Sepsis associated with acute lung injury over the period 2012–2021: a bibliometric analysis

Background: Sepsis associated with acute lung injury (ALI) is a common acute and severe disease with severe socioeconomic burden. The aim of this study is to explore the literatures of sepsis associated with ALI from a bibliometric perspective. Methods: Articles and reviews related to sepsis associated with ALI published from 2012 to 2021 in the Web of Science Core Collection were retrieved. Countries, affiliations, journals, authors, references, co-citation and keyword analysis in this field were visually analyzed using WOS citation reports, bibliometric.com, CtieSpace and VOSviewer software. Results: Over the last decade (2012–2021), marked progress has been made in the area of sepsis associated with ALI research. 836 papers were enrolled in this study. China accounts for the most contributors. Articles from the United States has the highest average cited. Shanghai Jiao Tong University, University of California System and Huazhong University of Science Technology were the main contributing institutions. Articles in International Immunopharmacology, Inflammation, Shock and Critical Care were cited the most. Matthay MA and Ware LB were the main contributors to this field. Inflammation and NF-κB have always been the focus of sepsis associated with ALI related research, and programmed cell death (including apoptosis, necroptosis and pyroptosis) may be the important direction of future research. Conclusion: Research on the sepsis associated with ALI is flourishing. The research on programmed cell death is a hot spot and may be a promising research field in the coming years.


Introduction
Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the body's response to infection (Singer et al., 2016). The global study of adult sepsis hospitalized patients showed that the overall mortality rate of sepsis patients was 26.7%, while the mortality rate of sepsis patients in intensive care unit (ICU) was 41.9% (Fleischmann-Struzek et al., 2020). According to studies in China, the annual medical cost of 230,000 septic patients treated in ICU is about $4.6 billion (Xie et al., 2020). Sepsis has become an important global public health problem. Acute lung injury (ALI) is one of the most common complications of sepsis. Study has shown that 6%-42% of ALI is caused by sepsis (Sessler et al., 1996). ALI caused by sepsis refers to acute hypoxic respiratory failure caused by sepsis, which is secondary to alveolar injury caused by dysregulation of inflammatory response. The pathophysiology of ALI is mainly manifested by severe inflammatory injury of alveolar capillary barrier, depletion of pulmonary surfactant, reduction of effective ventilation lung tissue, and reduction of lung compliance (Ranieri et al., 2012;Matthay et al., 2019). Since ALI was first described in 1967, people's understanding and definition of its clinicopathology have been constantly updated. Nowadays, the clinical diagnosis and treatment of ALI have always followed the Berlin definition in 2012 (Ranieri et al., 2012). Since ALI is a complex and clinically heterogeneous syndrome, the effective treatment strategies that can reach consensus today are limited to protective ventilation     therapy (auxiliary neuromuscular blockers and prone ventilation), while other anti-inflammatory drugs [e.g., glucocorticoids, macrophage colony stimulating factor (GM-CSF), statins, aspirin] and drugs to improve lung function (β receptor agonists, nitric oxide inhalation) did not significantly reduce the mortality of ALI (Bellani et al., 2016). ALI associated with sepsis involves multiple molecular mechanisms. Consequently, it is significant to quantitatively analyze the status quo, focus areas, and future prospects related to ALI associated with sepsis.
Bibliometrics is an interdisciplinary science that uses mathematical and statistical methods to study literature and bibliometrics features (Wu et al., 2022). Bibliometrics uses mathematical methods to break through the limitations of time and space, so that researchers can fully understand the current situation, hot spots and trends of a research field. Currently, bibliometric analysis has been used in many fields, including atherosclerosis, Parkinson's disease, gout and liver transplantation Li et al., 2022;Wang et al., 2022;Wen et al., 2022). To date, there is no literature about bibliometrics analysis of sepsis associated with ALI. To fill this gap, this study analyzed the characteristics and trends of publications related to sepsis associated with ALI through bibliometrics.

Data sources and search strategy
The search was conducted using the Web of Science (WOS) Core Collection database. All the literature was retrieved in WOS. The search terms were TS= (sepsis OR endotoxemia) AND TS= ((acute lung injury) OR (ALI) OR (acute respiratory distress syndrome) OR (respiratory distress syndrome) OR (ARDS)). The language is limited to English, and the document types are limited to

Bibliometric analyzing
"Citation Report" function of the web science was employed to evaluate the citation rates and the H-index. The "bibliometric.com" is a website for online bibliometric analysis (https://bibliometric. com/). CiteSpace (Vesion 5.8) is a widely used visual analysis software (Chen, 2004). VOSviewer (Vesion 1.16.18) is a software for plotting maps based on network data (van Eck and Waltman, 2010). We used WOS citation reports, bibliometric.com, CtieSpace and VOSviewer software for bibliometric analysis. Detailed procedures of the enrolment and analysis are illustrated in Figure 1. 3 Results

The research trends
We collected 836 publications from the Web of Science core collection published in 312 journals over the period 2012-2021. The number of publications related to sepsis associated with ALI by year was presented in Figure 2. In total, 836 publications have been cited 13,491 times, and the average number of citations per publication is 21.76 times.

Analysis of the top 10 countries
The top 10 most productive countries were shown in Table 1. Table 1 shows the total citations, average number of citations per publication, H-index and publications/population (per million people) of the top 10 countries. Among the top 10 countries, China ranked first in the sum of total publications (534), cited times (9,331) and H-index (43), but only ranked seventh in the average cited times of a single article (17.47). In terms of the total publications, the United States ranked second. However, the United States ranked first in the average number of citations per publication (38.31). It was followed by Japan, Germany, Brazil, Canada, Spain, South Korea, United Kingdom and Turkey. Canada ranked first in publications/population (per million people) (0.61). Figure 3A showed the total of publications by each country each year, and Figure 3B showed the cooperative relationship between each country. The results showed the greatest cooperation between China and the United States, and the United States cooperated with other countries more broadly.

Analysis of the top 10 affiliations
The top 10 productive affiliations were shown in Table 2. Shanghai Jiao Tong University had the highest the sum of total publications (32), followed by University of California System (25) (19) and Harvard University (17). University of California System ranked first in terms of the average number of citations per publication (71.24), the highest cited times (1,781) and H-index (17). Nanjing Medical University ranked first in publications/students (per thousand people) (1.33). Although the total publications of Nanjing Medical University in China were relatively high, their average number of citations per publication was far behind other high-yield universities. It may be related to the low quality of the published articles and the relatively obscure journals.

Analysis of the top 10 journals
The top 10 most active journals were shown in Table 3. International Immunopharmacology (IF = 5.714, 2021) was the most active journal in sepsis associated with ALI research, with

Analysis of the top 10 authors
The top 10 authors with the most publications were shown in Table 4. 4,366 authors contributed to sepsis associated with ALI related publications. Matthay MA was the most productive which

FIGURE 4
The mapping on journals of sepsis associated with ALI. The relationship between 288 identified journals (the minimum number of citations of journals exceeds 20) and the total link strength. 3.6 Analysis of the top 10 most cited publications Table 5 shows the 10 most cited articles, and the range of citations was from 158 to 439. "The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis (Schmidt et al., 2012)  The mapping on authors of sepsis associated with ALI. The relationship between 179 identified authors (the minimum number of citations of journals exceeds 15) and the total link strength.  Figure 4 shows the relationship between 288 identified journals (the minimum number of citations of journals exceeds 20) and the total link strength using VOSviewer. As presented in Table 6 Figure 5 shows the relationship between 179 identified authors (the minimum number of citations of journals exceeds 15) and the total link strength using VOSviewer. As presented in Table 7, the top 10 authors by total link strength were as follows: Matthay MA (total link strength = 1,753 times), Ware LB (1,439 times), Rubenfeld GD (1,239 times), Abraham E (935 times), Ranieri VM (933 times), Matute-Bello G (780 times), Singer M (768 times), Calfee CS (742 times), Bernard GR (714 times) and Hotchkiss RS (666 times). Therefore, Matthay MA was the predominant author in sepsis associated with ALI globally according to co-citation analysis. Figure 6 shows the relationship between 193 identified references (the minimum number of citations of journals exceeds 10) and the total link strength using VOSviewer. As presented in Table 8, the top 10 references by total link strength were as follows: Rubenfeld GD, "Incidence and outcomes of acute lung injury (Rubenfeld et al., 2005) (Bernard et al., 1994)", American Journal of Respiratory and Critical Care Medicine, 1994 (320 times). Therefore, "Incidence and outcomes of acute lung injury (Rubenfeld et al., 2005)" was the predominant reference in sepsis associated with ALI globally according to co-citation analysis. The authors of this literature conducted a prospective, population-based cohort study at 21 hospitals using a validated screening protocol to identify patients meeting consensus criteria for ALI.

The analysis of keywords
Keywords usually reflect the theme of research, and systematic analysis of keywords reflect the research hotspot in a specific field. When analyzing the keywords, we combined some different versions of the same terms, including different spelling versions (e.g., "nfkappa-b", "nuclear factor-kappa b" and "NF-κB"), and abbreviated terms (e.g., "LPS" and "lipopolysaccharide"). Table 9 shows the top 20 keywords, with most of them falling into two groups. One group is mechanisms involved in sepsis associated with ALI, such as inflammation, NF-κB, cytokines and oxidative stress. The other group is research methods involved in sepsis associated with ALI, including keywords like LPS (lipopolysaccharide), CLP (cecal ligation and puncture), and macrophages. In Figure 7A, we used VOSviewer software to show the primary keywords more compact. As presented in Figure 7B, the blue keywords appeared earlier, while the yellow keywords appeared later. The results of co-occurrence analysis indicated that programmed cell death (PCD) might become the hot spot of future sepsis associated with ALI research. The evolution of a knowledge domain can be represented by citation bursts. Citation burst refers to the literature that has attracted the attention of scholars in a specific field during a specific period of time. CiteSpace has a burst detection function, which we use to find the top 25 terms with the most cited bursts ( Figure 7C). Keywords related to ALI, such as nitric oxide synthase, pneumonia, and interleukin-6, began to burst at an early stage. Subsequently, keywords such as mechanical ventilation began to burst, indicating that the focus of the study has shifted to the treatment of ALI. It is also noteworthy that TLR4 and NF-κB only had bursts recently.

Discussion
Bibliometrics plays a very important role in improving the ability of literature retrieval and utilization, helping beginners to rapidly enter a particular field. For the first time, we reported the bibliometric analysis to review the progress of sepsis associated with ALI related research in worldwide in the past decade. At present, research on the sepsis associated with ALI is flourishing. In the initial phase, the definition of ALI and diagnostic criteria predominated and, nowadays, the focus of interest is on understanding the pathophysiological mechanisms that lead to apoptosis, necroptosis and pyroptosis. The research on programmed cell death is a hot spot and may be a promising research field in the coming years. Among the top 10 countries, China ranked first in the total number of publications, cited times and H-index, which indicated that China is a high-yield country in the study of sepsis associated with ALI, and the United States ranked first in average number of citations per publication, which means that the United States has more influence in this field. Seven Chinese affiliations came in the top 10 affiliations in the research of sepsis associated with ALI, the United States affiliations only three came in the top 10 affiliations, but the United States affiliations had a relatively high cited times, average number of citations per publication and H-index. Among the top journals, International Immunopharmacology ranked first in the sum of total publications, Inflammation first in H-index, Critical Care ranked first in cited times, average number of citations per publication and IF. Six authors of the United States came in the top 10 authors in the research of sepsis associated with ALI, Chinese and Spain each have two authors came in the top 10 authors. Matthay MA has published the most papers. His important contribution to this field is he screened a number of markers and therapeutic targets related to sepsis associated with ALI through clinical and basic research.
Although China ranked first in the sum of total publications, only two authors have come in the top 10 authors in the world, indicating that China still needs to increase investment in this field to lead the research trend. Among the top 10 most cited publications, "The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis" ranked first, which was published in Nature Medicine in 2012 and has been cited 439 times in total. The article found that heparinase inhibition could alleviating sepsis-induced ALI and mortality in mice. From the perspective of co-cited journals, Critical Care Medicine had been the most co-cited journal. From the perspective of co-cited authors, Matthay MA had been the most co-cited author. Among the 24,236 co-cited references retrieved, Table 8 shows the top 10 references by total link strength, of which "Incidence and outcomes of acute lung injury" is the most frequently cited.
In the results, a systematic bibliometric analysis has been conducted on the studies on sepsis associated with ALI published in WOS from 2012 to 2021. Table 9 shows the top 20 keywords, with most of them falling into two groups. One group is mechanisms involved in sepsis associated with ALI, such as inflammation, NF-κB, oxidative stress and cytokines. The other group is research methods involved in sepsis associated with ALI, including keywords like LPS, CLP, and macrophages. NF-κB is an important nuclear transcription factor in cells. It is related to the inflammatory changes of many human diseases, such as ALI, rheumatoid arthritis, heart and brain diseases (Gong et al., 2021;Jiao et al., 2021;Wang et al., 2021;Xie et al., 2022). Many studies have demonstrated that NF-κB pathways are involved in sepsis associated with ALI (Wang et al., 2014;Li et al., 2016;Wang et al., 2020;Du et al., 2021). There are five members of NF-κB family, including RelA (p65), RelB, NF-κB1 (P50), NF-κB2 (P52) and c-Rel (Jimi and Katagiri, 2022). Commonly referred to as NF-κB protein, it refers to NF-κB1 dimer protein formed by P65/p50 subunit. The classical NF-κB pathway can be activated by various stimuli (e.g., TNF-α, LPS, IL-1β). It is mediated by cell surface receptors, such as TLR, TNF-R and antigen receptors, and activated by various adaptor proteins and signaling kinase IKK (including IKKα, IKKβ and IKKγ). Activation of the IKK complex leads to phosphorylation of the NF-κB inhibitor protein IκBα, which ultimately leads to proteasome degradation and release and translocation of NF-κB dimers, such as p50-RelA (p65), to the nucleus to drive transcription of target genes. The activation of immune response genes ultimately leads to sepsis associated with ALI ( Figure 8).
The results of co-occurrence analysis suggested that PCD might become a research hotspot of sepsis associated with ALI in the future, and before 2017, most studies focused on the study of complications and inflammation. PCD is a genetically regulated process leading to the death of cells. It plays a critical role in organismal development, homeostasis, and pathogenesis (Liang and He, 2022). At present, it is found that besides apoptosis, PCD also includes necroptosis and pyroptosis. According to our study, PCD has been extensively involved in sepsis associated with ALI studies in recent years.
It is important to clarify the future research direction of sepsis associated with ALI. Therefore, the recent articles with high citation Frontiers in Physiology frontiersin.org rate should be divided into subgroups to analyze their research hotspots. As presented in Figure 9, the top 100 cited articles were used for bibliographic coupling and divided into 6 clusters according to the research direction. Cluster #1 contains 28 articles, the main research topic is the effect of different drugs on sepsis associated with ALI. Schmidt EP et al., in 2012 found that heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. Cluster #2 contains 25 articles, the main research topic is the pathogenesis of sepsis associated with ALI. Cheng KT et al., in 2017 discovered that caspase-11-mediated endothelial pyroptosis underlies sepsis-induced ALI (Cheng et al., 2017). Toll-like receptor 4 (TLR4) activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation (Tauseef et al., 2012). Cluster #3 contains 21 articles, the main research topic is clinical study of sepsis associated with ALI. In CITRIS-ALI randomized clinical trial, a 96-h infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury (Fowler et al., 2019). Many common drugs, including statins (Mansur et al., 2015;Dinglas et al., 2016;Needham et al., 2016), hydrocortisone (Tongyoo et al., 2016), carbon monoxide (Fredenburgh et al., 2018) and aspirin (Toner et al., 2015), have been tested in clinical trials for the treatment of sepsis-induced ALI. Cluster #4 contains 12 articles, the main research topic is the role of intracellular substances in sepsis associated with ALI. Zhou et al., in 2019 demonstrated that human endothelial progenitor cell (EPC) exosomes are beneficial in LPS-induced ALI mice (Zhou et al., 2019). Jiang J et al. identified that targeting NOX4 may be an innovative therapeutic option that is markedly effective in treating sepsis-induced ALI (Jiang et al., 2020). Cluster #5 contains 10 articles, the main research topic is markers and therapeutic targets of sepsis associated with ALI. Reilly JP et al. found that plasma angiopoietin-2 as a potential causal marker in sepsis-associated ALI development (Reilly et al., 2018). Cluster #6 contains 4 articles, the main research topic is application of mesenchymal stem cells (MSC) in sepsis associated with ALI. Human MSC-derived microvesicles were therapeutically effective following E. coli sepsis-induced ALI in mice .

Limitations
There are some limitations in the present study. First of all, we chose WOS as the only literature search database, which may have The mapping on keywords of sepsis associated with ALI (A) Visualization of 151 identified keywords in sepsis associated with ALI; (B) Overlay visualization of the 151 identified keywords in sepsis associated with ALI based on the average time they appeared in the publications. The blue keyword appeared earlier, while the yellow keyword appeared later. (C) The top 25 terms with the most cited bursts.
Frontiers in Physiology frontiersin.org missed some publications, resulting in database bias. Second, only literatures published during 2012-2021 were included, articles published before were missed. Finally, some of the latest highquality articles may not be enrolled in top 10 journals and top 10 most cited publications due to the low number of citations. However, we believe that this work can still be used to present the overall situation and trends in this field.

Conclusion
China is a major producing country, and the United States has more influence in this field. Shanghai Jiao Tong University, University of California System and Huazhong University of Science Technology were the main contributing institutions to sepsis associated with ALI. International Immunopharmacology,

FIGURE 8
The mechanism of NF-κB in sepsis associated with ALI (Created with BioRender.com).

FIGURE 9
The mapping on top 100 cited references of sepsis associated with ALI.
Frontiers in Physiology frontiersin.org 13 Inflammation, Shock and Critical Care have published the latest studies and novel progress in this field. Matthay MA and Ware LB were the main contributors to this field. Inflammation and NF-κB have always been the focus of sepsis associated with ALI related research, and PCD (including apoptosis, necroptosis and pyroptosis) may be the important direction of future research. Overall, our study will provide useful reference for further research on sepsis associated with ALI.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.