|Year : 2021 | Volume
| Issue : 1 | Page : 1
Recent Advances of MicroRNA in Sepsis-associated Acute Lung Injury
Xuehao Lu, Feng Zhang, Longzhu Li, Meilian Li, Hai Hu, Zhongkai Qu, Chuiyan Qiu, Zhigang Wang, Haiyan Yin, Hui Liu
Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China
|Date of Submission||30-Mar-2021|
|Date of Acceptance||08-Jun-2021|
|Date of Web Publication||23-Aug-2021|
Prof. Haiyan Yin
Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Avenue West, Guangzhou 510220, Guangdong Province
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|| |
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. 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%. 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. 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. 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. 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). 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. 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*). 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. 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.,, 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. 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. 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. 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. 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.
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., Various PAMPs and DAMPs activate toll-like receptors (TLRs) on the surface of macrophages, and transmit intracellular signals that activate NF-κB and other inflammatory pathways and the release of inflammatory cytokines (IL-6, TGF-, IL-1, etc.). 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. Inflammasomes are polymeric protein complexes composed of caspases, Nod-like Receptor Proteins (NLRPs), and a caspase recruitment domain. These mature cytokines participate in the innate immune response and trigger inflammation, which ultimately leads to ALI. Therefore, inhibition of NF-κB pathway is considered as a potential therapeutic approach to prevent lung injury in sepsis.
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. 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. 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. 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. 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|| |
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 3: Regulatory effects of microRNAs on microvascular endothelial cells|
Click here to view
Regulatory effects of microRNAs on macrophages
Macrophages play a crucial role in the activation and proliferation of the inflammatory response in the lung. 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. Similarly, MiR-802, miR-27a, miR-106a, and miR-223 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. In RAW264.7 macrophages, miR-92a had an anti-inflammatory effect on LPS-induced ALI by inhibiting the PTEN/AKT/NF-κB signaling pathway.
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.
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. 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. 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. 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.
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. 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. 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. 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. 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.
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.
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.
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. MiR-34a can also inhibit excessive autophagy of Alveolar TypeIIepithelial cells by targeting foxO3. MiR-200b/c can reduce early pulmonary fibrosis in lung injury by targeting Zb1/2. MiR-92a can also improve LPS-induced ARDS by promoting cell migration. These miRNAs and their target genes have the potential to become new treatments for sepsis.
| Summary and Prospect|| |
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. 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. 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.
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., It's application makes it possible to apply MiRNA to sepsis-related lung injury although there are no clinical trials to apply it perfectly. 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.
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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al.
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10.
Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: An evidence-based review. Crit Care Med 2004;32:S548-53.
Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al.
Acute respiratory distress syndrome. Nat Rev Dis Primers 2019;5:18.
Bartel DP. Metazoan microRNAs. Cell 2018;173:20-51.
Du T, Zamore PD. Beginning to understand microRNA function. Cell Res 2007;17:661-3.
Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol 2019;20:5-20.
Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al.
TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005;436:740-4.
Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 2009;136:215-33.
Wen XQ, Qian XL, Sun HK, Zheng LL, Zhu WQ, Li TY, et al.
MicroRNAs: multifaceted regulators of colorectal cancer metastasis and clinical applications. Onco Targets Ther 2020;13:10851-66.
Ebrahimi SO, Reiisi S, Shareef S. miRNAs, oxidative stress, and cancer: A comprehensive and updated review. J Cell Physiol 2020;235:8812-25.
Ryu J, Ahn Y, Kook H, Kim YK. The roles of non-coding RNAs in vascular calcification and opportunities as therapeutic targets. Pharmacol Ther 2021;218:107675.
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012;122:2731-40.
Yang CY, Chen CS, Yiang GT, Cheng YL, Yong SB, Wu MY, et al.
New insights into the immune molecular regulation of the pathogenesis of acute respiratory distress syndrome. Int J Mol Sci 2018;19:588.
Sharp C, Millar AB, Medford AR. Advances in understanding of the pathogenesis of acute respiratory distress syndrome. Respiration 2015;89:420-34.
Bakowitz M, Bruns B, McCunn M. Acute lung injury and the acute respiratory distress syndrome in the injured patient. Scand J Trauma Resusc Emerg Med 2012;20:54.
Guillamat-Prats R, Camprubí-Rimblas M, Bringué J, Tantinyà N, Artigas A. Cell therapy for the treatment of sepsis and acute respiratory distress syndrome. Ann Transl Med 2017;5:446.
Bianchi ME. DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 2007;81:1-5.
Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol 2013;93:329-42.
Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Bravo-San Pedro JM, et al.
Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol 2015;6:588.
Xiang M, Fan J. Pattern recognition receptor-dependent mechanisms of acute lung injury. Mol Med 2010;16:69-82.
Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol 2014;5:461.
Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008;42:145-51.
Cornut M, Bourdonnay E, Henry T. Transcriptional regulation of inflammasomes. Int J Mol Sci 2020;21:8087.
Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397-411.
Herold S, Mayer K, Lohmeyer J. Acute lung injury: How macrophages orchestrate resolution of inflammation and tissue repair. Front Immunol 2011;2:65.
Liu SF, Malik AB. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 2006;290:L622-45.
Perl M, Lomas-Neira J, Venet F, Chung CS, Ayala A. Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Respir Med 2011;5:115-26.
Yu L, Chen Y, Tooze SA. Autophagy pathway: Cellular and molecular mechanisms. Autophagy 2018;14:207-15.
Kumar V. Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury. Front Immunol 2020;11:1722.
Matthay MA, Zemans RL. The acute respiratory distress syndrome: Pathogenesis and treatment. Annu Rev Pathol 2011;6:147-63.
Yang J, Chen Y, Jiang K, Zhao G, Guo S, Liu J, et al.
MicroRNA-182 supplies negative feedback regulation to ameliorate lipopolysaccharide-induced ALI in mice by targeting TLR4. J Cell Physiol 2020;235:5925-37.
You Q, Wang J, Jia D, Jiang L, Chang Y, Li W. MiR-802 alleviates lipopolysaccharide-induced acute lung injury by targeting Peli2. Inflamm Res 2020;69:75-85.
He R, Li Y, Zhou L, Su X, Li Y, Pan P, et al.
miR-146b overexpression ameliorates lipopolysaccharide-induced acute lung injury in vivo
and in vitro
. J Cell Biochem 2019;120:2929-39.
Ju M, Liu B, He H, Gu Z, Liu Y, Su Y, et al.
MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway. Cell Cycle 2018;17:2001-18.
Liu Y, Guan H, Zhang JL, Zheng Z, Wang HT, Tao K, et al.
Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1. Am J Physiol Cell Physiol 2018;314:C449-55.
Yang J, Chen Y, Jiang K, Yang Y, Zhao G, Guo S, et al.
MicroRNA-106a Provides Negative Feedback Regulation in Lipopolysaccharide-Induced Inflammation by targeting TLR4. Int J Biol Sci 2019;15:2308-19.
Khan MJ, Singh P, Dohare R, Jha R, Rahmani AH, Almatroodi SA, et al.
Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4. Genes (Basel) 2020;11:966.
Chen L, Xie W, Wang L, Zhang X, Liu E, Kou Q. MiRNA-133a aggravates inflammatory responses in sepsis by targeting SIRT1. Int Immunopharmacol 2020;88:106848.
Fu L, Zhu P, Qi S, Li C, Zhao K. MicroRNA-92a antagonism attenuates lipopolysaccharide (LPS)-induced pulmonary inflammation and injury in mice through suppressing the PTEN/AKT/NF-κB signaling pathway. Biomed Pharmacother 2018;107:703-11.
Xi X, Yao Y, Liu N, Li P. MiR-297 alleviates LPS-induced A549 cell and mice lung injury via targeting cyclin dependent kinase 8. Int Immunopharmacol 2020;80:106197.
Yang P, Xiong W, Chen X, Liu J, Ye Z. Overexpression of miR-129-5p Mitigates Sepsis-Induced Acute Lung Injury by Targeting High Mobility Group Bo×1. J Surg Res 2020;256:23-30.
Cao Y, Liu Y, Ping F, Yi L, Zeng Z, Li Y. miR-200b/c attenuates lipopolysaccharide-induced early pulmonary fibrosis by targeting ZEB1/2 via p38 MAPK and TGF-β/smad3 signaling pathways. Lab Invest 2018;98:339-59.
Chen Z, Dong WH, Chen Q, Li QG, Qiu ZM. Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1
. Int J Biol Sci 2019;15:2627-40.
Cheng D, Zhu C, Liang Y, Xing Y, Shi C. MiR-424 overexpression protects alveolar epithelial cells from LPS-induced apoptosis and inflammation by targeting FGF2 via the NF-κB pathway. Life Sci 2020;242:117213.
Li W, Qiu X, Jiang H, Han Y, Wei D, Liu J. Downregulation of miR-181a protects mice from LPS-induced acute lung injury by targeting Bcl-2. Biomed Pharmacother 2016;84:1375-82.
Ge J, Yao Y, Jia H, Li P, Sun W. Inhibition of miR-21 ameliorates LPS-induced acute lung injury through increasing B cell lymphoma-2 expression. Innate Immun 2020;26:693-702.
Li P, Yao Y, Ma Y, Chen Y. MiR-150 attenuates LPS-induced acute lung injury via targeting AKT3. Int Immunopharmacol 2019;75:105794.
Song L, Zhou F, Cheng L, Hu M, He Y, Zhang B, et al.
MicroRNA-34a Suppresses Autophagy in Alveolar Type II Epithelial Cells in Acute Lung Injury by Inhibiting FoxO3 Expression. Inflammation 2017;40:927-36.
Suo T, Chen GZ, Huang Y, Zhao KC, Wang T, Hu K. miRNA-1246 suppresses acute lung injury-induced inflammation and apoptosis via the NF-κB and Wnt/β-catenin signal pathways. Biomed Pharmacother 2018;108:783-91.
Yan Y, Lu K, Ye T, Zhang Z. MicroRNA-223 attenuates LPS-induced inflammation in an acute lung injury model via the NLRP3 inflammasome and TLR4/NF-κB signaling pathway via RHOB. Int J Mol Med 2019;43:1467-77.
Ke XF, Fang J, Wu XN, Yu CH. MicroRNA-203 accelerates apoptosis in LPS-stimulated alveolar epithelial cells by targeting PIK3CA. Biochem Biophys Res Commun 2014;450:1297-303.
Fei L, Sun G, You Q. miR-642a-5p partially mediates the effects of lipopolysaccharide on human pulmonary microvascular endothelial cells via eEF2. FEBS Open Bio 2020;10:2294-304.
Xu F, Zhou F. Inhibition of microRNA-92a ameliorates lipopolysaccharide-induced endothelial barrier dysfunction by targeting ITGA5 through the PI3K/Akt signaling pathway in human pulmonary microvascular endothelial cells. Int Immunopharmacol 2020;78:106060.
Xu F, Yuan J, Tian S, Chen Y, Zhou F. MicroRNA-92a serves as a risk factor in sepsis-induced ARDS and regulates apoptosis and cell migration in lipopolysaccharide-induced HPMEC and A549 cell injury. Life Sci 2020;256:117957.
Fang Y, Gao F, Hao J, Liu Z. microRNA-1246 mediates lipopolysaccharide-induced pulmonary endothelial cell apoptosis and acute lung injury by targeting angiotensin-converting enzyme 2. Am J Transl Res 2017;9:1287-96.
Siddiqui MR, Akhtar S, Shahid M, Tauseef M, McDonough K, Shanley TP. miR-144-mediated Inhibition of ROCK1 Protects against LPS-induced Lung Endothelial Hyperpermeability. Am J Respir Cell Mol Biol 2019;61:257-65.
Hiraiwa K, van Eeden SF. Contribution of lung macrophages to the inflammatory responses induced by exposure to air pollutants. Mediators Inflamm 2013;2013:619523.
Ju M, Liu B, He H, Gu Z, Liu Y, Su Y, et al.
MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway. Cell Cycle 2018;17:2001-18.
Rajasekaran S, Pattarayan D, Rajaguru P, Sudhakar Gandhi PS, Thimmulappa RK. MicroRNA regulation of acute lung injury and acute respiratory distress syndrome. J Cell Physiol 2016;231:2097-106.
van Zandwijk N, Pavlakis N, Kao SC, Linton A, Boyer MJ, Clarke S, et al.
Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: A first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol 2017;18:1386-96.
Bader AG. miR-34-A microRNA replacement therapy is headed to the clinic. Front Genet 2012;3:120.
Montgomery RL, Yu G, Latimer PA, Stack C, Robinson K, Dalby CM, et al.
MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol Med 2014;6:1347-56.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017;16:203-22.
Jiang ZF, Zhang L, Shen J. MicroRNA: Potential biomarker and target of therapy in acute lung injury. Hum Exp Toxicol 2020;39:1429-42.
[Table 1], [Table 2], [Table 3]