A bibliometric and visualized analysis of hepatic ischemia-reperfusion injury (HIRI) from 2002 to 2021

Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a complex pathological phenomenon dominated by the innate immune system and involves a variety of immune cells. This condition frequently occurs during hepatectomy, liver transplantation or hemorrhagic shock. HIRI represents an important factor in the poor prognosis of patients after liver surgery. However, there is still a lack of effective intervention to reduce the incidence of HIRI. In this study, we aimed to describe the overall structure of scientific research on HIRI over the past 20 years and provide valuable information and guidelines for future researchers. Bibliometric analysis was used to comprehensively review developments in HIRI and changes in our understanding of HIRI over the past two decades. We identified a total of 4267 articles on HIRI that were published over the past 20 years of which basic research was predominant. Collaboration network analysis revealed that China, the University of California Los Angeles, and Ronald W Busuttil were the most influential country, institute, and scholar, respectively. Co-occurrence cluster analysis revealed that ischemic preconditioning, liver cirrhosis, hepatic I/R injury, autophagy, acute liver failure, oxygen, donation after circulatory death, Nlrp3, remote organ, and microdialysis were the top 10 clusters. Keyword burst detection indicated that autophagy, inflammation, and early allograft dysfunction represent the current research hotspots. In summary, this is the first bibliometric analysis of HIRI research. Our timely analysis of these hotpots and research trends may provide a framework for future researchers and further promote research on the key mechanisms and therapeutic measures in this field.

Highlights

• •This is the first bibliometric analysis of research relating to hepatic ischemia-reperfusion injury (HIRI).
• •Between 2002 and 2021, China had the largest number of publications, while the United States had the most citations.
• •Ronald W Busuttil and Jerzy W Kupiec-Weglinski were the most productive and the most collaborative authors in the HIRI field.
• •The current hotspots in HIRI research are autophagy, inflammation, and early allograft dysfunction.

1. Introduction

Liver disease has become a major cause of illness and death worldwide over the past decades. Recent research reported that over 2 million people die from liver disease every year [1]. Liver surgery, such as liver transplantation and partial liver resection, is an important treatment for various liver diseases. According to the China Liver Transplant Registry (CLTR), liver transplantation cases in China account for more than one third of all cases worldwide [2]. Between 2015 and 2020, 24,423 adult patients underwent liver transplantation in China [3]. However, hepatic ischemia-reperfusion injury (HIRI) presents in many surgical procedures and represents a major complication that may lead to severe outcomes such as liver failure and even death [4,5]. Ischemia-reperfusion injury is a two-stage aseptic inflammatory response caused by a limited blood supply and subsequent recovery of the blood supply [6]. HIRI has been proven to be the leading cause of multiple liver surgical complications, including hepatic failure, early graft dysfunction and acute or chronic rejection [7,8]. A number of studies have proven that the mechanisms underlying HIRI are very complex and involve a variety of cells and a large number of cytokines and mediators, including multiple cell death mechanisms [9,10]. During the first stage of ischemia, hepatocytes and Kupffer cells are exposed to hypoxia; this leads to the production of reactive oxygen species (ROS), calcium overload, organelle damage, and eventually causes hepatocyte injury or death along with the release of damage associated patterns (DAMPs), which further amplifies the inflammatory response [11,12]. Subsequently, as the blood refills the circulation system, the entry of DAMPs elicits an immunological cascade, and a series of immune cells are recruited to the liver, thus leading to more severe liver injury [7]. The infiltration of neutrophils plays a main contributing factor in cellular damage [13]. Furthermore, accumulating evidence indicates an immune-regulatory function of platelets in the progression of HIRI [14]. Previous research suggested that the type of ischemia (cold or warm), extent (partial or total), and the duration/timing of ischemia (from minutes to hours), together with the occurrence of liver regeneration (associated with liver resection), may all affect the degree of damage [15]. However, thus far, the mechanisms underlying the occurrence of HIRI have not been fully elucidated. Moreover, little is known about how we might treat HIRI.

Bibliometric analysis refers to a quantitative analysis tool that uses mathematical and statistical methods to generate a comprehensive view of a certain research field by analyzing the number of publications, authors, countries and regions, references, keywords, and other parameters from selected publications during a certain period [[16], [17], [18], [19]]. This method has become increasingly more advanced and has been widely applied in many fields. However, a bibliometric article that provides a comprehensive summary and analysis of publication characteristics and research trends and hotspots relating to HIRI has yet to be reported. Thus, in the present study, we evaluate past and present publication trends in HIRI and attempt to advance research in this field by analyzing publications from 2002 to 2021.

2. Methods

2.1. Data sources and search strategies

The data used in this study was extracted from the Web of Science Core Collection (WoSCC) for the period 2002 to 2021 on May 19, 2022. To avoid database update bias, we completed all data extraction and data downloads on the same day. We retrieved relevant publications through the following search strategy: TI = (hepatic OR liver OR hepatology) AND TS = ((liver ischemia-reperfusion injury) OR (hepatic ischemia-reperfusion injury) OR (hepatic ischemia-reperfusion) OR (liver ischemia-reperfusion) OR (hepatic reperfusion) OR (liver reperfusion) OR (hepatic I/R)) NOT (TI = (guideline OR recommendation OR consensus OR “case report” OR meta OR review)) AND Language = English AND Document type = Article. Only the Science Citation Index-Expanded (SCI-E) was selected. Then, the raw data were downloaded from WoSCC as text files involving full records. After the primary data search, two researchers (Xiaoqi Lin and Yanyu Zhou) screened all manuscripts individually to ensure that they were all relevant to the subject of this study. A detailed flowchart of the criteria used to include and exclude publications is shown in Fig. 1.

Fig. 1.

Flowchart for including and excluding publications.

2.2. Bibliometric online platform analysis

All data, including full records and cited references, of the retrieved articles were downloaded from the WoSCC database and saved as .txt format for further analysis. We processed the data systematically by the website of bibliometrics, the Online Analysis Platform of Literature Metrology (https://bibliometric.com/app), Bibliometrix, CiteSpace V5.8 R3 (Drexel University, Philadelphia, PA, USA) and VOSviewer 1.6.15 (Leiden University, Leiden, The Netherlands).

The Online Analysis Platform of Literature Metrology was used to form a histogram to generate an annual publication trend from different countries and regions and the top 10 high-cited journals in HIRI research were identified. The keywords cloud involving the top 100 high-frequency keywords was generated via the R package bibliometrix. The collaborations between countries/regions and those between institutions were analyzed and visualized by VOSviewer software. Next, we analyzed and visualized the collaborations between authors, co-citation publications, citation bursts, cluster networks of co-cited references, and keyword bursts by using CiteSpace, the most popular and recognized analysis tool in bibliometric research. For keywords burst detection, we removed those keywords with little real significance such as ‘tissue’ and ‘rat liver’.

3. Results

3.1. Quantity and trends analysis of published papers

In total, 7825 publications met the inclusion criteria in the SCI-E of WoSCC. Furthermore, 3558 publications were excluded after screening, of which 2335 were excluded because of language or article type, and the other 1223 were unrelated to our topic. Finally, a total of 4267 articles published between 2002 and 2021 were included in our study. The number of articles published per year and the contribution of main countries are shown in Fig. 2. The annual number of publications grew at a steady rate. Since 2002, there have been over 150 publications on HIRI every year (Fig. 2A). Furthermore, we counted the number of clinical research and basic research papers and found that basic research accounted for the majority of publications during the past two decades, although the number of clinical research papers showed a notable increase (Fig. 2B).

Fig. 2.

Quantity and trends analysis of published papers on the topic of Hepatic ischemia-reperfusion injury (HIRI) between 2002 and 2021. (A) The number of annual research publications and growth trends on the topic of HIRI from 2002 to 2021, including the export of results from Web of Sciences. (B) The proportion of basic and clinical research articles on the topic of HIRI from 2002 to 2021, including the export of results from Web of Sciences. (C) The number of annual research publications and growth trends of the top 10 countries/regions on the topic of HIRI from 2002 to 2022, including the export of results from the Online Analysis Platform of Literature Metrology. (D) Bar graph of the total number of citations from each country related to the 4267 retrieved HIRI articles during 2002–2021. The top 10 countries with the highest total number of citations are shown. Each bar corresponds to a country, and the length of each bar is positively correlated with the total number of citations.

Publications mainly originated from China, the USA, and Japan. Prior to 2012, the USA and Japan were the main sources of publications. Subsequently, China showed an increasingly contribution to HIRI research and overtook the USA (Fig. 2C). The number of citations reflects the impact of an article in a specific research area. Fig. 2D shows the total number of citations of all articles published by each country and presents the top ten countries according to the total number of publications. Over the past two decades, the USA had the most citations (33,262 citations). China and Germany ranked second and third with 19,919 and 10,192 citations, respectively. The top 10 countries with the highest total number of citations on HIRI research between 2002 and 2021 are listed in Table 1 sorted by the mean number of citations. The highest mean number of citations (52.81) originated from Switzerland. In addition, three countries with a mean number of citations exceeding 30 were the USA, UK, and Spain. Furthermore, China, which had the highest number of publications, had a mean of only 16.45 citations per article.

Table 1.

The top 10 countries with the highest total number of citations on HIRI research during 2002–2021 (sorted by the average number of citations).

Rank	Country	Number of Publications	Total number of citations	Average number of citations
1	Switzerland	93	4911	52.81
2	USA	871	33,262	38.19
3	England	155	5078	32.76
4	Spain	169	5338	31.59
5	Netherlands	126	3606	28.62
6	Germany	412	10,192	24.74
7	Italy	187	4526	24.20
8	South Korea	162	3104	19.16
9	Japan	497	9211	18.53
10	China	1211	19,919	16.45

3.2. Analysis of intercountry/region and inter-institutional cooperation

Over the past two decades, HIRI papers were published by at least 2716 institutions from 68 different countries/regions. Fig. 3 shows a distribution map of countries/regions and institutions. The nodes represent the countries or institutions producing the publications and the links between them indicate their cooperative relationships. The larger the node, the greater the number of publications, while a wider line implies a stronger relationship. Publications originated predominantly in China, which contributed 1211 articles, followed by the USA (871) and Japan (497) (Fig. 3A). The USA was identified as the country that cooperated the most with other countries, followed by Germany and China. Furthermore, yellow coloration reveals articles that had been published recently; blue coloration represents older publications.

Fig. 3.

Network map of the collaboration among 68 countries/regions and 2716 institutions involved in Hepatic ischemia-reperfusion injury (HIRI) research in 2002–2021. (A) Cooperative relationships between countries/regions on the topic of HIRI. The top 10 most productive countries/regions were China, the USA, Japan, Germany, Italy, Turkey, Spain, South Korea, England and Brazil. Data was exported from VOSviewer. (B) Cooperative network map of institutions involved in HIRI research. The top 10 most productive institutions were the University of California Los Angles, Nanjing Medical University, the University of Pittsburgh, Sun Yat Sen University, Shanghai Jiao Tong University, Zhejiang University, Huazhong University of Science and Technology, Kyoto University, Sungkyunkwan University, and Wuhan University. The size of the circle represents the number of articles published by each institution and the thickness of the connecting lines indicates the degree of cooperation between institutions. The yellow color implies that these documents were recently published, while the blue nodes represent documents published in earlier years.

The University of California Los Angles, Nanjing Medical University, and the University of Pittsburgh were the first, second and third productive institutions, contributing 127, 115, and 99 articles, respectively. Of these, the University of Pittsburgh had highest number of citations (6123). Shanghai Jiao Tong University was the most cooperative institution in this field over the past 20 years (Fig. 3B).

3.3. Co-authorship network and core author distribution

Fig. 4 shows the most productive authors of all the 19,856 authors identified. Ronald W Busuttil and Jerzy W Kupiec-Weglinski (Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation) and the Department of Surgery, David Geffen School of Medicine (University of California-Los Angeles, Los Angeles, CA, USA) were ranked first and second with 81 articles and 61 articles, respectively. This was followed by Xuehao Wang from China, David A Geller from the USA and Joan Rosello-Catafau from Spain. Unlike the cooperation among countries or institutions, productive authors preferred stable partnerships. However, no single node had a sufficiently high centrality (>0.1); this means that most authors had a limited impact on this field.

Fig. 4.

CiteSpace network of authorship in the field of Hepatic ischemia-reperfusion injury (HIRI) between 2002 and 2021. The top 12 authors with the most publications are shown. Each circle represents an author and the link between two circles represents collaboration between each other. Font size is positively associated with the number of articles published by a certain author.

3.4. Journal analysis

Over the past 20 years, 635 journals published articles related to HIRI. The top 10 most active journals, ranked by the number of total citations of the articles they published, along with their cited frequency and impact factor (IF), are listed in Table 2. Of these, seven journals were from the USA, while the other three originated from the Netherlands, Denmark, and China, respectively. Many journals were hepatology specialized journals while the other journals were related to surgery, especially transplantation, or gastroenterology. Liver Transplantation ranked first with 1858 total citations, followed by Hepatology (1777) and Transplantation (1536). The impact factors of only three journals exceeded 10, and the highest impact factor (25.083) was related to the Journal of Hepatology.

Table 2.

The top 10 most active journals that published articles on HIRI research from 2002 to 2021 (sorted by total citations).

Rank	Journal Title	Frequency	Total citations	Average citation per paper	Impact factor (2021)	JCR	Country
1	Liver Transplantation	232	1858	8.01	5.799	Q1	USA
2	Hepatology	116	1777	15.32	17.425	Q1	USA
3	Transplantation	168	1536	9.14	4.939	Q2	USA
4	Journal of Hepatology	85	1107	13.02	25.083	Q1	Netherlands
5	Journal of Surgical Research	228	1050	4.61	2.192	Q3	USA
6	American Journal of Transplantation	101	1005	9.95	8.086	Q1	Denmark
7	Transplantation Proceedings	354	992	2.80	1.066	Q4	USA
8	Annals of Surgery	40	762	19.05	12.969	Q1	USA
9	World Journal of Gastroenterology	110	570	5.18	5.742	Q2	China
10	American Journal of Physiology-Gastrointestinal and Liver Physiology	55	558	10.15	4.052	Q2	USA

3.5. Analysis of highly cited references in HIRI research

By analyzing the 4267 articles and their 73,403 references (excluding self-citations), we identified the top 10 high-cited references in HIRI research between 2002 and 2021; these are shown in Table 3. Visualization of co-cited references revealed a total of 1391 nodes and 6623 links (Fig. 5A). In this network, each node represents a cited article, and the size of each node is proportional to the total co-citation frequency of the associated article. Analysis showed that the highest-ranking cited reference was a review published by Nature Reviews Gastroenterology & Hepatology in 2013 [20]. Researchers identified relevant articles on experimental settings and the pathophysiology of HIRI by searching the PubMed database for articles published up to June 2012. These articles mainly discussed progress in large animal experiments and highlighted the contribution of innate-adaptive immune crosstalk and cell activation cascades to HIRI. References with the strongest burst strength of the 4267 articles on HIRI between 2002 and 2021 are shown in Fig. 5B. The red line indicates a sudden increase in usage frequency for a certain reference during that period. The blue line represents the total period of the 20 years. During the first decade, articles with citation bursts usually concerned preconditioning, thus reflecting a research boom in preconditioning at that time. However, over the past 10 years, research has focused on the complex mechanisms underlying HIRI. The strongest reference burst appearing in 2004 and lasted until the end of 2008; this referred to a review written by Hartmut Jaeschke in 2003 which had a strength of 47.62 [10]. The latest reference burst occurred in 2019 and related to a review published by Gene Expression in 2017 which discussed the mechanism of liver recovery and regeneration after HIRI [21].

Table 3.

The top 10 high-cited references of 4267 retrieved articles on HIRI research from 2002 to 2021 (sorted by cited frequency).

Rank	Title	First Author	Journal	Year	Cited Frequency	Burst	DOI
1	Ischemia-reperfusion injury in liver transplantation--from bench to bedside	Zhai Y	Nat Rev Gastro Hepat	2013	109	46	10.1038/nrgastro.2012.225
2	Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning	Jaeschke H	Am J Physiol-Gastr L	2003	107	47.62	10.1152/ajpgi.00342.2002
3	Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu	Peralta C	J Hepatol	2013	82	36.06	10.1016/j.jhep.2013.06.017
4	Protective strategies against ischemic injury of the liver	Selzner N	Gastroenterology	2003	79	35.02	10.1016/S0016-5085(03)01048-5
5	Liver ischemia/reperfusion injury: processes in inflammatory networks--a review	Abu-Amara M	Liver Transplant	2010	66	31.77	10.1002/lt.22,117
6	Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation	Zhai Y	Am J Transplant	2011	65	30.46	10.1111/j.1600-6143.2011.03579.x
7	Hepatic ischemia/reperfusion injury--a fresh look	Fondevilla C	Exp Mol Pathol	2003	63	27.87	10.1016/S0014-4800(03)00008-X
8	Hepatic ischemia-reperfusion injury	Serracino-Inglott F	Am J Surg	2001	61	26.82	10.1016/S0002-9610(00)00573-0
9	Factors in the pathophysiology of the liver ischemia-reperfusion injury	Montalvo-Jave EE	J Surg Res	2008	59	28.55	10.1016/j.jss.2007.06.015
10	Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury	Jaeschke H	Gastroenterology	2003	59	26.09	10.1016/S0016-5085(03)01209-5

Fig. 5.

Reference co-citation network analysis of publications on the topic of Hepatic ischemia-reperfusion injury (HIRI) between 2002 and 2021. (A) CiteSpace co-citation map of 73,403 references of 4267 documents on HIRI research in 2002–2021. The year of publication and first author of the top 10 most-cited publications are shown. Each circle represents a reference. The size of the circle is positively correlated with the frequency of citations, and links between two circles represent two references that were cited in the same article. The yellower nodes represent the fact that these papers have been frequently cited in recent years, while the redder nodes refer to references cited in earlier years. (B) References with the strongest burst strength of the 4267 citing articles on HIRI in 2002–2021. References marked in red indicate a sudden increase in usage frequency of this reference during that period. Blue represents a period of 20 years.

3.6. Analysis of Co-cited publications and clustered network

It is believed that references can reflect the content of an article, at least to some extent. Based on this, co-citation analysis can reveal the relevance of two documents by clarifying references that are co-cited by a group of publications. As shown in Fig. 6A, co-cited references were clustered into 10 major cluster labels, including ischemic preconditioning, liver cirrhosis, hepatic I/R injury, autophagy, acute liver failure, oxygen, donation after circulatory death, Nlrp3, remote organ, and microdialysis. The number of cluster labels was inversely correlated with the number of articles that each cluster included. This means that #0 cluster ischemic preconditioning was associated with the largest number of papers. Fig. 6B shows the timeline of distinct co-citation clusters and highlights a change in the hotpots of HIRI research over the past 20 years. Each circle represents a main cited article in a certain cluster, and the size of the circle on the timeline represents the citation rate. The cluster of ischemic preconditioning and the cluster of liver cirrhosis were the top two largest clusters in the HIRI field and both had citation bursts between 2001 and 2004. We also found that the latest prevalent co-citation clusters were autophagy, donation after circulatory death, and Nlrp3.

Fig. 6.

Analysis of co-occurring keywords for publications on the topic of Hepatic ischemia-reperfusion injury (HIRI) between 2002 and 2021. (A) Clustered networks of co-citation status of the investigated references and the 4267 citing articles via CiteSpace. The top 10 largest clusters of cited articles are shown. (B) A timeline view of the top 10 largest clusters of citing articles on HIRI research. Right side = cluster labels.

3.7. Analysis of research trend and burst detection with keywords

Fig. 7 shows the strongest keyword burst on HIRI during 2002–2021. The word cloud presented in Fig. 7A shows the top 100 high-frequency keywords in HIRI research over the last 20 years. Font size was positively associated with frequency. After deleting the keywords with little real significance, liver transplantation, apoptosis, inflammation, and oxidative stress were the keywords with the highest frequency. Keywords burst detection is a method that can provide an overview of a certain research area and catch hotspots. A red line indicates that the keyword was cited frequently over a specific period. In contrast, a blue line implies less popularity. We excluded keywords that had little or no research significance and listed the top 15 keywords with the strongest citation bursts in HIRI publications between 2002 and 2021 in Fig. 7B. We found that in the HIRI field, preservation injury was the largest hotspot during 2002–2006, with the highest strength (15.45). Since 2016, the most recent and strongest keyword burst was autophagy and inflammation.

Fig. 7.

Analysis of keywords and burst detection of publications on the topic of Hepatic ischemia-reperfusion injury (HIRI) between 2002 and 2021. (A) Word cloud of the top 100 high-frequency keywords on HIRI research via the R package bibliometrix. (B) Keywords with the strongest burst strength of the 4267 citing articles on HIRI research between 2002 and 2021. Keywords marked in red indicate a sudden increase in usage frequency of this keyword during that period. Blue represents a relatively unpopular time period.

4. Discussion

This is the first bibliometric and visual analysis of HIRI research between 2002 and 2021. Our timely analysis of the hotpots and research trends of HIRI may promote the development of this field.

4.1. Overall trends in the HIRI field

According to the steady increase in the number of publications each year, research in the HIRI field has attracted significant global attention. China and the USA were the two leading countries which contributed significantly to HIRI research over the past 20 years. With regards to the number of articles, the USA dominated this field in the first decade, although China caught up quickly and gained leadership over the last decade. However, with regards to the total number of citations, the USA far exceeded China and continued to rank first in terms of cooperative relationships with other countries/regions, thus reflecting the higher quality of its articles. In contrast, although China had the highest number of publications, the mean number of citations was only 16.45, thus indicating that most articles are rarely cited and that the quality of this research needs to be improved. The year 2012 was an important watershed for rapid growth in the number of publications in China since then. This is most likely related to the pilot project for organ donation after cardiac death (DCD) of organ transplantation in that year [22]. With economic and technological advances, the problems in liver transplantation in China have gradually changed from the limitation of surgery itself to the scarcity of donors. According to CLTR data, DCD was the source of livers in about 40 % of all liver transplants in China during the 2018–2020 period [3]. Furthermore, the popularization of DCD, with the development of organ storage techniques, was an important factor responsible for the development of liver transplantation in China. However, with the increasing incidence of end-stage liver disease and the subsequent rising demand for liver transplantation, the problem of the imbalance between organ supply and demand has not been solved [23]. According to statistics, less than 10 % of global transplantation needs are being met [1]. Therefore, expanding the donor pool (such as marginal donor grafts and donation after brain death (DBD)), improving storage conditions, and living donor liver transplantation, are important research directions [3].

Of the publications included in our analysis, basic research accounted for the vast majority (>70 %), while the number of clinical studies was relatively small and grew slowly. Although HIRI can occur in multiple situations, it creates most concern in cases involving liver transplantation. Owing to the current donor shortage, studies on liver transplantation have been limited in various ways. One of the most important factors is the moral debate relating to DBD [2].

4.2. Previous research focus in the HIRI field

Research on the role of the innate-adaptive immune system in HIRI process is of great importance in this field. Over the past 20 years, Ronald W Busuttil and Jerzy W Kupiec-Weglinski were the most productive authors. These authors maintained stable partnerships and their collaborative research focused on the innate-adaptive immune interaction in liver transplantation, involving the central role of platelet-leukocyte-endothelial cell interactions in HIRI [24]. The main research area of Ronald W Busuttil was liver transplantation and the factors affecting its prognosis. A 20-year retrospective analysis of 3200 consecutive patients receiving orthotopic liver transplantation (OLT) showed the most benefits of OLT in pediatric and non-urgent patients [25]. Furthermore, multiple factors, including the recipient, the etiology of liver disease, and donor characteristics, were found to influence long-term outcomes and became his later research direction [26]. Jerzy W Kupiec-Weglinski investigated how the innate immune system works in HIRI and revealed the cytoprotective functions of macrophage-derived heme oxygenase-1 (HO-1), which was proven to have therapeutic potential in human biopsy analysis [27,28].

Over the past 20 years, treatment strategies for HIRI were a key research focus. According to the timeline of references with the strongest burst strength, studies before 2011 focused on the protective strategies for HIRI, especially ischemic preconditioning, and the mechanisms of cell damage in HIRI [29,30]. In 2003, Pierre-Alain Clavien reported a prospective randomized study involving 100 patients, suggesting the protective effect of ischemic preconditioning on HIRI [31]. In the same year, Hartmut Jaeschke published a review in the American Journal of Physiology-Gastrointestinal and Liver Physiology which explored the mechanisms by which ischemic preconditioning protects against HIRI [10].Preventing preservation injury has also received significant attention. According to the analysis of keyword bursts, preservation injury, which refers to organ damage associated with ischemic in vivo preservation during transport from donor to recipient, was the most powerful keyword over the past two decades [32]. Although the major driver of tissue injury is reperfusion, pre-transplant injury can be triggered by ex vivo cold storage [33]. The shortage of organ donors has been a major global problem in liver transplantation, while studies on liver preservation protocols have effectively improved the quality and quantity of available organs.

4.3. Current research hotspots in the HIRI field

Current keyword bursts relate to autophagy, inflammation, and early allograft dysfunction. Many previous studies have identified the protection effects against HIRI provided by the activation of autophagy, while excessive autophagy is known to lead to apoptosis in hepatocytes and liver non-parenchymal cells [34,35]. The dual role of autophagy and the complex mechanism of HIRI may be responsible for the inconsistent findings of autophagy regulation in different HIRI studies [[36], [37], [38]]. An excessive inflammatory response is recognized as a key mechanism of ischemia-reperfusion injury [10]. As the largest immune organ in the human body, the liver contains large numbers of immune cells, such as Kupffer cells, dendritic cells, natural killer cells, and natural killer T cells; these play an important role in the inflammatory response to HIRI [39]. During liver transplantation, the occurrence of early allograft dysfunction (EAD) and primary non-function (PNF) is often associated with perioperative ischemia-reperfusion injury. Numerous studies have demonstrated that HIRI is one of the most important factors leading to EAD. The incidence of EAD can reach 43.7 in patients with HIRI [40]. Hepatic EAD and PNF increase the shortage of liver donors, and more importantly, these two factors are closely connected with the high rate of mortality after liver transplantation [41]. To improve outcomes, more basic studies and clinical trials are urgently needed to explore the underlying mechanism and potential treatment of HIRI and EAD.

This study is not without its limitations. Firstly, since the current version of CiteSpace can only analyze data from the WoSCC database, there may be some omissions of papers published in other databases. Nonetheless, the WoSCC database is the most recognized database for performing bibliometric analysis. Second, due to our search strategy, which included restrictions on publication types and language, we may have omitted some relevant articles. However, by including a sufficient number of articles, we believe that the potential influence of such articles has been limited to a minimum. Moreover, although this method was frequently adopted by previous studies, the use of citations to reflect an article's research content and influence still has limitations.

5. Conclusion

With the bibliometric tool, we summarized and analyzed publications in the HIRI field from 2002 to 2021. China and the United States made the largest contributions to the HIRI research field. Current research focused on autophagy and inflammation, suggesting that the regulation of these processes may represent a very promising option for alleviating HIRI. With the help of bibliometrics tools, our study defines the overall prospects in this field and provides valuable information for future studies.

Funding statement

This study was funded by the National Natural Science Foundation of China (No. 82371517, 82270916, 81771185, 81800748), Pudong New Area Health Commission Research Project (No. PW2022D-01), Science and Technology Commission of Shanghai Municipality (No. 20410760500), Shanghai Hospital Development Center (No. SHDC2020CR2055B), Innovation Program of Shanghai Municipal Education Commission (No. 2019-01-07-00-01-E00074) and Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation (No. 20DZ2254200).

Data availability statement

Data will be made available on request.

Ethics statement

Informed consent was not required for this study because all data used were derived from the Web of Science Core Collection (WoSCC) database and did not involve any animal and human participants.

CRediT authorship contribution statement

Xiaoqi Lin: Data curation, Formal analysis, Methodology, Writing – original draft. Yanyu Zhou: Data curation, Formal analysis, Methodology, Resources, Software, Writing - original draft. Lina Ye: Data curation, Formal analysis, Methodology, Software, Writing – original draft. Baoshan Wang: Formal analysis, Resources, Software. Yingfu Jiao: Formal analysis, Resources, Software, Writing – review & editing. Weifeng Yu: Funding acquisition, Investigation, Supervision, Writing – review & editing. Po Gao: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Supervision, Validation, Writing – review & editing. Liqun Yang: Conceptualization, Data curation, Funding acquisition, Investigation, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.