Hotspots and Frontiers of Host Immune Response in Idiopathic Pulmonary Fibrosis: A Bibliometric and Scientific Visual Research from 2000 to 2022

Background Idiopathic pulmonary fibrosis (IPF) is a disease with significant morbidity, progressive deterioration of lung function till death, and lack of effective treatment options. This study aims to explore the global research trends in IPF and immune response to predict the research hotspot in the future. Materials and methods. All related publications on IPF and immune response since the establishment of diagnostic criteria for IPF were retrieved using the Web of Science (WOS) database. VOSviewer, GraphPad Prism 6, CiteSpace version 5.6. R5 64-bit, and a bibliometrics online platform were used to extract and analyze the trends in relevant fields. Results From March 1, 2000, to September 30, 2022, a total of 658 articles with 25,126 citations met the inclusion criteria. The United States ranked first in number of publications (n = 217), number of citations (n = 14,745), and H-index (62). China ranked second in publications (n = 124) and seventh and fifth for citation frequency and H-index, respectively. The American Journal of Respiratory and Critical Care Medicine (impact factor = 30.528) published the most articles in the field. The author Kaminski N. from the United States was the most influential author with 26 publications and an H-index of 24. Among the 52 keywords that co-occurred at least 20 times, the main keywords were concentrated in “Inflammation related” and “Biomarker related” clusters. “biomarker” (AAY 2018.64, 25 times) was a newly emerged keyword. Conclusions The United States has an unequivocal advantage in IPF and immunization, but China shows a faster developing trend. The American Journal of Respiratory and Critical Care Medicine should be prioritized for leading articles. This study indicates that exploration of ideal immune-related biomarkers to provide evidence for the clinical work of IPF might be a hotspot in the near future.


Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal pulmonary disease of unknown etiology characterized by inexorable respiratory function failure, eventually leading to death [1,2]. More than 3 million people suffered from IPF worldwide before 2015 [3], and its incidence is increasing [4] due to harmonized nomenclature [5], standardized diagnostic criteria [6], and improved diagnostic tools [7]. With an aging population, the impact of IPF on the medical system and its burden on the social economy will worsen [8,9].
Currently, Pirfenidone and Nintedanib are the only two options approved by the FDA, and evidence-based guidelines recommend them as medicines for treatment of IPF alone or in combination [8,10,11]. However, these two medications cannot reverse the decline of lung function, disease progression, and death [12]. The prognosis of IPF is extremely poor with an average survival time of only 2.5-3.5 years from diagnosis [13]. When medical options have been exhausted, lung transplantation became the only treatment available for IPF. But in fact, lung transplantation benefits only a small number of IPF patients due to limitations including patient age, comorbidities, and scarcity of donor organs [12,14]. Challenges in IFP diagnosis and treatment are due to a lack of deep understanding of the pathogenesis [8].
Initially, IPF was considered to be associated with inflammation because of imaging and pathological findings. As such, corticosteroids and immunosuppressive/cytotoxic agents alone or in combination have been recommended treatment options [15]. However, subsequent studies found that immunosuppressive therapy did not provide adequate benefit and even increased the risk of death [16,17]. Thus, the hypothesis that inflammation leads to fibrosis has been questioned. Recent studies found that immune dysregulation may play a profibrotic role via immune regulation, rather than directly causing IPF [18,19]. Intrinsically, immune dysfunction has been related to various immune cells, such as peripheral blood mononuclear cells (PBMCs) [20], dendritic cells (DCs) [21], and pulmonary macrophages [22]. In addition, clinical guidelines still recommend corticosteroids for patients with acute exacerbations of IPF, albeit weakly [10]. Thus, a better understanding of the progress of research on immunity in IPF, an in-depth study of immune regulation mechanisms, and a search for new therapeutic targets to reverse immune disorders have attracted worldwide attention. An overall analysis of the published literature would help to quickly identify the research hotspots and development trends in host immune response associated with IPF.
Bibliometrics is a mathematical and statistical research method that analyzes the distribution structure and changing rules of a certain field quantitatively based on the published information. Bibliometrics has been reported to be used for subject trend analysis, frontier identification, and evolution prediction [23,24]. Bibliometrics is also used to evaluate the research contributions and collaborative relationships in a specific area across countries, institutions, journals, scholars, and articles [25], which can guide scholars to choose appropriate journals to publish their research results by analyzing citations and publication patterns [26][27][28]. More importantly, bibliometrics can also be used as a scientific basis for developing and implementing disease treatment guidelines [29].
Relying on the Web of Science (WOS) database, bibliometric analysis was adopted for the first time to quantitatively analyze the IPF and host immune response literature and evaluate the contributions and cooperation of different countries, institutions, and researchers in the field of IPF. The aim of this study was to reveal the current status and research trends in IPF and immune response, and predict future research hotspots to provide a theoretical basis for the pathogenesis and clinical research of IPF.

Data Source and Retrieval Strategies. Science Citation
Index-Expanded (SCI-E) of Thomson Reuters' WOS is considered to be the best database for bibliometric analysis and it is widely used in scientific research [30,31]. Thus, WOS Core Collection (WOSCC) was applied for the online literature retrieval in this study. The definition of IPF was constantly revised and advanced [32]. The initial international consensus statement defining the normalized diagnosis of IPF was produced co-operatively by the American Thoracic Society, the European Respiratory Society, and the American College of Chest Physicians, and it was published in February 2000 [15]. Thus, the timespan selected to retrieve the publications was from March 1, 2000, to September 30, 2022. To avoid alteration of the data involved during the database updates, data collection and download were completed within a single day on September 30, 2022. The retrieval strategy was as follows: TI = (Idiopathic Pulmonary Fibrosis) OR (Pulmonary Fibrosis, Idiopathic) OR (IPF) OR (cryptogenic fibrosing alveolitis) OR (CFA) OR (lone CFA) OR (idiopathic interstitial pneumonia) OR (Fibrosing Alveolitis, Cryptogenic) OR (Cryptogenic Fibrosing Alveolitides) OR (Fibrosing Alveolitides, Cryptogenic) OR (Pulmonary Fibrosis, Idiopathic) AND TS = immunology OR (immune response) OR (immunologic response) OR (immune dysfunction) OR immunosuppression OR macrophage OR monocyte OR neutrophil OR (natural killer cell) OR (NK cell) OR (innate lymphoid cell) OR (innate lymphocyte) OR ILC OR (dendritic cell) OR DC OR (T lymphocyte) OR (T cell) OR (regulatory T cell) OR (Treg) OR (B lymphocyte) OR (B cell) AND LANGUAGE: (English) AND DOCUMENT TYPES (Article OR Review). Data download and retrieval were independently conducted by two authors. Ethics committee approval was not required because all data were obtained from public databases. Details of literature inclusion, screening, and exclusion are shown in Figure 1.

Data Collection.
All data extracted and downloaded from qualified publications included titles, keywords, countries/ regions, institutions, authors, publication dates, published journals, citation frequency, and H-index, and this process was independently performed by two authors (LSR and ZPY). Microsoft Excel 2016 (Redmond, Washington, USA), GraphPad Prism 8 (GraphPad Prism Software Inc., San Diego, CA, USA), VOSviewer software (Leiden University, Leiden, Netherlands), CiteSpace version 6.1. R3 and bibliometrics online platform (http://bibliometric.com/) were applied to qualitatively and quantitatively analyze and construct a visual network of relationships among five entities: countries, institutions, journals, researchers, and keywords.

Bibliometric Analysis.
In this study, three evaluation parameters were used in the bibliometric analysis. The latest impact factor (IF), identified as an important index to measure academic impact of a journal or research output, was acquired from the latest issue of Journal Citation Reports (JCR) published in 2022 [24,25]. The H-index, defined as the H number of papers published by a country/scholar with at least H number of citations and known as a wellestablished quantitative indicator to evaluate the academic output of a country/research [33], was obtained from the WOS database. Relative research interest (RRI) was used to indicate the ratio between the published number in a specific field and publications' overall fields per year. VOSviewer is a software tool that was used to construct and visualize bibliometric networks [34], and it is used for keyword network construction and cluster analysis. Average appearing year (AAY) was applied to quantify the relative novelty of the keyword by coloring based on the chronological order of appearance.  However, the number of citations and H-index were 1,595 (6.35%) and 23, ranking seventh and fifth, respectively. Japan and Italy ranked third and fourth in terms of the number of publications with 110 (16.72%) and 62 (9.42%) articles, respectively. However, the number of citations was 3,623 (14.42%) and 1,742 (6.93%), respectively, which were higher than those of China. The H-index values of Japan, England, and Germany were 35, 29, and 24 respectively, which were also higher than those of China, although their publication volume was lower than that of China (Figure 3(a)).

Results
Visualized the top 20 countries with the most relevant publications, the United States was at the core of the thermodynamic map and cooperative relationship network with the largest cycle, reflecting the fact that the United States published the highest number of articles and had the closest cooperation with other countries, especially with Japan and China in Asia, as well as Britain and Germany in Europe (Figure 3(b)-3(d)). These countries/regions were colored based on the average publication time. Blue color represents early years, and yellow color represents more recently. China (AAY 2018.75) was the latest influential country in this area and is colored in bright yellow (Figure 3

Contributions of Institutions and Journals to Global
Research on IPF and Immune Response. The retrieved results of WOS showed that in terms of the number of papers published among the top 20 institutions, 12 institutions were from the United States, one was from Japan, and one was from China. The Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Pittsburgh, and University of California System comprised the top three institutions with 39 (5.93%), 37 (5.62%), and 32 (4.86%) publications, respectively (Figure 4(a)).
The cooperative relationships of the main organizations were quantified and visualized using Vosviewer. The minimum number of documents of an institution was set at 8, and we observed the distribution of the institutions engaged in IPF and immune response. The University of Pittsburgh in the United States was located at the center of the map with the largest node and the most complex and bulky network structure because of its greatest influence in this field (Figures 4(b) and 4(c)). Furthermore, the institutions were colored by VOSviewer according to the average time taken to make an impact; the blue color indicates the early years, and the yellow color represents relatively recent. Among them Hannover University Medical School (AAY 2020.75) in Germany, Nanjing University   Journal of Immunology Research Figure 5(d), in the field of IPF and immune response, research related to molecular/ biology/immunology mainly cited journals in the field of molecular/biology/genetics, while research related to medicine/medical/clinical mainly cited journals related to molecular/biology/genetics and health/nursing/medications.  Table 2.

Analysis of Keywords and Hotspots in Publications on IPF
and Immune Response. To explore the main focus of this field, based on the 658 publications on IPF and immune response, we extracted 2,934 keywords from the titles and abstracts of all publications and performed an analysis of 52 keywords that co-occurred at least 20 times using VOSviewer software ( Figure 6(a)). The diameter of each keyword circle indicates its co-occurrence frequency. The 52 keywords were grouped into four clusters in an acquiescent manner, and they were artificially named as follows: "Inflammation related" (cluster #1, red in the map), "Biomarker related" (cluster #2, green in the map), "Disease related" (cluster #3, blue in the map), and "Innate immune mechanism" (cluster #4, yellow in the map).
In each cluster, there were keywords with the highest cooccurrence frequency. For example, the most frequently occurring keywords in the "Inflammation related" cluster were "expression" (142 times), "inflammation" (76 times), "cells" (71 times), and "activation" (57 times). The most common keywords in the "Biomarker related" cluster were "idiopathic pulmonary fibrosis" (252 times), "diagnosis" (57 times), "acute exacerbation" (52 times), and "survival" (48 times). The main keywords in the "Disease related" cluster were "disease" (77 times), "pathogenesis" (75 times), "ipf" (58 times), Journal of Immunology Research "bronchoalveolar lavage" (56 times), and "bronchoalveolar lavage fluid" (40 times). The keywords "macrophages" (46 times), "pulmonary fibrosis" (41 times), and "growth factor" (32 times) appeared frequently in the "Innate immune mechanism" cluster. The details of these 52 keywords are shown in Supplementary 4. To present the time of appearance of each keyword, VOS software colored each keyword according to the average time of co-occurrence, with bright yellow representing the latest occurrence and blue representing the earliest occurrence ( Figure 6(b)). Analysis of these 52 keywords showed that    [15]. The United States ranked first in the world in terms of the number of publications, the number of citations, and the H-index. This fully demonstrates the outstanding contribution of the United States in the field of IPF and immune response. Consultation with the literature on IPF revealed that several revisions of the diagnostic criteria and treatment principles of IPF were jointly published by scholars from the United States and Europe [15,32,35], indicating that the United States and Europe have given more attention to this field compared with other countries. Moreover, the United States has a considerable advantage in immune research, which is supported by the number of articles and is likely related to comprehensive national strength, professional researchers, sufficient research funds, and extensive international cooperation [23,29,30]. Thus, the United States is at the leading level in this field due to several advantages. With respect to citations and H-index, Japan and England followed the United States closely (Figure 3(a)). China ranked second in the number of publications in this field; however, it lagged behind Japan and the United Kingdom in terms of citations and H-index, ranking seventh and fifth, respectively. The discrepancy between the number of publications in China, citations, and H-index has also been revealed in other studies [23,29,30], which could be attributed to several factors. The first reason is that China entered relatively late into the IPF and immune-related fields. Before 2013, only sporadic articles were published, and then the number gradually increased (Figure 2(a)). From 2019, the number of articles published in this field started to increase significantly, and China caught up with other countries and even exceeded their number of articles. The number of citations lags behind the number of publications. Therefore, the growth of citations in China will take more time. Second, regardless of the influence of gender and age, the incidence of IPF in China is lower than that in the United States and most other countries in the world [4]. Further, sporadic cases were scattered in different places, and diagnostic challenges increased the difficulty to carry out standardized clinical research. Third, China may need to expand international exchanges and cooperation in this field based on high-level scientific research to promote its own development and common progress (Figures 3(b) and 3(e)).
In terms of institutions, one paper may be completed by authors from several universities or medical institutions, and each university or medical institution may belong to different systems. The analysis of institutions by different software is not the same, resulting in inconsistent results. According to WOS results, the PCSHE was the most published institution in the field of pulmonary fibrosis and immune response with  the University of Pittsburgh ranking second (Figure 4(a)). PSCHE is a "state-related" institution composed of the universities within the state, including the University of Pittsburgh (https://www.passhe.edu/Pages/default.aspx). Therefore, for an independent institution, the University of Pittsburgh was in a dominant position in this field. This conclusion was confirmed by Vosviewer (Figures 4(b) and 4(c)). From another perspective, most of influential institutions in this field were from the United States and Europe (Figure 4(a)-4(c)). Considerable advances in this field and extensive international cooperation between the United States and some European countries have also promoted the development of several guidelines or guidances, which provide reliable evidence for clinical and scientific research [5,10,15,32,36]. In addition, Hannover Medical School in Germany (AAY 2020.75) and Nanjing University in China (AAY 2018.75) are the latest institutions to focus on this field and have had an impact on IPF and immune response research (Figure 4(d)). In a certain sense, adequate international cooperation can effectively improve the influence of countries, institutions, scholars, and publications. Our analysis indicates that China needs to increase international exchange and cooperation while improving the quality of research in the future. The analysis of journal contributions and citations can assist researchers to understand the importance of a field, and it can provide important assistance for efficient retrieval of academic frontier literature, writing, or publishing research results. According to this study, current outstanding achievements in IPF and immune response research were mainly published in journals related to the respiratory system, cell biology, and immunology. Among the top 10 journals in terms of publication volume, three journals had an impact factor of more than 10, and three journals had an impact factor between 5 and 10 ( Figure 5(a)). The American Journal of Respiratory and Critical Care Medicine published the highest number of articles with the most citations. It is worth noting that high-quality papers on IPF and immune response have been published in journals with high impacts, such as the Lancet Respiratory Medicine (IF = 102.642) and the New England Journal of Medicine (IF = 176.079). Thus, the medical community and academics are acknowledging the importance of IPF and immune response. Cells and Frontiers in Immunology were the latest journals to have an impact in this field, providing more publishing opportunities for the research in IPF and immune response field.
Regarding the most productive and influential author, Kaminski N. from Yale University School of Medicine in the United States ranked first in the field of IPF and immune in terms of publications and H-index. Kaminski N, who published 15 articles with impact factors greater than 30 and participated in the research entitled "Small Airways pathology in Idiopathic Pulmonary Fibrosis: A Retrospective Cohort Study" published in the Lancet Respiratory Medicine (IF = 102.642), was quantified as one of the most influential authors in IPF and immune response. Selman M. and Pardo A. from Mexico ranked first and second in terms of citation frequency because they had published many high-level articles in influential journals (Table 1).

Research Focus on IPF and Immune
Response. The number of times an article is cited and the impact factor value of the published journal objectively reflect the academic influence of the research in a field. The top ten cited articles in the fields of immune response and IPF were published in journals with an impact factor >5 and half of these had an impact factor >30 ( Table 2). The research content mainly focused on the mechanism and treatment of IPF, which also included the difficulty in overcoming IPF, an incurable disease. Among these articles, Selman M and Pardo A from Mexico participated in the research of four publications, and Kaminski N. from the United States participated in two studies along with the first two authors. These three authors were also the top three cited authors. This fully illustrates the importance of collaboration between authors. "Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy", being the most cited paper, was published in Annals of Internal Medicine (IF = 51.598). This article summarized the relevant literature from 1965 to 2000. Based on the evidence that inflammation was not a significant pathological manifestation of IPF, inflammation was determined as unnecessary for fibrosis and was not associated with the clinical stage and prognosis, and anti-inflammatory treatment could not improve the outcomes. Thus, the article concluded that inflammation was not a requisite for IPF [37]. The second paper in the list was a review on IPF published in the New England Journal of Medicine (IF = 176.079) in 2001, which proposed a role for the type of inflammatory response in regulating tissue damage, fibrosis, or both during the evolution of IPF. It was pointed out that an increase in the Th2 cytokine interleukin-(IL-) 13 in IPF could be used as a marker of the transition to a Th1 inflammatory response mediated by immunomodulators, such as interferon γ [38]. This theory was supported by the fourth paper on the list. This article cited a theory for the role of IL-13, as well as IL-1β, tumor necrosis factor-α, and other profibrotic mediators. It also proposed that a cascade amplification reaction played an important role in the pathogenesis of IPF, among which IL-13 could promote the proliferation of fibroblasts and synthesis of extracellular matrix (ECM) [39]. The sixth paper addressed the antifibrotic mechanism of osteopontin [40], which was thought to primarily exert an antifibrotic Th1 effect on T lymphocytes [41]. In addition, three papers clarified that IPF was caused, at least in part, by the imbalance between matrix metalloproteinase (MMP) family members, and that MMP expressed by immune cells played an important role. For example, MMP-1 was also observed in alveolar macrophages, MMP-9 in neutrophils, tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-3 in interstitial macrophages, and TIMP-4 in plasma cells [40,42,43]. These articles supported the notion that immune cells and inflammatory cytokines take a crucial role in the pathogenesis of IPF and might act as potential therapeutic targets for IPF in the future.
There is no doubt that the keywords with the highest cooccurrence frequency are considered the focus and difficulty of this field and are being widely studied. The analysis of keywords by VOSviewer showed that in addition to the name and location of IPF, such as "idiopathic pulmonary", keywords involved in the pathogenesis, such as "expression", "inflammation", "pathogenesis", "cells", and "activation", occurred most frequently. All these findings confirm that exploring the role of immunity in the pathogenesis of IPF remains the focus of current research.
With respect to the latest hotspot, the latest keywords with high co-occurrence are generally regarded as the research hotspots in this field. The term "biomarker" was the most newly occurring keyword. In addition, "mortality", "diagnosis", "prognosis", "biomarkers", and "regulatory t-cells" were the other five most emerging keywords among the top ten keywords, and these were concentrated in the "Biomarker related" cluster. The term "inflammation" in the "Inflammation related" cluster remains a major concern in the field (Figures 6(a) and 6(b)). These data indicate that being an incurable disease, rapid and clear diagnosis, effective treatment, and improved prognosis are currently the focus of research on IPF. Although an in-depth study of the pathogenesis is the theoretical basis for clinical work, there is an urgent need to identify effective biomarkers, especially immune-related biomarkers, closely related to the mechanism, diagnosis, and assessment of treatment response in the field. Therefore, it is not difficult to speculate that the exploration of immune-related biological markers may assist in the clinical diagnosis, differential diagnosis, assessment of disease stratification, disease development, and prognosis of IPF will be a research hotspot.
Although the "disease related" and "innate immune mechanism" clusters were likely to receive less attention compared to the "biomarker related" and "inflammation related" clusters, these two clusters focused on "mechanisms", "pathogenesis", and "macrophages", which were also closely related to immunity. This suggests that the study of IPF and immunity can provide a better understanding of the pathogenesis of IPF mechanisms.
To date, the etiology and mechanism of IPF remain clear, and the progression of IPF is variable, ranging from a chronic progressive stage for many years to a sudden acute exacerbation stage, which can be accompanied by various complications. So far, none of the medications for IPF have been able to reverse the process of fibrosis. In addition, there is no effective basis for early diagnosis, and it is necessary to integrate clinical symptoms, imaging, alveolar lavage fluid results, and even pathological biopsy to establish a diagnosis. By the time the diagnosis is confirmed, the disease is relatively serious, and the remaining survival time is very short. Furthermore, there is a lack of a standardized index to evaluate the effect of therapy. Based on these points, reliable and easily usable biological markers are urgently required to assist in early diagnosis, differential diagnosis, evaluation of disease severity, and evaluation of response to therapy, which could all be used as surrogate endpoints for clinical trials. Ideally, biological markers should be able to replace invasive methods, such as fiberoptic bronchoscopy and lung biopsy, as diagnostic tools. At present, the existing potential biomarkers for IPF are artificially classified into three categories according to their different biological characteristics as follows: those related to dysfunctional alveolar epithelial cells, those related to ECM remodeling and fibroblast differentiation, and those relevant to immune dysfunction [44,45]. Although the hypothesis of inflammation in the pathogenesis of IPF has been questioned, it is generally accepted that inflammations, both innate and adaptive immune responses, are involved in the process and are essential to almost all wound healing and fibrosis processes, including IPF [13,16]. Therefore, potential biomarkers of IPF related to immunity could also be involved in the innate and adaptive immune response systems.
Regarding the innate immune system, Prasse et al. [46] found that serum concentration of CC chemokine ligand-18 (CCL18) was associated with severity and mortality in IPF patients and it was used as the first biomarker to predict IPF mortality. CCL18, a marker of alveolar macrophage activation, mediated by Th2 cytokines [47,48], promotes collagen production by fibroblasts [49] and has been used as a diagnostic biomarker for IPF [50]. Toll-like receptors (TLRs) are important protein molecules in innate immunity and are bridging linking innate immunity and adaptive immunity. The influence of L412F polymorphism on the innate immune recognition receptor TLR3 in IPF has attracted much attention. O'Dwyer et al. [51] found that TLR3 L412F was associated with lung function decline and high mortality in a bleomycin-(BLM-) induced pulmonary fibrosis mouse model. McElroy et al. [52] revealed that this effect might be because 412 F-heterozygous patients were likely to suffer from bacterial and viral infections. Using the single-cell gene sequencing dataset, Li et al. [53] confirmed that lung macrophages express Toll-interacting protein (TOLLIP) which is an inhibitory adaptor protein that acts downstream of TLRs [54]. Oldham et al. [55] discovered that TOLLIP polymorphisms affect the efficacy of N-acetylcysteine in patients with IPF, and further showed that different genotypes have opposite effects on patients. Moreover, Bonella et al. [56] confirmed that the minor allele of TOLLIP rs5743890 was associated with acute exacerbation and high mortality rate. Therefore, TOLLIP could be used as a biomarker to stratify disease severity, assess prognosis, and aid in the selection of treatment options. It should be noted that many other proteins, such as Defensins, S100A12, and Chitinase-3-like protein 1 (YKL-40), which are closely related to the innate immune system, were also found to be potential biomarkers for acute exacerbation, poor survival, and worse functional status in IPF [44,45].
Studies have confirmed that many proteins related to the acquired immune system, such as anti-heat shock protein-(HSP-) 70 antibodies [57], C-X-C motif chemokine 13 (CXCL13) [58], anti-vimentin antibodies [59], and some T-cell subpopulations, might be associated with worse prognosis, acute exacerbations, and pulmonary hypertension. Thus, these proteins could be used as objective biomarkers in the diagnosis of IPF.
Ideal biomarkers for any pathology should be stable, accurate, sensitive and specific, and reproducible [50]. Although there were many biomarker candidates have been identified, none have met all of the conditions and addressed the needs of clinical and scientific research so far [45]. Therefore, in order to develop a more scientific and practical evaluation system, some researchers combined different types of biological markers, combined multiple potential biomarkers, or combined biomarkers with clinical data, achieving satisfactory benefits. For example, Clynick et al. [60] built a predictive model using osteopontin (OPN), polyamine spermidine (SPD), intercellular adhesion molecule-1 (ICAM1), and MMP7 to predict a patient's condition, and they applied OPN, MMP7, periostin (POSTN), and ICAM2 to predict the 1 year risk of exacerbation and death. Among these markers, ICAM1 and ICAM2 were associated with inflammation and immunity. These results were published in the European Respiratory Journal (IF = 33.795) in 2022. Due to the complexity of IPF, excavating or selecting ideal biomarkers to provide reliable clinical evidence and achieve individualized prediction is currently a research hotspot and will continue to be so in the future.
Of note, "regulatory T-cells" was a keyword that deserved attention in both frequency and time of co-occurrence in the IPF and immune literature, as shown using VOSviewer. Regulatory T cells (Tregs) play a crucial part in immune regulation and maintenance of immune tolerance. Similarly, researchers have found that Tregs may play exert different or even opposite regulatory effects through various signaling pathways at different stages of IPF. Reilkoff et al. [61] discovered that Tregs are increased in the peripheral blood and lung of IPF patients, which is positively correlated with disease progression. However, research by Kotsianidis suggested the opposite findings [62]. Although many current data are based on the analysis of the number of Tregs and their mechanism of action, and the conclusions obtained in mouse models and human samples are inconsistent, all findings suggest that Tregs do participate in the immune regulation of IPF. However, the mechanism remains unclear. Therefore, it is crucial to clarify the particular role of Tregs in IPF to study the pathogenesis and treatment of IPF.

Strengths and Limitations.
In this study, publications related to IPF and immune response were retrieved from the WOS core database, which is a comprehensive core journal citation index database. This study objectively analyzed the information and characteristics of IPF and immune response publications in the past 22 years and predicted future research hotspots in this field. The authors aimed to provide a more intuitive reference for researchers in this field. Furthermore, all data were retrieved and downloaded within 1 day, avoiding the result bias caused by data updates. However, there were some unavoidable limitations of this study that should be acknowledged. First, in terms of the inclusion criteria, our search strategy only included publications in English. The types of literature selected in this study were only papers and review papers, while other forms, such as conference, abstract, and editorial materials, were ignored. Limitations to these inclusion criteria may have resulted in some missing data. Second, according to the current data extraction methods, the latest publications could not obtain high citation frequency and keyword co-occurrence frequency due to the time limitation, which could have affected our conclusions to some extent. Third, to avoid the influence of common interstitial pneumonia, publications with clear diagnostic criteria used since March 2000 were selected, which could have resulted in missing data before the time node that may have affected the analysis results. Finally, we only selected the WOS core database and ignored the literature in the WOS noncore database and other databases, which could also have impacted the results. Future work methods should incorporate more complete data, track the latest developments in the field, and conduct a more comprehensive analysis.

Conclusion
In summary, this study comprehensively evaluated the research trends and hotspots in IPF and immune response. The United States has contributed the most to this field, but China also had a considerable number of publications, showing a prominent growth trend. The American Journal of Respiratory and Critical Care Medicine could be referred to for the latest research and progress in this field. Kaminski N., Flaherty K. R., and Selman M. were the most academically influential authors in the field. The role of inflammation and immune response in IPF received more attention and thus exploration of ideal biological markers related to the immune response for diagnosis, disease stratification, curative effect evaluation, and prognosis assessment of IPF may be the research hotspot in the future. We hope that this study will encourage more researchers in medicine, molecular biology, and immunology to pay attention to the field of IPF and immune response to break clinical bottlenecks as soon as possible.

Data Availability
The datasets for this study are available from the corresponding author upon reasonable request.