Bibliometric study of sepsis-associated liver injury from 2000 to 2023

Abstract

BACKGROUND

Sepsis-associated liver injury (SLI) is a severe and prevalent complication of sepsis.

AIM

To explore the literature on SLI via a bibliometric approach.

METHODS

Reviews and articles correlated with SLI published from January 1, 2000 to October 28, 2023 were searched from the Web of Science Core Collection. Then, the searched data were analyzed using VOSviewer, CiteSpace, and R language.

RESULTS

There were 787 publications involved in this paper, comprising 745 articles and 42 reviews. China, the United States, and Germany are the primary publication sources in this area. Studies related to SLI primarily focused on mechanisms of pathogenesis, as evidenced by analyzing keywords, references, and the counting of original research. These studies mainly involved tumor necrosis factor alpha, inflammation, oxidative stress, and nuclear factor-kappa B.

CONCLUSION

There is significant growth in the research on SLI. Current investigations primarily involve basic experiments that aimed at uncovering pathogenic mechanisms. According to the analyzed literature, the identified pathogenic mechanisms and potential therapeutic targets serve as the foundation for translating findings from basic research to clinical applications.

Key Words: Sepsis; Liver injury; Bibliometric analysis; Cite space; VOS viewer

Core Tip: NLRP3 inflammasome is the most recent keyword exhibiting the most significant citation bursts. The revelation of pathogenic mechanisms and potential therapeutic targets serves as the basis for translating from basic research to clinical application. In conclusion, our research will offer a helpful reference for subsequent studies on sepsis-associated liver injury.

INTRODUCTION

Sepsis, a condition marked by life-threatening organ dysfunction resulting from an aberrant host response to infection[1], has become a principal contributor to global health loss. According to a global epidemiological survey, there were 48.9 million incident sepsis cases registered and 11.0 million sepsis-associated deaths issued, which accounted for 19.7% of global mortality in 2017[2]. During systemic infections, the liver serves as both a host response target and an inflammatory process regulator[3]. The incidence of sepsis-associated liver injury (SLI) ranges from 34% to 46%, which is lower than in other organs due to the liver’s high regenerative capacity[4-6]. However, SLI is connected with severe sepsis complications. SLI patients’ mortality ranges from 54% to 68%, which is higher relative to the mortality rate in sepsis sufferers with respiratory system dysfunction[7-9]. Given the dangers of SLI, it has become a high-profile area of research. Over the past two decades, a substantial number of studies on SLI have been published, mainly addressing epidemiology, pathogenic mechanisms, etc. Despite the marked growth in the number of studies, the pathogenesis of SLI is not fully understood. Moreover, effective and targeted strategies for the treatment of SLI remain limited in clinical practice. Consequently, analysis of the current status, focus areas and future prospects is significant to improve our understanding of SLI.

Bibliometrics refers to the analysis of published information and its associated metadata, employing statistics to elucidate or illustrate relationships between published works[10]. Bibliometrics employs mathematical approaches to overcome the space and time limitations, allowing scholars to gain a comprehensive understanding of the current status, key points, and tendency in a specific study field. Nowadays, bibliometric analysis is widely utilized in the medical field, comprising areas such as lung cancer, heart failure, and pneumonia[7,11,12].

To the best of the author’s knowledge, a bibliometric analysis of SLI has not yet been undertaken. Consequently, our objective was to comprehensively screen publications related to SLI and utilize bibliometrics to disclose development proclivities and primary discoveries in this field.

MATERIALS AND METHODS

Data sources and search strategies

The Web of Science Core Collection (WoSCC) database was recruited for literature search. The query terms were shown as follows: Topic search = “liver injury” OR “liver damage” OR “hepatic injury” OR “hepatic damage” AND sepsis OR septic. Upon confining the language to English and publication types to reviews and articles, 1314 papers issued from January 1, 2000 to October 28, 2023 were searched from WoSCC. The abstracts and titles were independently screened by two reviewers to eliminate literature not pertinent to SLI. After reading the full text, a total of 787 publications specifically focusing on SLI were included (Figure 1).

Figure 1 Flowchart showing literature inclusion, exclusion and analysis process.

Statistics analysis

The publications with complete datasets and cited references were obtained from WoSCC for subsequent analysis. Bibliometric visualization was conducted using CiteSpace (version 6.1. R6) and VOSviewer (version 1.6.19). Each node in the collaborative network map denoted a distinct element, including journals, countries, and authors. The centrality was signified by a purple ring around a node, indicating the node’s importance and its significant impact in this field. The lines connecting nodes denoted cooperative alliances between institutions or countries, with thicker lines representing stronger cooperation. The SLI’s yearly publications and the institutions’ total publications were presented via a line graph. The R language was employed to draw the world map, illustrating the publications of different countries. The reference citation analysis (RCA) system was adopted to analyze the impact index of publications. The RCA system was accessible via the following uniform resource locator, https://www.referencecitationanalysis.com/.

RESULTS

Publication output

The number of publications in different periods provided insight into the level of research interest in SLI, indicating the speed and development of this field. After screening, 787 publications were included, comprising 745 articles (94.46%) and 42 reviews (5.54%). The research output on SLI from 2000 to 2023 was shown in Figure 2, which could be categorized as stable growth (2000-2017), accelerated growth (2018-2019), and a flourishing period (2020-2023). Of note, the total number of publications for 2023 was not counted, as data extraction was finalized on October 28, 2023. Even so, 58 relevant publications were still identified in 2023. A large number of papers were released between 2020 and 2023, demonstrating a burgeoning interest in the field in recent years.

Figure 2 Numbers of publications on sepsis-associated liver injury by year.

Country analysis

In total, 56 countries contributed related articles and reviews in this field. These countries’ distributions were depicted in Figure 3A, where the number and color depth indicated the publications’ number in different countries. To a certain degree, the quantity of publications across various states represented the level of interest in SLI within those regions. Referring to Figure 3B, the top ten countries, ranked based on the publications’ number, were concentrated in Asia (China, Japan, South Korea and Türkiye, n = 477), the North American (the United stated, n = 171), Europe (Germany, the United Kingdom, Sweden and Netherland, n = 128) and Africa (Egypt, n = 18). Among these countries, China held the top spot with 358 publications, accounting for over one-third of the publications’ total number. In addition, Citespace Software was adopted to construct and visualize the country collaboration network (Figure 3C). Each node represented a country. The green ring represented the related publications from a specific year, and its size corresponded to the number of publications. Nodes encircled by purple rings exhibited significant centrality (centrality ≥ 0.01), suggesting their high influence and importance. Countries with higher publication counts, including the United States, China, the United Kingdom and Germany were identified by purple rings and multiple layers of green, demonstrating their sustained research attention and significant role in the SLI development throughout the period. Of note, Malaysia occupied the top five in centrality with only 2 publications, suggesting that quantity was not the only criterion for judging the impact of papers. Besides, the collaboration network showed that China, the United States and Germany, as the top three countries with regard to the publications’ quantity, had communication with most countries.

Figure 3 Publication count and collaboration network by country. A: The world map labeled with the country; B: Publication numbers by country; C: Co-authorship among countries that published at least 10 papers. Each node represented a country, and the green color ring represented publications in a specific year. Purple rings indicated high centrality.

Institutional analysis

Between 2000 and 2023, 500 institutions carried out research on SLI. The top 10 institutions that published related papers were shown in Figure 4A. The Shanghai Jiao Tong University (19 publications), the Huazhong University of Science and Technology (18 publications), and Southern Medical University (17 publications) ranked as the top three academies by the number of publications, demonstrating their great impact and broad interest in this sphere. Academies from China accounted for eight of the ten most productive institutions, indicating a high level of attention from Chinese researchers to this field. The centrality was ranked in Table 1, showing that the influence of institutions in this field did not vary significantly. An institutional collaboration network was established via CiteSpace, with the minimum publication count per agency set to 10. Besides, significant cooperation had been constructed among various institutions worldwide (Figure 4B). The Shanghai Jiao Tong University with the largest number of publications had established communication with 19 other institutions, such as Fudan University, Nanjing University, and Shandong University.

Figure 4 Institutional analysis. A: The top 10 institutions in term of publications; B: Distribution map and collaboration network among institutions. The map shows active cooperation among institutions, with thicker lines representing closer collaboration.

Table 1 Top 10 institutions in ranking of centrality.

Rank	Centrality	Institution
1	0.06	Huazhong University of Science and Technology
2	0.06	Capital Medical University
3	0.04	Southern Medical University
4	0.04	Saarland University
5	0.04	University of Jena
6	0.03	Shanghai Jiao Tong University
7	0.03	Second Military Medical University
8	0.03	Chinese Academy of Medical Sciences
9	0.03	University of Pittsburgh
10	0.03	Mackay Memorial Hospital

Journal analysis

The top 10 journals ranked by publication count were shown in Table 2. Shock (IF = 3.1) was the most active journal in SLI, with 44 publications, succeeded by Journal of Surgical Research (IF = 2.2), with 23 publications; International Immunopharmacology (IF = 5.6), with 21 publications; Frontiers in Pharmacology (IF = 5.6), with 17 publications; Frontiers in Immunology (IF = 7.3), with 15 publications; Critical Care Medicine (IF = 8.8), with 14 publications; Experimental and Therapeutic medicine (IF = 2.7), with 11 publications; American Journal of Physiology-Gastrointestinal and Liver Physiology (IF = 4.5), with 10 publications; Biomedicine & Pharmacotherapy (IF = 7.5), with 10 publications; Journal of Hepatology (IF = 25.7), with 10 publications. Shock, the most widely published journal in the field of SLI, is dedicated to publishing documents in the areas of clinical and basic researches of ischemia, inflammation, sepsis, trauma, shock, and related pathobiological states. The top 10 co-cited journals were presented in Table 2. The top three rankings were Critical Care Medicine with 1093 co-citations, Shock with 978 co-citations, and Hepatology with 898 co-citations, respectively. According to co-citation analysis, Critical Care Medicine held significant influence in the field of SLI. The relationship between 388 identified journals, each with more than 15 citations, was illustrated in Figure 5A. The citation links within the field of SLI were visualized in Figure 5B. The scattered dots on the left represented citing journals, the scattered dots on the right represented cited journals, and the colors distinguished the disciplines to which the journals belonged. A thicker citation link represented a closer alignment in research content between the journals where the research was published or cited. As exhibited in Figure 5B, the citing papers in immunology, biology and molecular fields (yellow citation link) were most closely associated with cited papers from molecular areas, biology, and genetics, health, nursing and medicine.

Figure 5 Journal analysis. A: Co-citation map of journal with the threshold of 15 times. Each node represents a journal; B: Dual-map overlay of journals in which research was published (left) or cited (right). Colors distinguished the disciplines, and the thickness of the lines represented a closer alignment in research content.

Table 2 The top 10 most active journals and the top 10 co-citation journals.

Rank	Journal	Publications	JCR (2022)	IF (2022)	Rank	Journal	Citations	JCR (2022)	IF (2022)
1	Shock	44	Q3	3.1	1	Critical Care Medicine	1093	Q1	8.8
2	Journal of Surgical Research	23	Q2	2.2	2	Shock	978	Q3	3.1
3	International Immunopharmacology	21	Q2	5.6	3	Hepatology	898	Q1	14
4	Frontiers in Pharmacology	17	Q1	5.6	4	Journal of Immunology	885	Q2	4.4
5	Frontiers in Immunology	15	Q1	7.3	5	Journal of Biological Chemistry	539	Q2	4.8
6	Critical Care Medicine	14	Q1	8.8	6	Journal of Hepatology	446	Q1	25.7
7	Experimental and Therapeutic medicine	11	Q3	2.7	7	Proceedings of The National Academy of Sciences of The United States of America	422	Q1	11.1
8	American Journal of Physiology- Gastrointestinal and Liver Physiology	10	Q2	4.5	8	Journal of Clinical Investigation	415	Q1	15.9
9	Biomedicine & Pharmacotherapy	10	Q1	7.5	9	Nature	409	Q1	64.8
10	Journal of Hepatology	10	Q1	25.7	10	Critical Care	406	Q1	15.1

JCR: Journal Citation Reports; Q1: Quarter 1; IF: Impact factor.

Top 10 co-cited and cited publications

The top 10 cited publications, consisting of six articles and four reviews, were shown in Table 3. All six articles were basic studies focusing on the molecular mechanisms and potential treatment targets of SLI. “Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage” (Akio Ohta, 2001) was the most frequently cited article in the field of SLI. It established the critical role of A2a adenosine receptors in the physiological negative feedback mechanism that limited and terminated tissue-specific and systemic inflammatory responses, including SLI. The top 10 co-cited publications were listed in Table 4, with two of them surpassing 100 co-citations. One of these two articles was “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)” (Mervyn Singer, 2016). In this literature, authors provided an updated definition and clinical criteria for sepsis, including Sequential Organ Failure Assessment score for investigating the function of organ such as liver. The other of these two articles was a review published in 2014 entitled “The role of the liver in sepsis”. This review summarized clinical outcomes in SLI invalids, discussed the function of liver injury in promoting sepsis, and described the hepatic immune response’ crucial role in managing sepsis and homeostasis progression. Burst detection was used to determine which journals attracted significant attention over a specified period. In Figure 6, the top 20 publications with the most significant citation bursts were presented, illustrating the different focuses of researcher over time. As the most co-cited reference, “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”, also exhibited the strongest citation bursts. The research by Angus et al[9] received widespread citations from 2004 to 2006, focusing on the epidemiology of severe sepsis and SLI. However, another study conducted by Gong et al[13], widely cited from 2020 to 2023, indicated the key effect of gut microbiota in SLI and the hepatoprotective effect of granisetron in the development of sepsis.

Figure 6 The top 20 references with the strongest citation bursts.

Table 3 The top 10 cited publications.

Rank	Title	Cited Frequency	First Author	Journal	Year	Type
1	Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage	1014	Akio Ohta	Nature	2001	Article
2	The hepatic microcirculation: Mechanistic contributions and therapeutic targets in liver injury and repair	334	Brigitte Vollmar	Physiological Reviews	2009	Review
3	The role of the liver in sepsis	301	Jun Yan	International reviews of Immunology	2014	Review
4	L-Glycine: A novel antiinflammatory, immunomodulatory, and cytoprotective agent	268	Zhi Zhong	Current Opinion in Clinical Nutrition and Metabolic Care	2003	Review
5	The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis	246	David J van Westerloo	Journal of Infectious Diseases	2005	Article
6	Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-κB related signaling	183	Wen-Hui Zhong	Biomedicine & Pharmacotherapy	2016	Article
7	Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice	182	Evie H Carchman	Hepatology	2011	Article
8	Clinical review: The liver in sepsis	179	Nicolas Nesseler	Critical Care	2012	Review
9	Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver	159	Judit K Sarady	Faseb Journal	2004	Article
10	Problotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis	149	Julia Ewaschuk	Hepatology	2007	Article

Table 4 The top 10 co-cited references.

Rank	Title	Times cited	Total link strength	First author	Journal	Year	Type
1	The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)	117	571	Mervyn Singer	JAMA	2016	Article
2	The role of the liver in sepsis	109	562	Jun Yan	International reviews of Immunology	2014	Review
3	Liver - guardian, modifier and target of sepsis	65	317	Pavel Strnad	Nature Reviews Gastroenterology & Hepatology	2017	Review
4	Immunodesign of experimental sepsis by cecal ligation and puncture	63	316	Daniel Rittirsch	Nature Protocols	2009	Article
5	Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care	63	263	D C Angus	Critical Care Medicine	2001	Article
6	Clinical review: The liver in sepsis	52	249	Nicolas Nesseler	Critical Care	2012	Review
7	Hepatic response to sepsis: Interaction between coagulation and inflammatory processes	50	209	J F Dhainaut	Critical Care Medicine	2001	Article
8	The epidemiology of sepsis in the United States from 1979 through 2000	48	231	Greg S Martin	New England Journal of Medicine	2003	Article
9	Incidence and prognosis of early hepatic dysfunction in critically ill patients-a prospective multicenter study	46	278	Ludwig Kramer	Critical Care Medicine	2007	Article
10	The pathophysiology and treatment of sepsis	41	147	Richard S Hotchkiss	New England Journal of Medicine	2003	Review

Top 10 publications in impact index

In bibliometric research, publication impact index rankings could help to find the latest highlight articles. The top 10 publications in impact index based on RCA were shown in Table 5, consisting of eight articles and two reviews. Both reviews were related to the gut-liver axis, which had been identified as a potential target for therapeutic intervention. All eight articles were related to the treatment of SLI, indicating that this topic remained of great interest to researchers. Two of the articles investigated the protective effects of granisetron and the herbal formula BaWeiBaiDuSan in SLI through the gut-liver axis, respectively. Besides, six articles reported that other molecules played a protective role in SLI, including CD39, 6-Gingerol, YAP1, obeticholic acid, PPARγ, and resveratrol. In addition to the gut-liver axis, these articles also mentioned other potential therapeutic targets, including P2X7 receptor inflammatory signaling pathway, Nrf2 pathway, ferroptosis resistance, ATF4-mediated autophagy activity, ROS/TXNIP/NLRP3 signaling pathway, and SIRT1-mediated HMGB1 nucleocytoplasmic translocation pathway.

Table 5 The top 10 publications in impact index based on reference citation analysis.

Rank	Title	Impact index	First author	Journal	Year	Type
1	Gut-liver crosstalk in sepsis-induced liver injury	19.5	Jian Sun	Critical Care	2020	Review
2	Intestinal microbiota mediates the susceptibility to polymicrobial sepsis-induced liver injury by granisetron generation in mice	18.2	Shen-Hai Gong	Hepatology	2019	Article
3	CD39 Limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury	15.3	Luiz Eduardo Baggio Savio	Journal of hepatology	2017	Article
4	Herbal formula Baweibaidusan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice	15	Xiao-Qing Fan	Acta Pharmaceutica Sinica B	2023	Article
5	The gut-liver axis in sepsis: Interaction mechanisms and therapeutic potential	15	Xue Zhang	Critical Care	2022	Review
6	6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway	11	Mu-Keng Hong	International Immunopharmacology	2020	Article
7	YAP1 protects against septic liver injury via ferroptosis resistance	10	Jin Wang	Cell and Bioscience	2022	Article
8	Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation	9.7	Xi Xiong	Biomedicine & Pharmacotherapy	2017	Article
9	PPARγ alleviates sepsis-induced liver injury by inhibiting hepatocyte pyroptosis via inhibition of the ROS/TXNIP/NLRP3 signaling pathway	8.5	Ze-Yu Li	Oxidative Medicine and Cellular Longevity	2022	Article
10	Novel role of resveratrol: Suppression of high-mobility group protein box 1 nucleocytoplasmic translocation by the upregulation of sirtuin 1 in sepsis-induced liver injury	7.9	Wei Xu	Shock	2014	Article

Author analysis

The embraced 787 documents included 4314 authors, and Table 6 presented the top 10 authors based on the number of publications. Christoph Thiemermann was the most prolific author, with 14 publications that accumulated 444 citations, averaging 31.7 citations per publication. Additionally, the top 10 authors predominantly came from China (4) and the United States (2). The top 10 authors by total link strength were displayed in Table 6. Brigitte Vollmar was the predominant author in the field of SLI (total link strength = 1600 times). Our analysis showed that the rankings of total link strength and publications were inconsistent for the same author, suggesting that the number of publications did not entirely capture the author’s influence in the corresponding field. Co-citation referred to instances where references, journals, or authors from multiple papers were cited together via another paper. A total of 154 authors, each co-cited no less than 10 times, were selected for co-citation author visualization. As shown in Figure 7, five clusters were identified, with the largest comprising 62 authors, and the others containing 47, 20, 16, and 9 authors, respectively.

Figure 7 The mapping on authors of sepsis-associated liver injury. The nodes represent authors, and the size of the node reflects the co-citation frequency of the author’s published articles.

Table 6 The top 10 authors with the most publications and the top 10 authors by total link strength.

Rank	Author	Country	Count	Total cites	Average cites	Rank	Author	Country	Citations	Total link strength
1	Christoph Thiemermann	United Kingdom	14	444	31.7	1	Brigitte Vollmar	Germany	58	1600
2	Asada Leelahavanichkul	Thailand	9	358	39.7	2	Hartmut Jaeschke	United States of America	97	1459
3	Henrik Thorlacius	Sweden	9	267	29.7	3	Richard S Hotchkiss	United States of America	157	1081
4	Brigitte Vollmar	Germany	8	460	57.5	4	Ping Wang	United States of America	86	908
5	Yu-Cai Zhang	China	8	140	17.5	5	Mervyn Singer	United Kingdom	133	897
6	Ping Wang	United States of America	8	325	40.6	6	Derek C Angus	United States of America	112	827
7	Ming-Yie Liu	China	7	189	27.0	7	W Wayne Lautt	Canada	23	796
8	Yun Cui	China	7	118	16.9	8	Jun Yan	China	110	701
9	Dur-Zong Hsu	China	7	189	27.0	9	Benedikt Pannen	Germany	19	566
10	Irshad H Chaudry	United States of America	6	288	48.0	10	Michael Bauer	Germany	34	562

Keywords analysis

Keywords typically reflect the research theme, and a comprehensive keyword analysis indicates the current study trend in a certain area. As shown in Table 7, the top 20 most cited keywords were sepsis, liver injury, gene expression, tumor necrosis factor alpha (TNF-α), inflammation, rat, activation, oxidative stress, nuclear factor-kappa B (NF-κB), nitric oxide, cecal ligation and puncture (CLP), Kupffer cell, cell, inhibition, apoptosis, mechanism, dysfunction, lipopolysaccharide (LPS), mortality, and liver. The top two keywords, “sepsis” and “liver injury”, were cited over 300 times, and six other keywords were cited more than 100 times. Analysis of these keywords revealed that the research hotspots on the mechanism of SLI mainly involved oxidative stress, inflammation, TNF-α, NF-κB, and Kupffer cell, etc. Besides, research methods used in SLI included rat models, cell studies, LPS, and CLP, etc. CiteSpace was used to analyze keywords. As shown in Figure 8A, the node size represented the keywords’ frequency, while the lines represented their correlations. The keywords (top 20) exhibiting the largest citation bursts were illustrated in Figure 8B. The top-ranked keyword “TNF-α” remained a research focus from 2000 to 2007, suggesting the key role of TNF-α in the mechanism of SLI based on earlier studies. Between 2019 and 2023, the keywords showing the strongest citation bursts were pathway (2019-2023), autophagy (2019-2023), dysfunction (2020-2021), and NLRP3 inflammasome 2020-2023). This suggested that additional mechanisms contributing to SLI were being discovered.

Figure 8 Keyword analysis. A: A visual map of keywords used at least 30 times; The node size represents the keywords’ frequency, while the lines represent their correlations; B: Top 20 keywords with the strongest citation bursts by year. TNF-α: Tumor necrosis factor alpha; NF-κB: Nuclear factor-kappa B; CLP: Cecal ligation and puncture; LPS: Lipopolysaccharides.

Table 7 The top 20 most cited keywords.

Rank	Keywords	Counts
1	Sepsis	335
2	Liver injury	327
3	Gene expression	164
4	TNF-α	144
5	Inflammation	140
6	Rat	123
7	Activation	118
8	Oxidative stress	115
9	NF-κB	94
10	Nitric oxide	92
11	CLP	86
12	Kupffer cell	83
13	Cell	79
14	Inhibition	67
15	Apoptosis	61
16	Mechanism	61
17	Dysfunction	57
18	LPS	57
19	Mortality	53
20	Liver	38

TNF-α: Tumor necrosis factor alpha; NF-κB: Nuclear factor-kappa B; CLP: Cecal ligation and puncture; LPS: Lipopolysaccharides.

DISCUSSION

We performed a bibliometric study to review the worldwide advancements in research related to SLI from 2000 to 2023. Our analysis indicated that SLI-related research had generally trended upwards since 2000. Currently, SLI has emerged as a significant research area in the field of sepsis.

Out of the 56 countries that published SLI-related studies, China contributed to over one-third of the total publications, indicating a strong interest among Chinese scholars in the field of SLI. However, the United States ranked first in centrality, indicating its significant influence in the field. Notably, Malaysia ranked fourth in centrality even though it only participated in two studies related to SLI. One of these two studies demonstrated that simvastatin attenuated hepatic inflammatory injury through the NF-κB/p6/survivin signaling pathway in an LPS experimental model. Such results may support the statins’ clinical use to prevent liver injury in sepsis, although further clinical studies are necessary[14]. Another of these two studies suggested that carbamazepine may protect against septic liver injury by fully activating autophagy[15]. These two studies provided potential therapeutic targets for the treatment of SLI and therefore had greater impact.

In the analysis of journals, Critical Care Medicine was the most co-cited journal, which had been identified as one of the top journals for sepsis. Shock, Critical Care Medicine, and Journal of Hepatology ranked in the top for both the publication number and co-citation frequency, indicating that substantial amounts of high-quality papers were published in these three journals. As demonstrated in the journals’ dual-map overlay, the journals mainly focused on immunology, molecular, and genetics.

Within the top 10 cited periodicals, the majority uncovered mechanisms and potential therapeutic targets of SLI through basic studies. Burst detection analysis of references could help to identify research hotspots over time. Of the publications with citation bursts from 2020 to 2023, only one was an article, and the rest were reviews. The research described in this article was considered as a focus of attention in recent years. In this article, researchers established the gut microbiota as an upstream controller in liver injury triggered by polymicrobial sepsis and identified granisetron as an anti-inflammatory compound, providing a novel therapeutic approach for SLI[13]. It is noting that findings mentioned above have been limited to animal models. Despite the discovery of a number of pathogenic mechanisms and therapeutic targets for SLI, there is still a lack of high-quality clinical trials to validate these potential treatments.

Keywords can provide a succinct description of an paper’s subject and are extensively utilized for publication retrieval and literature classification[16]. Most of the top 20 keywords could be divided into two categories. One category is in the early years of research (2000-2010), the primary focus was on understanding the fundamental mechanisms and pathways involved in SLI. Key cited keywords from this period include TNF-α, inflammation, oxidative stress, NF-κB and nitric oxide. TNF-α and NF-κB are the two most common molecules implicated in the pathogenesis of SLI. Generated via monocytes and macrophages in the process of acute inflammatory response, TNF-α is a cytokine related to inflammation, which can induce cell necrosis or apoptosis through diverse intracellular signaling mechanisms[17]. In the pathogenesis of sepsis, TNF-α released by Kupffer cells can activate immune cells and release a range of downstream inflammatory mediators through the activation of specific transmembrane TNF receptors, resulting in liver injury[3]. NF-κB, a significant intracellular nuclear transcription factor, is involved in a wide range of diseases, comprising Alzheimer’s disease, glioblastoma, and acute respiratory distress syndrome[18-20]. It can be triggered by LPS to enter the nucleus and function as a transcription factor to regulate transcription of various genes encoding pro-inflammatory cytokines, adhesion molecules and chemokines[21]. Hence, NF-κB signaling is the most important signaling pathway to trigger the inflammatory cascade in sepsis[22]. The other category is that of recent years (2011-2023), where research has shifted to basic experimental research rather than clinical research. Strongly cited keywords during this period include rat, LPS, CLP, and NLRP3 inflammasome. LPS, an essential component of the Gram-negative bacteria outer membrane, significantly affects sepsis through the innate immune system over-activation[23]. Consequently, intraperitoneal injection of LPS is one of the common methods to induce SLI model in rats[24]. Another classic method is CLP. This procedure involves ligating below the ileocecal valve post-midline laparotomy, accompanied by puncturing the cecum with a needle[25]. Since the cecum serves as the bacterial contamination’ endogenous cause, its perforation leads to bacterial peritonitis and subsequent mixed enteric bacteria translocation into the bloodstream. In an experimental setting, the CLP model is viewed as a realistic model for studying the underlying mechanisms of SLI[26].

The keyword NLRP3 inflammasome currently has the strongest citation bursts. The NLRP3 inflammasome assembles as a protein complex responding to cellular perturbations. This process results in the caspase-1 activation, promoting inflammatory cytokines’ release and maturation, involving interleukin (IL)-18 and IL-1β, and resulting in inflammatory cell death (pyroptosis)[27]. NLRP3 inflammasome is connected to diverse diseases, containing metabolic disorders, multiple sclerosis and inflammatory bowel disease[28-30]. In sepsis, excessive inflammasome activation and pyroptosis are associated with liver injury[31]. Therefore, blocking NLRP3 activation in different ways can attenuate sepsis-induced acute liver injury and may increase survival. For instance, silencing the NLRP3 gene 48 hours before inducing sepsis results in improved hyperbilirubinemia and reduced neutrophil infiltration in hepatic tissue[32]. Compared to silencing NLRP3 gene, inhibition of NLRP3 activation by drugs is more clinically feasible. Currently, several drugs have been shown to attenuate SLI by inhibiting NLRP3 inflammasome, such as cinnamomum osmophloeum, theaflavin, and Prim-O-glucosylcimifugin[33-35].

There are several limitations to our study. First, we only included the publications indexed in the WoSCC database, making it possible that certain momentous publications indexed in other databases were overlooked. Second, only English documents were enrolled. Third, we completed the literature search on October 28, 2023, which may have missed some of the literature published in 2023.

CONCLUSION

This study provides general characteristics of SLI research, including institutions, countries, journals, authors, keywords and references. Briefly, the total trend in publications from 2000 to 2023 has been upward. China, the United States, and Germany are the top three nations regarding the publication number. The three main contributing institutions are Shanghai Jiao Tong University, Huazhong University of Science and Technology, and Southern Medical University. The top three co-cited journals are Critical Care Medicine, Shock, and Hepatology. The most recent keyword showing the strongest citation bursts is NLRP3 inflammasome. The findings of pathogenic mechanisms and potential therapeutic targets serve as the basis for translating from basic research to clinical application. Collectively, our research is expected to tender a beneficial reference for future exploration to SLI.

ACKNOWLEDGEMENTS

The authors would like to thank the program from Ministry of Science and Technology of China for their support in publishing this article.