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. 2023 Aug 4;102(31):e34613. doi: 10.1097/MD.0000000000034613

A bibliometric analysis of exosomes in sepsis from 2004 to 2022

Yuanyuan Li a,*, Weina Wang a, Bo Zhang a, Lili Li b, Dengfeng Zhou a
PMCID: PMC10403034  PMID: 37543762

Abstract

The study aims to summarize topical and frontier issues in sepsis and exosomes and provide advice and resources for researchers working in related disciplines. Publications on exosomes in sepsis from 2004 to 2022 were extracted from the Web of Science Core Collection database. VOSviewer 1.6.18 and CiteSpace 6.1.3 were used to conduct the bibliometric analysis. The number of publications on exosomes in sepsis showed a rapidly rising trend globally. China and the United States were the most published countries. Shanghai Jiao Tong University is the most prolific institution. Frontiers in Immunology was one of the journals with the highest number of papers. Journal of Immunology was the most co-cited journal. Ping Wang was the most productive author. Clotilde Thery was the author who has been cited the most times among co-cited authors. Singer m, 2016, Jama-j am med assoc was the most co-cited reference. “Mesenchymal stem cells derived exosomes,” “microRNAs,” “apoptosis,” and “immunomodulatory therapy” are the current research hot spots and frontiers. This study provides a comprehensive overview of the current status and trends in sepsis and exosomal research. Researchers working in this area will benefit from the hot spots and trends of exosomes in sepsis discovered through this study.

Keywords: bibliometric analysis, exosomes, hot spots, sepsis

1. Introduction

Sepsis is a common disease and major cause of death in the intensive care unit and is characterized by organ dysfunction due to infection. Epidemiological data showed that there were 48.9 million cases of sepsis annually, of which 11 million die, accounting for one-fifth of global deaths.[1] In China, the incidence of sepsis in intensive care unit is 20.6%, and the mortality is 35.5%,[2] imposing a great medical burden on society and families. Currently, the primary methods of treating sepsis include organ support therapy, early antibiotic usage, and management of the infection source. Unfortunately, there is still no specialized therapy available for sepsis,[3] making it critically necessary to find an early diagnosis and treatment.

Exosomes, vesicles with a diameter of 40 to 100 nm and containing lipids, proteins, mRNA, microRNAs, etc.,[4] were discovered in sheep reticulocytes for the first time in 1983.[5] It is an important mediator of intercellular communication, with its mediated transfer of mRNA and microRNA not only enabling the exchange of genetic material between cells,[6,7] but also acting as a diagnostic marker for sepsis.[8] Almost all types of cells in the human body can produce exosomes, with mesenchymal stem cell-derived exosomes being widely used in sepsis treatment research.[9–12] In addition, multiple immune and non-immune cell-derived exosomes can play an immunomodulatory role, offering a new strategy for sepsis treatment.[13]

Bibliometric analysis is a valuable method for exploring and analyzing vast scientific data, enabling a deeper understanding of the progression and potential frontiers within a particular field.[14] This analysis encompasses 2 main categories: performance analysis and scientific mapping. Performance analysis assesses the contributions of various research components, while scientific mapping focuses on the interconnections between these components.[15] Many scholars have devoted themselves to the research of exosomes in sepsis, but the trends and hot frontiers in this field are still unclear. Therefore, this study aims to provide an in-depth analysis of the development and hot frontier issues in the field using bibliometric methods to inform and inspire scholars in their research on related issues. Although numerous scholars have dedicated themselves to studying exosomes in sepsis, the current trends and forefront of this field remain unclear. Consequently, this study aims to conduct an extensive bibliometric analysis to uncover the developments and hot frontier issues, providing insights and inspiration for scholars undertaking research in related areas.

2. Methods

2.1. Search strategies and data collection

All research data in accordance with the present study were searched from the Science Citation Index Expanded and Social Science Citation Index of the Web of Science Core Collection database. The database includes a wide range of top academic publications and research findings with significant global influence and authority. The search formula was TS = (sepsis OR “severe sepsis” OR “septic shock” OR endotoxemia OR SIRS OR “systematic inflammatory response syndrome”) AND TS = (exosome OR exosomes). The search period runs from January 1, 2004, to October 31, 2022. Owing to the daily renewal of the database, data retrieval was performed in a single day on November 21, 2022. The detailed enrollment and screening process was presented in Figure 1. The prerequisites for admission are review, article, and English articles. Conversely, exclusion criteria include meeting abstracts, editorial materials, book chapters, conference papers, news, information, news reports, errant or retracted documents, and irrelevant documents. The original data collection was carried out independently by 2 researchers, and conflicting results were resolved by discussion. Then all of these data, including references and total records, were exported in.txt format for further bibliometric analysis.

Figure 1.

Figure 1.

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Publications screening flowchart.

2.2. Data analysis

In our study, the science mapping was completed using VOSviewer1.6.18 and CiteSpace 6.1.3. VOSviewer1.6.18 is a Java-based free software developed by Nees Jan van Eck and Ludo Waltman in 2009, which is mainly oriented to literature data and focuses on the visualization of scientific knowledge.[16] It completed the following analyses: the cooperation analysis of countries and institutions, journal and co-cited journal analysis, author and co-cited author analysis, co-cited references analysis, and keyword co-occurrence analysis. CiteSpace 6.1.3, another software developed by professor Chaomei Chen, is used to identify new trends and advances in the scientific literature.[17] In our study, it was primarily utilized for keyword clustering analysis, reference with citation bursts analysis, and keyword bursts analysis.

2.3. Ethics and consent

This study does not involve animal or human subjects and thus does not require ethical approval.

3. Results

3.1. Annual publications and trend

A total of 228 studies met our inclusion criteria, including 176 articles and 52 reviewed articles. The changes in the number of publications over time may provide a better understanding of the progress of exosomes in sepsis. Figure 2 showed the chronological distribution of publications published in the area of exosomes in sepsis. The entire process can be separated into Phase I (2004–2014) and Phase II (2015–2022). The number of papers published in Phase I is comparatively small, with 2.5 on average per year. While the number of documents published in Phase II has grown rapidly, with 25.4 on average per year. Although the number of publications fluctuated in some years, there was a rising tendency on the whole, especially after 2019. In 2021, the number of publications peaked (n = 58), accounting for 25.4% of the total publications from 2004 to 2022.

Figure 2.

Figure 2.

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The annual number of publications.

3.2. Distribution of countries and institutions

There were a total of 33 countries contributed to the study of exosomes in sepsis, and the top 10 countries in terms of publications in the field included China, the United States, Germany, Japan, South Korea, Canada, the United Kingdom, Brazil, France and Italy (Table 1). Among these countries, China has the most publications (n = 107, 36.53%), followed by the United States (n = 79, 26.96%) and Germany (n = 13, 4.44%). Subsequently, the countries with a number of publications greater than or equal to 1 publication were visualized using VOSviewer (Fig. 3). As shown in Figure 3, the node’s size corresponds to the number of papers published; The line between nodes represents the strength of association, and the thicker the line is, the more papers published in collaboration between the 2 countries. China and the United States have worked closely together. In addition, the distribution of countries publishing in this field is extremely uneven, and the “top effect” is highly apparent, with most of the publications coming from China and the United States.

Table 1.

Top 10 countries and institutions on the research of exosomes in sepsis.

Rank Country Counts Institution Counts
1 China 107 Shanghai Jiao Tong University 12
2 United States 79 The Feinstein Institutes for Medical Research 10
3 Germany 13 Fudan University 9
4 Japan 11 Southern Medical University 7
5 South Korea 10 China medical University 6
6 Canada 8 Nanjing Medical University 6
7 United Kingdom 8 University of Pittsburgh 6
8 Brazil 7 Zhejiang University 6
9 France 7 Long Island Jewish Medical Center 5
10 Italy 7 Mie University 5
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Figure 3.

Figure 3.

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The visualization of countries on the research of exosomes in sepsis.

A total of 391 institutions published papers on the research of exosomes in sepsis worldwide. Six of the top 10 institutions are in China, two in the United States, one in the United Kingdom, and one in Japan (Table 1). The top 3 institutions in terms of the number of publications were Shanghai Jiao Tong University (n = 12, 2.1%), the Feinstein Institute for Medical Research (n = 10, 1.75%), and Fudan University (n = 9, 1.57%) (Table 1). Shanghai Jiao Tong University and Fudan University are located in China, and the Feinstein Institute for Medical Research is positioned in the United States. And then, the institutions with at least 2 published papers were chosen for visualization (Fig. 4). The higher the density in Figure 4, the closer it is to red, conversely, to blue. From the graph, we can see more visually the leading position of Shanghai Jiao Tong University and the Feinstein Institute for Medical Research in the research of exosomes in sepsis.

Figure 4.

Figure 4.

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The visualization of institutions on the research of exosomes in sepsis.

3.3. Journals coupling analysis and co-cited journals analysis in exosomes and sepsis

Between 2004 and 2012, studies on exosomes in sepsis were published in 140 journals worldwide. The top 10 journals in terms of the number of publications were shown in Table 2. Frontiers in Immunology was the most published journal (n = 12, 5.26%) with an impact factor of 8.787. Six of the top 10 journals listed were Q1 journals, two Q2 journals, and two Q3 journals. The impact factors of these journals ranged from 3.322 to 19.344, among which Critical care had the highest impact factor (IF = 19.344, n = 83.51%). Then, the VOSviewer was used to visualize the journals with a threshold of 2 publications (Fig. 5). Four major clusters were formed with Frontiers in Immunology, Critical Care, Stem Cell Research & Therapy, and Shock as the core, corresponding to the 4 clusters in the diagram. Furthermore, it showed that Frontiers in immunology was widely associated with Critical Care, Shock, Scientific Reports, etc.

Table 2.

Top 10 journals and co-cited journals for research of exosomes in sepsis.

Journal Counts IF/Q Co-cited Journal Co-citation IF/Q
Frontiers in Immunology 12 8.787/Q1 Journal of Immunology 344 5.430/Q2
Critical Care 8 19.344/Q1 PLOS One 336 3.752/Q2
Shock 8 3.533/Q3 Critical Care Medicine 280 9.296/Q1
Scientific Reports 6 4.997/Q2 Critical Care 256 19.344/Q1
Stem Cell Research & Therapy 6 8.088/Q1 Scientific Reports 250 4.997/Q2
Biochemical and Biophysical Research Communications 5 3.322/Q3 Blood 239 25.669/Q1
Critical Care Medicine 4 9.296/Q1 Shock 231 3.533/Q3
Frontiers in Cellular and Infection Microbiology 4 6.073/Q1 Frontiers in Immunology 205 8.787/Q1
Frontiers in Microbiology 4 6.064/Q2 Journal of Extracellular Vesicles 201 17.337/Q1
International Journal of Molecular Sciences 4 6.208/Q1 American Journal of Respiratory and Critical Care Medicine 201 30.528/Q1
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IF = impact factor.

Figure 5.

Figure 5.

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The visualization of journals coupling on the research of exosomes in sepsis.

Meanwhile, we counted the top 10 co-cited journals related to the research of exosomes in sepsis (Table 2), and Journal of Immunology (co-citation = 344) was the most cited journal, followed by PLoS One (co-citation = 336), Critical Care Medicine (co-citation = 280). Among these journals, six were Q1 journals, three Q2 journals, and one Q3 journal. The impact factors of these journals varied between 3.533 and 30.528, and the American Journal of Respiratory and Critical Care Medicine (IF = 30.528) had the highest impact factor. Subsequently, we used VOSviewer to visualize the co-cited journals and set the minimum co-citations equal to 50. Figure 6 showed that the co-citation network of the co-cited journals was composed of 3 clusters corresponding to the 3 colors. The journals clustered in green were mainly in the field of critical care medicine and were cited mainly to provide background knowledge on sepsis. The journals clustered in red and blue were mainly journals in the field of cell biology with many exosome-related studies and empirical support for the research.

Figure 6.

Figure 6.

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The visualization of co-cited journals on the research of exosomes in sepsis.

3.4. Authors coupling analysis and co-cited authors analysis in exosomes and sepsis

A total of 1425 authors contributed to the research on exosomes in sepsis. Among the top 10 authors, the most published author was Ping Wang (n = 11, 0.6%), while the second was Rongqian Wu(n = 7, 0.4%). Both of them worked at the Feinstein Institute for Medical Research. Then, the scholars whose published papers were greater than or equal to 3 were selected for visualization through VOSviewer (Fig. 7A). It can be seen from the figure that Ping Wang had active cooperation with Rongqian Wu, Monowar Aziz, Weifeng Dong, and others. There were 9360 co-cited authors, of which five were co-cited more than 50 times (Table 3). Then, we visualized the co-cited authors with a minimum number of citations of 20 by VOSviewer (Fig. 7B). The figure consisted of 4 clusters corresponding to its 4 colors.

Figure 7.

Figure 7.

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The visualization of authors coupling (A) and co-cited authors (B) on the research of exosomes in sepsis.

Table 3.

Top 10 authors and co-cited authors on the research of exosomes in sepsis.

Rank authors Count Co-Cited authors Citations
1 wang, ping 11 thery, c 54
2 wu, rongqian 7 singer, m 53
3 park, eun jeong 5 zhou, y 53
4 park, kyong-su 5 hotchkiss, rs 51
5 shimaoka, motomu 5 wang, xh 51
6 aziz, monowar 4 valadi, h 37
7 cantaluppi, vincenzo 4 raposo, g 34
8 cook, james a 4 essandoh, k 33
9 dong, weifeng 4 azevedo, lcp 30
10 fan, guo-chang 4 miksa, m 28
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3.5. Co-cited references analysis in exosomes and sepsis

Co-citation occurs when 2 papers are cited in a third paper’s reference list. A total of 11,597 articles on the research of exosomes in sepsis were co-cited globally from 2004 to 2002. We listed the top 10 co-cited references (Table 4) and drew the density map of co-cited references using VOSviewer software (Fig. 8A), from which we can very clearly note singer m, 2016, Jama-j am med assoc which had the highest number of citations at 51.

Table 4.

Top 10 co-cited references on the research of exosomes in sepsis.

Rank Co-cited reference Citations
1 singer m, 2016, jama-j am med assoc, v315, p801 51
2 valadi h, 2007, nat cell biol, v9, p654 37
3 wang xh, 2015, sci rep-UK, v5 26
4 azevedo lcp, 2007, crit care, v11 24
5 essandoh k, 2015, bba-mol basis dis, v1852, p2362 24
6 gambim mh, 2007, crit care, v11 24
7 janiszewski m, 2004, crit care med, v32, p818 24
8 raposo g, 2013, j cell biol, v200, p373 24
9 song yx, 2017, stem cells, v35, p1208 21
10 zhou y, 2018, mol ther, v26, p1375 20
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Figure 8.

Figure 8.

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The visualization of co-cited references on the research of exosomes in sepsis (A) and the top 10 references with strong citation bursts (B).

3.6. Reference with citation bursts analysis in exosomes and sepsis

Reference with citation bursts refers to an abrupt rise in the number of citations for a given reference during a particular time, as measured by strength. The bigger the strength, the higher the intensity of citation bursts, indicating the more significant influence of the reference in the field. The figure of reference with citation bursts analysis related to the research of exosomes in sepsis was shown in Figure 8B. It can be seen from the figure that the top 3 references in terms of strength were Singer M, 2016, JAMA-J AM MED ASSOC (strengh = 5.43), Essandoh k, 2015, BBA-MOL BASIS DIS (strengh = 4.82) and Real JM, 2018, CRIT CARE (strengh = 4.52). The primary components of the references in Figure 9 were listed in Table 5.[4,12,18–25]

Figure 9.

Figure 9.

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Keyword cluster analysis (A) and keywords with the strongest citation bursts on the research of exosomes in sepsis (B).

Table 5.

The main research contents of the ten references with strong citation bursts.

Rank Strength Main research content
1 3.4 Mesenchymal stromal cell-derived exosomes’ effect on the lung and inhibit pulmonary hypertension.[18]
2 4.82 The role of extracellular and intracellular microRNAs in sepsis.[19]
3 4.35 The introduction of extracellular vesicles.[4]
4 4.13 Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis.[12]
5 4.13 The role of exosome-delivered microRNAs in modulating the inflammatory response to endotoxin.[20]
6 5.43 The newest definitions for sepsis and septic shock.[21]
7 4.52 Exosomal miRNAs related to inflammation and cell cycle regulation.[22]
8 3.48 The role of exosomes in the development of acute lung injury.[23]
9 3.18 Minimal information for studies of extracellular vesicles 2018 (MISEV2018).[24]
10 3.18 The cell biology of extracellular vesicles.[25]
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3.7. Analysis of keyword co-occurrence, clustering and bursts in exosomes and sepsis

Keywords provide a central summary of the thesis. The top 20 high-frequency keywords were displayed in Table 6 from our co-occurrence analysis of keywords using VOSviewer. It suggested that the research of exosomes in sepsis was closely related to microRNAs, mesenchymal stem cells (MSCs), inflammation, macrophages, apoptosis, and so on. Then, we did the cluster analysis of keywords by CiteSpace, and the high-frequency keywords can be grouped into 8 clusters (Fig. 9A). The score of modularity Q was 0.5767 (>0.3), and the weighted mean silhouette value was 0.7981 (> 0.7), indicating that the cluster structure was significant and the result convincing.[26] At present, the main research directions can be summarized as follows: cluster (#3), cluster (#4), cluster (#5), and cluster (#6) were classified into the research of the source, secretion, and biological composition of exosomes; cluster (#0), cluster (#1), cluster (#2) and cluster (#7) were related to the research of the development and treatment of the exosomes in sepsis.

Table 6.

Top 20 keywords on the research of exosomes in sepsis.

Rank Keywords Count Rank Keywords Count
1 exosome 153 11 macrophage 27
2 sepsis 123 12 mesenchymal stem cells 27
3 inflammation 71 13 microvesicles 26
4 extracellular vesicle 67 14 apoptosis 23
5 microRNA 40 15 acute kidney injury 19
6 expression 38 16 microparticles 19
7 septic shock 32 17 injury 17
8 acute lung injury 31 18 mechanism 15
9 activation 27 19 stromal cells 15
10 cells 27 20 biomarker 14
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Keyword bursts refer to a significant increase in the frequency of keywords within a certain period. Cells, apoptotic cells, microRNAs, and proteins were the keywords with a strength more than or equal to 3 from 2004 to 2022, and apoptotic cells were the first and most extensive study (2006–2015) (Fig. 9B). Before 2015, research on exosomes in sepsis was relatively simple, mainly focusing on investigating the contents of exosomes and apoptotic cells. Since 2015, the research on exosomes in sepsis has evolved, incorporating microRNAs, MSCs, cell apoptosis, immune response, etc. This was consistent with the trends of the annual number of publications mentioned above.

4. Discussion

4.1. Current status and trends of research in the field of exosomes and sepsis

The number of publications related to exosomes in sepsis has generally increased in recent years, with the average number of papers published nearly doubling since 2019. This indicates the field of exosomes in sepsis is receiving more and more attention from academics around the world. It is constantly evolving and has significant room for growth.

With 186 publications combined, China and the United States published far more than any other nation, accounting for 63.48% of all studies on exosomes in sepsis published between 2004 and 2022. And 80% of the top 10 research institutions in terms of the number of articles published were located in China and the United States. China and the United States worked closely but didn’t collaborate as much with other nations. This powerfully demonstrates how cooperation between many nations can advance research in a particular area and how multidisciplinary and multicenter collaboration can effectively advance the development of scientific research.

It appears that high-quality journals in the area favor the research of exosomes in sepsis because 60% of the top 10 journals in terms of the number of publications were Q1 journals. Frontiers in immunology (IF = 8.187, Q1) had the most publications. Among the co-cited journals, Journal of immunology (IF = 5.430, Q2) was cited most, which had a significant impact on the development of exosomes in sepsis.

The most productive authors were Ping Wang (n = 12, 0.6%) and Rongqiang Wu (n = 7, 0.4%). Among the co-cited authors, Clotilde Thery (54 citations) was the most cited author, followed by Mervyn Singer (53 citations), and Yue Zhou (53 citations). Clotilde Thery was a prominent researcher on the primary function of exosomes and established the gold standard for the extraction, separation, and identification of exosomes.[27] Mervyn Singer was one of the primary proponents of the definition of Sepsis 3.0. And Yue Zhou published an article in Molecular therapy in 2018, where he found that endothelial progenitor cell-derived exosomes were able to prevent microvascular dysfunction by delivering miR-126, allowing for improved prognosis in sepsis,[28] providing very effective experimental support for sepsis and exosome research.

4.2. Knowledge base in exosomes and sepsis

The knowledge base, made up of co-cited reference collections, is the foundation for the evolution of knowledge in the research field.[29] The first, second, and eighth most cited references in the top 10 co-cited references primarily provided background information,[4,7,21] laying the theoretical groundwork for subsequent research on exosomes in sepsis. The fourth co-cited reference discovered that platelet-derived exosomes in septic shock patients could cause cardiac dysfunction.[30] The sixth and seventh postulated a new mechanism of vascular dysfunction in sepsis: platelet-derived exosomes trigger the death of vascular endothelial cells through the generation of peroxynitrite and NADPH oxidase.[31,32] In terms of treating sepsis, the third and ninth co-cited publications presented a new mechanism of mesenchymal stem cell therapy for sepsis, that is, exosome miR-223 contributes to the cardioprotective impact generated by MSCs,[12] and exosome miR-146a helps to increase the therapeutic effect of interleukin-1 primed MSCs on sepsis.[33] This reflects that future research on sepsis and exosomes should focus on both pathogenesis and precise treatment, which is also consistent with the results of the keyword clustering analysis.

4.3. Research hotspots and frontiers in exosomes and sepsis

The pattern of references marks the nature of the scientific research frontier, according to world-renowned scientometrician Price.[34] Keywords are the author’s summary and refinement of the content of the paper, and keywords analysis can also help us effectively summarize the hotspots and frontiers of the field. Combined with the reference with citation bursts analysis and keywords analysis, we outlined several hot spots and frontiers in the research of exosomes in sepsis as follows:

4.3.1. Exosomal miRNAs and sepsis.

miRNAs are a class of 19~25 nucleotide single-stranded non-coding RNAs that can regulate the post-transcriptional silencing of target genes.[35] The study of exosomal miRNAs entered a new phase when Valadi et al[7] discovered that exosome-mediated miRNA transfer was a novel method for exchanging genetic material between cells in 2007. Exosomal miRNAs are closely related to the occurrence, diagnosis, treatment, and prevention of sepsis.

Firstly, exosomal miRNAs have a significant role in the pathogenesis of sepsis. For example, human endothelial cell-derived exosome miRNA-99a/b could drive sustained inflammatory responses in sepsis by inhibiting mTOR expression.[36] Plasma-derived exosome miR-1-3p in sepsis induces endothelial dysfunction by targeting SERP1.[37] Secondly, exosomal miRNAs can be used as diagnostic markers for sepsis. Real et al[22] showed that 65 exosomal miRNAs were significantly altered in the exosomes of patients with sepsis compared to healthy volunteers. The expression of 28 miRNAs was different at the time of inclusion and 7 days later (18 miRNAs were up-regulated, and ten were down-regulated). Tian et al[8] found that hsa_circRNA_104484 and hsa_circRNA_104670 could be used as new diagnostic markers for sepsis. Finally, exosomal miRNAs may be the most promising tool for the treatment of sepsis, providing organ protection and improving patient prognosis. For example, Biomimetic immunosuppressive exosomes with specific miRNA proportions,[38] MSC-derived exosomal miR-141,[9] miR-27b,[10] miR-146b,[11] and miR-223,[12] endothelial cell-derived exosomal miR-125b-5p[39] and endothelial progenitor cell-derived exosomal miR-21-5p[40] and miR-126[28] have shown promising potential in treating sepsis.

4.3.2. MSC-derived exosomes and sepsis.

MSCs are adult stem cells with the potential for self-renewal and multidirectional differentiation. MSCs have been shown to improve bacterial clearance, decrease inflammation, stimulate tissue regeneration, and repair in treating sepsis, which may be related to paracrine mechanisms.[41] In 2010, Lai et al[42] discovered MSCs protect the myocardium through paracrine exosomes, emphasizing for the first time the mediating role of exosomes in tissue regeneration after MSC transplantation. MSC-derived exosomes can deliver mRNA, miRNA, cytokines, immunomodulators, and other bioactive substances to target cells. These substances help regulate the phenotype of immune cells, inhibit inflammation, activate autophagy, inhibit apoptosis, and oxidative stress of injured cells.[43] Compared to MSCs, MSC-derived exosomes not only have the biological properties of the source cells but also have a selective assembly, targeted delivery, efficient repair, high stability, safety, and easy preservation.[44] Previous studies have demonstrated the widespread use of MSC-derived exosomes in the treatment of sepsis. For example, bone marrow MSC-derived exosomes can deliver microRNA-141 targeting PTEN and activate β protein to reduce myocardial damage in sepsis. Adipose tissue MSC-derived exosomes ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells.[45] Human umbilical cord MSC-derived exosomes lower IRAK1 expression and limit NF-kappa B activity by increasing miR-146b levels, which lessens sepsis-related acute kidney damage in sepsis-stricken mice. In conclusion, MSC-derived exosomes are promising for the treatment of sepsis and can be used as a tool to load drugs or gene therapy molecules for precision targeting and a new era of cell-free regenerative medicine.[46]

4.3.3. Apoptosis associated with exosomes and sepsis.

Apoptosis is a physiological cell death coded by genes in the process of ontogeny to maintain the stability of the body’s internal environment and regulate the development of the body.[47] It can happen naturally or be provoked by outside stimuli like a pathogenic microbial infection. Previous studies have shown that platelet-derived exosomes can induce endothelial cell apoptosis through the production of NADPH oxidase, superoxide, NO, and peroxynitrite, revealing a new mechanism of vascular dysfunction in sepsis.[30,31] Additionally, the host can benefit from the innate immune system and adaptive immune system apoptosis by reducing the inflammatory response caused by sepsis, but immunosuppression brought on by a high number of immune cell apoptosis is a significant contributor to organ dysfunction and increased mortality in sepsis.[48] For example, Ping Wang and Rongqiang Wu, who published the most papers in the field of exosomes in sepsis worldwide, proposed in 7 articles that immature dendritic cells promote apoptosis by releasing exosomes containing milk fat globule epidermal growth factor 8, which can therefore reduce the immediate systemic inflammatory response of sepsis.[49–55] Exosomes from the plasma of sepsis patients were shown to inhibit T lymphocyte apoptosis by down-regulating the hsa-miR-7-5p gene, which decreased mortality in sepsis model mice, according to research by Deng et al.[56] This offers a fresh method of treating sepsis.

4.3.4. Regulation of the immune system in sepsis by exosomes.

Immune disorders play a crucial role in the onset, progression, and prognosis of sepsis.[57] A variety of immune cells and non-immune cells can produce exosomes and play an immunomodulatory role by participating in antigen presentation and recognition signaling pathways.[13] For example, it has been demonstrated that dendritic cell-derived exosomes can increase apoptosis and decrease systemic inflammatory responses in sepsis by delivering milk fat globule epidermal growth factor 8.[53] Mononuclear macrophage-derived exosomes are involved in the downregulation of protein regulatory networks, including immune responses.[58] By targeting JMJD3 and reducing NF-kappa B signaling, MSC-derived exosome-delivered microRNA-27b minimizes the generation of proinflammatory cytokines in sepsis-induced mice. Adipose tissue-derived stem cell-derived exosomes alleviate inflammation by regulating the Nrf2/HO-1 axis in macrophages.[59] However, other studies have shown that the release of extracellular cold-induced RNA binding protein by macrophage-derived exosomes can cause the production of cytokines and the migration of neutrophils, resulting in sepsis inflammation.[60] Reducing exosome production by macrophages with GW4869 can inhibit inflammation and cardiac dysfunction induced by sepsis.[19] In summary, the significance of exosomes in the immunological regulation of sepsis has been extensively researched. However, more research is still needed to determine the precise mechanism of action and associated signaling pathways.

4.4. Strengths and limitations of the study

Compared with traditional reviews, VOSviewer and Citespace, 2 widely used bibliometrics tools, were used to display the visual distribution of national institutions, journals, co-cited publications, authors, co-cited authors, and keywords in the research of exosomes in sepsis. However, there are still some limitations in this study. Only journal articles from the Science Citation Index Expanded and Social Science Citation Index of the Web of Science Core Collection database were used for this analysis, which would have resulted in an incomplete data collection. In addition, we have only included studies published in English, which may be underestimated for non-English writing papers.

5. Conclusions

In summary, this study provides a comprehensive overview of the current status, trends, hotspots, and frontiers of global research on exosomes in sepsis from 2004 to 2022. Over the years, there has been a noticeable increase in the volume of publications related to sepsis and exosomes research, accompanied by an improvement in the impact factors of associated journals. It is evident that China and the United States have taken the lead in this field, with a substantial number of publications. Close collaboration and exchange between these 2 nations have been observed, although cooperation with the rest of the world appears to be comparatively limited. Moving forward, it is crucial to strengthen and facilitate collaborations between countries. Future research directions should prioritize the investigation of MicroRNAs, MSC-derived exosomes, apoptosis, and immunomodulatory therapy in the context of sepsis. Firstly, there is a need to explore the specific mechanisms by which these factors contribute to the development and progression of sepsis. Secondly, the study of therapeutic strategies involving exosomes holds significant promise for precision treatment of sepsis. It is important to note that, apart from fundamental research, equal attention should be given to the translation of research findings into clinical applications. This implies a focus on utilizing exosomes as potential therapies for patients suffering from sepsis. Overall, this study emphasizes the importance of understanding the status quo and future directions of exosome research in sepsis. By addressing these areas of investigation, we can make significant strides in advancing the understanding and treatment of sepsis, ultimately improving patient outcomes.

Author contributions

Conceptualization: Yuanyuan Li.

Data curation: Yuanyuan Li.

Investigation: Weina Wang.

Methodology: Yuanyuan Li.

Software: Yuanyuan Li, Weina Wang, Bo Zhang, Lili Li.

Supervision: Dengfeng Zhou.

Visualization: Weina Wang, Bo Zhang, Lili Li.

Writing – original draft: Yuanyuan Li.

Writing – review & editing: Yuanyuan Li, Dengfeng Zhou.

Abbreviations:

IF
impact factor
MSCs
mesenchymal stem cells

YL and WW contributed equally to this work.

The authors have no funding and conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

How to cite this article: Li Y, Wang W, Zhang B, Li L, Zhou D. A bibliometric analysis of exosomes in sepsis from 2004 to 2022. Medicine 2023;102:31(e34613).

Contributor Information

Weina Wang, Email: weinawang1225@163.com.

Bo Zhang, Email: 95201184@qq.com.

Lili Li, Email: 1185154159@qq.com.

Dengfeng Zhou, Email: 18971406617@163.com.

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