|Year : 2018 | Volume
| Issue : 8 | Page : 982-989
Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome
Qian Wang, Song-Fan Yan, Yu Hao, Sheng-Wei Jin
Department of Anesthesia and Critical Care, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
|Date of Submission||23-Oct-2017|
|Date of Web Publication||12-Apr-2018|
Dr. Sheng-Wei Jin
Department of Anesthesia and Critical Care, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang 325027
Source of Support: None, Conflict of Interest: None
Objective: Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by the injury of alveolar epithelium, which impairs active fluid transport in the lung, and impedes the reabsorption of edema fluid from the alveolar space. This review aimed to discuss the role of pro-resolving mediators on the regulation of alveolar fluid clearance (AFC) in ARDS.
Data Sources: Articles published up to September 2017 were selected from the PubMed, with the keywords of “alveolar fluid clearance” or “lung edema” or “acute lung injury” or “acute respiratory distress syndrome”, and “specialized pro-resolving mediators” or “lipoxin” or “resolvin” or “protectin” or “maresin” or “alveolar epithelial cells” or “aspirin-triggered lipid mediators” or “carbon monoxide and heme oxygenase” or “annexin A1”.
Study Selection: We included all relevant articles published up to September 2017, with no limitation of study design.
Results: Specialized pro-resolving mediators (SPMs), as the proinflammatory mediators, not only upregulated epithelial sodium channel, Na,K-ATPase, cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporins levels, but also improved Na,K-ATPase activity to promote AFC in ARDS. In addition to the direct effects on ion channels and pumps of the alveolar epithelium, the SPMs also inhibited the inflammatory cytokine expression and improved the alveolar epithelial cell repair to enhance the AFC in ARDS.
Conclusions: The present review discusses a novel mechanism for pulmonary edema fluid reabsorption. SPMs might provide new opportunities to design “reabsorption-targeted” therapies with high degrees of precision in controlling ALI/ARDS.
数据来源: 截止2017年9月1日，所有发表在PubMed上的文章。查询关键词为：“alveolar fluid clearance”或“lung edema”或“acute lung injury”或“acute respiratory distress syndrome”和“specialized pro-resolving mediators”或“lipoxin”或“resolvin”或“protectin”或“maresin”或“alveolar epithelial cells”或“aspirin-triggered lipid mediators”或“carbon monoxide and heme oxygenase”或“annexin A1” 。
Keywords: Acute Lung Injury; Acute Respiratory Distress Syndrome; Alveolar Fluid Clearance; Specialized Pro-resolving Mediator
|How to cite this article:|
Wang Q, Yan SF, Hao Y, Jin SW. Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome. Chin Med J 2018;131:982-9
|How to cite this URL:|
Wang Q, Yan SF, Hao Y, Jin SW. Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome. Chin Med J [serial online] 2018 [cited 2018 Apr 25];131:982-9. Available from: http://www.cmj.org/text.asp?2018/131/8/982/229890
| Introduction|| |
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common, devastating clinical syndrome that affects large numbers of patients and has a mortality of up to 40%. The injury of alveolar epithelium impairs active fluid transport mechanisms in the lung, preventing reabsorption of edema fluid from the alveolar space, which is a key step in the resolution of ALI/ARDS. It is also widely accepted that edema fluid must be cleared for patients with ALI/ARDS to survive.
Fluid and solute reabsorption from the alveolus is critical in clearing fluid from lungs in pathologic conditions, such as ALI/ARDS and hydrostatic pulmonary edema. The primary mechanism driving fluid clearance from the alveolus is the active transportation of Na + ions from airspaces into the lung interstitium. This solute transportation drives osmotic water transportation and accordingly alveolar fluid clearance (AFC). Na + ions enter alveolar epithelial cells at the apical surface, primarily through amiloride-sensitive sodium channels, such as the epithelial sodium channel (ENaC), and are pumped out on the basolateral surface by Na, K-ATPase.,, Furthermore, the cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporins are also important in mediating the AFC.
Specialized pro-resolving mediators (SPMs) are produced by cells of the innate immune, which are formed via the stereoselective conversion of essential fatty acids that include arachidonic acid, eicosapentaenoic acid, n-3 docosapentaenoic acid and docosahexaenoic acid (DHA). They are grouped into four families, lipoxins, resolvins, protectins, and maresins. These mediators share basic biological effects in regulating host responses, such as inhibiting the production of proinflammatory cytokines and chemokines, regulating the neutrophils trafficking, stimulating the macrophages phagocytosis of apoptotic cells, bacteria, and cellular debris via G-protein coupled receptors (GPCRs)-dependent manner.,, Recent studies ,, have demonstrated that SPMs could regulate the AFC in ARDS to protect the lung function. Therefore, the present review will focus on: (1) mechanisms underlying the regulation of the AFC in the normal lung and ARDS and (2) mechanisms underlying the pro-resolving mediators' regulation on the AFC.
| Inflammation Resolution|| |
The acute inflammatory response is protective, evolving to permit repair of injured tissues and eliminate foreign invaders, which leads to complete resolution of leukocyte infiltrates and clearance of cellular debris. Recently, new evidences have demonstrated that the resolution of inflammation might be an active and tightly regulated process.,,,,,, SPMs have been demonstrated to exert potent immune-resolving effects, such as cell proliferation, migration, clearance of apoptotic cells, and microorganisms.,, Therefore, the effective and timely resolution of inflammation might be the key step to keep effective host defense and restitution of homeostasis.
| Inflammation Resolution in the Lung-Alveolar Fluid Clearance|| |
In the normal lung, vectorial ions transport across the alveolar epithelial cells to create an osmotic gradient that drives fluid from the airspaces into the lung interstitum.,
Alveolar epithelial Type I (ATI) and Type II (ATII) cells, alveolar and endothelium permeability, amiloride-sensitive sodium channels-ENaC, Na, K-ATPase, CFTR, aquaporin 5, inflammatory cytokines, and pro-resolving mediators regulate the AFC together to maintain the alveolar homeostasis.,,, The bacteria or exogenous microorganisms invade lung tissue, leading to lung injury and ARDS. It is well recognized that the AFC is reduced in ARDS, which is associated with the morbidity and mortality of ARDS., Therefore, it is critical to reveal the reasons of AFC reduction to understand the pathogenesis of ARDS.
First, ARDS is characterized by large amounts of neutrophil infiltration and diffuse alveolar damage, including the damage of both lung endothelium and epithelium. Excessive neutrophilic influx into the alveolar space leads to the generation of reactive oxygen species and proinflammatory factors, which could disrupt the alveolar-capillary barrier; therefore, the ability to clear alveolar edema fluid is reduced., Alveolar and endothelium permeability is critical for AFC. If permeability is increased, it is impractical to improve AFC since the fluid will come back to the alveolar space. Active AFC is very important but the lung recovery depends on the barrier repair and AFC facilitates ALI/ARDS recovery when blood-gas barrier regains integrity. The reduction in the rate of AFC in ARDS is associated with decreased survival., Therefore, it is critical to investigate the mechanisms underlying the reduction of AFC in ARDS in order to better understand the pathogenesis of this condition.
Second, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-8, and transforming growth factor-β1 (TGF-β1) were found in ARDS pulmonary edema fluid.,,, Under controlled conditions, this inflammatory response is important for pathogen clearance. However, when excessive levels of cytokines are present, they might cause alveolar injury and decreased AFC.,,, Previous study  showed that cytokine expression was increased and the ion transport protein expression was decreased in the ARDS edema fluid compared to a plasma control, indicating that the levels of cytokines might be increased in alveolar epithelium during ARDS, leading to a decreased expression of alveolar ion channels and accumulation of AFC. Furthermore, the inflammatory pulmonary edema fluid could also cause alveolar cell injury and necrosis, leading to altered epithelial tight junctions.,
Third, the damaged lung endothelium and epithelium lead to loss of the ion channels and pumps, which are key regulators of AFC. Moreover, the alveolar epithelium damage will lead to an increase in the permeability of the alveolar-capillary barrier, which in combination with changes in hydrostatic and oncotic pressures, might lead to the formation of pulmonary edema.,
Fourth, hypoxemia that due to ventilation-perfusion mismatch, intrapulmonary shunts, and an increased lung dead spaces, might result in the need for positive pressure ventilation. Otherwise, the low oxygen or high carbon dioxide could downregulate the ENaC transcription and trafficking; in addition, the Na, K-ATPase functions are also impaired.,, Therefore, supplemental oxygen and correction of hypercapnia might improve the resolution of alveolar edema.
| Specialized Pro-Resolving Mediators for the Therapy of Acute Respiratory Distress Syndrome|| |
Damage to the lung results in activation of the immune system, which not only leads to the release of several proinflammatory proteins and neutrophilic influx into the alveolar space but also leads to the release of pro-resolution lipids mediators, such as lipoxins, resolvins, protectins, and maresins.,
Lipoxins are arachidonic acid metabolites formed during inflammation via transcellular biosynthetic routes that elicit distinct anti-inflammatory and pro-resolution bioactions, including the suppression of neutrophil activation and upregulation of monocyte ingestion of apoptotic neutrophils. Lipoxins are included in the first class of lipid mediators that are “switched on” in the resolution phase of an inflammatory response and can function as “braking signals” in inflammation. Lipoxins, as potential novel therapeutic agents, have been extensively studied in various inflammatory diseases and are able to interact with the lipoxin A4 (LXA4) receptor (ALX) to mediate anti-inflammatory actions.,,, A previous study showed that LXA4 dramatically blocked the allergic pleural eosinophil influx, and concurrently inhibited the earlier edema and neutrophilia that was associated with allergic reaction. The data clearly demonstrated that LXA4 had no effect on AFC in healthy, perfused, intact rat lungs. However, treatment with LXA4 might promote the AFC in oleic acid (OA)-induced ALI, with the outcome of decreased pulmonary edema. Furthermore, treatment with LXA4 might not only upregulate the ENaC-α and ENaC-γ subunit protein expression but also increase the Na, K-ATPase β1 subunit protein expression and Na, K-ATPase activity. Finally, evidence has shown that the BML-111 (ALX agonist) had similar effects as those of LXA4, and the beneficial effects of LXA4 could be abrogated by BOC-2 (ALX antagonist) in OA-induced ALI, suggesting that LXA4 might promote AFC by interacting with a specific GPCR, denoted ALX. The mechanism of the salutary effect of LXA4 might involve the ALX-cGMP signaling pathway.
Another study  has demonstrated that treatment of rats with LXA4 could significantly inhibit IL-6, TNF-α production, and increase AFC with the outcome of decreased pulmonary edema in lung tissue. The inhibitor of CFTR could abolish the beneficial effects of LXA4. Furthermore, it has also been demonstrated that treatment with LXA4 could upregulate the CFTR protein expression in vivo and in primary ATII cells. Finally, the study has also provided evidence that lipopolysaccharide (LPS) could decrease CFTR protein expression via PI3K/Akt signaling pathway and the LXA4 could suppress LPS-stimulated phosphorylation of Akt.
LXA4 has been shown to be able to promote alveolar epithelial repair by stimulating the epithelial cells wound repair and proliferation; blocking the negative effects of soluble Fas ligand/TNF-α; and augmenting the epithelial cell proliferative response. The effects of LXA4 might be PI3K dependent and are mediated via the LXA4 receptor. Higgins et al. have shown that LXA4 might play a protective role in bronchial epithelium by stimulating tight junction repair, delaying and reducing the invasion of cystic fibrosis (CF) bronchial epithelial cells induced by P. aeruginsosa.
Resolvins are v-3 DHA-derived metabolites, and are biosynthesized during the resolution phase of inflammatory response, including halted transendothelial migration of human neutrophils,,, upregulation of monocyte ingestion of apoptotic neutrophils, and enhanced macrophage phagocytosis of zymosan and apoptotic polymorphonuclear neutrophils (PMNs). Previous studies have shown that resolvin D1 (7S,8R,17S-trihydro-xy-4Z,8E,10Z,12E,14E, 19Z-docosahexaenoic acid; RvD1) exerts potent anti-inflammatory and pro-resolving actions in several animal models of sepsis, peritonitis, taraxis, and ALI., Furthermore, a recent study  has shown that RvD1 could improve the survival rate and attenuated ALI induced by LPS. It has also been shown that RvD1 could accelerate the airway mucous metaplasia in the resolution of established allergic airway responses. Recently, two GPCRs of RvD1 have been identified and validated using a GPCR/arrestin-coupled system, namely, Orphan GPR32 and ALX. Extracellular signals interact with GPCRs to activate adenylate cyclase/guanylyl cyclase and stimulate formation of the second messenger cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP), which activates protein kinase A/protein kinase C. Indeed, β2 AR agonists have been shown to enhance AFC transport via a cAMP-dependent mechanism under physiological conditions  and in experimental models of lung injury, as well as in one prospective study of extravascular lung edema in patients with ALI. In contrast, PI3K has been identified to be involved in the regulation of ENaC-mediated AFC by insulin. There has been evidence for the pro-resolution actions of RvD1 in ARDS. Treatment with RvD1 could improve the AFC and decrease pulmonary edema in LPS-induced ALI in rats. RvD1 might regulate AFC via upregulating the protein expression of ENaC-α, -γ and Na, K-ATPase α1, β1 subunits and increasing the activity of Na, K-ATPase. RvD1 could increase Na + currents in primary ATII cells, and enhance the subcellular distribution of ENaC and Na, K-ATPase. Moreover, the beneficial effects of RvD1 were abrogated by BOC-2, LY294002, and Rp-cAMP, indicating that RvD1 might increase the ENaC expression to promote AFC via the ALX/PI3K/cAMP signaling pathway. In addition, RvD1 and RvD2 could inhibit the IL-17, TNF-α, and IFN-γ production, and enhance the tissue repair.
Protectins are novel lipid mediators that are involved in anti-inflammation and resolution. Protectin DX, an isomer of protectin D1, is believed to have anti-inflammatory effects including inhibition of neutrophil activation and regulation of inflammatory cytokines. It is produced by double lipoxygenase-mediated reaction in murine perritonitis exudates, in suspensions of human leukocytes, or by soybean 15-lipoxygenase incubated DHA., A recent study has demonstrated that protectin DX could block neutrophil infiltration in murine peritonitis by 20–25% at a dose of 1 ng/mouse. In addition, protectin D1 could also inhibite TNF-α, IFN-γ secretion, and enhance tissue repair.,
Maresins are newly described macrophage-derived mediators of inflammation resolution, which are produced from essential omega-3 fatty acids and biosynthesized via 12-lipoxygenase., Maresin1 (7,14-dihydroxyd-ocosa-4Z, 8Z, 10, 12, 16Z,19Z-hexaenoic acid, MaR1) has been shown to be a potent mediator to stop PMN infiltration and stimulate macrophages phagocytosis.,, Zhang et al. reported that MaR1 not only upregulated ENaC, Na, K-ATPase protein expression but also enhanced Na, K-ATPase activity in LPS-induced ALI, and be able to alleviate pulmonary edema, enhance AFC, and attenuate lung injury via activation of the ALX/PI3K/Nedd4-2 pathway. In addition, MaR1 was engaged in healing, tissue regeneration, and the reducing of IL-17, TNF-α, and IFN-γ production.
| Aspirin-Triggered Lipid Mediators|| |
As a classic anti-inflammatory agent, aspirin induces a shift from the synthesis of proinflammatory to pro-resolving lipid mediators termed as aspirin-triggered lipoxins (ATL) and aspirin-triggered resolvins (AT-Rv)., ATL and AT-Rv share the pro-resolution effects of LXA4 and RvD1, respectively, and act via the same intracellular pathways.
Previous study has shown that posttreatment with ATL could inhibit TNF-α, nitric oxide (NO), and malondialdehyde production, with the outcome of decreased pulmonary edema, lipid peroxidation, and the infiltration of neutrophils in lung tissues. Another study has shown that 15-epi-lipoxin A4 could inhibit myeloperoxidase signaling and enhance resolution of ALI. In addition, ATLa, an ATL synthetic analog, could inhibit the lung production of IL-1β, IL-17, TNF-α, and TGF-β in BLM-challenged mice. ATLa could restore the balance of inducible NO synthase (iNOS)-positive and arginase-positive cells in the lungs, suggesting a prevalence of M2 versus M1 macrophages.
Early treatment with exogenous AT-RvD1 (1 h post infection) could enhance the clearance of Escherichia More Details coli and P. aeruginosa in vivo and lung macrophage phagocytosis of fluorescent bacterial particles in vitro. AT-RvD1 could also increase the efferocytosis of these cells in vitro and accelerate neutrophil clearance during pneumonia in vivo. Moreover, treatment with AT-RvD1 has shown a reduced level of proinflammatory cytokines IL-6 and IL-8 in IL-1β stimulated A549 cells. AT-RvD1 could reduce the IL-1β-mediated alveolar epithelial cell activation. AT-RvD1 could significantly reduce the lung vascular permeability in the mice with lung injury and decrease the neutrophils, inflammatory cytokines, and chemokines in the BALF. Furthermore, secretion of TNF-α, IL-6, keratinocyte cell-derived chemokine, and MIP-1α from IgG immune complex-stimulated alveolar macrophages or neutrophils could be significantly decreased by AT-RvD1. Animals treated with AT-RvD1 have been shown to have improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 could inhibite neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 could also significantly decrease the levels of BALF proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and decrease the nuclear factor-κB-phosphorylated p65 nuclear translocation. Therapeutic treatment with exogenous AT-RvD1 could significantly reduce the pneumococcal load during the acute phase of infection (days 4–6 postpneumococcal inoculation). AT-RvD1 could also significantly reduce the neutrophil elastase activity and restore total antimicrobial activity, reduce the number of infiltrating lung neutrophils and monocytes/macrophages, and limit the movement of excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs through binding ALX.
| Heme Oxygenase and Carbon Monxide|| |
Heme oxygenase (HO), a ubiquitous inducible stress-response protein, is a stress response gene that has been extensively investigated in ALI/ARDS. HO-1 catalyzes the oxidative degradation of heme to biliverdin-IX alpha, iron, and carbon monoxide (CO), all exerting anti-oxidative and anti-inflammatory activities. Recent studies have demonstrated that HO-1 or CO can confer cytoprotection in ARDS models, based on anti-apoptotic, anti-inflammatory, and anti-proliferative properties.[88.89]
Chiang et al. found that resolvins and lipoxins in turn upregulated HO-1 in macrophages, demonstrating mutual amplification of these two pro-resolving pathways. ATL could promote the formation of HO-1 and its activity in the lung tissues. RvD1 increased HO-1 expression, which might contribute to the protection of the tight junction. In addition, RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. Therefore, RvD1 might possess the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of tight junction in LPS-induced ALI mice, at least in part, by upregulating HO-1 expression.
In the lung, CO could suppress LPS-induced lung alveolitis and associated edema formation. This protection appears to be partially due to LPS-induced iNOS and NO production. CO could prevent the up-regulation of iNOS and NO in the lung. Studies of primary lung macrophages in vitro have revealed that CO could inhibit LPS-induced cytokine production in lung macrophages. The administration of CO could prevent pulmonary microvascular permeability alteration noted after ischemia-reperfusion (I/R) of the lower limbs. Histologically, CO administration inhibited neutrophilic sequestration observed after I/R. Exogenous administration of CO by inhalation at low doses could prevent ALI post-I/R in this model. CO could promote resolution of inflammation via enhancing bacterial kiling, repressing proinflammatory cytokines such as TLR-2, -4, -5, and -9 expression, initiating the production of anti-inflammatory cytokines such as IL-10 in macrophages, enhancing efferocytosis of apoptotic cells or bacteria by macrophages, and improving the expression of lipoxygenases which are key synthetases of SPMs.
Annexin A1 (ANXA1), a 37 kDa monomeric protein, is an endogenous regulator of anti-inflammatory and pro-resolving as well as a mediator of glucocorticoids (GCs) action., A previous study  has shown that ANXA1 could potently downregulate PMN migration into inflammatory sites and accelerate their apoptosis, upregulate the monocytes migration into inflammatory sites. Administration of the active N-terminal peptide of AnxA1 (Ac2-26) in I/R-induced lung injury could significantly attenuate the lung edema and proinflammatory cytokine production recovered in BALF, and reduce oxidative stress, apoptosis, neutrophil infiltration, and lung tissue injury, possibly via the activation of the N-formyl peptide receptor. In addition, Ac2-26 administration could be effective to reduce pro-resolving mediators, such as IL-2, IL-4, IL-10, and IL-13, and induce the release of pro-resolving mediators, such as IL-10.
| Discussion|| |
ALI and its more severe form ARDS are relatively common syndromes in critically ill patients, and are associated with high morbidity and mortality. Pulmonary edema is a hallmark in ALI/ARDS and a life-threatening condition., It is widely accepted that resolution of alveolar edema is key for patient's survival. Previously, clinical studies have shown that impaired alveolar fluid transport mechanisms contribute to the development, severity, and outcome of pulmonary edema in humans. The AFC process is crucial to efficient gas exchange in the lung, and ALI/ARDS patients with intact AFC have lower morbidity and mortality than those with compromised AFC.
SPMs are chemical mediators that are involved in the resolution process in response to injury, infection, or allergy. Pro-resolving mediators include the arachidonic acid-derived lipoxins and the omega-3 fatty acid-derived resolvins, protectins, maresins, CO, HO-1, and ANXA1. During acute inflammation, polyunsaturated fatty acid metabolism switches from pro-inflammatory mediators to pro-resolving mediators. SPMs could inhibit proinflammatory cytokine production, prevent leukocyte infiltration, and promote the removal of inflammatory leukocytes by natural killer cell-mediated leukocyte apoptosis. Moreover, SPMs also promote macrophage phagocytosis and epithelial cell repair, and improve the ENaC, Na, K-ATPase, CFTR to upregulate the AFC in ARDS.
| Conclusion|| |
In this review, we have discussed how the pro-resolving mediators regulate the AFC in both physiologic and pathologic conditions. We suggest that declined AFC in ARDS might be associated with the impaired vectorial ion transportation in injured lungs. Recent studies have also suggested that pro-resolving mediators might enhance the alveolar epithelium repair, inhibit the inflammatory cytokines, and upregulate the ion channel activity and protein expression in a receptor-dependent manner to increase the AFC, and thus may serve as promising agents for the treatment of ARDS [Figure 1].
|Figure 1: Mechanisms underlying the effects of specialized pro-resolving mediators on alveolar fluid clearance in acute respiratory distress syndrome. In normal lungs, ATI and ATII cells, alveolar and endothelium permeability, ion channels, and inflammatory cytokines regulate the AFC together to maintain balance and re-establish alveolar homeostasis. In ARDS, SPMs enhance the alveolar epithelium repair, inhibite the inflammatory cytokines, upregulate the ion channel activity and protein expression to improve the AFC and recovery the lung function. SPMs: Specialized pro-resolving mediators; AFC: Alveolar fluid clearance; ARDS: Acute respiratory distress syndrome; ATI/ATII cells: Alveolar epithelial Type I/Type II cells; ENaC: Epithelial sodium channel; CFTR: Cystic fibrosis transmembrane conductance regulator; AQP5: Aquaporins.|
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Financial support and sponsorship
This work was supported by grants from the National Natural Science Foundation of China (No. 81570076, No. 81571862, and No. 81400059), the Natural Science Foundation of Zhejiang Province (No. LY18H010005), and the Wenzhou Science and Technology Bureau Project (No. Y20170034).
Conflicts of interest
There are no conflicts of interest.
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