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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 3  |  Issue : 1  |  Page : 1

Recent Advances of MicroRNA in Sepsis-associated Acute Lung Injury


Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China

Date of Submission30-Mar-2021
Date of Acceptance08-Jun-2021
Date of Web Publication23-Aug-2021

Correspondence Address:
Prof. Haiyan Yin
Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Avenue West, Guangzhou 510220, Guangdong Province
China
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DOI: 10.4103/jtccm.jtccm_14_21

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  Abstract 


Sepsis is one of the most common severe diseases in clinic. With the progression of the disease, it is very likely to occur acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Despite years of research, the mortality rate from sepsis-associated lung injury remains high. MicroRNAs (miRNAs) are a class of non-coding small RNAs with the function of regulating gene expression. In recent years, miRNAs have become a research hotspot in the field of biomedicine. Therefore, this review summarizes a large body of evidence implicating miRNAs and their target molecules in ALI/ARDS originating largely from studies using animal and cell culture model systems of ALI/ARDS. First, the pathophysiology and potential molecular mechanism of sepsis-associated ALI were briefly discussed at the cellular level, and the regulatory effect of miRNA on sepsis-associated ALI was summarized from the molecular mechanism so as to provide the possibility to find new targets for the treatment of sepsis-associated lung injury. Finally, some promising methods and some shortcomings of existing research are introduced.

Keywords: Acute lung injury, acute respiratory distress syndrome, microRNA, sepsis


How to cite this article:
Lu X, Zhang F, Li L, Li M, Hu H, Qu Z, Qiu C, Wang Z, Yin H, Liu H. Recent Advances of MicroRNA in Sepsis-associated Acute Lung Injury. J Transl Crit Care Med 2021;3:1

How to cite this URL:
Lu X, Zhang F, Li L, Li M, Hu H, Qu Z, Qiu C, Wang Z, Yin H, Liu H. Recent Advances of MicroRNA in Sepsis-associated Acute Lung Injury. J Transl Crit Care Med [serial online] 2021 [cited 2021 Nov 30];3:1. Available from: http://www.tccmjournal.com/text.asp?2021/3/1/1/324285




  Introduction Top


Sepsis is a serious, life-threatening organ dysfunction caused by the host's uncontrolled response to infection and is one of the most common acute and critical diseases in the clinic.[1] As the disease progresses, sepsis can develop into septic shock and multiple organ dysfunction syndrome. The lung, which receives blood from all tissues and organs, is highly susceptible to the release and activation of various inflammatory mediators and cytokines, leading to sepsis-associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). ALI is not only the earliest occurrence and the highest incidence but also progresses rapidly. Its clinical manifestation is progressive and refractory hypoxemia, which seriously affects the prognosis of patients. The incidence rate of ALI/ARDS in sepsis patients is 40% to 60% and the mortality rate is 35% to 40%.[2] The current management of ARDS focuses on the diagnosis and treatment of infection, respiratory support, fluid management, and general supportive treatment such as nutritional support.[3] There is currently no effective drug therapy for ARDS, so it is important to find innovative, safe, and effective drug therapy for the prevention and treatment of sepsis-associated ALI.

MicroRNA (miRNA) is a regulatory noncoding small RNA of about 22-nt that can be produced by almost all cells in the body.[4] About 30% of miRNAs are transcribed from introns of protein-coding genes, while others are transcribed from specific miRNA genes in noncoding regions of the genome. The synthesis of miRNAs is a multistep process.[4] MiRNAs produced in the cell nucleus, most of them are initially transcribed by RNA polymerase II, in a few cases by RNA polymerase III. It is transcribed into a capped and polyadenylated transcript known as primary miRNA (pri-miRNA).[5] In the nucleus, the two ends of pri-miRNAs were cleaved by the Drosha/DGCR8 complex to further form the precursor miRNAs (pre-miRNAs), which was 70-100nt in length.[6] An individual pri-miRNA can either produce a single miRNA or expresses two or more miRNAs. These pre-miRNAs were transferred to the cytoplasm by Exportin-5, which was treated by the Dicer/TRBP complex to form a 19–25 nt double-stranded mature miRNA duplexes (miRNA-miRNA*).[7] One of the duplexes (miRNA*) was degraded, whereas the miRNA strand was recognized by the RNAiSED silencing complex containing enzymes of the Argonaute (AGO-2) family. The enzyme complex binds to the 3' or 5'-untranslated region or open reading frame or promoter region of the target mRNA, and gene silencing occurs by inhibiting the translation or degradation of the target mRNAs.[8] Conserved nucleotide sequence, known as "seed sequences," are located at 2–7 nucleotides at the 5' end of miRNA and are the basis for pairing with target mRNAs. Each miRNA can target hundreds of different mRNAs, and a single mRNA can also be targeted by multiple miRNAs. The activity of miRNA can be regulated by controlling the transcription of miRNA and the subsequent production and function of miRNA. Increasing evidence suggests that miRNAs are involved in the development and progression of tumors, cardiovascular disease, and inflammation.[9],[10],[11] Recent studies have shown that miRNAs also play an important role in sepsis-associated ALI.

Pathophysiology of sepsis-associated acute lung injury

In sepsis, the immune system is activated, and antigen-presenting cells (including monocytes, macrophages, dendritic cells, and endothelial cells) are activated when the pathogen invades. These activated antigen-presenting cells release a large number of pro-inflammatory cytokines and chemokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, IL-8, angiogenin-2, vascular endothelial growth factor, and platelet-activating factor.[12] Pro-inflammatory signals accelerate vascular endothelial dysfunction and promote more inflammatory cells such as neutrophils, monocytes, macrophages, and lymphocytes inflows, the formation of such a vicious pro-inflammatory circulation. At this point, the immune system of the patient with sepsis has become out of control, leading to reversible or irreversible damage to the lung microcirculation. It is characterized by increased permeability of pulmonary epithelial cells and pulmonary endothelial cells, massive influx of alveolar macrophages and neutrophils, and apoptosis.[13] The damaged endothelial cells lead to increased capillary permeability and exudation of protein-rich fluid into the alveolar cavities, which constitutes the exudative phase of ARDS.[14] In addition, damage to alveolar epithelial cells results in increased fluid flow into the alveolar cavity, reduced clearance of fluid from the alveolar cavity, and reduced production of alveolar surfactant. With sepsis-induced apoptosis and necrosis of alveolar epithelial cells, alveolar exudate is further increased, leading to alveolar edema and hyaline membrane formation.[15] Increased alveolar permeability, exudation of inflammatory cells, proteins, and water, resulting in reduced lung tissue volume, reduced lung compliance, gas diffusion, exchange, and metabolic disorders, and ultimately respiratory failure.[16]

Molecular mechanism of inflammatory response to sepsis-associated acute lung injury

In sepsis-associated ALI, inflammation occurs in immune cells, particularly macrophages, that are activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which leads to an inflammatory response.[17],[18] Various PAMPs and DAMPs activate toll-like receptors (TLRs) on the surface of macrophages[19],[20] and transmit intracellular signals that activate NF-κB and other inflammatory pathways[21] and the release of inflammatory cytokines (IL-6, TGF-, IL-1, etc.).[22] At the same time, the maturation and secretion of some pro-inflammatory cytokines also requires the activation of inflammasomes, which is a key part of the innate immune system.[23] Inflammasomes are polymeric protein complexes composed of caspases, Nod-like Receptor Proteins (NLRPs), and a caspase recruitment domain.[24] These mature cytokines participate in the innate immune response and trigger inflammation, which ultimately leads to ALI.[25] Therefore, inhibition of NF-κB pathway is considered as a potential therapeutic approach to prevent lung injury in sepsis.[26]

The molecular mechanism of apoptosis in sepsis-associated acute lung injury

Apoptosis is the second prominent feature of sepsis, and apoptosis of alveolar epithelial cells has been shown to be pathologically associated with the development of ALI.[27] Apoptosis- and autophagy-related molecules and pathways, including Bcl-2, Bax, Caspase-3/9, LC3-II/I, and Beclin-1, regulate cell activity and homeostasis in the progression of ARDS.[28] Mitochondria are the key factors of apoptosis. Bcl-2 is a gene mainly deposited on the outer membrane of mitochondria, which can regulate the permeability of the mitochondrial outer membrane. Bcl-2 can prevent mitochondria from releasing cytochrome C, thereby inhibiting cell apoptosis by inhibiting the activation of caspase-3.

The mechanism of microcirculatory dysfunction in sepsis-associated acute lung injury

Vascular endothelial cell injury appears to be a key event in the pathogenesis of sepsis.[29] Once activated during sepsis, endothelial cells convert to procoagulant, antifibrinolysis, and pro-adhesion states, leading to pathological changes in hemostasis, leukocyte transport, inflammation, barrier function, and microcirculation.[30] Thus, destruction of endothelial integrity and function may play a key role in the development of sepsis. Therefore, vascular endothelial cells may be a potential key target for inhibiting and preventing the progression of sepsis-associated organ dysfunction.


  Regulatory Effects of miRNAs on Sepsis-associated Acute Lung Injury Top


At present, a large number of studies have shown that the miRNAs to sepsis-associated ALI in mice model and cell model have regulatory effects. We summarized the target genes of macrophages [Table 1], alveolar epithelial cells [Table 2], and pulmonary vascular endothelial cells [Table 3] from the three major cell models and their roles in sepsis-associated ALI.
Table 1: Regulatory effects of microRNAs on macrophages

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Table 2: Regulatory effects of microRNAs on alveolar epithelial cells

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Table 3: Regulatory effects of microRNAs on microvascular endothelial cells

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Regulatory effects of microRNAs on macrophages

Macrophages play a crucial role in the activation and proliferation of the inflammatory response in the lung.[57] Yang et al. have shown that miR-182 is inhibited in lung tissue and macrophages under LPS stimulation, and overexpression of miR-182 significantly reduces the production of inflammatory cytokines (IL-6, TNF-α, and IL-1) and inhibits NF-κB activation and inflammatory cytokine secretion by directly targeting TLR4.[31] Similarly, MiR-802,[32] miR-27a,[34] miR-106a,[36] and miR-223[50] can inhibit the expression of inflammatory cytokines by inhibiting the NF-κB pathway by directly or indirectly targeting the TLR4. These studies suggest that the TLR4/NF-κB pathway plays an important role in the development of ALI/ARDS.

The inflammatory regulatory effect of miR-92a has been confirmed in a number of recent studies, and the production of inflammatory factors can be reduced by inhibiting the expression of miR-92a in RAW264.7 macrophages.[39] In RAW264.7 macrophages, miR-92a had an anti-inflammatory effect on LPS-induced ALI by inhibiting the PTEN/AKT/NF-κB signaling pathway.[39]

Recent studies have shown that miR-199a mediates the expression of inflammatory factors in sepsis-induced lung injury by regulating alveolar macrophage, and that miR-199a antagonists can reduce the opposite effect. The authors found that downregulation of miR-199a-3p alleviated its inhibition of NLRP-1 and led to the activation of NLRP-1, leading to inflammatory factor expression. Notably, Chen et al. found that transcription factor FOXP3 can bind to histone deacetylase 1 and C-terminal-binding protein 2 to form a CHFTC protein complex, which specifically binds to the promoter of miR-199a-3p and inhibits its expression. These differences are related to the polarization of macrophages, at the same time, miRNA involvement in disease is time, cell, and injury model dependent.[43]

Regulatory effects of microRNAs on alveolar epithelial cells

The initial response of the lung to injury is called the exudative phase of ARDS, which is characterized by innate immune cell-mediated damage to the alveolar endothelial and epithelial barrier.[3] Apoptosis plays an important role in the homeostasis and pathogenesis of many human diseases. Epithelial cells are exposed to various environments and internal stresses. Epithelial cells' apoptosis is the pathophysiological consequence of injury.[58] Li et al. found that Bcl-2 was one of the target genes of miR-181a through miRNA-related database analysis. The overexpression of miR-181a significantly downregulated Bcl-2. When miR-181a was inhibited, the LPS-induced apoptosis of A549 cells was significantly reduced, while the expression of Bcl-2 was significantly increased. This suggests that miR-181a promotes LPS-induced apoptosis by targeting Bcl-2.[45] In another study, the authors found that miR-21 can directly target Bcl-2, and the expression of Bcl-2 is negatively regulated by miR-21. In addition, overexpression of Bcl-2 reversed miR-21-induced apoptosis and inflammation in human pulmonary alveolar epithelial cells.[46]

Regulatory effects of microRNAs on microvascular endothelial cells

Endothelial cells injury results in translocation of pro-inflammatory mediators and bacterial products, leading to worsening systemic inflammation.[3] In a recent study, the authors found that the recovery of angiotensin-converting enzyme 2 (ACE-2) attenuated the apoptotic response of pulmonary microvascular endothelial cells (PMVECs) transfected with miR-1246. ACE2 overexpression reversed miR-1246-induced inhibition of Bcl-2 and Bcl-xL expression and increased Bax expression. These evidences indicate that miR-1246 can induce apoptosis of PMVECs by targeting ACE2.[55] In addition, in another study, the downregulation of miR-1246 effectively increased cell proliferation and decreased apoptosis and induced the expression of Wnt and β-catenin protein. Inhibition of the expression of Wnt and β-catenin protein by Wnt inhibitor reduced the function of miRNA-1246 downregulation-induced cell proliferation and apoptosis in ALI cell model, suggesting that miRNA-1246 perhaps mediates ALI-induced lung apoptosis through Wnt/β-catenin activation.[49] In another study, Cheng et al. found that miR-424 plays a protective role in LPS-induced apoptosis and inflammation of alveolar epithelial cells by targeting FGF2, which may be associated with the inhibition of the NF-κB signaling pathway.[44] These studies suggest that the NF-κB pathway may also be one of the therapeutic approaches to regulate apoptosis.

In a recent study, the authors found that high expression of miR-144 inhibits LPS-induced upregulation of Rho-associated coiledcoil-forming protein kinase-1 (ROCK1) activity, leading to upregulation of myosin phosphoatese-targeting subunit-1 (MyPT-1) activity, accompanied by myosin Light chain (MLC) phosphorylation, and reduction of actin contractility. It has been shown that miR-144 has similar regulatory effects on ROCK1 activation, MYPT-1 and MLC phosphorylation, vascular permeability, and inflammation in vivo. These results suggest that miR-144 inhibits ROCK1-mediated signal transduction and thus enhances endothelial barrier function after inflammatory pulmonary vascular injury.[56]

In one of the previous studies, miR-1246 knockdown impaired the LPS-induced increase in total cells and neutrophil counts, inflammatory cytokines, and protein levels in the BALF. This suggests that miR-1246 silencing can reduce LPS-induced pulmonary vascular permeability, possibly by targeting ACE2.[55]

In the previous study, the authors also demonstrated that one of the target genes of miR-92a is IGTA5 and that inhibition of miR-92a protects the pulmonary endothelial cell barrier by increasing cell migration, inhibiting inflammatory responses, and promoting angiogenesis.[53]

Other regulatory effects of microRNAs

In addition to the aforementioned regulatory effects on sepsis-induced ALI, miRNAs have also shown some other effects. MiR-34a can promote the development of ALI by targeting Kruppel-like factor 4 (Klf4), inhibiting the M2-type polarization of macrophages toward anti-inflammatory and inhibiting cell proliferation.[37] MiR-34a can also inhibit excessive autophagy of Alveolar TypeIIepithelial cells by targeting foxO3.[48] MiR-200b/c can reduce early pulmonary fibrosis in lung injury by targeting Zb1/2.[42] MiR-92a can also improve LPS-induced ARDS by promoting cell migration.[54] These miRNAs and their target genes have the potential to become new treatments for sepsis.


  Summary and Prospect Top


MiRNA is a powerful regulator of survival and maintenance of the functional characteristics of alveolar epithelial cells and endothelial cells. By inhibiting apoptosis of alveolar epithelial cells and endothelial cells, miRNAs can reduce cell damage, thereby improving the permeability of endothelial cells and reducing the release of various inflammatory factors.[59] By specifically regulating miRNAs expression in alveolar epithelial cells or endothelial cells, we were able to ameliorate sepsis-associated ALI. At the same time, miRNAs can also regulate macrophage polarization, reduce pulmonary fibrosis, and regulate autophagy and cell migration, showing great capacity in the prevention and treatment of sepsis-associated ALI. Therefore, regulating miRNAs may be a potential method for treating sepsis-associated ALI.

Although research on miRNAs has been going on for decades, there are still some unanswered questions. The current studies are all about the regulatory effects of a single miRNA on a single or several target genes. Since a miRNA can regulate hundreds of target genes and may affect different cell pathways, its regulation of target genes is extremely complex in the process of disease occurrence and development, and its synergistic or antagonistic effects among them are also important. Therefore, it is necessary to construct a systematic biological method to study miRNAs. At the same time, it is necessary to establish a more reliable and easier to understand regulatory target database to predict and study miRNA regulatory target correlation through bioinformatics methods based on big data. In addition, only one study elucidated the mechanism of miRNA expression abnormalities in sepsis-associated ALI.[43] A great deal of research is still needed to improve the relevant possible mechanisms. It is also not clear whether miRNA expression is the same at each stage of disease development. Most of the current studies are based on animal or cell models and lack clinical validation with large samples. At present, most miRNA-related clinical studies focus on the prediction and diagnosis of diseases.

Due to its stability, circulating miRNAs may become a new biomarker for the diagnosis of sepsis-associated organ dysfunction. However, relevant studies are still at the initial stage, requiring further proof based on clinical samples and time. In terms of miRNA therapy for disease, a phase 1 clinical trial has shown that miR-16 mimic-loaded microcells have shown promising results in the treatment of malignant pleural mesothelioma, but their safety and early signs of activity require further clinical studies.[60]

Since miRNA is important for various cell homeostasis functions, their role extends to many disease manifestations other than cancer. In mouse models of hepatitis, heart disease and diabetes-related renal fibrosis, miRNA mimics, or inhibitors have been successfully delivered in vivo. The miRNA sponge is an important tool for the study of miRNA dysfunction in vivo and in vitro. MiRNA sponges are described as transcripts with repeated MiRNA antisense sequences that act as competitive inhibitors to isolate endogenous MiRNA from its target.[61],[62] It's application makes it possible to apply MiRNA to sepsis-related lung injury although there are no clinical trials to apply it perfectly.[63] As we known, many miRNAs are either upregulated or downregulated in ALI/ARDS, these also associated with the biomarkers. However, it is unclear which miRNAs are specific and sensitive enough to be applied as clinical biomarkers. Because of the clinical application of MiRNA involves genetic technology, the crucial question is biosafety and ethical requirements. Therefore, it is considerable to select the appropriate concentrations of miRNAs and optimal cell/tissue-dependent delivery systems for effective treatment of ALI/ARDS.[64]

Source of foundation

This study was supported by grants from the National Natural Science Foundation of China (82072232 and 81871585); Project in the Natural Science Foundation of Guangdong Province (2018A030313058); and Planned Science and Technology Project of Guangzhou, China (201804010308).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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