The Inhibitory Effect of Curcumin on Virus-Induced Cytokine Storm and Its Potential Use in the Associated Severe Pneumonia

Abstract

Coronavirus infection, including SARS-CoV, MERS-CoV, and SARS-CoV2, causes daunting diseases that can be fatal because of lung failure and systemic cytokine storm. The development of coronavirus-evoked pneumonia is associated with excessive inflammatory responses in the lung, known as “cytokine storms,” which results in pulmonary edema, atelectasis, and acute lung injury (ALI) or fatal acute respiratory distress syndrome (ARDS). No drugs are available to suppress overly immune response-mediated lung injury effectively. In light of the low toxicity and its antioxidant, anti-inflammatory, and antiviral activity, it is plausible to speculate that curcumin could be used as a therapeutic drug for viral pneumonia and ALI/ARDS. Therefore, in this review, we summarize the mounting evidence obtained from preclinical studies using animal models of lethal pneumonia where curcumin exerts protective effects by regulating the expression of both pro- and anti-inflammatory factors such as IL-6, IL-8, IL-10, and COX-2, promoting the apoptosis of PMN cells, and scavenging the reactive oxygen species (ROS), which exacerbates the inflammatory response. These studies provide a rationale that curcumin can be used as a therapeutic agent against pneumonia and ALI/ARDS in humans resulting from coronaviral infection.

Full text

fcell-08-00479 June 10, 2020 Time: 20:51 # 1
REVIEW
published: 12 June 2020
doi: 10.3389/fcell.2020.00479
Edited by:
Giulia De Falco,
Queen Mary University of London,
United Kingdom
Reviewed by:
Gabriele Margiotta,
Istituto Nazionale della Previdenza
Sociale, Italy
Changyan Chen,
Northeastern University, United States
*Correspondence:
Ying Ying
yingying@ncu.edu.cn
Specialty section:
This article was submitted to
Molecular Medicine,
a section of the journal
Frontiers in Cell and Developmental
Biology
Received: 25 April 2020
Accepted: 22 May 2020
Published: 12 June 2020
Citation:
Liu Z and Ying Y (2020) The
Inhibitory Effect of Curcumin on
Virus-Induced Cytokine Storm and Its
Potential Use in the Associated
Severe Pneumonia.
Front. Cell Dev. Biol. 8:479.
doi: 10.3389/fcell.2020.00479
The Inhibitory Effect of Curcumin on
Virus-Induced Cytokine Storm and
Its Potential Use in the Associated
Severe Pneumonia
Ziteng Liu1,2 and Ying Ying1,3*
1Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, School of Basic Medical Sciences,
Nanchang University, Nanchang, China, 2Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang,
China, 3Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
Coronavirus infection, including SARS-CoV, MERS-CoV, and SARS-CoV2, causes
daunting diseases that can be fatal because of lung failure and systemic cytokine
storm. The development of coronavirus-evoked pneumonia is associated with excessive
inflammatory responses in the lung, known as “cytokine storms,” which results in
pulmonary edema, atelectasis, and acute lung injury (ALI) or fatal acute respiratory
distress syndrome (ARDS). No drugs are available to suppress overly immune response-
mediated lung injury effectively. In light of the low toxicity and its antioxidant, anti-
inflammatory, and antiviral activity, it is plausible to speculate that curcumin could be
used as a therapeutic drug for viral pneumonia and ALI/ARDS. Therefore, in this review,
we summarize the mounting evidence obtained from preclinical studies using animal
models of lethal pneumonia where curcumin exerts protective effects by regulating the
expression of both pro- and anti-inflammatory factors such as IL-6, IL-8, IL-10, and
COX-2, promoting the apoptosis of PMN cells, and scavenging the reactive oxygen
species (ROS), which exacerbates the inflammatory response. These studies provide
a rationale that curcumin can be used as a therapeutic agent against pneumonia and
ALI/ARDS in humans resulting from coronaviral infection.
Keywords: curcumin, coronavirus, cytokine storm, pneumonia, lung injury
INTRODUCTION
During the Spanish influenza pandemic in 1917–1918, it was found that the deaths were not
just seen in the elderly with weak immunity, but also young individuals with normal immunity.
As part of a robust immune response in severe cases, the virus triggers overaction of immune
systems, producing a large number of inflammatory factors, which causes severe damage to the lung
and manifests acute respiratory distress syndrome (ARDS), resulting in high mortality. The same
damaging effects of immune over-reaction were observed in outbreaks of severe acute respiratory
syndrome coronavirus (SARS-CoV) (Huang et al., 2005;Channappanavar and Perlman, 2017),
middle east respiratory syndrome CoV (MERS-CoV) (Channappanavar and Perlman, 2017), highly
pathogenic avian influenza viruses (including H5N1 and H7N9) (Kalil and Thomas, 2019), and
novel coronavirus (SARS-CoV2) (Yao et al., 2020).
Frontiers in Cell and Developmental Biology | www.frontiersin.org 1June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 2
Liu and Ying Curcumin and Viral Pneumonia
Inflammation under physiological conditions is a protective
mechanism that acts to eliminate exogenous agents invading to
living bodies, remove necrotic tissues and cells, and promote
damage repair (Netea et al., 2017). Being said that the
inflammation initiates a protective immune response when it is
confined to locally affected tissues. However, when the negative
regulatory mechanism is suppressed, a persistent and extensive
inflammatory reaction occurs, which can reach pathological
levels causing fatally systemic damage (Torres et al., 2017). Such
an inflammatory response, including overproduction of immune
cells and pro-inflammatory cytokines, is defined as the cytokine
storm that usually occurs in viral infection and causes acute lung
injury (ALI) and ARDS. Resulting symptoms include congestion,
atelectasis, and pulmonary edema, which affects oxygen exchange
in the lung and eventually lead to death (Wheeler and Bernard,
2007). There is no effective regime for cytokine storm and
resultant lung injury. Therefore, drugs to suppress the cytokine
storm are urgently needed to treat deadly virus infection that
causes lung damage and ARDS.
Curcumin[(1E,6E)-1,7bis(4-hydroxy-3-methoxyphenyl)-1,6-
heptadiene-3,5-dione] is a natural medicine mainly extracted
from plants of the Curcuma longa that has a long history to be
used in humans in treating diseases without overt side effects.
Numerous in vitro and in vivo studies indicate that curcumin has
antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic
activity (Xu et al., 2018). Several clinical investigations have
reported beneficial effects in treating cardiovascular diseases,
metabolic syndrome, or diabetes, and infectious diseases,
especially viral infection (Yang et al., 2014;Basu et al., 2013;
Amalraj et al., 2017;Alizadeh et al., 2018;Asadi et al., 2019).
All of these clinical findings point to that curcumin alleviates
these diseases mainly via modulation of immune responses.
Indeed, some preclinical studies have suggested that curcumin
could inhibit the cytokine storm induced by the viral infection
(Dai et al., 2018;Richart et al., 2018;Praditya et al., 2019;Vitali
et al., 2020). Therefore, in this review, we outline the relationship
between virus infections and cytokine storm and discuss the
potential use of curcumin in treating viral infection-triggered
ARDS. We hope to provide useful information and references for
clinicians in combating devastating severe pneumonia caused by
SARS-CoV2, a current global pandemic.
VIRAL INFECTION AND CYTOKINE
STORM
Cytokine storm arises from different factors that could derive
from autoimmune, inflammatory, iatrogenic, and infectious
origins (Behrens and Koretzky, 2017). It is characterized by the
production of excessive amounts of inflammatory cytokines as
a result of unchecked feedforward activation and amplification
of immune cells. Its clinical manifestations include systemic
inflammation, multi-organ failure, hyperferritinemia, which
is referred to as “cytokine storm syndrome” and could be
lethal if untreated.
Under physiological conditions, the steady-state cytokine
levels are maintained by negative and positive feedback
regulation of their expression (Behrens and Koretzky, 2017).
A large amount of virus in the body will induce over-reacted
innate and adaptive immune response, triggering extravagant
cytokines release and lymphocytes activation. Common to
cytokine storm syndromes engendered by all insults is a loss of
negative regulation of the production of inflammatory cytokines,
which in turn drives a positive feedback regulation, leading to
exponentially growing inflammation and multi-organ failure.
At an early stage, virus infection induces host cells to
generate cytokines and chemokines, inflammatory mediators,
and apoptosis of the host cells, which then attracts immune cells
to the damaged areas (Liu et al., 2016). Macrophages, dendritic
cells, and mast cells engulf antigen fragments, virus, and virus-
bearing damaged cells, which triggers the production of the
inflammatory mediators. Myeloid cells, including monocytes,
neutrophils, and dendritic cells, contain multiple pattern
recognition receptors (PRRs) on their surfaces to help them
recognize and bind to viruses via Pathogen-associated molecular
patterns (PAMPs) such as viral RNA/DNA, or damage-associated
molecular patterns (DAMPs) from necrotic tissue and cells
in aseptic inflammation. Subsequently, the immune cells are
activated and produce pro-inflammatory cytokines, including
tumor necrosis factor-α(TNF-α), interleukin (e.g., IL-1β, IL-
6), and interferon-gamma (IFN-γ) (Taniguchi and Karin, 2018).
The release of cytokine causes increased vascular permeability;
consequently, the leukocytes increasingly migrate to damaged
tissues through margination, rolling, adhesion, transmigration,
and chemotaxis. Activated leukocytes simultaneously release
prostaglandins and inflammatory factors, and activate the
complement system, producing C3a and C5a components
that kill pathogens (Medzhitov, 2008;Straub et al., 2015;
Netea et al., 2017).
An additional effect of cytokines is to activate NADPH oxidase
in leukocytes, leading to the generation of reactive oxygen species
(ROS) such as superoxide, hydroxyl radicals, and singlet oxygen
(Liu et al., 2016). On the one hand, ROS helps to remove proteins,
lipids, and nuclear acids of the damaged cells and activate
immune cells to eliminate foreign microorganisms through
extracellular mechanisms (Zhang et al., 2016). On the other
hand, ROS acts as a second messenger to regulate intracellular
signaling events. For example, it activates the nuclear factor-
κB (NF-κB) to promote further production of pro-inflammatory
cytokines such as TNF-α, IL-6, IL-8, and other inflammatory
factors (Baldwin, 1996;Cohen et al., 2009;Zhang et al., 2016;
Hellebrekers et al., 2018;Khan and Khan, 2018). Therefore,
pro-inflammatory cytokines and ROS exert forward feedback
regulation of their production.
The inflammatory response can be turned off by the anti-
inflammatory cytokine IL-10 (Opal and DePalo, 2000). The
positive and negative regulatory inputs maintain normal innate
immunity. However, if the balance is disturbed in some cases,
for instance, inhibition of the immuo-suppressor cytokine
IL-10, a cytokine storm takes place. Infections from such
viruses as Ebola, avian influenza, dengue, and coronavirus,
can lead to cytokine storms, producing a massive amount
of pro-inflammatory cytokines. The concerted action of these
inflammatory mediators causes the destruction of tissues and
Frontiers in Cell and Developmental Biology | www.frontiersin.org 2June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 3
Liu and Ying Curcumin and Viral Pneumonia
cells, manifested by clinical syndromes such as extensive
pulmonary edema, alveolar hemorrhage, ARDS, and multiple
organ failures (Matthay and Zimmerman, 2005;Lau et al., 2013;
Sordillo and Helson, 2015;Channappanavar and Perlman, 2017;
Amini et al., 2018) (Figure 1).
There is clear evidence from coronavirus infected patients
with both high cytokine levels and pathological changes in the
lung (Wang et al., 2007;Channappanavar et al., 2016;Chen et al.,
2020;Wu et al., 2020). For example, in plasma of COVID-19
patients, high concentrations of IL-2, IL-6, and IL-7 have been
observed (Chen et al., 2020;Green, 2020;McGonagle et al.,
2020;Wu et al., 2020). In particular, IL-6 was significantly
elevated in critically ill patients with ARDS compared to patients
without ARDS and was statistically significantly correlated with
death (Wu et al., 2020). Both patients with mild or severe
symptoms had pneumonia, and 29% of patients developed ARDS
(Wang et al., 2020).
CURCUMIN INHIBITS INFLAMMATORY
REACTION
Inhibition of the Production of
Pro-Inflammatory Cytokine
Numerous in vivo and in vitro studies have been shown that
curcumin and its analogs markedly inhibit the production and
release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8,
TNF-α(Avasarala et al., 2013;Zhang et al., 2015;Dai et al., 2018;
Zhang et al., 2019). In line with this, Zhang et al. (2019) have
observed that direct pulmonary delivery of solubilized curcumin
dramatically diminishes pro-inflammatory cytokines IL-1β, IL-
6, TNF-αin the BAL cells, the lung and serum of mice with
severe pneumonia induced by Klebsiella. In addition, curcumin
also decreases expression of many other inflammatory mediators,
including MCP1(CCL2), MIPI1 (CCL3), GROα(CXCL1), GROβ
(CXCL2), IP10 (CXCL10), SDF1 (CXCL12), MMP-2, IFN-γ,
and MMP-9, which regulate the activity of immune cells and
inflammatory responses and promote fibrosis in the lung after
infection (Sordillo and Helson, 2015;Dai et al., 2018).
The mechanism underlying curcumin modulation of
inflammation has been extensively investigated and engages
diverse signaling pathways, among which NF-κB plays an
essential role (Cohen et al., 2009;Salminen et al., 2011;Han
et al., 2018). It was reported that curcumin effectively regulates
NF-κB signaling through multiple mechanisms (Figure 2): First,
curcumin inhibits activation of IKKβ(Cohen et al., 2009). In a
study of patients with head and neck cancer receiving curcumin,
reduced activity of IKKβwas observed in saliva samples,
associated with a decrease in the expression of IL-8, TNF-α,
and IFN-γ(Kim et al., 2011). Second, curcumin enhances the
expression or stability of IκBα(Jobin et al., 1999;Han et al., 2018;
Chen et al., 2019). Curcumin inhibits the IκBαdegradation,
phosphorylation of IκB serine 32 to block the cytokine-mediated
FIGURE 1 | The diagram of lung injury caused by virus-induced cytokine storms. (A) The viruses attack alveolar epithelial cells and are recognized by dendritic cells
and macrophages, which then release cytokines. (B) Cytokines and chemokines help white blood cells in the blood reach the alveoli. (C) Antigen-presenting cells
(dendritic cells) activate lymphocytes. Activated lymphocytes produce and release large amounts of cytokines while attacking infected alveolar epithelial cells.
(D) Induce cytokine storm, and capillary leak syndrome. (E) Causes atelectasis, pulmonary edema, pulmonary congestion, and ARDS.
Frontiers in Cell and Developmental Biology | www.frontiersin.org 3June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 4
Liu and Ying Curcumin and Viral Pneumonia
FIGURE 2 | Curcumin inhibits the production of pro-inflammatory cytokine by targeting the NF-κB pathway. Curcumin targets NF-κB signaling through inhibiting
activation of IKKβ, enhancing expression or stability of IκBα, activating AMPK, and targeting P65.
NF-κB activation and thus pro-inflammatory gene expression
(Jobin et al., 1999). Third, curcumin activates AMPK (Han et al.,
2018). It has been documented that curcumin blocks NF-κB
signaling upon infection with Influenza A virus (IAV) as a
consequence of AMPK activation (Han et al., 2018). Fourth,
curcumin acts on p65 to disturb the NF-κB pathway (Xu and Liu,
2017). Infection with IAV led to a decrease of p65 in the cytosol
of macrophages and a corresponding increase in the nucleus,
where it forms a functional complex with NF-κB, ultimately
upregulating transcription of pro-inflammatory cytokines. In
contrast, the use of curcumin blocks the nuclear translocation
of NF-κB and p65, downregulating transcription of the cytokine
genes (Xu and Liu, 2017).
Other inflammatory mediators have been reported to be
regulated by curcumin. One of them is cyclooxygenase 2 (COX-
2), a key enzyme for the synthesis of prostaglandin (Khan
and Khan, 2018). In an animal model of chronic obstructive
pulmonary disease, it has been shown that curcumin treatment
effectively inhibits the degradation of IκBαand disturbs the
production of COX-2 (Yuan et al., 2018). In addition to
disrupting the NF-κB pathway, curcumin inhibits the virus-
induced expression of TLR2/4/7, MyD88, TRIF, and TRAF6
genes, and blocks IAV-induced phosphorylation of Akt, p38, JNK
as well (Sordillo and Helson, 2015;Dai et al., 2018).
Regulation of Anti-inflammatory
Cytokines
In contrast to its negative effect on pro-inflammatory molecules,
curcumin has been shown to regulate anti-inflammatory
cytokines positively, in particular IL-10 (Larmonier et al., 2008;
Chen et al., 2018;Mollazadeh et al., 2019;Chai et al., 2020).
The latter is an essential negative regulator for inflammatory
responses and is secreted by the dendritic cells that bind
to DAMP released from damaged cells during aseptic or
antigenic inflammatory reactions. IL-10 acts on inflammatory
monocytes to reduce the release of TNF-α, IL-6, and ROS,
thereby alleviating tissue damage caused by the continuous
inflammatory response (Bamboat et al., 2010). Moreover, IL-
10 drives the differentiation of Tregs (Mollazadeh et al.,
2019). An early study has shown that IL-10 reduces the
expression of intercellular adhesion molecule-1 (ICAM-1) on
pulmonary vascular and TNF-αlevels, which cause reduction
of the expression of myeloperoxidase and the number of
neutrophils in BAL fluids, consequently alleviating the lung
damage (Mulligan et al., 1993).
Many studies have revealed that curcumin and curcuminoids
potently increase the expression, production, and activity of IL-
10 (Larmonier et al., 2008;Chen et al., 2018;Mollazadeh et al.,
2019;Chai et al., 2020). Chai et al. (2020) have depicted the effect
of curcumin on ALI/ARDS using cecal ligation and puncture
(CLP)-induced ALI mouse model. In this study, curcumin
noticeably attenuates lung injury by inducing the differentiation
of regulatory T cells (Tregs) and upregulating IL-10 production.
Similar effects have been observed in the neuropathic model,
colitis model, and other inflammatory diseases. Therefore, in
the context of inflammation, curcumin can act as a double-
edged sword, downregulating pro-inflammatory cytokines, and
upregulating anti-inflammatory IL-10 (Chai et al., 2020).
Frontiers in Cell and Developmental Biology | www.frontiersin.org 4June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 5
Liu and Ying Curcumin and Viral Pneumonia
SCAVENGES ROS
It has been described that curcumin acts to directly scavenge
ROS as a polyphenolic antioxidant (Wang et al., 2008).
Curcumin has two active groups, one hydroxy hydrogen on
the benzene ring that has an anti-oxidation effect and the
other a β-diketone moiety. In vitro experiments have shown
that curcumin effectively scavenges on ROS removal and anti-
oxidation, curcumin has been shown effective at scavenging the
superoxide anion radical produced by illuminating riboflavin
and the OH−produced by the Fenton reaction. Curcumin also
inhibits the peroxidation of lecithin and DNA oxidative damage
caused by ROS (Wang et al., 2008).
The ability of curcumin to scavenge ROS can be indirect
via enzymatic regulation. For example, curcumin can upregulate
superoxide dismutase 2 (SOD2), a key enzyme to convert O2−
to H2O2, which is then reduced to H2O by glutathione (GSH)
redox system (Forrester et al., 2018). In a study examining
liver damage in rats, the GSH redox system was shown to be
inhibited by the folic acid antagonist Methotrexate, resulting in
hepatic oxidative damage. Curcumin is able to reverse this effect
and enhance the effectiveness of SOD so as to maintain the
oxidant/antioxidant balance and mitigate liver damage (Hemeida
and Mohafez, 2008). Recently, curcumin was reported to oppose
the effect of ROS on pro-inflammatory cytokine expression (e.g.,
IL-1b, IL-18) by downregulation of the thioredoxin interacting
protein/NLR pyrin domain containing 3 (TXNIP/NLRP3)
(Ren et al., 2019).
ANTIVIRAL ACTIVITY OF CURCUMIN
Many studies have documented that curcumin disrupts the viral
infection process via multiple mechanisms, including directly
targeting viral proteins, inhibiting particle production and gene
expression, and blocking the virus entry, replication, and budding
(Wen et al., 2007;Basu et al., 2013;Ou et al., 2013;Du et al.,
2017;Kannan and Kolandaivel, 2017;Yang et al., 2017;Dai
et al., 2018;Praditya et al., 2019). A recently in vitro study has
demonstrated that curcumin inhibits respiratory syndrome virus
(RSV) by blocking attachment to host cells (Yang et al., 2017). In
this study, curcumin was also found to prevent the replication of
RSV in human nasal epithelial cells. Additional evidence suggests
that curcumin inhibits Porcine reproductive and RSV (PRRSV)
attachment, possibly by disrupting the fluidity of viral envelopes
(Du et al., 2017). Curcumin also obstructs virus infection by
inhibiting PRRSV-mediated cell fusion, virus internalization, and
uncoating (Du et al., 2017).
For a century, different subtypes of IAV, H1N1, H2N2, H3N2,
and H5N1 have been the leading cause of pandemic outbreaks
in the world. It has been reported that curcumin and its
derivatives have a high binding affinity to hemagglutinin (HA),
a major capsid glycoprotein of influenza virus that mediates virus
attachment (Kannan and Kolandaivel, 2017). Ou et al. (2013)
have demonstrated that curcumin interacts with HA and disturbs
the integrity of membrane structure to block virus binding to
host cells and prevent IAV entry. In another study with cells
infected by IAV, it was found that curcumin directly inactivates
various strains of IAV, disturbs their adsorption, and inhibits
their replication (Dai et al., 2018). Further, the study showed that
curcumin inhibits IAV absorption and replication by activating
the NF-E2-related factor 2 (Nrf2)-hemeoxygenase-1 (HO-1)-
axis, a classical anti-inflammatory and antioxidative signaling,
which possesses antiviral activity (Dai et al., 2018).
Furthermore, curcumin acts against SARS-CoV (Wen et al.,
2007). Accordingly, a study on the anti-SARS-CoV activity
of 221 phytocompounds revealed that 20 µM of curcumin
exhibits significant inhibitory effects in a Vero E6 cell-based
cytopathogenic effect (CPE) assay. The authors presented
evidence for a mild effect of curcumin against SARS-CoV
replication and the inhibitory effect of curcumin on SARS-
CoV 3CL protease activity, which is essential for the replication
of SARS-CoV. This study provides promising evidence for
curcumin as a potential anti-SARS-CoV agent (Wen et al., 2007).
CURCUMIN ALLEVIATES EXUDATION
AND EDEMA CAUSED BY
INFLAMMATION
Inflammation plays a pivotal role in the pathogenesis of lung
complications of viral infection, as manifested by lung edema,
hemorrhage, neutrophil infiltration, and alveolar thickening.
Studies indicate that curcumin and its analogs are capable of
attenuating lung injury (Suresh et al., 2012;Avasarala et al.,
2013;Zhang et al., 2015;Xiao et al., 2019). Polymorphonuclear
neutrophils (PMNs) infiltration is associated with pulmonary
edema and could release oxidants and proteases, which
consequently damage the alveolar-capillary membrane, leading
to leakage of plasma proteins out of blood vessels, thereby
causing pulmonary edema (Matthay and Zimmerman, 2005).
It has been shown that curcumin can inhibit the infiltration
of PMNs, including (GR1+), CD4+, CD19+B cells, NK
cells, and CD8+T cells, and promote the apoptosis of
PMN by increasing the level of P-p38 (Avasarala et al.,
2013). More recently, Xiao et al. (2019) have reported
that curcumin analog C66 protects lipopolysaccharide (LPS)-
induced ALI through suppression of the JNK pathway and
subsequent inhibition of inflammatory cytokine expression.
Similar protective effects of curcumin have been reported in
the rodent model of ventilator-induced lung injury (Wang
et al., 2018) and Staphylococcus S.aureus-induced ALI (Xu
et al., 2015) as evidenced by attenuation of inflammatory
cell infiltration, lung edema due to its anti-inflammatory
and antioxidant effects. In a chronic obstructive pulmonary
disease model, curcumin treatment effectively reduces the
degree of airway inflammation and disrupts airway remodeling
by inhibiting the proliferation of bronchial epithelial cells
(Yuan et al., 2018).
Mechanistically, curcumin protects the lung by inhibiting
inflammation and production of ROS through regulation of
multiple signaling pathways engaging peroxisome proliferator-
activated receptor γ(PPARγ) (Cheng et al., 2018), JNK (Xiao
et al., 2019), NF-κB (Suresh et al., 2012;Wang et al., 2018),
Frontiers in Cell and Developmental Biology | www.frontiersin.org 5June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 6
Liu and Ying Curcumin and Viral Pneumonia
and Nrf2 (Dai et al., 2018;Han et al., 2018). Notably,
the role of curcumin in regulating Nrf2/HO-1 has been
reported in IAV infection (Dai et al., 2018;Han et al.,
2018). The Nrf2 enhances the expression of HO-1, an
immunoregulatory and anti-inflammation molecule, and other
enzymes for maintaining redox homeostasis. The increased
expression of HO-1 can alleviate the pathological remolding
of the lung during viral infection and increase the survival
rate in mice following IAV infection. Curcumin has been
shown to stimulate transcription of Nrf2 and thus enhance
HO-1 expression in vivo, protecting alveoli from merging,
inflating and enlarging, and decreasing inflammatory exudation
of proteins to alveoli spaces after infection (Dai et al., 2018;
Han et al., 2018).
CURCUMIN SUPPRESSES FIBROSIS
The ALI after the viral infection is often followed by
pulmonary fibrosis, which can lead to the death. It has
been reported that curcumin can inhibit pulmonary fibrosis.
Thus, in paraquat-treated mice, collagen deposition in the
lung causes diffused fibrosis, while treatment with curcumin
reduces collagen deposition and decelerates the development
of pulmonary fibrosis (Chen et al., 2017). In the radiation-
induced lung damage model, cytokine accumulation and collagen
deposition occur in the interstitial space, concurrent with fibrosis
of the lung tissue (Amini et al., 2018). However, curcumin
reduces the expression of cytokines such as IL-4 and TGF-β,
inhibits the infiltration of macrophages and lymphocytes, and
ameliorates fibrosis (Amini et al., 2018). In another study on
ALI using a mouse model infected with reovirus, curcumin
treatment effectively inhibits the production of collagen and
procollagen I mRNA (Avasarala et al., 2013). α-SMA, a marker
of epithelial to mesenchymal transition, and Tenascin-C (TN-
C), both of which are indicators of pulmonary fibrosis, are
highly expressed in the adult lung parenchyma after ALI. The
high expression of E-cadherin, accompanied by cell proliferation
and repair, is associated with pulmonary remodeling after
lung injury. Treatment with curcumin reduces the expression
of TN-C, α-SMA, and E-cadherin attenuates myofibroblast
differentiation and mitigates pulmonary fibrosis. Furthermore,
curcumin decreases the expression of the TGF-βreceptor
II (TGF-ß RII), suggesting that it prevents TGF-β-mediated
pulmonary fibrosis. In bleomycin/SiO2/amiodarone-induced
pulmonary fibrosis experiments, it was also demonstrated that
curcumin directly reduces the expression of TGF-βprotein and
its mRNA (Avasarala et al., 2013). All these studies support that
curcumin alleviates pulmonary fibrosis.
THE POTENTIAL ROLE OF CURCUMIN
IN THE PREVENTION AND TREATMENT
OF CORONAVIRUS INFECTION
In the last two decades, coronavirus infection has gained much
attention for its high mortality. The consensus from recent
research is that the cytokine storm plays a crucial role in
the development and progression of fatal pneumonia. Among
those who experienced SARS-CoV infection in 2003, many
manifested ALI and developed ARDS, and the death rate
was greater than 10% (Peiris et al., 2004). Similar syndromes
are seen in the MERS-CoV, H5N1, H7N9, and SARS-CoV2
infection. The high mortality rate from fatal pneumonia is
due to the over-activation of immune cells in the lung
(Channappanavar and Perlman, 2017).
FIGURE 3 | The effects of curcumin in virus associated with severe pneumonia. Curcumin inhibits virus-induced lung injury through its antivirus, anti-inflammation,
antioxidant activity. In addition, curcumin could suppress fibrosis by targeting TGF-βsignaling. Abbreviations: Nrf2, nuclear factor erythroid-derived 2; NF-κB, nuclear
factor-κB; PPARγ, peroxisome proliferator-activated receptor γ; TNF-α, tumor necrosis factor-alpha; COX2, cyclooxygenase-2; IκB, inhibitor of kappa B; IL,
interleukin; JNK, c-Jun N-terminal Kinase; TN-C, tenascin-C; α-SMA, alpha-smooth muscle actin.
Frontiers in Cell and Developmental Biology | www.frontiersin.org 6June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 7
Liu and Ying Curcumin and Viral Pneumonia
Targeting cytokine storm is considered as an essential strategy
for CoV infections. In clinical settings, glucocorticoids have
been used to treat fatal viral pneumonia and shown therapeutic
benefits. In the treatment of patients with SARS in 2003,
glucocorticoids were widely used to suppress the cytokine storm
in severe cases (Buchman, 2001). However, it has been found
that large doses of glucocorticoids create many side effects such
as osteoporosis and secondary infection with other pathogenic
microbes, and small doses have little effect on improving lung
injury (Buchman, 2001). These clinical findings indicate that
it is increasingly important to seek alternative agents with
effectiveness and low toxicity.
Many studies on virus-induced pneumonia have highlighted
the potential usage of curcumin in the improvement of lung
index and survival rate (Avasarala et al., 2013;Xu and Liu, 2017;
Dai et al., 2018;Han et al., 2018;Lai et al., 2020). Curcumin
mitigates the severity of viral pneumonia through inhibiting the
production of inflammatory cytokines and NF-κB signaling in
macrophages (Xu and Liu, 2017;Han et al., 2018). Curcumin
has also been shown to activate Nrf2 in association with reduced
oxidative stress and inhibit TLR2/4, p38/JNK MAPK, and NF-
κB in response to IAV infection; and as a result, pneumonia is
improved (Dai et al., 2018).
Up to now, it has been claimed that curcumin benefits human
health and prevents diseases (DiSilvestro et al., 2012;Zhu et al.,
2019). A recent study suggested that a low dose of curcumin
(80 mg/day) produced a variety of health-promoting actions,
such as direct and indirect antioxidant actions (DiSilvestro et al.,
2012). Additionally, accumulating evidence from animal studies
has shown that curcumin prevents the development of severe
pneumonia. Thus, pre-treatment of curcumin (5 mg/kg/day)
inhibits paraquat-induced lung inflammation and structural
remodeling of the lung at an early phase of ALI (Tyagi et al.,
2016). Bansal and Chhibber (2010) have demonstrated that pre-
treatment of mice with curcumin (150 mg/kg) for 15 days
before Klebsiella pneumonia infection prevents the tissue from
injury and reduces ALI-associated pneumonia by the anti-
inflammatory action of curcumin. The similar protective role
of curcumin has been found in preclinical studies of viral-
induced pneumonia. Treatment with curcumin (50 mg/kg/day)
beginning at 5 days prior to reovirus 1/L infection protects
CBA/J mice from the development of ALI/ARDS and suppresses
subsequent fibrosis (Avasarala et al., 2013). Lai et al. (2020) have
reported that pre-infection or post-infection administration of
curcumin significantly improves the lung index and prolongs
the survival rate. Interestingly, the fatality rate is also reduced
by pre-administration with curcumin (Lai et al., 2020). All
these studies suggest that curcumin administration could have
both prophylactic and therapeutic effects on virus-induced
pneumonia and mortality.
Clinical investigations have suggested that curcumin
might be effective in improving inflammation and the
treatment of virus infections. A clinical trial conducted by
Alizadeh et al. (2018) have demonstrated that curcumin
nanomicelle supplement ameliorates oxidative stress, and reduces
inflammatory biomarker, including TNF-α, compared to a
placebo. Furthermore, a phase II randomized controlled study
has reported that the topical application of curcumin and
curcumin polyherbal cream has a higher HPV clearance rate
than the placebo (Basu et al., 2013).
Currently, no data in humans on the link between curcumin
and coronavirus infection have been available, but in light
of and its preventative and therapeutic role in viral infection
and cytokine storms common to all viral infections, curcumin
could conceivably be considered as an attractive agent for the
management of coronavirus infections.
CONCLUSION
Cytokine storm syndrome triggered by viral infections is the
culprit of death. It is exacerbated by unchecked regulation of the
production of pro-inflammatory cytokines and ROS, leading to
pneumonia, ALI, multiple organs failures, and eventually death.
No effective therapy is available for the cytokine storm syndrome
and associated lung and other organ failures. Curcumin is a
natural plant extract with high safety and low toxicity such
that people take it as a diet supplement, and growing evidence
from preclinical studies demonstrates that it effectively inhibits
viral infection, alleviates the severity of lung injury through
offsetting the cytokine storm, inhibits subsequent fibrosis, and
increases survival rates (Figure 3). Additionally, its anti-SARS-
CoV replication and 3CL protease have been reported in an
in vitro study (Wen et al., 2007). In sum, the preclinical studies
we have reviewed here motivate a call for attention to the
clinical investigation of curcumin as a therapeutic agent for
the cytokine storm syndrome following coronavirus infections,
especially pneumonia caused by the coronavirus.
AUTHOR CONTRIBUTIONS
ZL contributed to the preparation of the manuscript and editing.
YY contributed to the literature research, revision, and final
approval of the manuscript.
FUNDING
This study was supported by the National Natural Science
Foundation of China (Nos. 81560299 and 81660163), and
Innovation and Entrepreneurship grant from Jiangxi Province
Bureau of Foreign Experts.
ACKNOWLEDGMENTS
We are grateful to Professor Zhijun Luo for his comments,
constructive suggestions, and generous help in the preparation
of this manuscript.
Frontiers in Cell and Developmental Biology | www.frontiersin.org 7June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 8
Liu and Ying Curcumin and Viral Pneumonia
REFERENCES
Alizadeh, F., Javadi, M., Karami, A. A., Gholaminejad, F., Kavianpour, M., and
Haghighian, H. K. (2018). Curcumin nanomicelle improves semen parameters,
oxidative stress, inflammatory biomarkers, and reproductive hormones in
infertile men: a randomized clinical trial. Phytother. Res. 32, 514–521. doi:
10.1002/ptr.5998
Amalraj, A., Varma, K., Jacob, J., Divya, C., Kunnumakkara, A. B., Stohs,
S. J., et al. (2017). A novel highly bioavailable curcumin formulation
improves symptoms and diagnostic indicators in rheumatoid arthritis patients:
a randomized, double-blind, placebo-controlled, two-dose, three-arm, and
parallel-group study. J. Med. Food 20, 1022–1030. doi: 10.1089/jmf.2017.
3930
Amini, P., Saffar, H., Nourani, M. R., Motevaseli, E., Najafi, M., Ali Taheri, R.,
et al. (2018). Curcumin mitigates radiation-induced lung pneumonitis and
fibrosis in rats. Int. J. Mol. Cell. Med. 7, 212–219. doi: 10.22088/ijmcm.Bums.
7.4.212
Asadi, S., Gholami, M. S., Siassi, F., Qorbani, M., Khamoshian, K., and Sotoudeh,
G. (2019). Nano curcumin supplementation reduced the severity of diabetic
sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: a
randomized double-blind placebo- controlled clinical trial. Complement. Ther.
Med. 43, 253–260. doi: 10.1016/j.ctim.2019.02.014
Avasarala, S., Zhang, F., Liu, G., Wang, R., London, S. D., and London, L. (2013).
Curcumin modulates the inflammatory response and inhibits subsequent
fibrosis in a mouse model of viral-induced acute respiratory distress syndrome.
PLoS One 8:e57285. doi: 10.1371/journal.pone.0057285
Baldwin, A. S. Jr. (1996). The NF-κB and IκB proteins: new discoveries and insights.
Annu. Rev. Immunol. 14, 649–683.
Bamboat, Z. M., Ocuin, L. M., Balachandran, V. P., Obaid, H., Plitas, G., and
DeMatteo, R. P. (2010). Conventional DCs reduce liver ischemia/reperfusion
injury in mice via IL-10 secretion. J. Clin. Investig. 120, 559–569. doi: 10.1172/
jci40008
Bansal, S., and Chhibber, S. (2010). Curcumin alone and in combination with
augmentin protects against pulmonary inflammation and acute lung injury
generated during Klebsiella pneumoniae B5055-induced lung infection in
BALB/c mice. J. Med. Microbiol. 59(Pt 4), 429–437. doi: 10.1099/jmm.0.016
873-0
Basu, P., Dutta, S., Begum, R., Mittal, S., Dutta, P. D., Bharti, A. C., et al. (2013).
Clearance of cervical human papillomavirus infection by topical application of
curcumin and curcumin containing polyherbal cream: a phase II randomized
controlled study. Asian Pac. J. Cancer Prev. 14, 5753–5759. doi: 10.7314/apjcp.
2013.14.10.5753
Behrens, E. M., and Koretzky, G. A. (2017). Cytokine storm syndrome: looking
toward the precision medicine era. Arthritis Rheumatol. 69, 1135–1143. doi:
10.1002/art.40071
Buchman, A. L. (2001). Side effects of corticosteroid therapy. J. Clin. Gastroenterol.
33, 289–294. doi: 10.1097/00004836-200110000- 00006
Chai, Y. S., Chen, Y. Q., Lin, S. H., Xie, K., Wang, C. J., Yang, Y. Z., et al. (2020).
Curcumin regulates the differentiation of naïve CD4+T cells and activates IL-10
immune modulation against acute lung injury in mice. Biomed. Pharmacother.
125:109946. doi: 10.1016/j.biopha.2020.109946
Channappanavar, R., Fehr, A. R., Vijay, R., Mack, M., Zhao, J., Meyerholz,
D. K., et al. (2016). Dysregulated type I interferon and inflammatory
monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-
infected mice. Cell Host Microbe 19, 181–193. doi: 10.1016/j.chom.2016.
01.007
Channappanavar, R., and Perlman, S. (2017). "Pathogenic human coronavirus
infections: causes and consequences of cytokine storm and immunopathology.
Semin. Immunopathol. 39, 529–539. doi: 10.1007/s00281-017-
0629-x
Chen, B., Li, H., Ou, G., Ren, L., Yang, X., and Zeng, M. (2019). Curcumin
attenuates MSU crystal-induced inflammation by inhibiting the degradation
of IκBαand blocking mitochondrial damage. Arthritis Res. Ther. 21:193. doi:
10.1186/s13075-019- 1974-z
Chen, H., Yang, R., Tang, Y., Xu, J., Feng, Y., Liu, S., et al. (2017). Effects of
curcumin on pulmonary fibrosis and functions of paraquat-challenged rats.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 29, 973–976.
Chen, L., Lu, Y., Zhao, L., Hu, L., Qiu, Q., Zhang, Z., et al. (2018). Curcumin
attenuates sepsis-induced acute organ dysfunction by preventing inflammation
and enhancing the suppressive function of Tregs. Int. Immunopharmacol. 61,
1–7. doi: 10.1016/j.intimp.2018.04.041
Chen, X., Zhao, B., Qu, Y., Chen, Y., Xiong, J., Feng, Y., et al. (2020). Detectable
serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically
elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin.
Infect. Dis. doi: 10.1093/cid/ciaa449 [Epub ahead of print].
Cheng, K., Yang, A., Hu, X., Zhu, D., and Liu, K. (2018). Curcumin attenuates
pulmonary inflammation in lipopolysaccharide induced acute lung injury in
neonatal rat model by activating peroxisome proliferator-activated receptor
γ(PPARγ) pathway. Med. Sci. Monit. 24, 1178–1184. doi: 10.12659/msm.90
8714
Cohen, A. N., Veena, M. S., Srivatsan, E. S., and Wang, M. B. (2009). Suppression
of interleukin 6 and 8 production in head and neck cancer cells with
curcumin via inhibition of Iκβ kinase. Arch. Otolaryngol. Head Neck Surg. 135,
190–197.
Dai, J., Gu, L., Su, Y., Wang, Q., Zhao, Y., Chen, X., et al. (2018). Inhibition
of curcumin on influenza A virus infection and influenzal pneumonia
via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways. Int.
Immunopharmacol. 54, 177–187. doi: 10.1016/j.intimp.2017.11.009
DiSilvestro, R. A., Joseph, E., Zhao, S., and Bomser, J. (2012). Diverse effects of a low
dose supplement of lipidated curcumin in healthy middle aged people. Nutr. J.
11:79. doi: 10.1186/1475-2891- 11-79
Du, T., Shi, Y., Xiao, S., Li, N., Zhao, Q., Zhang, A., et al. (2017). Curcumin
is a promising inhibitor of genotype 2 porcine reproductive and respiratory
syndrome virus infection. BMC Vet. Res. 13:298. doi: 10.1186/s12917-017-
1218-x
Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., and Griendling, K. K.
(2018). Reactive oxygen species in metabolic and inflammatory signaling. Circ.
Res. 122, 877–902. doi: 10.1161/circresaha.117.311401
Green, M. S. (2020). Did the hesitancy in declaring COVID-19 a pandemic reflect a
need to redefine the term? Lancet 395, 1034–1035. doi: 10.1016/s0140-6736(20)
30630-9
Han, S., Xu, J., Guo, X., and Huang, M. (2018). Curcumin ameliorates severe
influenza pneumonia via attenuating lung injury and regulating macrophage
cytokines production. Clin. Exp. Pharmacol. Physiol. 45, 84–93. doi: 10.1111/
1440-1681.12848
Hellebrekers, P., Vrisekoop, N., and Koenderman, L. (2018). Neutrophil
phenotypes in health and disease. Eur. J. Clin. Invest. 48(Suppl. 2):e12943.
doi: 10.1111/eci.12943
Hemeida, R., and Mohafez, O. M. (2008). Curcumin attenuates methotraxate-
induced hepatic oxidative damage in rats. J. Egypt. Natl. Canc. Inst. 20,
141–148.
Huang, K. J., Su, I. J., Theron, M., Wu, Y. C., Lai, S. K., Liu, C. C., et al. (2005).
An interferon-γ-related cytokine storm in SARS patients. J. Med. Virol. 75,
185–194. doi: 10.1002/jmv.20255
Jobin, C., Bradham, C. A., Russo, M. P., Juma, B., Narula, A. S., Brenner, D. A.,
et al. (1999). Curcumin blocks cytokine-mediated NF-κB activation and pro-
inflammatory gene expression by inhibiting inhibitory factor I-κB kinase
activity. J. Immunol. 163, 3474–3483.
Kalil, A. C., and Thomas, P. G. (2019). Influenza virus-related critical illness:
pathophysiology and epidemiology. Crit. Care 23:258.
Kannan, S., and Kolandaivel, P. (2017). Antiviral potential of natural compounds
against influenza virus hemagglutinin. Comput. Biol. Chem. 71, 207–218. doi:
10.1016/j.compbiolchem.2017.11.001
Khan, M. A., and Khan, M. J. (2018). Nano-gold displayed anti-inflammatory
property via NF-kB pathways by suppressing COX-2 activity. Artif. Cells
Nanomed. Biotechnol. 46, 1149–1158. doi: 10.1080/21691401.2018.1446968
Kim, S. G., Veena, M. S., Basak, S. K., Han, E., Tajima, T., Gjertson, D. W., et al.
(2011). Curcumin treatment suppresses IKKβkinase activity of salivary cells
of patients with head and neck cancer: a pilot study. Clin. Cancer Res. 17,
5953–5961. doi: 10.1158/1078-0432.ccr-11-1272
Lai, Y., Yan, Y., Liao, S., Li, Y., Ye, Y., Liu, N., et al. (2020). 3D-quantitative
structure-activity relationship and antiviral effects of curcumin derivatives as
potent inhibitors of influenza H1N1 neuraminidase. Arch Pharm Res. doi: 10.
1007/s12272-020- 01230-5 [Epub ahead of print].
Frontiers in Cell and Developmental Biology | www.frontiersin.org 8June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 9
Liu and Ying Curcumin and Viral Pneumonia
Larmonier, C. B., Uno, J. K., Lee, K. M., Karrasch, T., Laubitz, D., Thurston, R.,
et al. (2008). Limited effects of dietary curcumin on Th-1 driven colitis in IL-
10 deficient mice suggest an IL-10-dependent mechanism of protection. Am.
J. Physiol. Gastrointest. Liver Physiol. 295, G1079–G1091. doi: 10.1152/ajpgi.
90365.2008
Lau, S. K., Lau, C. C., Chan, K.-H., Li, C. P., Chen, H., Jin, D.-Y., et al. (2013).
Delayed induction of pro-inflammatory cytokines and suppression of innate
antiviral response by the novel Middle East respiratory syndrome coronavirus:
implications for pathogenesis and treatment. J. Gen. Virol. 94(Pt 12), 2679–
2690. doi: 10.1099/vir.0.055533-0
Liu, Q., Zhou, Y.-H., and Yang, Z.-Q. (2016). The cytokine storm of severe
influenza and development of immunomodulatory therapy. Cell. Mol.
Immunol. 13, 3–10. doi: 10.1038/cmi.2015.74
Matthay, M. A., and Zimmerman, G. A. (2005). Acute lung injury and the acute
respiratory distress syndrome: four decades of inquiry into pathogenesis and
rational management. Am. J. Respir. Cell Mol. Biol. 33, 319–327. doi: 10.1165/
rcmb.F305
McGonagle, D., Sharif, K., O’Regan, A., and Bridgewood, C. (2020). The role
of cytokines including interleukin-6 in COVID-19 induced pneumonia and
macrophage activation syndrome-like disease. Autoimmun. Rev. 19:102537.
doi: 10.1016/j.autrev.2020.102537
Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature 454,
428–435. doi: 10.1038/nature07201
Mollazadeh, H., Cicero, A. F. G., Blesso, C. N., Pirro, M., Majeed, M., and
Sahebkar, A. (2019). Immune modulation by curcumin: the role of interleukin-
10. Crit. Rev. Food Sci. Nutr. 59, 89–101. doi: 10.1080/10408398.2017.135
8139
Mulligan, M., Jones, M., Vaporciyan, A. A., Howard, M., and Ward, P. (1993).
Protective effects of IL-4 and IL-10 against immune complex-induced lung
injury. J. Immunol. 151, 5666–5674.
Netea, M. G., Balkwill, F., Chonchol, M., Cominelli, F., Donath, M. Y., Giamarellos-
Bourboulis, E. J., et al. (2017). A guiding map for inflammation. Nat. Immunol.
18, 826–831.
Opal, S. M., and DePalo, V. A. (2000). Anti-inflammatory cytokines. Chest 117,
1162–1172.
Ou, J. L., Mizushina, Y., Wang, S. Y., Chuang, D. Y., Nadar, M., and Hsu,
W. L. (2013). Structure–activity relationship analysis of curcumin analogues
on anti-influenza virus activity. FEBS J. 280, 5829–5840. doi: 10.1111/febs.
12503
Peiris, J. S., Guan, Y., and Yuen, K. Y. (2004). Severe acute respiratory syndrome.
Nat. Med. 10(Suppl. 12) S88–S97. doi: 10.1038/nm1143
Praditya, D., Kirchhoff, L., Brüning, J., Rachmawati, H., Steinmann, J., and
Steinmann, E. (2019). Anti-infective properties of the golden spice curcumin.
Front. Microbiol. 10:912. doi: 10.3389/fmicb.2019.00912
Ren, Y., Yang, Z., Sun, Z., Zhang, W., Chen, X., and Nie, S. (2019). Curcumin
relieves paraquat-induced lung injury through inhibiting the thioredoxin
interacting protein/NLR pyrin domain containing 3-mediated inflammatory
pathway. Mol. Med. Rep. 20, 5032–5040.
Richart, S. M., Li, Y. L., Mizushina, Y., Chang, Y. Y., Chung, T. Y., Chen,
G. H., et al. (2018). Synergic effect of curcumin and its structural analogue
(Monoacetylcurcumin) on anti-influenza virus infection. J. Food Drug Anal. 26,
1015–1023. doi: 10.1016/j.jfda.2017.12.006
Salminen, A., Hyttinen, J. M., and Kaarniranta, K. (2011). AMP-activated
protein kinase inhibits NF-κB signaling and inflammation: impact on
healthspan and lifespan. J. Mol. Med. 89, 667–676. doi: 10.1007/s00109-011-
0748-0
Sordillo, P. P., and Helson, L. (2015). Curcumin suppression of cytokine release
and cytokine storm. A potential therapy for patients with Ebola and other severe
viral infections. In Vivo 29, 1–4.
Straub, J. M., New, J., Hamilton, C. D., Lominska, C., Shnayder, Y., and Thomas,
S. M. (2015). Radiation-induced fibrosis: mechanisms and implications for
therapy. J. Cancer Res. Clin. Oncol. 141, 1985–1994. doi: 10.1007/s00432- 015-
1974-6
Suresh, M. V., Wagner, M. C., Rosania, G. R., Stringer, K. A., Min, K. A., Risler, L.,
et al. (2012). Pulmonary administration of a water-soluble curcumin complex
reduces severity of acute lung injury. Am. J. Respir. Cell Mol. Biol. 47, 280–287.
doi: 10.1165/rcmb.2011-0175OC
Taniguchi, K., and Karin, M. (2018). NF-κB, inflammation, immunity and cancer:
coming of age. Nat. Rev. Immunol. 18, 309–324. doi: 10.1038/nri.2017.142
Torres, J., Mehandru, S., and Colombel, J. (2017). F, Peyrin-Biroulet L. Crohn’s
disease. Lancet 389, 1741–1755.
Tyagi, N., Dash, D., and Singh, R. (2016). Curcumin inhibits paraquat induced
lung inflammation and fibrosis by extracellular matrix modifications in mouse
model. Inflammopharmacology 24, 335–345. doi: 10.1007/s10787-016- 0286-z
Vitali, D., Bagri, P., Wessels, J. M., Arora, M., Ganugula, R., Parikh, A., et al.
(2020). Curcumin can decrease tissue inflammation and the severity of HSV-
2 infection in the female reproductive mucosa. Int. J. Mol. Sci. 21:337. doi:
10.3390/ijms21010337
Wang, W., Ye, L., Ye, L., Li, B., Gao, B., Zeng, Y., et al. (2007). Up-regulation of
IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine
macrophages via NF-kappaB pathway. Virus Res. 128, 1–8. doi: 10.1016/j.
virusres.2007.02.007
Wang, X., An, X., Wang, X., Bao, C., Li, J., Yang, D., et al. (2018). Curcumin
ameliorated ventilator-induced lung injury in rats. Biomed. Pharmacother. 98,
754–761. doi: 10.1016/j.biopha.2017.12.100
Wang, X.-M., Zhang, J.-S., Gao, Y.-T., and Dai, Y. (2008). Scavenging effects of
curcumin on active oxygens and its anti-oxidation in vitro.Sci. Technol. Food
Ind. 7, 94–98.
Wang, Y., Wang, Y., Chen, Y., and Qin, Q. (2020). Unique epidemiological and
clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-
19) implicate special control measures. J. Med. Virol. [Epub ahead of print].
Wen, C.-C., Kuo, Y.-H., Jan, J.-T., Liang, P.-H., Wang, S.-Y., Liu, H.-G., et al.
(2007). Specific plant terpenoids and lignoids possess potent antiviral activities
against severe acute respiratory syndrome coronavirus. J. Med. Chem. 50,
4087–4095. doi: 10.1021/jm070295s
Wheeler, A. P., and Bernard, G. R. (2007). Acute lung injury and the acute
respiratory distress syndrome: a clinical review. Lancet 369, 1553–1564.
Wu, C., Chen, X., Cai, Y., Xia, J., Zhou, X., Xu, S., et al. (2020). Risk factors
associated with acute respiratory distress syndrome and death in patients with
coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med.
[Epub ahead of print].
Xiao, Z., Xu, F., Zhu, X., Bai, B., Guo, L., Liang, G., et al. (2019). Inhibition Of
JNK phosphorylation by curcumin analog C66 Protects LPS-induced acute lung
injury. Drug Des. Dev. Ther. 13, 4161–4171. doi: 10.2147/dddt.S215712
Xu, F., Diao, R., Liu, J., Kang, Y., Wang, X., and Shi, L. (2015). Curcumin attenuates
staphylococcus aureus-induced acute lung injury. Clin. Respir. J. 9, 87–97. doi:
10.1111/crj.12113
Xu, X.-Y., Meng, X., Li, S., Gan, R.-Y., Li, Y., and Li, H.-B. (2018). Bioactivity, health
benefits, and related molecular mechanisms of curcumin: current progress,
challenges, and perspectives. Nutrients 10:1553. doi: 10.3390/nu10101553
Xu, Y., and Liu, L. (2017). Curcumin alleviates macrophage activation and lung
inflammation induced by influenza virus infection through inhibiting the NF-
κB signaling pathway. Influenza Other Respir. Viruses 11, 457–463. doi: 10.1111/
irv.12459
Yang, X. X., Li, C. M., Li, Y. F., Wang, J., and Huang, C. Z. (2017). Synergistic
antiviral effect of curcumin functionalized graphene oxide against respiratory
syncytial virus infection. Nanoscale 9, 16086–16092. doi: 10.1039/c7nr06
520e
Yang, Y. S., Su, Y. F., Yang, H. W., Lee, Y. H., Chou, J. I., and Ueng, K. C. (2014).
Lipid-lowering effects of curcumin in patients with metabolic syndrome: a
randomized, double-blind, placebo-controlled trial. Phytother. Res. 28, 1770–
1777. doi: 10.1002/ptr.5197
Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., et al. (2020). In vitro antiviral
activity and projection of optimized dosing design of hydroxychloroquine for
the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2). Clin. Infect. Dis. [Epub ahead of print].
Yuan, J., Liu, R., Ma, Y., Zhang, Z., and Xie, Z. (2018). Curcumin attenuates
airway inflammation and airway remolding by inhibiting NF-κB signaling and
COX-2 in cigarette smoke-induced COPD mice. Inflammation 41, 1804–1814.
doi: 10.1007/s10753-018- 0823-6
Zhang, B., Swamy, S., Balijepalli, S., Panicker, S., Mooliyil, J., Sherman, M. A.,
et al. (2019). Direct pulmonary delivery of solubilized curcumin reduces
severity of lethal pneumonia. FASEB J. 33, 13294–13309. doi: 10.1096/fj.20190
1047rr
Frontiers in Cell and Developmental Biology | www.frontiersin.org 9June 2020 | Volume 8 | Article 479

fcell-08-00479 June 10, 2020 Time: 20:51 # 10
Liu and Ying Curcumin and Viral Pneumonia
Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y., et al. (2016). ROS and
ROS-mediated cellular signaling. Oxid. Med. Cell. Longev. 2016:4350965. doi:
10.1155/2016/4350965
Zhang, Y., Liang, D., Dong, L., Ge, X., Xu, F., Chen, W., et al. (2015). Anti-
inflammatory effects of novel curcumin analogs in experimental acute lung
injury. Respir. Res. 16:43.
Zhu, L. N., Mei, X., Zhang, Z. G., Xie, Y. P., and Lang, F. (2019). Curcumin
intervention for cognitive function in different types of people: a systematic
review and meta-analysis. Phytother. Res. 33, 524–533. doi: 10.1002/ptr.
6257
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2020 Liu and Ying. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Frontiers in Cell and Developmental Biology | www.frontiersin.org 10 June 2020 | Volume 8 | Article 479