Preventive effect of ursolic acid derivative on particulate matter 2.5-induced chronic obstructive pulmonary disease involves suppression of lung inflammation

Article abstract of DOI:10.1002/iub.2201

Respiratory diseases like chronic obstructive pulmonary disease (COPD) are associated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present study, the effect of synthesized ursolic acid derivatives on mice model of PM2.5-induced COPD was investigated in vivo. The mice model of COPD was established by the administration of 25 μL of PM2.5 suspension through intranasal route daily for 1 week. The levels of oxidative stress markers and inflammatory cytokines like tumor necrosis factors-α and interleukin-6 in the mice bronchoalveolar fluids increased markedly on administration with PM2.5. However, treatment with ursolic acid derivative caused a significant suppression in PM2.5-induced increase in oxidative stress markers and inflammatory cytokines in dose-dependent manner. Hematoxylin and eosin staining showed excessive inflammatory cell infiltration in pulmonary tissues in mice with COPD. The inflammatory cell infiltration was inhibited on treatment of the mice with ursolic acid derivative. The ursolic acid derivative treatment increased level of superoxide dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was also prevented on treatment with ursolic acid derivative. Thus, ursolic acid derivative inhibits pulmonary tissues damage in mice through suppression of inflammatory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of therapeutic importance for treatment of PM2.5-induced COPD.

Full text of DOI:10.1002/iub.2201

Received: 4 October 2019
DOI: 10.1002/iub.2201
Accepted: 31 October 2019
R E S E A R C H C O M M U N I C A T I O N
Preventive effect of ursolic acid derivative on particulate
matter 2.5-induced chronic obstructive pulmonary disease
involves suppression of lung inflammation
1
2
3
4
3
Cuini Li | Junxian Chen | Weiwei Yuan | Wei Zhang | Hong Chen
|
3
Hongtao Tan
1
Department of Pharmacy, Guangzhou
Abstract
Haizhu District Changgang Street
Community Service Center, Guangzhou,
Guangdong, China
Respiratory diseases like chronic obstructive pulmonary disease (COPD) are asso-
ciated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present
study, the effect of synthesized ursolic acid derivatives on mice model of
PM2.5-induced COPD was investigated in vivo. The mice model of COPD was
established by the administration of 25 μL of PM2.5 suspension through intrana-
sal route daily for 1 week. The levels of oxidative stress markers and inflammatory
cytokines like tumor necrosis factors-α and interleukin-6 in the mice
bronchoalveolar fluids increased markedly on administration with PM2.5. How-
ever, treatment with ursolic acid derivative caused a significant suppression in
PM2.5-induced increase in oxidative stress markers and inflammatory cytokines
in dose-dependent manner. Hematoxylin and eosin staining showed excessive
inflammatory cell infiltration in pulmonary tissues in mice with COPD. The
inflammatory cell infiltration was inhibited on treatment of the mice with ursolic
acid derivative. The ursolic acid derivative treatment increased level of superoxide
dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was
also prevented on treatment with ursolic acid derivative. Thus, ursolic acid deriva-
tive inhibits pulmonary tissues damage in mice through suppression of inflamma-
tory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of
therapeutic importance for treatment of PM2.5-induced COPD.
2
The First College of Clinical Medicine,
Guangzhou University of Chinese
Medicine, Guangzhou, Guangdong, China
3
Department of Traditional Chinese
Medicine, Huizhou Huiyang Maternity
and Child Health Care Hospital, Huizhou,
Guangdong, China
4
Department of Respiratory Medicine, The
First Affiliated Hospital of Guangzhou
University of Chinese Medicine,
Guangzhou, Guangdong, China
Correspondence
Hongtao Tan, Department of Traditional
Chinese Medicine, Huizhou Huiyang
Maternity and Child Health Care
Hospital, Huizhou, Guangdong 516001,
China.
Email: tht_04@163.com
K E Y W O R D S
anti-inflammatory, bronchitis, cell infiltration, chronic obstructive pulmonary disease,
particulate matter
1
| INTRODUCTION
and have adversely impacted human health. Increased
concentration of particulate matter (PM), particularly
Pulmonary diseases are caused commonly by the inhala-
tion of contaminated air in most of the regions of China
PM2.5 in the atmosphere has led to a sharp rise in the
mortality and morbidity rate because of respiratory
Abbreviations: BALF, bronchoalveolar fluids; COPD, Obstructive pulmonary disease; CrO3, Chromium trioxide; IL‑6, interleukin‑6; PM2.5,
Particulate matter 2.5; TNF‑α, Tumor necrosis factors‑α; TCM, Traditional Chinese Medicine.
©
2019 International Union of Biochemistry and Molecular Biology
IUBMB Life. 2019;1–9.
wileyonlinelibrary.com/journal/iub
1

2
LI ET AL.
1
diseases. The PM present in atmosphere having diame-
ter greater than 2.5 μm is represented by PM2.5. The
characteristic features of PM2.5 that make it harmful
include its potential to aggregate toxic heavy metals, pol-
lutants of organic nature, bacteria, and viruses from the
reduction, the use of dust respirator, and planting more and
more trees alone cannot solve the problem. Therefore, novel
and effective strategies need to be developed for the treat-
ment of PM2.5-induced respiratory diseases.
TCM derived from the plant source has been shown to
be of importance for the treatment of respiratory diseases
2,3
air. Moreover, PM2.5 remains in atmosphere for long
duration and on inhalation deposits in lungs resulting in
serious health diseases. Studies have demonstrated that
PM2.5 induces reactive oxygen species (ROS) and pro-
inflammatory mediator production in lungs leading to
lung damage and injury.
tion of pulmonary tissues following PM2.5 inhalation has
shown marked tissue damage.
Chronic obstructive pulmonary disease (COPD) is associ-
ated with the blocking of lung airways because of degenera-
tion of lung parenchyma and inflammation. Over the past
decade, the rate of morbidity and mortality of COPD patients
has increased gradually which promoted knowledge about
its pathogenesis globally.
excessive exposure to cigarette smoking and atmosphere
22–24
like chronic pneumonia, bronchitis, asthma, and COPD.
2
,3
The mechanism of TCM is believed to involve antibacterial
action, relaxing bronchial smooth muscle, and inhibition of
22–24
inflammatory factors.
Triterpenes serve as potent mole-
4
–6
Histopathological examina-
cules because of significant biological activities and presence
of amenable functionalities. Three members of triterpene
family, namely, betulinic, oleanolic, and ursolic acid are
7,8
25
found abundantly in plants. These three triterpenes possess
promising anti-cancer,26a, b anti-inflammatory,26c and so
forth, properties. Ursolic acid 1, molecule has pentacyclic
structure and present in abundance in the peels of Malus
9
27
pumila Mill. This molecule possesses anti-inflammatory,
9,10
The main causes of COPD are
antiallergic, antibacterial, antiviral, antitumor, and cytotoxic
28–32
activity.
The present study was designed to investigate
2
–4,11
containing PM2.5.
PM having aerodynamic dia-
the effect of ursolic acid derivatives on PM2.5-induced COPD
in vivo in the mice model. The study demonstrated that
ursolic acid derivative inhibited acute PM2.5-induced COPD
through suppression of inflammation cytokines and by oxi-
dative factors in the mice bronchoalveolar fluid (BALF).
These data suggest that ursolic acid derivative acts as a
potential candidate for the treatment of PM2.5-induced
COPD (Figure 1).
meter ≤ 2.5 μm (PM2.5) has adversely impacted health of
human beings worldwide. These small sized particles are
responsible for respiratory system disorders as well as circu-
latory diseases. Researchers from the United States have
shown that increase in PM2.5 concentration to 10 μg/m will
enhance mortality to 0.3–1.2% on short-term exposure and
to 6–13% on long-term exposure. According to researchers
from Europe, mortality of the people exposed for long-term
to air pollution will increase 7% with increase in PM2.5 con-
centration to 5 μg/m
reveals that globally 88% population is already exposed to
3
12
3
.13
World Health Organization report
2 | MATERIALS AND METHODS
2.1 | Synthesis of the compounds (7a-7o)
3
14
PM2.5 level above 10 μg/m , which is harmful to humans.
In China and Japan, increased PM2.5 concentration is con-
sidered to be important environmental problem. The cur-
rently used antibiotics and traditional Chinese medicines
The ursolic acid was oxidized using chromium trioxide
(CrO ), sulfuric acid (H SO ), and acetone to form the
3
2
4
(
TCMs) are believed to inhibit respiratory diseases, including
corresponding oxidized compound 4 in 98% yield
(Scheme 1). The compound 4 was subjected to condensa-
tion reaction with H NNH using potassium hydroxide as
base in ethanol for 6 hr to afford the hydrazone 5. The
compound 5 was reacted with various substituted
α,β-unsaturated ketones under acidic condition to form
the library of compounds (6a-6o) in excellent yields. The
compounds (6a-6o) were treated with palladium acetate
15–18
COPD through anti-inflammatory mechanism.
ever, the presently available antibiotics have limitation of
inducing side effects like weight loss, vomiting, diarrhea,
How-
2
2
19–21
and headaches.
There is urgent need for the develop-
ment of effective treatment strategies for PM2.5-induced
respiratory diseases because the emission of PM is increasing
day-by-day. The controlling measures like PM2.5 emission
FIGURE 1 Chemical structure
of ursolic, betulinic, and oleonolic
acids

LI ET AL.
3
SCHEME 1 Synthesis of ursolic
acid derivatives
and potassium carbonate in chlorobenzene containing
molecular sieves to deliver the corresponding cyclized
compounds (7a-7o).
of urban airborne PM2.5 over 2 weeks. The sampling filter
membrane was partitioned into 2 × 2 cm sections and sub-
sequently subjected to ultrasonic oscillation in the ultrapure
water at room temperature (110 kHz; five times, 40 min
each). The filtrate was collected by filtration through gauze
and centrifuged for 25 min at 16,000× g at room tempera-
ture. After discarding, the supernatant precipitate collected
was put in physiological saline (PS), sterilized in autoclave,
2.2 | Animals
A total of 50 adult male mice (age, 8 weeks and weight,
8–22 g) were obtained from the Experimental Animal Cen-
ꢀ
1
and stored at 4 C after freeze-drying.
ter of Soochow University (Suzhou, China).The mice were
placed in pathogen-free conditions under 12 hr/12 hr light/
ꢀ
dark cycles at room temperature (23 ± 2 C) and 50–70%
2.4 | Establishment of COPD mice model
humidity. The experimental protocols for the mice were per-
formed according to the experimental practices and stan-
dards of the Animal Welfare and Research Ethics
Committee, Zhangjiagang City, Jingfeng People's Hospital
Forty mice were administered 25 μL of PM2.5 suspension
through intranasal route for 1 week daily. The mice in con-
trol group were given equal volumes of PS. The mice admin-
istered with PM2.5 suspension were divided randomly into
four groups of 10 animals each: untreated group, low dose
ursolic acid derivative (LUAD) treatment group (30 mg/kg
ursolic acid derivative), medium dose ursolic acid derivative
(
Suzhou). The study was approved by the Animal Care
Committee, Zhangjiagang City, Jingfeng People's Hospital
Suzhou).
(
(MUAD) treatment group (50 mg/kg ursolic acid deriva-
2
.3 | Collection of PM2.5
tive), and high dose ursolic acid derivative (HUAD) treat-
ment group (100 mg/kg ursolic acid derivative). The ursolic
acid derivative was given for 1 week to the mice once daily.
The mice were monitored daily to record their behavior like
The Thermo Anderson sampler (PDR-1500; Thermo Fisher
Scientific, Inc., Waltham, MA) was used for the collection

4
LI ET AL.
condition of body hair, sensitivity, and respiratory murmur.
On the 21st of PM2.5 administration, the mice were
sacrificed to excise the lungs and collect the BALF.
acid and evaluated against COPD. Oxidation of ursolic
acid 1 was carried out using Jones reagent at 0 C in ace-
ꢀ
tone to get the C-3 oxidized compound 4 (Scheme 1).
Condensation reaction of compound 4 with hydrazine to
afford compound 5 was followed by reaction with
α,β-unsaturated ketones under acidic condition to obtain
the library of compounds (6a-6o). Cyclization of the com-
pounds (6a-6o) was achieved on exposure to palladium
acetate and potassium carbonate in chlorobenzene con-
taining molecular sieves to obtain the corresponding
cyclized compounds (7a-7o; Table 1). All the synthesized
compounds were screened against PM2.5-induced COPD
that led to the identification of 7a and 7 m as the two
most active compounds.
2.5 | Collection and analysis of BALF
The 1 mL volumes of 1× phosphate buffer saline were
injected to the mice lungs and maximum possible volumes
were withdrawn for detection of various markers using the
16
reported protocol. The collected BALF was subjected to
ꢀ
centrifugation for 20 min at 4 C using reported methodol-
16
ogy. Following centrifugation, the supernatants collected
were subjected to analysis of lactate dehydrogenase (LDH),
alkaline phosphatase (ALP), acidic phosphatase (ACP), nit-
ric oxide (NO), nitric oxide synthase (NOS), malonyldial-
dehyde (MDA), and superoxide dismutase (SOD) levels
using the commercially available kits in accordance with
the manual protocol. The levels of TNF-α and IL-6 in the
mice BALF were determined using ELISA kits as per man-
ual protocol.
3.2 | Suppression of pulmonary
inflammation by ursolic acid derivative
(7a) in mice with PM-induced COPD
In the present study, effect of ursolic acid derivative (7a)
on LDH, ACP, ALP, and ALB in the BALF of mice with
COPD was analyzed to determine the changes in lung
biomembrane and parenchyma (Figure 2). The level of
LDH, ACP, ALP, and ALB in the untreated mice was
markedly higher compared to the normal group. This
indicated higher pulmonary inflammation in the
untreated mice than those in the normal group. In the
ursolic acid derivative (7a) treated mice, a significant
reduction in LDH, ACP, ALP, and ALB level was
observed in dose-based manner compared to the
untreated group. The reduction of LDH, ACP, ALP, and
ALB level was maximum in the mice treated with
100 mg/kg dose of ursolic acid derivative (7a).
2.6 | Analysis of lung histology
The upper lobes of left lung were used for analysis of his-
topathological changes. The excised lung tissue samples
were subjected to fixing for 24 hr with 10% buffered for-
ꢀ
malin at 25 C. Following fixing, the lung tissues were
dehydrated using gradient ethanol, paraffin embedded,
and then sliced into 2 μm thin sections. The slices were
subjected to H&E staining for 20 min at room tempera-
ture to examine the infiltration of inflammatory cells.
Examination of tissue sections was performed by light
microscopy for analysis of inflammation, cell infiltration,
tissue degeneration, and accumulation of pus cells.
3.3 | Suppression of oxidative stress
marker level by ursolic acid derivative
(7a) in mice with PM-induced COPD
2.7 | Statistical analysis
The values are presented as the mean ± SD of three exper-
iments performed three times. The one-way analysis of the
variance followed by Fisher's least significant difference
test was used for comparison between groups. p < .05 was
considered to indicate a statistically significant difference.
Effect of ursolic acid derivative (7a) on SOD and NOS
activity and level of NO and MDA in BALF of mice with
COPD was analyzed using ELISA kits (Figure 3). Treat-
ment of the mice with ursolic acid derivative (7a) lead to
a significant increase in the SOD activity compared to
untreated group. The activity of NOS was decreased in
the mice with COPD on treatment with ursolic acid
derivative (7a) in dose-dependent manner. Ursolic acid
derivative (7a) treatment of the mice with COPD also
decreased the levels of NO and MDA in BALF signifi-
cantly (p < .05) in comparison to the untreated group.
Thus, ursolic acid derivative (7a) suppresses PM-induced
oxidative stress in the mice with COPD.
3
3
| RESULTS
.1 | Synthesis of compounds
The library of 15 novel ursolic acid derivatives (7a-7o)
was synthesized using four-step procedure from ursolic

LI ET AL.
5
TABLE 1 The library of ursolic acid derivatives synthesized
3
.4 | Suppression of inflammatory
level of TNF-α and IL-6 in the BALF of untreated mice was
significantly higher in comparison to the normal group.
Ursolic acid derivative (7a) treatment of the mice caused a
marked decrease in the level of both TNF-α and IL-6
in dose-based manner. Treatment of the mice with PM-
induced COPD with ursolic acid derivative (7a) decreased
TNF-α and IL-6 level to minimum at 100 mg/kg dose.
cytokines by ursolic acid derivative (7a) in
mice with PM-induced COPD
The present study analyzed the effect of ursolic acid deriv-
ative (7a) on TNF-α and IL-6 level in the BALF of mice
with PM-induced COPD using ELISA kits (Figure 4). The

6
LI ET AL.
FIGURE 2 Ursolic acid
derivative (7a) decreases PM-
induced increase in LDH, ACP,
ALP, and ALB levels in mice with
COPD. In the mice BALF levels of
LDH, ACP, ALP, and ALB were
measured using ELISA kits. *p < .05
and **p < .02 versus the normal
group
FIGURE 3 Ursolic acid
derivative (7a) regulates PM-induced
changes in MDA, NO, NOS, and
SOD, in mice with COPD. In the
mice BALF levels of MDA, NO,
NOS, and SOD were measured using
ELISA kits. *p < .05 and **p < .05
versus the normal group
FIGURE 4 Ursolic acid derivative (7a) decreases PM-
induced TNF-α and IL-6 level in mice with COPD. The mice
BALF was analyzed for TNF-α and IL-6 levels using
(
a) western blot assay (b) ELISA kits, respectively. *p < .05
and **p < .05 versus the normal group

LI ET AL.
7
FIGURE 5 Ursolic acid derivative (7a) suppresses PM-induced inflammation of pulmonary tissues in mice with COPD. Pulmonary
tissue histopathological changes were examined using hematoxylin and eosin staining of tissue samples in the control, model, and treatment
groups. Magnification, ×200
3
.5 | Inhibition of pulmonary
ursolic acid derivatives against the PM2.5-induced COPD
in mice model in vivo.
inflammation and damage by ursolic acid
derivative (7a) in mice with PM-
induced COPD
PM present in the air is the leading cause of ROS genera-
tion and results in the thickening of bronchial alveolar
33
wall. Exposure to the PM, particularly to PM2.5 for long-
term is linked with the development of respiratory diseases.
It is reported that PM2.5 causes chronic inflammation in
the lungs, which leads to various pulmonary diseases like
H&E staining revealed excessive infiltration of the inflam-
matory cells, accumulation of pus, and degradation of the
alveolar septae in the untreated mice (Figure 5). There was
no inflammatory cell infiltration and pus accumulation in
the mice of normal group. Treatment of the mice with
ursolic acid derivative (7a) markedly inhibited inflamma-
tory cell infiltration, accumulation of pus, and pulmonary
tissue degradation. The pulmonary histological features of
mice treated with 100 mg/kg doses of ursolic acid derivative
34
COPD, pulmonary hypertension, and so forth. There has
been a gradual rise in the incidence rate of respiratory dis-
eases like pneumonia, asthma, and COPD over past decade
because of increase in percentage of PM2.5 in the air. The
PM2.5-induced respiratory diseases are serious concern
worldwide and therefore efforts are put forward to treat
35–37
(7a) were almost similar to those in the normal control
these diseases using TCMs.
It is reported that inflam-
group. This data proved that ursolic acid derivative exhibits
therapeutic effect on PM2.5-induced COPD through sup-
pression of inflammatory cytokines and oxidative factors.
Therefore, ursolic acid derivative has potential to be devel-
oped as the therapeutic agent for respiratory disease
treatment.
mation of lungs induced by cigarette smoke is prevented by
tuberostemonine treatment via suppression of chemokine
38
expression and inflammatory cell infiltration. Resveratrol
treatment of the house dust mite-induced asthma prevents
16
inflammation of pulmonary airways. The functioning of
lungs is improved in the mouse model of PM2.5-induced
lung injury through inhibition of inflammatory cell infiltra-
39
tion by GubenZhike. Mechanistic studies have shown that
environmental toxin inoculation leads to allergic airway
inflammation and identified B cells and antigen-specific
IgG1 as the potent target for treatment of pulmonary dis-
4
| DISCUSSION
Taking into consideration, the wide range of biological
activities of ursolic acid, its availability in abundance,
and bioavailability in the living systems, the present
study was designed to synthesize and evaluate a series of
4,40
eases.
The present study explored the effect of ursolic
acid derivative (7a) on LDH, ACP, ALP, and ALB in the
BALF of mice with COPD. Treatment of the PM-induced

8
LI ET AL.
COPD mice with ursolic acid derivative (7a) significantly
reduced LDH, ACP, ALP, and ALB level in dose-based
manner compared to the untreated group. Thus, ursolic
acid derivative (7a) treatment of mice with PM-induced
COPD exhibited therapeutic effect on pulmonary damage
by inhibiting cell infiltration and pulmonary tissue damage.
Studies have demonstrated that exposure to PM2.5 leads
to innate immune cell and epithelial cell activation
resulting in release of inflammatory cytokines, proteases,
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activity of NOS in mice with COPD. The secretion of NO
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1
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5
| CONCLUSION
In summary, ursolic acid derivative has potential to inhibit
the PM2.5-induced pulmonary damage through suppres-
sion of inflammatory cytokines and anti-oxidant molecule
level. Thus, ursolic acid derivative may be developed as an
effective therapeutic agent for COPD treatment.
1
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