A bibliometric analysis of macrophages associated with chronic obstructive pulmonary disease from 2005 to 2025

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction (1,2). Notably, COPD currently ranks as the third leading cause of death in China and represents a significant disease burden globally (3,4), Current epidemiological projections estimate that the global prevalence of COPD may approach 600 million cases by 2050, underscoring its growing public health impact (5).

Alveolar macrophages (AMs) represent the predominant and functionally essential immune cell population residing in pulmonary tissues, localized at the airway lumen and alveolar surfaces where they directly interface with the airway microenvironment and epithelial cells (6). These cells serve as central orchestrators of innate immune defense, executing critical roles in phagocytic clearance, inflammation modulation, tissue repair, and secretory regulation through the release of diverse inflammatory mediators and cytokines (7-9). During stable COPD, macrophages predominantly exhibit M2 polarization, which is involved in chronic inflammation and tissue remodeling (10). In the AMs of smokers and COPD patients, M1 polarization levels decrease while M2 polarization shows no significant change (11). However, other studies suggest that smoking may promote M2 polarization by altering macrophage metabolism (12,13). During acute exacerbations, macrophages may shift toward pro-inflammatory M1 polarization to drive acute inflammatory responses (14,15). Nevertheless, some patients may still maintain a dominant M2 polarization state (16). This dynamic polarization state is closely associated with disease exacerbations and long-term prognosis. Targeted regulation of macrophage polarization could become a novel therapeutic approach for COPD management. Therefore, there is a need for a comprehensive exploration of the mechanisms of macrophages in COPD and related research trends to elucidate the pathogenesis of COPD and identify novel therapeutic targets.

Despite advancements in COPD research, the exponential growth of literature on macrophage-related mechanisms has created challenges in comprehensively mapping the field’s intellectual landscape. Traditional narrative reviews often suffer from subjectivity and fragmented perspectives, limiting their ability to identify macro-level trends, emerging hotspots, or interdisciplinary connections. Bibliometrics, a quantitative methodology employing mathematical and statistical analyses of scholarly literature, offers an objective framework to dissect research dynamics (17). Tools such as CiteSpace and VOSviewer (18) enable the visualization of complex bibliographic data into knowledge maps, revealing patterns in co-citation networks, keyword clustering, and temporal evolution of research themes (19). These analyses help pinpoint seminal publications, influential authors, collaborative networks, and conceptual shifts within a discipline (20,21).

This study utilizes CiteSpace and VOSviewer to analyze publications retrieved from the Web of Science Core Collection (WoSCC). By integrating co-occurrence, co-citation, and burst detection algorithms, we aim to delineate the intellectual structure of macrophage-related COPD research, including key contributors and institutional collaborations, and identify research hotspots and emerging frontiers. This analysis will provide a data-driven roadmap to guide translational research, optimize clinical interventions, and foster interdisciplinary innovation in COPD therapeutics. We present this article in accordance with the BIBLIO reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-683/rc).

Methods

Data collection and search strategy

A search was carried out in the WoSCC using the following search criteria: ((((((TS=(Monocyte-Derived Macrophage*)) OR TS=(Macrophage*, Monocyte-Derived)) OR TS=(Monocyte Derived Macrophage*)) OR TS=(Macrophage*)) OR TS=(Macrophage*, Monocyte-Derived)) AND ((((((TS=(Chronic Obstructive Pulmonary Disease*)) OR TS=(COPD)) OR TS=(Chronic Obstructive Lung Disease*)) OR TS=(Chronic Airflow Obstruction)) OR TS=(Chronic Obstructive Airway Disease*)). The search period was defined between January 1, 2005, and February 26, 2025. The data extraction and downloads were carried out on February 26, 2025, to avoid any bias in database updates, ensuring that all processes were completed on the same day. Exclusion criteria included: (I) document types other than original article and review articles (22,23) (such as meta-analysis, book chapter, conference summaries comments, letters, editorial material, and others); (II) written in non-English; and (III) repeated publishing. The records were exported in complete citation formats and stored as plain text files. A total of 2,840 documents themed on “macrophage” and “COPD” were downloaded from the WoSCC. We excluded meeting abstracts (n=246), book chapters (n=15), proceedings papers (n=25), editorial materials (n=24), letters (n=11), early access (n=2), retracted publications (n=6), corrections (n=1), and data papers (n=1). Non-English studies (n=25) were also excluded. This study eventually included 2,484 studies, comprising 2,064 articles and 420 reviews (online table available at https://cdn.amegroups.cn/static/public/jtd-2025-683-1.xlsx). Figure 1 shows the flowchart of the bibliometric analysis process.

Figure 1 Flowchart of the screening process. WoSCC, Web of Science Core Collection.

Data collection and cleaning

Two researchers independently conducted the primary data search and discussed potential discrepancies. Extraction of publishing characteristics from the database was performed comprehensively, including the number of papers and citations, H-index, year of publication, countries/regions, institutions, authors, journal, references, and keywords. Subsequently, we excluded duplicate studies, authors, and spelling errors. The original data were independently checked by two reviewers for duplications and potential errors to avoid inaccuracies due to varied citation versions.

Statistical analysis

In this study, we conducted a comprehensive bibliometric analysis using CiteSpace (v6.3.3R) and VOSviewer (v1.6.20) to delineate the intellectual landscape of macrophage-related research in COPD. The WoSCC served as the primary data source, encompassing peer-reviewed articles published between 2005 and 2025 (retrieval date: February 26, 2025). Key bibliometric indicators, including average citations per article, total citation counts, H-index (a measure of scholarly productivity and impact), 2024 journal impact factors (IFs), and Journal Citation Reports (JCRs), were extracted to evaluate academic influence and interdisciplinary trends.

CiteSpace, developed by Prof. Chen Chaomei, was employed for multivariate temporal analysis and dynamic visualization of knowledge networks. Its algorithmic framework enables the identification of burst terms (keywords experiencing abrupt citation surges), betweenness centrality (nodes bridging disparate research clusters), and time-zone projections to trace thematic evolution. Parameters were optimized as follows: time slicing (1-year intervals), node selection thresholds (g-index =25), and pruning methods (pathfinder network scaling) to minimize redundancy while preserving structural coherence. This approach facilitates the detection of research frontiers.

VOSviewer, a density-based visualization tool, complemented CiteSpace by generating co-occurrence networks and cluster density maps. Bibliographic data were processed through its built-in thesaurus normalization to merge synonymous terms. The software’s association strength normalization algorithm quantified node proximity, with cluster resolution set to 1.0 to balance granularity and interpretability. Key metrics included link strength (frequency of co-occurrence between entities) and total link strength (TLS, aggregated associations per node).

Results

The annual trend of paper publication quantity

As shown in Figure 2, the number of publications on macrophage-related research in COPD from 2005 to 2025 is depicted by the orange line, while the blue line represents the corresponding citation counts. Between 2005 and 2024, the number of publications generally shows an upward trend. Starting from around 50 in 2005, it gradually increased, reaching a peak in 2021. However, there is a sharp decline in 2025. This significant drop might be attributed to incomplete data collection, and may not fully cover the research output of that year. The number of citations also exhibits a continuous growth pattern from 2005 to 2024. It started at a very low level in 2005 and steadily increased.

Figure 2 Trends in the growth of publications and the number of citations.

Contributions of countries/regions

Table 1 presents the top 10 countries/regions in terms of publication volume, The USA dominates with 715 publications, nearly double that of China (n=458) and significantly surpassing England (n=373). While the USA leads in total output, its average citation count (60.69 per paper) is surpassed by Canada (75.81), England (68.81), and France (63.52), suggesting nuanced variations in research impact. The H-index, a composite metric of productivity and influence, further underscores the USA supremacy (H-index =102), followed distantly by England (H-index =81), while China (H-index =47) and Germany (H-index =47) lag despite moderate publication volumes. Centrality values, reflecting a country’s role as a collaborative hub, reveal England (0.30) and the USA (0.29) as central nodes, whereas China (0.04) and Japan (0.02) exhibit limited integration into global networks. TLS, quantifying international collaboration intensity, peaks for the USA (TLS =381) due to sheer scale, but the Netherlands (TLS =178) demonstrates exceptional collaborative efficiency relative to its modest output (n=140). China’s position as the second-largest contributor by volume contrasts sharply with its low average citations (19 citations), H-index (H-index =47), and centrality (centrality =0.04), indicating a systemic gap between quantity and quality. This discrepancy may stem from limited international partnerships (TLS =87, the second-lowest among the top 10 nations) or nascent research maturity in specialized subfields. Conversely, Canada’s high citation impact (75.81 citations) and England’s dual strength in centrality and citations suggest entrenched expertise and cross-border synergy. Germany (centrality =0.11, TLS =157) and the Netherlands (centrality =0.14, TLS =178) further exemplify how mid-sized research ecosystems achieve disproportionate influence through strategic collaboration. Japan’s low centrality (centrality =0.02) and TLS (TLS =65) despite moderate output (n=173) signal isolation risks, while France’s high citations (63.52 citations) paired with minimal output (n=93) hint at niche specialization.

Figure 3A shows the trend of the top 10 countries in terms of annual publications. The number of publications in the USA and China is generally at a relatively high level. The USA reached a publication peak around 2014 and has fluctuated since then. The number of publications in China has grown rapidly in the later period and exceeded that of other countries during 2021–2022, reaching a relatively high value. The number of publications in other countries such as the England and Germany is relatively stable, and the overall quantity is lower than that of the United States and China. Australia is in a wave of momentum. Figure 3B visually illustrates the dispersion and inclusion of these nations.

Figure 3 Visual map of countries in related domain. (A) The trend of the top 10 countries in terms of annual publications. (B) Map regarding the geographical spread of publications among different countries. TLS, total link strength.

Analysis of institutions and authors

As shown in Table 2, the data delineate a hierarchical landscape dominated by Anglo-American institutions, with Imperial College London (England) emerging as the unequivocal leader (n=172), nearly triple the output of runner-up University of Manchester (n=69). Its dominance extends to citation impact (average 93.05 citations per paper) and scholarly influence (H-index =65). The USA institutions collectively claim five positions, though with fragmented productivity: Pennsylvania Commonwealth System of Higher Education (PCSHE) achieved the highest average citations (93.81), while US Department of Veterans Affairs and Veterans Health Administration (VHA) achieved moderate citation rates (44.98–45.66). European representation includes Inserm (France) and University of Groningen (Netherlands): Inserm’s high centrality (centrality =0.08) and citation efficiency (60.14 citations) suggest strategic alignment with EU-funded initiatives like the Innovative Medicines Initiative, whereas Groningen’s studies yield robust per-paper impact (67.13 citations). Notably, AstraZeneca (England) ranks 6, underscoring industry-academia synergy in drug discovery, though its lower centrality (centrality =0.10) hints at proprietary collaboration limits. Harvard University (USA) and University of California System exemplify bifurcated USA strategies: Harvard’s moderate output (n=51) but high citations (62.75 citations) align with precision medicine paradigms, while University of California System’s broader network engagement (centrality =0.08) supports multi-center trials on macrophage heterogeneity. Paradoxically, PCSHE (USA) achieves citation excellence (93.81 citations) despite mid-tier productivity (n=56), likely through high-impact journals (NEJM, Lancet Respiratory). Critical disparities emerge in institutional roles: Imperial College London’s centrality (centrality =0.16) cements its role as a global hub, whereas University of Manchester (centrality =0.03) and Groningen (centrality =0.02) remain peripheral despite moderate output.

Table 3 shows the top 10 authors with the highest publication volume, British scholar Barnes PJ leads with 77 publications, far surpassing the Singh D (n=59) and Adcock I (n=40). Australian scholars Hodge S (n=23) and Hansbro PM (n=21) are the non-European representatives in the top 10. While Barnes PJ tops H-index (H-index =49), his average citation rate (128.08 citations per paper) is slightly eclipsed by Adcock I (132.5 citations per paper). In contrast, Singh D’s high output (n=59) is marred by low impact (average citations: 34.36; H-index: 28). Dutch scholar Timens W (n=26, 90.08 citations per paper) and American scholar Rahman I (n=21, 108.76 citations per paper) exemplify “high-impact, low-volume” profiles. Australian scholars Hansbro PM (55.67 citations per paper) and Hodge S (53.39 citations per paper) occupy a mid-tier influence zone. Imperial College London consolidates its “superlab” status, with its top four scholars (Barnes PJ, Adcock I, Donnelly LE, and Chung KF) contributing 174 publications—49.9% of the top 10 scholars’ total output. Dutch institutions University of Groningen (Timens W) and Utrecht University (Folkerts G) collectively account for 36.4% of the Netherlands’ national output (Table 1), reflecting Europe’s clustered excellence. The USA scholar Rahman I (University of Rochester), the sole American in the top 10, leverages the nation’s biomedical infrastructure for high citations (108.76 citations per paper), yet his isolated ranking exposes fragmentation in USA expertise distribution.

Figure 4A illustrates the publication counts and collaborative connections among various institutions. Imperial College London stands out as the leading contributor in this domain. Figure 4B shows Collaboration networks among the authors regarding macrophage in COPD, and the nodes with different colors represent cooperation between different clusters of authors.

Figure 4 Visual representation of relevant institutions and authors. (A) A visual node diagram of institutions. (B) Collaboration networks among the authors regarding macrophage in COPD. COPD, chronic obstructive pulmonary disease.

Analysis of journals

Data shown in Table 4 reveal the top 10 journals ranked by the number of publications and the most cited journals in the field. The data reveal a dual dynamic in scholarly communication, specialized respiratory journals dominate publication volume, while high-impact clinical journals drive citation networks. Respiratory Research leads with 115 publications, reflecting its niche focus on mechanistic studies, though its modest IF (IF =4.7) contrasts sharply with its most-cited journal, the American Journal of Respiratory and Critical Care Medicine (AJRCCM, IF =19.3). This asymmetry highlights how mid-tier journals serve as primary platforms for foundational research, while their outputs are often validated through citations in elite clinical journals. PloS One (rank 3, 86 papers) and Scientific Reports (rank 10, 45 papers) exemplify open-access megajournals’ growing role in disseminating methodological or negative-result studies, despite their lower IFs (2.9–3.8).

The American Journal of Physiology-Lung Cellular and Molecular Physiology (rank 2, IF =3.6) and Frontiers in Immunology (rank 9, IF =5.7) illustrate divergent strategies: the former prioritizes basic science on macrophage signaling pathways, while the latter bridges immunology and translational COPD research. Notably, AJRCCM (rank 6) and European Respiratory Journal (rank 7, IF =16.6) achieve outsized influence as co-citation hubs, with their high IFs (19.3 and 16.6) amplifying the visibility of studies they reference, such as those in chest (co-cited 1,479 times) and thorax (1,537 times). The New England Journal of Medicine (NEJM, IF =96.2), though absent from the top 10 publishing journals, ranks ninth in co-citations (1,240 times), underscoring its role as a gold-standard validator for transformative clinical findings. These journals primarily focus on respiratory diseases, molecular immunology, and molecular biology, suggesting that researchers in related fields may prioritize them for their submissions.

Figure 5 reveals the top 10 journals ranked by the number of publications and the most cited journals in the field.

Figure 5 Visual representation of related journals and cited journals. (A) Visual map for the network among journals. (B) Visual map of cited journals about macrophage in COPD. The size of the node is directly proportional to the number of published articles, and the colors reflect their evolution over time. COPD, chronic obstructive pulmonary disease.

Analysis of co-cited references and references bursts

Table 5 displays the top 10 most frequently co-cited references. The list is anchored by three iterations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (ranks 3, 4, 6, 10), collectively cited 238 times, reflecting their indispensable role in standardizing COPD diagnosis and management. These consensus documents, published in AJRCCM (IF =19.3), synthesize evolving insights into macrophage-driven inflammation and airway remodeling. Notably, Barnes PJ appears twice (ranks 1 and 5), cementing his status as a pioneer in COPD immunopathology. His 2016 review (Journal of Allergy and Clinical Immunology, 95 citations) remains the most cited work. Hogg JC’s 2004 NEJM article (rank 2, 90 citations) revolutionized COPD understanding by demonstrating small-airway obstruction as a macrophage-mediated process, bridging histopathology and functional decline. Similarly, Ito K’s 2005 NEJM study (rank 8, 44 citations) identified histone deacetylase (HDAC) suppression in COPD macrophages, a landmark in epigenetic research. Shaykhiev R’s 2009 work (rank 9, 43 citations) revealed smoking-induced AM polarization, a concept now central to therapeutic targeting of M1/M2 imbalances. The oldest article (Pauwels RA, 2001) and the newest (Vogelmeier CF, 2017) both focus on GOLD guidelines, emphasizing their iterative refinement. However, 70% of the list predates 2010, underscoring the enduring influence of early mechanistic work. Only Barnes’ 2016 review breaks this pattern, likely due to its synthesis of omics-era data.

Figure 6A illustrates the co-citation network of references. Each node represents a reference, with the overall size of the node reflecting the citation count of the reference. From the color distribution of nodes, it presents a transition from cool tones to warm tones on the whole. This indicates that as time goes by, new references continuously emerge, reflecting the continuous accumulation and update of knowledge in the field of COPD research, which helps researchers discover a collection of research results with closely logical correlations in this field. Figure 6B displays the results of co-cited document clustering. representative clusters have formed, such as “#0 exacerbations”, “#1 pm2.5”, “#2 immune infiltration”, “#3 mmp-12”, “#4 reactive oxygen species”, “#5 inflammatory cells”, “#6 ampk”, “#7 histone acetylation”, “#8 interleukin-8”, and “#9 phosphodiesterase inhibitor”. These clusters reflect different research emphases in COPD-related macrophage studies, covering mechanisms of disease exacerbation, environmental impact, immune regulation, enzyme function, oxidative stress, inflammatory cell networks, metabolic control, and epigenetic regulation. They comprehensively reflect research hotspots in this field. Figure 6C displays the top 20 references with the strongest citation bursts. The Barnes PJ [2016] has an extremely high burst strength of 36.07, which is the highest in the list. This indicates that during the period from 2017 to 2021, this literature received extremely high attention in COPD research. Another example is the Hogg JC [2004]. The burst strength is 31.14 and was widely cited between 2005 and 2009, indicating that it laid an important foundation or triggered key discussions for COPD research during this period. The “Begin (emergence start year)” and “End (emergence end year)” of different literatures are various. For example, the Pauwels RA [2001] has an emergence time of 2005–2006. A shorter emergence period may mean that it solved a specific research problem at that time and attracted short-term attention. While the Belchamber KBR [2019] has an emergence time that lasts from 2020 to 2025 (data statistics cut-off time), indicating that this research has been a hot spot in the field of COPD in recent years and may involve cutting-edge and continuously concerned research directions.

Figure 6 Visual representation of related reference. (A) References co-citation network for macrophages research in COPD. (B) CiteSpace analyzes the results of co-cited document clustering. (C) 20 references with the strongest citation bursts in macrophage in COPD. COPD, chronic obstructive pulmonary disease.

Keywords analysis

As illustrated in Table 6, Inflammation (760 occurrences, TLS =3,688) and AMs (541 occurrences, TLS =2,576) are the key focuses, which is consistent with the emphasis on macrophage-related inflammatory responses in relevant studies. Oxidative stress (338 occurrences, TLS =1,691) and activation (291 occurrences, TLS =1,633) highlight the important role of macrophage functional changes in the development of COPD. Airway inflammation (327 occurrences, TLS =1,608) and lung inflammation (124 occurrences, TLS =630) reflect the research’s attention to different parts of inflammatory responses in the respiratory system. Emphysema (292 occurrences, TLS =1,453) and smoke-induced emphysema (110 occurrences, TLS =577) appear as important pathological manifestations, but the frequency of emphysema is significantly lower than that of COPD (1,115 occurrences, TLS =4,288), which shows that emphysema is only a part of COPD research, not equivalent to COPD. Cigarette smoke (227 occurrences, TLS =1,112) is a key etiological factor, which is closely related to the occurrence and development of COPD and its related pathological changes such as emphysema. NF-kappa-b (NF-κB) (211 occurrences, TLS =1,026) and necrosis-factor-alpha (168 occurrences, TLS =792) are important molecular markers in the inflammatory signaling pathway, reflecting the in-depth exploration of the molecular mechanism of macrophage-mediated inflammation. Apoptosis (127 occurrences, TLS =597) is involved in the process of cell death and tissue damage, which is related to the progression of COPD. Mice (139 occurrences, TLS =739) indicate the application of animal models in research, but it should be noted that the emphysema model in animal studies may be different from clinical COPD-related emphysema. Induced sputum (112 occurrences, TLS =586) is a clinical sample source, which is of great significance for the translation of basic research to clinical practice. In general, the distribution of these keywords reflects the comprehensiveness of COPD research, which not only takes COPD as the core, but also distinguishes related pathological manifestations, molecular mechanisms, etiological factors and research methods, and does not equate COPD with emphysema.

Figure 7A shows the keywords co-occurrence network visualized by the VOSviewer, each node in the diagram represents a keyword, and the connections between nodes indicate the relationship of keywords co-occurring in the literature. Nodes such as “COPD” and “inflammation” are relatively large and in a more core position, indicating that they are the core research topics in this field. The node of “alveolar macrophages” is also relatively large and is connected to “COPD” and “inflammation” through connections, indicating the key role of AMs in COPD and inflammation research. It is worth noting that although the node size of ‘epithelial cells’ in the keyword co-occurrence network is small, it has a significant correlation with ‘alveolar macrophages’, indicating that the interaction between the two has been partially studied. Figure 7B indicates the timeline analysis of keywords. #0 COPD: as the core cluster, its line runs through the entire time axis, and the starting node is relatively large, indicating that since 2000, the research on COPD itself has been in an important position and has continuously received attention. It is the basis and core content of research in this field. #1 gene expression: the cluster line also appears relatively early, and there are multiple nodes distributed in the time process, indicating that gene expression has been an important direction in COPD research since the early days. With the passage of time, there are continuous related studies, reflecting the enduring research enthusiasm for exploring the pathogenesis of COPD from the genetic level. #2 oxidative stress: the line has continuous distribution on the time axis, indicating that oxidative stress has always been a concerned field in COPD research, reflecting that researchers have long been concerned about the relationship between oxidative stress and the occurrence and development of COPD, and may be continuously exploring related therapeutic targets. #3 cystic fibrosis: compared with other clusters, this cluster line is relatively short and has fewer node distributions, indicating that although cystic fibrosis is related to COPD research, within the entire time span, its research heat and attention are relatively low, and it may be partially studied as a comparison or related field. #4 matrix metalloproteinases: judging from the appearance time and node distribution, matrix metalloproteinase-related research has received attention within a certain period of time. Especially, the nodes are more prominent in some years, indicating that the research on the role of such proteases in lung tissue changes in COPD research is a hot spot in a specific period. #5 release: the nodes on the line are relatively dispersed, indicating that research related to the release of various substances is a continuous but not a concentrated popular direction in the field of COPD. The research content may be relatively extensive and dispersed. #6 immune cells: the line runs through the time axis and has multiple nodes, indicating that immune cells have been continuously concerned in the research of COPD, reflecting the importance of immune mechanisms in the pathogenesis and treatment research of COPD. Relevant research continues to deepen over time. #7 nf kappa b: there is a certain distribution on the time axis, indicating that the role of NF-κB in the research of COPD is also a research direction. Especially, the nodes are obvious in some years, indicating that the research on the role of this factor in inflammation and immune regulation of COPD is relatively concentrated in these periods. #8 inhaled corticosteroids: The clustering line reflects the situation of inhaled glucocorticoids in the treatment research of COPD. There are node distributions from the beginning to the subsequent time, indicating that the research on this type of drug has existed since the beginning, and its application and effect in treatment are continuously explored over time. #9 alveolar macrophage: the line and node distributions show that AMs are also an important content in the research of COPD. There are relevant studies from the early stage to the later stage, indicating that the research on the role of this key lung immune cell in COPD has been ongoing. Figure 7C shows the burst analysis of the top 20 keywords in the study. The burst strength of “necrosis factor alpha” reaches 17.27, which is the highest in the table. This indicates that during the period from 2005 to 2013, this keyword received extremely high attention in relevant research. This may be because important progress has been made in the research on TNF-α in aspects such as the inflammatory mechanism of COPD, or because it is a potential therapeutic target, which has triggered extensive discussions and citations by many scholars. The burst strength of “interleukin 8” is 6.83, and the emergence intensity of “nitric oxide” is 7.57. These keywords also received a considerable degree of attention during their respective emergence periods. They are usually closely related to the inflammatory response and pathophysiological process of COPD, reflecting the importance of these molecules in COPD research and becoming research hotspots in specific periods. Keywords with relatively low burst strength: For example, the emergence intensity of “mechanisms” is 5.67. Although the value is relatively not high, due to its broadness, it has maintained a certain degree of emergence heat from 2011 to 2025, indicating that the research on various mechanisms of COPD is a long-term continuous process that runs through a long research history. Keywords with short-term emergence: “chronic bronchitis” emerged from 2005 to 2009 for 4 years; “bronchoalveolar lavage fluid” emerged from 2005 to 2010 for 5 years. These keywords have a relatively short emergence time. It may be that in a specific period, there are new discoveries or research progress in aspects such as the relationship between chronic bronchitis and COPD, or the application of bronchoalveolar lavage fluid in the diagnosis and pathological research of COPD, triggering a short-term research boom. “Bronchial epithelial cells” emerged from 2006 to 2010 for 4 years; the association with “necrosis factor alpha” and “interleukin 8” clearly points to the inflammatory mechanism. During those years, scholars should have focused on exploring how smoking/pollutants stimulate bronchial epithelial cells to release inflammatory factors. “Acute exacerbation” emerged in 2009 partially overlapped with the research period on bronchial epithelial cells. This suggests that subsequent studies may have shifted focus to the mechanisms by which epithelial cells contribute to disease progression. “Induced emphysema” emerged from 2006 to 2014 for 8 years; “smoke induced emphysema” emerged from 2005 to 2012 for 7 years. Their emergence duration is relatively long, indicating that induced and smoke-induced emphysema, as important research contents related to COPD, have continuously had new research results and discussions for a long time, reflecting the continuous attention to smoking and other factors in the research on the pathogenesis of COPD. The “nlrp3 inflammasome” was still emerging from 2019 to 2025. The “macrophage polarization” continued to emerge from 2020 to 2025. And “pathogenesis” has been moderately popular from 2005 to 2025. This shows that the research directions represented by these keywords are the frontiers and continuous hotspots of current COPD research.

Figure 7 Visual representation of keyword in this filed. (A) The cluster of keywords of studies on macrophages research in COPD. (B) Timeline viewer related to macrophage in COPD. (C) Top 20 keywords with the strongest citation bursts. The color of the connection line corresponds to the color of the node. Keywords connected by lines of the same color belong to the same cluster. COPD, chronic obstructive pulmonary disease.

Discussion

General information

The number of publications within a certain period indicates research speed and trends in a particular field (24). From 2005 to 2025, the domain of COPD-associated macrophage research has experienced significant growth in research articles globally. The USA, China, and England are the major countries publishing articles on macrophages in COPD. The USA has a high publication volume with robust international collaboration, reflecting its continued prominence in academic leadership and high academic standing in this field. England, anchored by institutions like Imperial College London and leading authors such as Barnes PJ, Singh D, and Adcock I, maintains strong influence through high H-index and network centrality, underscoring its role as a hub for foundational research. China, as the second-largest contributor by volume, faces challenges in translating quantity to impact: its average citations and centrality remain low, reflecting limited international collaboration and a need for deeper integration into global research networks. Notably, Australia presents a unique case in this global landscape. it demonstrates remarkable efficiency when adjusted for population—its per capita publication rate (6.28 per million people) far exceeds that of larger nations like the USA (2.17 per million people) and China (0.33 per million people). This “small but impactful” model is driven by standout researchers such as Hodge S (University of Adelaide) and Hansbro PM (University of Technology Sydney). Its international collaboration intensity is moderate, yet it has carved a niche in translational research. In contrast, smaller European nations like the Netherlands and Canada optimize influence through strategic partnerships, achieving high citation efficiency despite modest output. Collectively, the data reveal a multifaceted global hierarchy: the USA and England dominate through scale and network centrality; Canada, France, and the Netherlands excel in impact via collaboration; Australia exemplifies how a focused, population-adjusted approach can drive niche excellence; and China navigates the transition from volume to quality. These patterns underscore that biomedical leadership increasingly hinges on balancing scale, collaboration, and specialized innovation—insights that inform strategic resource allocation and policy interventions to foster equitable progress in COPD research.

Imperial College London topped the list with 172 papers, not only surpassing other institutions in quantity but also forming an absolute advantage with an average citation rate of 93.05 times, an H-index of 65, and a centrality of 0.16, achieving ‘both quantity and quality’. This has established the UK’s academic discourse power in this field. The top 10 institutions reveal a ‘diverse ecosystem’ in the field, where academic institutions lead in exploring fundamental mechanisms, clinical institutions provide real-world evidence, and enterprises drive the transformation of research outcomes. AstraZeneca is the only corporate institution among the top 10, frequently collaborating with units such as McMaster University, University of Manchester, Institut National de la Sante et de la Recherche Medicale (Inserm), and MedImmune. These collaborating units form a closed loop of “corporate needs-academic validation”. However, it is necessary to be wary of potential ‘research direction imbalance’ caused by corporate resources. In the future, balanced cooperation across different types of institutions, such as joint funding by academic and corporate institutions for basic-to-translational projects, is needed to promote comprehensive development in the field.

Literature is a critical conduit for disseminating research outcomes. Efficient scientific communication hinges on the publication of research results in internationally accredited peer-reviewed journals. Consequently, researchers can accurately identify the most appropriate platforms for their manuscripts by analyzing journal sources. Respiratory Research, the American Journal of Physiology: Lung Cellular and Molecular Physiology, the American Journal of Respiratory Cell and Molecular Biology, the International Journal of Chronic Obstructive Pulmonary Disease, the American Journal of Respiratory and Critical Care Medicine, the European Respiratory Journal, and Chest are the top 10 journals with the highest publication frequencies. These periodicals are highly relevant to the subject of COPD, indicating the precision of their retrieval approaches and the reliability of the bibliographical data scrutinized. Therefore, researchers submitting their work in this field can give precedence to these journals. Journal impact is evaluated by the frequency of its co-citations, indicating the significant contribution of the journal to the scientific community. Journals with high citations can identify the leading research sources within a particular field of study. Among the co-cited journals, the American Journal of Respiratory and Critical Care Medicine ranks first, followed by the European Respiratory Journal, and American Journal of Respiratory Cell and Molecular Biology. This shows that these journals have published more potential breakthroughs in this field, attracting close attention from scholars.

Among the top 10 most-cited literatures, they cover the pathogenesis, clinical management, and therapeutic targets of COPD. In terms of the pathogenesis of COPD, Barnes PJ, 2016 systematically reviewed the interaction between innate and adaptive immunity in COPD, emphasizing the chronic inflammation mediated by neutrophils, macrophages, and Th17 cells. Barnes PJ, 2003 conducted early research on the mechanisms of oxidative stress, protease-antiprotease imbalance, and apoptosis in COPD, laying the foundation for subsequent studies on molecular mechanisms. Hogg JC, 2004 demonstrated that fibrosis and mucus plug formation in the small airways of COPD patients are the main structural basis for airflow limitation. Molet S, 2005 found that MMP-12 was significantly elevated in the lung tissue of COPD patients, revealing its role in the formation of emphysema. Ito K, 2005 proposed that decreased HDAC activity leads to over-expression of pro-inflammatory genes, which is associated with glucocorticoid resistance. Shaykhiev R, 2009 revealed that smoking drives the polarization of AMs towards the pro-inflammatory M1 phenotype by inhibiting the PPAR-γ pathway, weakening the anti-inflammatory and repair functions of the M2 phenotype. In terms of clinical management, Pauwels RA, 2001 established the GOLD framework, emphasizing the importance of smoking cessation and lung function screening. Rabe KF, 2007 first proposed a staging system based on lung function and symptoms, promoting the individualized management of COPD. Vestbo J, 2013 introduced the assessment of acute exacerbation risk, optimizing the comprehensive treatment plan. Vogelmeier CF, 2017 updated the ABCD assessment tool, strengthening the evidence-based recommendations for inhalation therapy and pulmonary rehabilitation. In terms of therapeutic targets, Molet S, 2005, although mainly elaborating on the association between MMP-12 and COPD in the pathogenesis, also provided a basis for subsequent research on inhibiting MMP-12 activity as a therapeutic target, suggesting that inhibiting MMP-12 activity may alleviate the progression of emphysema. Ito K, 2005 proposed that HDAC agonists may reverse the abnormal expression of inflammatory genes, providing ideas for targeted therapy. Shaykhiev R, 2009 provided a basis for PPAR-γ agonists as therapeutic targets, indicating that activating PPAR-γ can polarize macrophages towards the M2 phenotype, promoting the resolution of inflammation.

Analysis of research hotspots

Notably, analyzing references and keywords can detect research hotspots, identify new trends, and identify sudden changes in discipline development. It can also highlight active or cutting-edge research topics. Herein, keywords and references analysis revealed macrophage polarization, oxidative stress, and epigenetic regulatory as research priorities.

Macrophage polarization and inflammation regulation

AMs are key regulators of the alveolar microenvironment. When exposed to environmental stimuli such as cigarette smoke and air particles, AMs can be activated into M1 or M2 macrophages. M1 macrophages primarily release inflammatory factors like TNF-α, IL-β, and IL-6. Their markers mainly include inducible nitric oxide synthase (iNOS) and CD86, which exhibit antibacterial and cytotoxic activities along with immune-stimulating effects (25), M2 macrophages primarily release anti-inflammatory factors TGF-β and IL-10. Their markers mainly include CD206 and Arg-1, playing roles in supporting angiogenesis, clearing debris, and tissue remodeling (26,27). There are significant differences in macrophage polarization characteristics between acute exacerbations and stable phases of COPD. During stable phases, COPD predominantly exhibits M2 polarization, particularly in smokers and patients with COPD, where this phenotype is closely associated with chronic inflammation and tissue remodeling processes (28). As disease severity increases, both M1 and M2 polarization levels intensify simultaneously, sometimes even forming mixed phenotypes where the same macrophage co-expresses iNOS and CD206 (29). While M2 polarization contributes to tissue repair during stable phases, it may induce fibrosis, whereas M1/M2 imbalance correlates with emphysema progression (30). In acute exacerbations, M1 polarization dominates, while the proportion of non-polarized macrophages significantly decreases compared to stable phases, with their phagocytic function also showing marked impairment. Clinically, detecting the polarization types of macrophages and cytokine levels in the alveolar lavage fluid of patients with COPD can serve as indicators for diagnosis and disease assessment. For example, an increased proportion of M1 macrophages and elevated levels of TNF-α and IL-6 are associated with decreased lung function and higher frequency of acute exacerbations in patients (31). Another study found that an increase in M2 macrophage numbers is associated with the severity of COPD. The quantity and percentage of M2 macrophages were significantly higher in GOLD stages 3–4 compared to stages 1–2 (32). It should be noted that current research has certain controversies and limitations: the traditional M1/M2 dichotomy is difficult to adapt to the complex pulmonary microenvironment of COPD, and macrophages often present mixed or dynamic phenotypes (33-35); animal models mostly rely on cigarette smoke-exposed mice, and their macrophage polarization characteristics differ from the heterogeneity of human COPD (36).

Oxidative stress and NLR family pyrin domain containing 3 (NLRP3) inflammasome

Smoking and air pollution are major triggers of oxidative stress in COPD, and these harmful particulate matters (PMs) activate reactive oxygen species (ROS) generation (37). Inflammatory factor synthesis and release and ROS production in moderation can help lung tissue to remove stress damage and promote tissue repair, but excessive inflammatory factor synthesis and release and ROS production can exacerbate lung tissue damage and promote disease progression (38). One important regulator of inflammation and innate immune responses is the NLRP3 inflammasome, which belongs to the NLR family, has been proven to play a role in the development of COPD (39). ROS-induced oxidative stress plays a crucial role in promoting the assembly and activation of the NLRP3 inflammasome (40), After NLRP3 inflammasome activation, the release of inflammatory factors such as IL-1β and IL-18 can activate polymorphonuclear neutrophils, leading to the production of large amounts of ROS and triggering an inflammatory response. An increase in ROS in the lungs of mice can induce endoplasmic reticulum stress and mitochondrial dysfunction, promoting the activation of the NF-κB signaling pathway and the nuclear translocation of NF-κB, which subsequently leads to the activation of the NLRP3 inflammasome, enhancing the expression of IL-1β, and exacerbating airway inflammation and lung tissue damage. Clinically, it has been found that COPD smokers have elevated levels of NLRP3 in their lung tissue and serum (41). The pharmacological inhibition of MCC950 on NLRP3 significantly alleviated airway inflammation induced by Cigarette Smoke (CS) in a dose-dependent manner (42). Therefore, the combined use of clinical antioxidant therapy and MCC950 is expected to synergistically reduce lung inflammation, which is crucial for alleviating patient symptoms and preventing disease progression.

Epigenetic regulatory mechanism

The pathogenesis of COPD is characterized by significant gene-environment interactions. Epigenetic regulation can mediate the functional remodeling of lung tissue cells, such as airway epithelial cells and fibroblasts, by dynamically and reversibly modulating gene expression through processes like DNA methylation and histone modification, including acetylation, methylation, and phosphorylation, without involving changes in the DNA sequence (43). This process drives the irreversible pathological processes of airway inflammation, fibrosis, and emphysema. It plays a crucial role in gene transcription and chromatin remodeling, significantly influencing the immune system under different inflammatory conditions by reshaping chromatin in the epigenetic regulation of gene expression (44). In a PM-induced COPD mouse model, key enzymes involved in the new NAD⁺ synthesis pathway in macrophages lead to a decrease in kynurenine pathway expression and subsequent histone acetylation. This suggests that histone acetylation is responsible for the increased expression of pro-inflammatory genes in macrophages exposed to PM (45). Research indicates that changes in the expression and activity of HDAC are associated with the severity of COPD in patients (46,47). In the peripheral blood monocytes of patients with severe COPD, the expression levels of HDAC2 are significantly reduced. During COPD exacerbations, the activity of HDAC2 in macrophages is decreased and negatively correlated with viral load and markers of inflammation and nitrosative stress. HDAC3 is a positive regulatory molecule for NF-κB-mediated inflammation and can inhibit IL-4-induced M2 polarization, suggesting that HDAC3 inhibition could be a potential treatment for preventing inflammation in COPD (48). Epigenetic reprogramming in macrophages is a potential new strategy for treating COPD.

Limitations and future directions

This study employed bibliometric methods to analyze the literature on macrophages and COPD from 2005 to 2025. It has certain advantages but also limitations. The data is only sourced from WoSCC, and the retrieval strategy restricts the inclusion of some literature, and the number of literatures is relatively insufficient. Overall, although the study has certain value, future research can expand the data sources and optimize the retrieval strategy to improve the understanding of this field. While our analysis identifies inflammation and macrophage polarization as current hot topics, these trends should not overshadow the critical importance of epithelial dysfunction, airway remodeling, and microbial-host interactions. The interaction between macrophages and airway epithelial cells constitutes a pivotal component of COPD inflammation. Although this aspect is briefly addressed in the text, it represents a crucial direction for future research to explore.

Conclusions

From 2005 to 2025, research on COPD-related macrophages has made significant progress in multiple hot fields. Research achievements in macrophage polarization, oxidative stress, and epigenetic regulation have provided an important basis for understanding the pathogenesis of COPD. To tackle COPD’s complexity and clinical validation challenges, future research should enhance cross-disciplinary collaboration, combining experts from respiratory medicine, immunology, and bioinformatics to explore pathogenesis. More accurate animal models, such as those built with gene-editing, are needed. Clinical trial designs should be optimized, like using adaptive designs for better efficiency. Also, international cooperation should be strengthened to share resources and data, accelerating research progress and improving treatment outcomes.

Acknowledgments

The authors would like to thank the National Natural Science Foundation of China and the Anhui Province Key Laboratory of the Application and Transformation of Traditional Chinese Medicine in the Prevention and Treatment of Major Pulmonary Diseases for supporting that work.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-683/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-683/prf

Funding: This work was supported by the National Natural Science Foundation of China Joint Key Project (No. U20A20398), National Natural Science Foundation of China (No. 82374399), Key Project of the Scientific Research Program for Higher Education Institutions in Anhui Province (No. 2024AH051047), Anhui Province Traditional Chinese Medicine Inheritance and Innovation Research Project (No. 2024CCCX077).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-683/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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