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The intricate involvement of macrophages in pulmonary emphysema signifies their pivotal role in disease pathogenesis and progression. Dysregulated macrophage behavior, marked by altered activation states, promotes chronic inflammation, protease release, and oxidative stress, exacerbating tissue damage and alveolar destruction. Targeting macrophages emerges as a promising therapeutic avenue to modulate immune responses, restore tissue homeostasis, and mitigate disease severity. Recent advances have highlighted macrophage heterogeneity, signaling pathways, and their impact on lung tissue remodeling. Understanding the complexities of macrophage involvement offers insights into novel therapeutic strategies and potential interventions aimed at modulating their behavior to halt disease progression. Future prospects involve precision therapies, multi-target approaches, and comprehensive studies to validate the efficacy and safety of macrophage-targeted interventions, paving the way for transformative management strategies in pulmonary emphysema.
Research Institute of Medical and Health Sciences (RIMHS), College of Medicine, University of Sharjah, United Arab Emirates
*Address all correspondence to: bselvakumar@sharjah.ac.ae
1. Introduction
Chronic obstructive pulmonary disease (COPD) is a multifaceted respiratory disorder characterized by irreversible airflow limitation, where pulmonary emphysema stands as a significant pathological feature [1, 2]. Macrophages emerge as pivotal players within this complex intricate disease landscape, orchestrating a delicate balance between lung homeostasis and destructive inflammation [3]. This chapter delves into the profound interplay between macrophages and pulmonary emphysema, unraveling their nuanced roles, underlying mechanisms, and the promising therapeutic avenues they unveil. From their foundational functions in healthy lung physiology to their dysregulated behavior in the diseased state, the involvement of macrophages holds both the keys to understanding disease progression and the promise of targeted interventions. Exploration of macrophage phenotypes, their intricate interaction networks, and their impact on lung tissue integrity unveils the complex dynamics driving emphysematous changes. From their pivotal role in immune responses to their contribution to proteolytic cascades and oxidative stress, the multifaceted nature of macrophages in driving tissue damage becomes apparent. In light of this complex interplay, this chapter navigates through emerging research, therapeutic strategies, and the challenges posed in targeting macrophages for therapeutic benefit. By scrutinizing experimental models, recent breakthroughs, and potential interventions, this exploration seeks to shed light on novel avenues for combating the relentless progression of pulmonary emphysema. Amidst the complexities lie opportunities, and herein lies the exploration of macrophage involvement in pulmonary emphysema—a journey encompassing insights, mechanisms, and the promising vistas of therapeutic perspectives.
1.1 Overview of pulmonary emphysema
Pulmonary emphysema represents a debilitating condition within the spectrum of COPD, characterized by irreversible damage to the lung’s air sacs (alveoli) and progressive impairment of respiratory function [4]. This disease manifests through the destruction of alveolar walls, leading to enlarged airspaces, decreased elasticity of lung tissue, and compromised gas exchange. Emphysema typically results from prolonged exposure to noxious particles or gases, notably cigarette smoke, causing chronic inflammation and oxidative stress in the lungs [5]. Clinically, patients experience dyspnea, coughing, and reduced exercise tolerance as the disease advances. Emphysema significantly impacts respiratory mechanics, impairing the expulsion of air from the lungs and causing hyperinflation [6]. Understanding the pathological alterations in lung structure and function characteristic of pulmonary emphysema is crucial for devising targeted interventions and therapeutic strategies aimed at managing this debilitating respiratory condition.
1.2 Importance of macrophages in lung physiology and pathology
Macrophages hold a pivotal role in maintaining lung homeostasis, contributing significantly to both physiological functions and pathological responses within the pulmonary microenvironment [3]. In lung physiology, these versatile immune cells serve as key sentinels, patrolling the airways and alveoli to clear inhaled particles, pathogens, and cellular debris. Beyond their role in host defense, macrophages actively participate in tissue repair, contributing to the clearance of apoptotic cells and promoting resolution of inflammation [7]. Their capacity to modulate immune responses, release signaling molecules, and regulate tissue remodeling underscores their importance in orchestrating a delicate balance between immune surveillance and tolerance within the lungs. However, in the context of lung pathology such as pulmonary emphysema, macrophages exhibit dysregulated behaviors. Prolonged exposure to harmful agents, such as cigarette smoke or environmental pollutants, can lead to an altered macrophage phenotype, marked by increased pro-inflammatory responses, impaired phagocytic function, and the release of destructive enzymes and reactive oxygen species. This dysregulated macrophage behavior contributes significantly to the progression of lung diseases, amplifying inflammation and tissue damage and exacerbating respiratory dysfunction [8]. Understanding the dichotomous roles of macrophages in lung physiology and pathology is crucial for unraveling their contributions to disease progression and identifying therapeutic avenues to restore immune balance and mitigate tissue damage in lung disorders.
1.3 Objective and scope of the chapter
The primary objective of this chapter is to comprehensively explore and elucidate the intricate involvement of macrophages in the pathogenesis, progression, and potential therapeutic interventions in pulmonary emphysema. By delving into the multifaceted roles of macrophages within the pulmonary microenvironment, this chapter aims to dissect their contributions to disease mechanisms, including inflammation, tissue destruction, and immune dysregulation. Moreover, the chapter seeks to underscore the impact of macrophage dysfunction on disease severity, offering insights into potential targets for therapeutic modulation and interventions aimed at restoring immune homeostasis and mitigating lung tissue damage in pulmonary emphysema.
This chapter will delineate the diversity of macrophage phenotypes present in pulmonary emphysema, exploring their functional diversity, plasticity, and the intricacies of their roles in maintaining lung homeostasis and contributing to disease pathology. In addition, it will elucidate the underlying mechanisms through which macrophages exacerbate tissue destruction, including the release of proteases, oxidative stress, and their interactions with other immune cells and structural components of the lung. The chapter will analyze the impact of macrophage-driven inflammation and immune dysregulation on disease progression, emphasizing their role in perpetuating chronic inflammation and impairing tissue repair mechanisms. Moreover, it will discuss current and emerging therapeutic strategies aimed at modulating macrophage behavior, restoring immune balance, and mitigating lung tissue damage. This includes pharmacological interventions, potential drug targets, and innovative approaches for targeting macrophages in the treatment of pulmonary emphysema. Finally, the chapter will address challenges in targeting macrophages therapeutically, potential limitations, and future research directions required to further elucidate the complexities of macrophage involvement and develop effective therapeutic interventions for pulmonary emphysema.
The pathogenesis of pulmonary emphysema is multifactorial, involving intricate interactions between environmental exposures, inflammatory responses, and structural alterations in lung tissue.
2.1 Etiology and risk factors
Pulmonary emphysema is primarily associated with prolonged exposure to noxious particles or gases, notably cigarette smoke, which remains the leading cause worldwide [9]. Other risk factors include occupational exposures to pollutants, genetic predispositions, and alpha-1 antitrypsin deficiency. These factors lead to chronic inflammation and oxidative stress within the lungs, triggering a cascade of events that result in alveolar destruction and impaired repair mechanisms [9].
2.2 Structural changes in the lung parenchyma
The hallmark of pulmonary emphysema is the irreversible destruction of the alveolar walls, leading to enlarged airspaces and decreased elasticity of lung tissue. This pathological process involves the breakdown of the alveolar septa, which normally provide structural support and maintain the alveolar structure [10]. The loss of these walls results in the coalescence of small airspaces into larger ones, diminishing the lung’s surface area for gas exchange and impairing its elastic recoil.
2.3 Role of inflammation and immune responses
Chronic inflammation plays a pivotal role in emphysema pathogenesis. In response to noxious stimuli, resident immune cells, including macrophages, neutrophils, and T lymphocytes, are activated, leading to the release of pro-inflammatory cytokines and proteolytic enzymes [11, 12, 13]. These inflammatory mediators perpetuate tissue damage by activating pathways that degrade the extracellular matrix, particularly elastin, essential for maintaining lung elasticity. Moreover, oxidative stress induced by the production of reactive oxygen species further exacerbates tissue injury and impairs repair mechanisms, contributing to the perpetuation of alveolar destruction [14].
Overall, the pathogenesis of pulmonary emphysema involves a complex interplay between environmental insults, inflammatory responses, and structural alterations in lung tissue. Understanding these intricate mechanisms is critical for developing targeted interventions aimed at mitigating inflammation, preserving lung architecture, and restoring lung function in individuals affected by this debilitating respiratory condition.
Macrophages play pivotal roles in maintaining tissue homeostasis, contributing to immune surveillance, tissue repair, and modulation of inflammatory responses [7]. Their functional diversity, phenotypic plasticity, and activation states underscore their significance in lung physiology.
3.1 Functions of tissue macrophages
Macrophages patrol the airways and alveoli, clearing inhaled particles, pathogens, and cellular debris, acting as the first line of defense against respiratory threats. Macrophages regulate immune responses by secreting cytokines, chemokines, and growth factors, influencing the activation and function of other immune cells within the lung microenvironment. These cells can facilitate tissue repair by phagocytosing apoptotic cells, assisting in extracellular matrix turnover, and promoting resolution of inflammation to restore lung architecture after injury by releasing various pro-repair mediators and growth factors [7].
3.2 Plasticity of macrophages
Macrophages demonstrate remarkable plasticity, transitioning between activation states in response to microenvironmental cues. This plasticity enables them to adapt their functional phenotypes, allowing for a dynamic response to changing microenvironmental signals [15]. Macrophages exhibit phenotypic diversity influenced by their microenvironment, displaying a spectrum of activation states ranging from classical (M1) to alternative (M2) activation, each associated with distinct functional profiles [16]. Inflammatory stimuli like lipopolysaccharide (LPS) or interferon-gamma (IFN-γ) induce M1 phenotype and secrete pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, promoting microbicidal activity. Macrophages that are exposed to anti-inflammatory signals such as IL-4 or IL-13 drive themselves to M2 phenotype and exhibit tissue repair, immunoregulatory, and anti-inflammatory functions. They release cytokines like IL-10 and TGF-β, contributing to tissue healing and suppressing inflammation. However, an unbalanced secretion of these anti- and pro-inflammatory mediators could cause tissue destructive- and remodeling-associated disease conditions.
Understanding the intricacies of macrophage biology in lung homeostasis, including their diverse functions, phenotypic plasticity, and activation states, is pivotal for comprehending their contributions to lung diseases like pulmonary emphysema. Dysregulated macrophage behavior can significantly impact disease pathogenesis, highlighting the importance of modulating their responses for therapeutic interventions in lung disorders.
Macrophages, crucial components of the lung’s immune defense, wield a paradoxical influence on tissue integrity. While essential for pathogen clearance and tissue repair, dysregulated or chronically activated macrophages can induce substantial damage to lung tissue. Their uncontrolled activation causes the release of inflammatory molecules, such as cytokines and reactive species and can incite a cascade of events leading to inflammation, extracellular matrix degradation, and compromised structural integrity. These cells, when interacting with neutrophils or epithelial cells, can exacerbate tissue injury through amplified inflammatory responses and impaired repair mechanisms. Consequently, in chronic conditions like COPD or certain infections, macrophages play a pivotal role in precipitating alveolar destruction and airspace enlargement, ultimately contributing to the pathogenesis of respiratory diseases characterized by tissue degradation.
4.1 Altered macrophage phenotype in emphysematous lungs
In emphysematous lungs, the phenotype and behavior of macrophages undergo profound alterations, contributing significantly to disease progression. Prolonged exposure to noxious agents, such as cigarette smoke, induces a shift in macrophage activation, leading to a dysregulated phenotype characterized by an imbalance between pro-inflammatory and reparative functions [8, 9]. These altered macrophages, often skewed toward an M1-like pro-inflammatory state, display impaired phagocytic activity, reduced capacity for resolving inflammation, and an augmented release of proteases and reactive oxygen species. For example, an excess secretion of MMP-12 (macrophage elastase) by alveolar macrophages is known to mediate the development of lung injury and emphysema [17].
This skewed activation state perpetuates chronic inflammation, exacerbates tissue damage, and compromises repair mechanisms, fostering an environment conducive to alveolar destruction and impaired lung function. Understanding and targeting these altered macrophage phenotypes in emphysema are critical for developing therapeutic strategies aimed at modulating their behavior, restoring immune balance, and mitigating lung tissue damage in this debilitating respiratory condition.
4.2 Impaired phagocytic activity and clearance of cellular debris
In pulmonary emphysema, impaired phagocytic activity and compromised clearance of cellular debris by macrophages significantly contribute to disease pathology. Macrophages, critical in maintaining lung homeostasis, typically phagocytose cellular remnants, debris, and apoptotic cells, play a pivotal role in tissue repair and resolution of inflammation. However, in emphysematous lungs, this essential function is hindered [17].
Prolonged exposure to noxious stimuli, especially cigarette smoke, leads to alterations in macrophage phenotypes, reducing their ability to efficiently clear apoptotic cells and debris. Dysfunctional macrophages in emphysema exhibit diminished expression of phagocytic receptors and impaired recognition of apoptotic cells [18]. Consequently, the clearance of cellular debris becomes compromised, allowing the accumulation of apoptotic cells, extracellular matrix fragments, and other debris within the lung microenvironment. This impaired phagocytic activity not only disrupts tissue repair mechanisms but also perpetuates inflammation. The accumulation of apoptotic cells and debris triggers an inflammatory response, perpetuating a cycle of tissue damage and chronic inflammation, exacerbating the progression of emphysematous changes in the lung parenchyma [19].
Restoring efficient phagocytic function in macrophages represents a potential therapeutic target in pulmonary emphysema. Strategies aimed at enhancing macrophage phagocytosis and clearance mechanisms could mitigate tissue damage, resolve inflammation, and potentially halt the progression of this debilitating respiratory condition.
4.3 Inflammatory responses and release of protease
In pulmonary emphysema, macrophages play a pivotal role in perpetuating inflammation through intricate signaling pathways and exacerbate tissue damage via oxidative stress and the generation of reactive oxygen species (ROS) [20, 21]. Activated macrophages in emphysematous lungs stimulate inflammatory signaling cascades, including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways [22, 23]. These pathways drive the production and release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), amplifying the inflammatory milieu within the lung microenvironment [20]. Moreover, macrophage-derived ROS, including superoxide anion and hydrogen peroxide, contribute to oxidative stress. The excessive production of ROS overwhelms antioxidant defenses, inducing cellular damage, lipid peroxidation, and DNA alterations [24]. This oxidative stress exacerbates inflammation, disrupts cellular functions, and contributes significantly to lung tissue injury, fostering the progressive destruction of alveolar structures characteristic of pulmonary emphysema. In pulmonary emphysema, macrophages produce an array of pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6, iNOS, COX-2, and chemokines (like CXCL8)) in emphysematous lungs. These molecules recruit and activate other immune cells, perpetuating the inflammatory cascade and contributing to tissue damage [20]. In addition, macrophages generate ROS as part of their inflammatory response. Excessive ROS production contributes to oxidative stress, causing damage to cellular components and exacerbating tissue injury [20, 21].
Macrophages contribute significantly to the inflammatory milieu through the release of various proteases, exacerbating tissue damage and perpetuating the progression of the disease. The altered phenotype of macrophages in emphysematous lungs, influenced by chronic exposure to noxious agents like cigarette smoke, leads to dysregulated immune responses, notably an increase in pro-inflammatory mediators and proteases. Macrophages in emphysematous lungs release elevated levels of matrix metalloproteinases (MMPs), particularly MMP-2, MMP-9, and MMP-12 [25]. These proteases target the extracellular matrix components, including elastin, collagen, and proteoglycans, contributing to the breakdown of alveolar walls and impairing lung tissue integrity [26]. In addition, macrophages release neutrophil elastase, further amplifying the proteolytic cascade. Neutrophil elastase cleaves elastin fibers [27], leading to loss of lung elasticity and airspace enlargement, characteristic of emphysema.
The sustained release of proteases and inflammatory mediators by macrophages in emphysema results in an imbalance between tissue destruction and repair mechanisms. This chronic inflammatory state perpetuates alveolar destruction, impairs tissue healing, and disrupts the delicate lung architecture, ultimately leading to the characteristic airspace enlargement seen in pulmonary emphysema. Targeting the dysregulated release of proteases and inflammatory mediators from macrophages represents a potential therapeutic strategy to mitigate tissue damage and halt disease progression in pulmonary emphysema. Understanding and targeting these pathways involved in macrophage-driven inflammation and oxidative stress may offer potential therapeutic avenues for mitigating tissue damage and managing the progression of emphysematous changes in the lungs.
4.4 Interaction with other cells
In emphysema, macrophages become activated due to exposure to irritants like cigarette smoke, pollution, or other inhaled toxins. These activated macrophages interact with various cell types in the lung microenvironment and influence lung tissue damage and promote the development of emphysematous lungs.
Neutrophils: Macrophages can interact with neutrophils to regulate inflammation and tissue repair. In response to tissue damage and inflammation, neutrophils are recruited to the lungs. Macrophages and neutrophils often collaborate in immune responses. However, dysregulated interactions between these cells may lead to increased inflammation and tissue injury due to excessive release of inflammatory molecules and oxidative stress. For example, abnormal apoptotic events in smokers’ and in emphysematous lungs by macrophages are observed to contribute to the development of emphysema [28].
Epithelial Cells: Macrophages interact with epithelial cells through cytokines, chemokines, and cell–cell contacts. Dysfunctional crosstalk between macrophages and epithelial cells can contribute to tissue damage and impaired repair mechanisms [28].
Macrophages can influence fibroblast activity, affecting the repair processes in emphysematous lungs. T cells also interact with macrophages, modulating the inflammation in emphysema (Figure 1).
Figure 1.
Mechanisms of macrophage-mediated lung damage. Schematic diagram shows the healthy alveoli in the left side with resident alveolar macrophages maintaining alveolar homeostasis. The right side of the diagram shows the emphysema alveoli with enlarged alveolar space due to series of tissue damage majorly mediated by macrophages such as (1) altered phenotypes, (2) reduced or inhibited phagocytic activity, (3) release of pro-inflammatory cytokines and tissue destructive proteases, and (4) interaction with other cell types within the alveoli resulting in tissue destruction.
Targeting macrophages has emerged as a potential therapeutic strategy for treating emphysema. Since macrophages play a crucial role in the inflammatory response and tissue damage seen in emphysema, several approaches are being explored to modulate their function for therapeutic benefit.
5.1 Modulation of macrophage polarization
Macrophages have different activation states, broadly classified as M1 (pro-inflammatory) and M2 (anti-inflammatory/reparative). Shifting the balance from M1 to M2 phenotype can potentially reduce inflammation and promote tissue repair. This could be achieved through pharmacological agents or biological factors to promote a reparative response, fostering tissue repair and reducing inflammation [29]. In an in vivo study, a nature product propolis was observed to reverse the cigarette smoke-induced emphysema through macrophage alternative activation [30]. However, currently, there are very few studies available and there is huge demand in this area of research.
5.2 Phagocytic enhancement
Enhancing macrophage phagocytosis and clearance of apoptotic cells and debris is being investigated [31]. Stimulating phagocytic receptors or using nanoparticles to enhance debris clearance might mitigate tissue damage [32]. However, these studies have to be tightly regulated to prevent the exaggerated phagocytosis that can increase the severity of the disease.
5.3 Anti-inflammatory agents
Drugs that specifically target inflammatory pathways in macrophages can help reduce their activation and the subsequent release of inflammatory mediators. This approach aims to dampen the chronic inflammation seen in emphysema. Corticosteroids and inhibitors targeting specific inflammatory pathways, such as TNF-α or IL-1β antagonists, are under scrutiny to dampen excessive inflammation and limit tissue damage [33, 34]. Moreover, compounds with antioxidant properties, like N-acetylcysteine (NAC) or natural antioxidants, are explored to counteract oxidative stress and reduce ROS-mediated tissue injury [35, 36].
Moreover, macrophages release proteases that contribute to tissue destruction in emphysema. Inhibiting these proteases may help preserve lung structure and function [37]. However further studies are demanding. In addition, growing evidence has shown promising results with stem cell therapies. Therefore, exploring the use of stem cells to modulate macrophage activity and promote tissue repair in emphysema can add further advancement in the treatment strategies. Recent studies have showed that mesenchymal stem cells (MSCs) or their extracellular vesicles are observed to interact with macrophages and skew them to a tissue repair phenotype to resolve inflammation and induce repair mechanisms [38, 39, 40].
Clinical trials are underway to test the efficacy and safety of various drugs and interventions targeting macrophages in emphysema. However, the complexity of the disease and the multifaceted role of macrophages require a thorough understanding of their behavior in the context of emphysema to develop effective targeted therapies.
Recent advances in understanding macrophage dynamics in emphysema taking advantages of advanced techniques like single-cell RNA sequencing, researchers have identified distinct macrophage subpopulations in emphysematous lungs, delineating their heterogeneity, activation states, and functional diversity. In addition, imaging technologies with high-resolution imaging methods, such as intravital microscopy and multiphoton microscopy, enable real-time visualization of macrophage behavior in the lung microenvironment, offering insights into their interactions and responses during disease progression. Furthermore, metabolic profiling studies focusing on the metabolic reprogramming of macrophages in emphysema highlight alterations in their metabolic pathways, unveiling potential therapeutic targets to modulate macrophage function. These research advances in experimental models and technological innovations offer a deeper understanding of macrophage dynamics in pulmonary emphysema. By elucidating the complexities of macrophage responses and their impact on disease progression, these insights pave the way for the development of targeted therapies aimed at modulating macrophage behavior and managing emphysematous lung disease.
Biological therapies using monoclonal antibodies targeting specific macrophage receptors like IL-5, IL-7, PD-1, IL-19 [41, 42, 43, 44], or signaling pathways [45, 46] are under investigation to modulate macrophage behavior and immune responses selectively. In addition, cell-based therapies utilizing stem cells or engineered macrophages to promote tissue repair, modulate inflammation, or enhance phagocytic activity show promise as an innovative therapeutic approach [39, 40].
In addition, the role of the microbiota in influencing macrophages in emphysema and COPD is an area of growing research interest. The respiratory tract is not sterile, and the lung microbiota can modulate the immune response and contribute to the pathogenesis of lung diseases, including emphysema and COPD. Studies suggest that alterations in the lung microbiota composition may contribute to inflammation in COPD and emphysema [47]. Changes in microbial diversity and abundance may influence the activation state of macrophages. The lung microbiota can influence macrophage function by interacting with pattern recognition receptors (PRRs) on macrophages. PRRs recognize microbial components, leading to the activation of macrophages and the release of inflammatory mediators [7]. Moreover, microbial metabolites produced by the lung microbiota can have immunomodulatory effects. Short-chain fatty acids (SCFAs), for example, are microbial metabolites that have been shown to influence macrophage polarization and function. Dysbiosis, an imbalance in the composition of the microbiota, has been associated with COPD and emphysema [48]. Dysbiosis may contribute to chronic inflammation and alter the local immune response, including the activity of macrophages.
In the future, modulating the lung microbiota has been proposed as a therapeutic strategy for COPD and emphysema. Probiotics, prebiotics, and fecal microbiota transplantation are being explored to restore microbial balance and potentially influence macrophage behavior. Tailoring therapies based on individual disease phenotypes and patient-specific characteristics might enhance treatment efficacy and add advances in precision medicine. Moreover, multi-target approaches including combining therapies targeting different aspects of macrophage dysfunction, inflammation, and tissue repair pathways could offer synergistic benefits in managing pulmonary emphysema. In parallel, comprehensive long-term studies focusing on safety, efficacy, and the potential for disease modification are needed to validate the therapeutic strategies targeting macrophages in pulmonary emphysema. Harnessing these therapeutic strategies targeting macrophages, inflammatory pathways, and oxidative stress holds promise in altering disease progression, preserving lung function, and ameliorating the burden of pulmonary emphysema. However, further research and clinical trials are essential to validate their efficacy, safety, and long-term impact in managing this complex respiratory condition.
Experimental models play a crucial role in understanding macrophage involvement and dynamics in pulmonary emphysema (Table 1). Several animal models have been utilized to study the role of macrophages. (1) Smoke-induced models in which exposure of rodents (mice or rats) to cigarette smoke (CS), mimicking the chronic exposure seen in human smokers. These models replicate emphysematous changes, including airspace enlargement, inflammation, and altered macrophage phenotypes, resembling human emphysema pathophysiology [57]. These models provide better mimicking features with human emphysema; nevertheless, the duration of the models require a long period exposure, (2) enzyme-induced models, where intratracheal administration of proteolytic enzymes like elastase or papain induces alveolar damage and emphysematous changes, allowing for the study of macrophage responses and disease progression [49, 50]. These models can provide simple methodology with low cost; however, the consistency with human emphysema is not satisfactory, and (3) Genetically modified models, which usually use transgenic or gene knockout technology by which targeting specific genes associated with macrophage function or inflammation aids in understanding the mechanistic aspects of macrophage involvement in emphysema development [58, 59]. Although these models can be more models can be targeted to understand function of genes, they demand high-end techniques with high costs.
Induction substance
Mode of administration
Animal
Mechanism
References
Elastase (papain, pig pancreatic elastinase (PPE), and human neutrophil elastase (HNE)
Intratracheal
Tat and hamster
Elastase disrupts protease–antiprotease balance and accelerates the rupture and fusion of alveolar walls to induce emphysema.
Smoke stimulation (part exposure: nose or head only)
Guinea pig, C57BL/6J mice
Long-term CS exposure induces inflammatory responses leading to narrowing of bronchial lumen and cartilage tissue, causing rupture and fusion of alveoli and the formation of emphysema, mimicking human conditions
Genetic manipulation (Platelet-derived growth factor-β (PDGF-β), TNF-α, IL-6, and IL-11
Gene-targeted and/or genetically modified
Usually mice
Loss or hindered function of these genes impairs the normal development of alveoli. Excessive expression of certain genes like PDGF-β may disrupt the balance between alveolar damage and repair, leading to emphysema.
Macrophages serve as central players in the pathogenesis of pulmonary emphysema, orchestrating a delicate balance between immune surveillance and tissue repair. Their dysregulated activation states and inflammatory responses profoundly impact disease progression, influencing the destruction and remodeling of lung parenchyma. Understanding their multifaceted roles offers insights into potential therapeutic interventions targeting macrophages to alleviate tissue damage and halt disease progression.
Macrophages in pulmonary emphysema exhibit altered phenotypes, skewed toward pro-inflammatory states, impairing phagocytosis and promoting release of proteases and oxidative stress. Their dysregulated behavior perpetuates chronic inflammation, exacerbating tissue damage, contributing significantly to alveolar destruction, and impairing repair mechanisms. Targeting macrophages emerges as a promising therapeutic strategy, aiming to modulate their behavior, restore immune balance, and mitigate tissue damage in emphysematous lungs.
Unraveling the intricate involvement of macrophages in pulmonary emphysema sheds light on novel avenues for therapeutic intervention. While significant strides have been made, there is a need for (1) tailoring interventions based on patient-specific phenotypes for improved efficacy in a Precision Therapy approach, (2) combination therapies targeting multiple aspects of macrophage dysfunction and tissue repair pathways, and (3) comprehensive investigations assessing safety, efficacy, and disease-modifying potential of macrophage-targeted therapies by long-term studies. Looking ahead, harnessing the potential of targeted macrophage modulation and innovative therapies and advancing our understanding of macrophage behavior holds promise in reshaping the management and outlook for individuals affected by pulmonary emphysema. This comprehensive understanding of macrophage involvement paves the way for transformative approaches aimed at attenuating disease progression and improving clinical outcomes in this challenging respiratory condition.
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Written By
Balachandar Selvakumar
Submitted: 16 January 2024Reviewed: 18 January 2024Published: 19 June 2024
Open access peer-reviewed chapter
