accumulation of lung retinol
and a decrease in ATRA [12], suggesting an abnormality
in retinoid metabolism and signaling. These findings
raised the question as to whether smoke-associated
COPD similarly result in abnormalities in retinoid me-
tabolism and signaling by altering intracellular levels of
vitamin A, and as a consequence ATRA, its active me-
Tocopherols (vitamin E) are a group of essential
micronutrients that act mainly as lipophilic antioxidants
which protect polyunsaturated fatty acids from oxidative
damage, thus maintaining fluidity and integrity of cellu-
*Corresponding author.
opyright © 2013 SciRes. OJRD
lar membranes [13]. Since smokers subject their lungs to
an increased burden of oxidative damage, a reduction in
lung tocopherol-levels could be a consequence that con-
tributes to the degree of severity of COPD. Although a
systemic vitamin E deficiency is normally unseen in the
Western world, circulating levels of vitamin E can be
reduced in premature infants with bronchopulmonary
dysplasia who are also selenium deficient [14].
Lutein, a dietary carotenoid that serves as a powerful
antioxidant, plays an important role in ocular health and
in the prevention of cardiovascular disease, stroke and
lung cancer [15]. In previous studies we showed that lu-
tein accumulates in guinea pig [16] and human lungs [17].
Although not much is known about the specific role of
lutein in lung, a report [18] identified β-cryptoxanthin
and lutein as natural ligands for the nuclear retinoic acid
receptors (RAR)—especially RARα and RARγ. The ca-
rotenoids β-carotene and lycopene failed to show a simi-
lar activity.
Although the role of dietary antioxidant β-carotene
remains controversial [19]; an epidemiological study re-
ported an inverse correlation between serum β-carotene
and the incidence of lung cancer [20]. In contrast, two
intervention trials (ATCB, CARET) showed that high
doses of β-carotene given to smokers actually raised
rather than lower their chances of developing lung cancer
[21,22]. β-Carotene like lutein is deposited in human
lung tissue [17].
We hypothesized that there is a lung deficiency of vi-
tamin A and vitamin E and some carotenoids in COPD
patients with emphysema, and further that there is a rela-
tionship between the severity of emphysema and the lev-
els of these nutrients. Dietary carotenoids were included
because of their roles as potential effectors on the vita-
min A-signaling pathway and contributors to the anti-
oxidant capacity of the cells.
We therefore analyzed lung tissues from 20 COPD pa-
tients classified as having mild, moderate or severe em-
2. Materials and Methods
Human lung samples, preparation/extraction. Frozen
human lung samples were obtained from the Lung Tissue
Research Consortium (LTRC) of the National Heart,
Lung, and Blood Institute, Bethesda, MD. Until extrac-
tion for analysis, samples were stored at 80˚C. The
LTRC provided us with de-identified information re-
garding lung tissue donors including age, gender, smok-
ing habits, FEV1% values, and the location from which
the samples were taken. The characteristics of the human
subjects whose biopsies were used for HPLC-analyses
are described in Table 1. Nine subjects were categorized
as having “severe emphysema” with FEV1% value <50
(average age was 52.6 ± 6.7 years), 8 subjects were cate-
Table 1. Characteristics of subjects.
ID Gender* Age FEV1% Smoking Origin*
192361 F 50 12 yes RM
242420 M 63 14 yes LL
294945 F 52 15 yes RM
122541 F 55 19 yes RM
157421 M 46 20 yes RM
12861 M 51 22 yes LL
132625 F 63 24 yes RM
295167 M 49 27 yes LL
126571 M 44 40 yes RM
200930 F 78 52 yes RL
26458 M 73 54 yes RL
183561 M 83 57 yes RU
271851 M 77 68 yes LU
144462 F 73 69 yes RM
158231 F 61 72 yes LU
178967 F 72 72 yes RL
30753 M 75 77 no LL
260111 F 61 84 yes RM
261361 F 63 89 yes RL
176562 M 73 105 yes LLO
*Abbreviations: M = male; F = female; LLO = left lower; LL = left ling; LU
= left upper; RL = right lower; RM = right middle; RU = right upper.
Secondhand smoke; FEV1%-range: <50 severe, 50 - 80 moderate, >80
gorized as having “moderate emphysema” with FEV1%
values ranging between 50 - 80 (average age was 72.3 ±
7.8 years), and 3 subjects were categorized as having
“mild emphysema” with FEV1% values > 80% (average
age was 65.7 ± 4.4 years). The average age of all 20 sub-
jects was 62.9 ± 11.7 years; 52.4% were male and 47.6%
were female. Amongst these subjects, only one was a non-
smoker but was subjected to cigarette smoke at home.
HPLC analysis, chemicals and reagents. Chemical and
reagent resources, and High Pressure Liquid Chromatog-
raphy (HPLC)-analyses were carried out as described
earlier [17]. On average 100 mg of each lung was ho-
mogenized, extracted and analyzed by HPLC for the
analytes of 1) retinol and their found storage forms reti-
nyl palmitate (RP) and retinyl stearate (RS), 2) toco-
pherols (α, β/γ and δ) and 3) carotenoids (lutein and
β-carotene). Values are expressed as mean ± standard
error of the mean (SEM). Statistical analyses were per-
formed using GraphPad Prism Version 5.04 (GraphPad
software, San Diego, CA). Statistical significances (P-
values) were calculated using an unpaired t-test (www. to each of 8 analytes concentrations in
Copyright © 2013 SciRes. OJRD
mild vs. moderate***, moderate vs. severe** and mild vs.
3. Results
3.1. HPLC Analysis
Figure 1 provides overlaid chromatograms of two repre-
sentative lung samples from a patient with either severe
(lower trace) or moderate emphysema (upper trace) at
three different wavelengths in order to detect retinoids
(Figure 1(a)), tocopherols (Figure 1(b)) and carotenoids
(Figure 1(c)).
3.2. Vitamin A
Samples were extracted and analyzed by HPLC for the
analytes retinol (ROH) and their found storage forms RP
and RS. Values for the total vitamin A content were cal-
culated by adding found values for ROH, RP and RS per
sample, given as nmol retinol per gram lung tissue. The
mean and the corresponding SEM for each analytes in
each group (mild: n = 3; moderate: n = 8; severe: n = 9)
was calculated and plotted as a bar graph in Figure 2(a).
Results using an unpaired t-test for vitamin A metabo-
lites showed that difference in ROH-levels between the
mild and the severe group were significant (*). However,
the changes in total vitamin A were significantly differ-
ent not only between the mild and severe group, but also
between the moderate and the severe group (data not
shown). The differences between RP values for moderate
vs severe group (**) were highly significant (P < 0.005).
Since our collection of samples comprises a wide
range of FEV1% in patient values (Table 1), we plotted
those values against total vitamin A concentrations (Fig-
ure 2(b)) in order to determine if there was a linear rela-
tionship. The resulting graph demonstrates a significant
inverse relationship between the total vitamin A lung lev-
els as a function of the severity of emphysema in those
patients (r2 = 0.3035, P = 0.0145). Amongst the deter-
mined vitamin A-analytes, only the data for retinol
showed a similar behavior, although with a smaller cor-
relation coefficient (r2 = 0.2651).
As an allover trend, vitamin A values tended to de-
crease with increasing severity of emphysema.
3.3. Vitamin E
Samples were extracted and analyzed by HPLC for their
vitamin E content, which included analytes for α, β/γ and
δ-tocopherol. The mean and the corresponding SEM for
each analytes in each group (α-, β/γ-tocopherol: mild: n =
3; moderate: n = 7; severe: n = 9; γ-tocopherol: mild: n =
3; moderate: n = 8; severe: n = 9) was calculated and
plotted as a bar graph in Figure 3. Results from the un-
paired t-test for tocopherol analytes showed that only the
Figure 1. Chromatograms of two representative lung sam-
ples (upper: moderate, lower: severe) at different detection
wavelengths. A: λ = 350 nm for vitamin A analytes; B: λ =
292 nm for vitamin E analytes; and C: λ = 450 nm for lutein
and β-carotene. To allow for a direct comparison, the chro-
matograms were normalized to the same weight of lung
sample. Numbers refer to each corresponding peak in both
overlaid chromatograms. Peak assignments: (a) 1-all-trans
retinol, 2-all-trans retinyl acetate (Internal Standard), 3-
all-trans retinyl palmitate, and 4-all-trans retinyl stearate;
(b) 5-δ-tocopherol, 6-β/γ-tocopherol, and 7-α-tocopherol; (c)
8-lutein, and 9-β-carotene. It should be noted that the ap-
plied separation method17 does not distinguish between the
two isomers γ-tocopherol and β-tocopherol. Values will
therefore represent always a sum of both analytes.
Copyright © 2013 SciRes. OJRD
Figure 2. Vitamin A values (a) Bar graph of the mean and
the corresponding SEM for the found values of retinol, ret-
inyl palmitate and retinyl stearate, expressed in nmol reti-
nol per gram wet weight lung tissue in each group (mild: n
= 3; moderate: n = 8; severe: n = 9). Significances (P < 0.05)
from unpaired t-test are indicated by *) for mild vs. severe
and **) for moderate vs. severe values; (b) Demonstration
of an inverse linear correlation between the degree of em-
physema, expressed in FEV1%-values and the calculated
amount of total vitamin A (= [ROH] + [RP] + [RS]) given in
nmol retinol per gram wet weight lung tissue.
changes in δ-tocopherol levels between the moderate and
severe group (**, Figure 3(c)) were statistically highly
significant (P < 0.005). Although not statistically sig-
nificant, there was a decrease of 25.8% in α-tocopherol
levels in the severe group compared to samples in the
mild group (Figure 3(a)). Changes of β/γ-tocopherol-
levels between the groups were not significantly different
from each other, however amongst the tested vitamin E
analytes; it is the only one that showed increased levels
with increasing severity, for e.g. the β/γ-tocopherol-lev-
els in the severe group were 21.8% higher on average
than in the mild group (Figure 3(b)).
3.4. Carotenoids
We also assayed for the carotenoids lutein and beta-
carotene. The mean and the corresponding SEM for the
analytes lutein (mild: n = 3; moderate: n = 7; severe: n =
9) and beta-carotene (mild: n = 3, moderate: n = 8, severe:
n = 9) in each group was calculated and plotted as a bar
graph (Figure 4). The levels of beta-carotene between
Figure 3. Vitamin E values. Bar graph of the mean and the
corresponding SEM for the found values of (a) α-tocopherol;
(b) β/γ-tocopherol and (c) δ-tocopherol, expressed in g per
gram wet weight lung tissue in each group (α-, β/γ-toco-
pherol: mild: n = 3; moderate: n = 7; severe: n = 9; δ-toco-
pherol: mild: n = 2; moderate: n = 8; severe: n = 9). Signifi-
cances (P < 0.05) from unpaired t-test are indicated by **)
for moderate vs. severe. It should be noted that α-toco-
pherol-levels are found to be an order of magnitude higher
than those for γ/β-tocopherol, which are again an order of
magnitude higher than in the detected δ-tocopherol-levels.
the groups did not change. In contrast, changes in lutein
levels between the moderate and severe group were sta-
tistically significant (**, Figure 4). Interestingly, lung
tissue harvested from subjects in the moderate group
accumulated almost twice the lutein than samples from
the other two groups.
4. Discussion
There have been a number of human studies that have
Copyright © 2013 SciRes. OJRD
Figure 4. Carotenoid values. Bar graph of the mean and the
corresponding SEM for the found values of lutein and β-
carotene, expressed in μg per gram wet weight lung tissue in
each (lutein: mild: n = 3, moderate: n = 7, severe: n = 9;
β-carotene: mild: n = 3, moderate: n = 8, severe: n = 9),
Significances (P < 0.05) from unpaired t-test are indicated
by **) for moderate vs. severe lutein values.
attempted to correlate intake of various micronutrients to
the outcomes of COPD, asthma, bronchopulmonary dys-
plasia and lung cancer using either by nutritional surveys
or blood chemistries with a variety of outcomes and con-
clusions [4,5]. They lacked, however, information about
the concentration and composition of the analytes in the
lung tissue, per se. To our knowledge, we report here for
the first time the HPLC-analysis of micronutrients vita-
mins A and E and the carotenoids lutein and β-carotene
in lung samples from human COPD subjects with vary-
ing degrees of emphysema.
In the case of vitamin A and its metabolites, earlier
studies showed that the risk for COPD increased with
decreasing serum vitamin A [23,24]; and that daily oral
doses of vitamin A (25,000 IE) for 30 days attenuated the
symptoms [25].
Although the overall homeostatic regulation of plasma
retinol values was unaffected by the pathologic condi-
tions of COPD, Paiva et al. [4] found a positive correla-
tion between serum retinyl esters and FEV1/FVC-values
in healthy smokers and in patients with moderate to se-
vere COPD; again there was an improvement in pulmo-
nary functions after vitamin A supplementation. Al-
though smokers with COPD usually do not have a sys-
temic vitamin A deficiency [4], a local deficiency may
occur as a result of chronic exposure to cigarette smoke.
Our results show that lung vitamin A levels fell with
the progression of disease, as judged by FEV1% values.
This local vitamin A deficiency may be caused by an
increased demand for its active form ATRA, followed by
a depletion of intra-cellular retinyl ester stores. We have
found a highly statistically significant decrease in RP
levels in the severe vs. moderate groups. This could be
explained by an increased preference of retinyl ester hy-
drolase towards the palmitate-ester over the stearate-ester.
Indeed, a report [26] showed that palmitate is the pre-
ferred fatty acyl moiety over stearate.
In addition, exposure to the environmental toxicant
benzo [a] pyrene decreased the uptake of vitamin A into
lung cells [27] and led to a local vitamin A deficiency in
lung tissues [28]. The cellular uptake of retinol into tar-
get tissue is mainly mediated by the membrane-bound
STRA6-receptor [29]. Since vitamin A is depleted in
lungs of COPD-patients, ATRA-levels could also be sig-
nificantly reduced. This is important because ATRA is
required for the activation of STRA6-gene expression
[29]. Thus, it seems likely that reduced STRA6-levels
would aggravate a local vitamin A-deficiency. We are
currently investigating this question in our laboratory.
Since a systemic supplementation may have severe
toxic side effects, others have proposed the uptake of
either vitamin A or ATRA in the lung by inhalation. Bi-
esalski et al. [30] demonstrated that inhalation of an RP-
aerosol can successfully improve the vitamin A status of
preschool children. Furthermore, Kohlhäufl et al. [31]
reported a complete reversal of metaplasia/dysplasia in
44% (and partial remission in 12%) of biopsies from
smokers with premalignant lesions of the bronchial epi-
thelium who were administered aerosolized vitamin A.
Interestingly, a recent case study [32] on a 45-year-old
patient with severe emphysema, a never smoker individ-
ual on a 6-month controlled ATRA-inhalation therapy,
showed signs of improvement in daily life in terms of the
hours spent without oxygen supplementation and a re-
duction in inflammatory markers such as serum IL-13.
Although our data do not reveal if the local vitamin
A-deficiency is a cause or a consequence of COPD, a
therapy with inhalable formulations of vitamin A may be
beneficial for the alleviation of symptoms while avoiding
potential side effects by administration of this vitamin.
However a recent study demonstrated the increased sus-
ceptibility to the development of cigarette smoke-in-
duced lung emphysema in mice with low but not defi-
cient vitamin A status [33].
The most abundant tocopherol in the human lung, α-
tocopherol, fell 25.8% from values in the mild to severe
groups. The reduced availability of this antioxidant may
be scientifically important, since these patients face an
increased oxidative stress burden due to cigarette smoke.
In a recent case-control study with 1088 lung cancer pa-
tients and 1414 healthy matched controls, investigators
[34] reported that an increased intake of dietary α-toco-
pherol accounted for a 34% - 53% reduction in lung
cancer risk. Thus the found 25.8%-reduction in α-toco-
pherol levels in lungs in our study may be a critical risk
factor for the development of lung cancer in COPD pa-
tients. Since α-tocopherol inhibits retinyl ester hydrolase
(REH) activity [35], the drop in α-tocopherol-levels may
also reduce its ability to inhibit REH, resulting in a re-
duction in RP.
There is emerging evidence that tocopherols in addi-
Copyright © 2013 SciRes. OJRD
tion to their antioxidant properties have other distinct
functions, for example they can have direct and indirect
effects on several enzymes involved in signal transduc-
tion [36] and anti-inflammatory effects [37]. Recent evi-
dence suggested that δ- and α-tocopherol and their me-
tabolites are more potent inhibitors of cyclooxygenase-2
(COX-2) than α-tocopherol [37,38]. Interestingly, an-
other report [39] showed that the expression of COX-2 in
lungs of COPD patients with lung cancer was signifi-
cantly increased compared to control subjects. This study
together with our observation of finding decreased α- and
δ-tocopherol levels in these patients, suggest the in-
volvement of low tocopherols and high COX-2 levels in
COPD-related lung cancer.
Our findings that lutein levels significantly decrease
whereas beta-carotene levels do not change cannot be
simply explained by differences in dietary consumption.
There is increasing evidence that the uptake, distribution
and their function in the body are tightly regulated by
different enzymes. Beta-carotene, for e.g. is transported
primarily in very low-density lipoproteins (VLDL) and
low-density lipoproteins (LDL), whereas lutein has a
preference for high-density lipoproteins (HDL) [40]. In
combination with specific cell surface receptors, the
apolipoprotein components of the lipoproteins assist the
carotenoids to their specific target tissue. Cellular LDL-
receptors mediate beta-carotene uptake [40], whereas
lutein uses class B scavenger receptors [41]. Interestingly,
the steroidogenic acute regulatory domain 3 (StARD3)
protein, also known as MLN64, has recently been identi-
fied as a lutein-binding protein in the human retinal mac-
ula [40]. Furthermore, StARD3 is involved in intra-cel-
lular cholesterol transport [41]. Since StARD3 is ex-
pressed in many tissues including lung [42], we hypothe-
size that this protein may mediate lutein uptake in lung
and when its function is compromised under significant
oxidative stress, this leads to a reduction of lung lutein
Our overall results suggest that with increasing sever-
ity of emphysema in COPD patients, the levels of retinol
and total vitamin A (retinol + ester) are reduced in lung.
Together with changes seen in lutein and α- and δ-toco-
pherol, critical components of the cellular antioxidative
defense have been reduced.
Among the COPD subjects included in this study,
most were firsthand smokers, only one was secondhand
smoker and none represented nonsmoker. Also there was
no non-diseased control group. The limitation of the cur-
rent study needs to be controlled by inclusion of these
additional groups. It will be interesting to investigate
whether blood levels of the nutrients of the COPD sub-
jects vary with the degree of emphysema. Furthermore,
we are currently investigating whether expression of cer-
tain mediators of retinoid action (trafficking, metabolism
and signaling) in lung of COPD patients vary with the
degree of emphysema.
5. Acknowledgements
This work was supported by NIH grant 1R03 HL095419-
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