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August 20, 2020
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.
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), middle east respiratory syndrome CoV (MERS-CoV), highly pathogenic avian influenza viruses (including H5N1 and H7N9), and novel coronavirus (SARS-CoV2).
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. 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. 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. 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. Several clinical investigations have reported beneficial effects in treating cardiovascular diseases, metabolic syndrome, or diabetes, and infectious diseases, especially viral infection. 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. 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.
Cytokine storm arises from different factors that could derive from autoimmune, inflammatory, iatrogenic, and infectious origins. 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. 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. 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). 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.
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. 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. 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. 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. 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 cells, manifested by clinical syndromes such as extensive pulmonary edema, alveolar hemorrhage, ARDS, and multiple organ failures.
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. 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-α in 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.
The mechanism underlying curcumin modulation of inflammation has been extensively investigated and engages diverse signaling pathways, among which NF-κB plays an essential role. It was reported that curcumin effectively regulates NF-κB signaling through multiple mechanisms. First, curcumin inhibits activation of IKKβ. In a study of patients with head and neck cancer receiving curcumin, reduced activity of IKKβ was observed in saliva samples, associated with a decrease in the expression of IL-8, TNF-α, and IFN-γ. Second, curcumin enhances the expression or stability of IκBα. Curcumin inhibits the IκBα degradation, phosphorylation of IκB serine 32 to block the cytokine-mediated NF-κB activation and thus pro-inflammatory gene expression. Third, curcumin activates AMPK. It has been documented that curcumin blocks NF-κB signaling upon infection with Influenza A virus (IAV) as a consequence of AMPK activation. Fourth, curcumin acts on p65 to disturb the NF-κB pathway. 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.
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. In an animal model of chronic obstructive pulmonary disease, it has been shown that curcumin treatment effectively inhibits the degradation of IκBα and disturbs the production of COX-2. 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.
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. A recently in vitro study has demonstrated that curcumin inhibits respiratory syndrome virus (RSV) by blocking attachment to host cells. 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. Curcumin also obstructs virus infection by inhibiting PRRSV-mediated cell fusion, virus internalization, and uncoating.
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 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. 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.
Furthermore, curcumin acts against SARS-CoV. 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 .
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%. 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.
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. 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. 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. Curcumin mitigates the severity of viral pneumonia through inhibiting the production of inflammatory cytokines and NF-κB signaling in macrophages. 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.
Up to now, it has been claimed that curcumin benefits human health and prevents diseases. 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. 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 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 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. 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 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.
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.
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. Additionally, its anti-SARS-CoV replication and 3CL protease have been reported in an in vitro study. 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.
For full text and references, go to: https://doi.org/10.3389/fcell.2020.00479
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