Unknotting the crosstalk between COPD and neuroinflammation

Abstract

COPD is a progressive respiratory illness that is mostly caused by air pollution, biomass fuel exposure, or long-term cigarette smoking. It is increasingly being referred to as a multisystem inflammatory disease rather than a pulmonary-only one. As a result of chronic airway inflammation in COPD, pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are released throughout the body, causing systemic oxidative stress. Cardiovascular disease, skeletal muscular atrophy, osteoporosis, metabolic syndrome, and neurological impairment manifested as depression, anxiety, and cognitive impairment are among the several comorbidities associated with this systemic inflammation. Similarly, neuroinflammation, which is characterized by the activation of astrocytes and microglia that produce cytokines and ROS, causing neuronal damage and altered brain function, is closely linked to COPD, according to limitations. The integrity of the blood-brain barrier is also negatively impacted by chronic hypoxemia and due to oxidative stress in COPD, which permits inflammatory chemicals to enter the central nervous system and cause neurodegeneration. The systemic neural inflammatory connection is evident in the higher levels of biomarkers such as CRP, IL-6, and TNF-α in COPD. Thus, understanding the lung-brain axis provides valuable insight into the broader impact of COPD, and therapeutic approaches that reduce inflammation and oxidative stress may improve neurological and respiratory outcomes, offering a more all-encompassing approach to COPD management.

Graphical abstract

Introduction

COPD is an extremely complicated and a multi-faceted disease. The factors which contribute to the development and deterioration of COPD include: cigarette smoking, exposure to environmental toxins, genetic predisposition (e.g., α−1 antitrypsin deficiency, etc.), age-related changes in organ function, and the presence of comorbidities such as obesity and cardiovascular disease [1, 2]. COPD is caused by the interaction of these risk factors, rather than any one of them directly influencing the initiation, following which, the chronic nature of COPD is maintained by the interaction of several mechanisms that all lead to a state of chronic inflammation within the airways and progressive airway narrowing. Importantly, whilst COPD can be said to be responsible for the presence of chronic inflammation in the brain, the connection between COPD and effects on the CNS can be thought of as being multifactorial, whereby both disease processes contribute to each other; thus the effects of systemic inflammation, hypoxemia, oxidative stress and shared comorbidity pathways can be demonstrated to mediate the relationship between COPD and the CNS as well as through each other. Studies of COPD and its associated extrapulmonary disorders, such as cardiovascular disease, metabolic syndrome, anxiety and depression, and cognitive impairments, frequently show elevated serum markers of systemic inflammation for each of the disorders [3, 4]. For instance, high levels of IL-6 and CRP in patient populations with COPD have been associated with increased incidence of cardiac comorbidity and mortality, while the combination of hypoxia and systemic cytokine upregulation has been related to detrimental cognitive outcomes [5, 6]. These findings appear to underscore the idea that COPD in fact precipitates an inflammatory condition that may be affecting the central nervous system through a “systemic influence rather than through a specific cause-and-effect relation in the classic sense of a so-called neuroinflammatory disease per se. The fact that it is part of a complex network of pathological processes with a strong association with both ‘lifestyle and age’ puts focus on the multifaceted nature of the effect by means of multiple mechanisms and comorbid factors. The excessive use of cigarette tobacco is the main cause of suffering from COPD. It is also caused by other irritants such as biomass and pollution. Because of being exposed to these irritants for a long period of time, the airways become inflamed, and release chemicals called pro-infllamatory Cytokines include IL-1β, TNF-α, and IL-6 [7]. The patients with COPD commonly develop cardiovascular illness, wasting of skeletal muscles, osteoporosis, metabolic syndrome, and diabetes. Furthermore, COPD is increasingly linked, together with other complications, to psychiatric and neurological disorders such as anxiety, depression, and cognitive impairment, in tune with the contribution of hypoxia and systemic inflammation to brain dysfunction [8]. It is remarkable that among the promoting factors of these systemic consequences, which compromise cellular metabolism far beyond the lung and the integrity of organs, oxidative stress and chronic hypoxemia play major roles. In summary, COPD should be regarded as a multisystem disease rather than a lung disease alone; after initial injury to the lung, the oxidative and inflammatory reactions overflow into other organs such as the heart, muscles, bones, and even the brain. Examining the new concepts of lung-brain crosstalk and its role in neuroinflammation is based on this larger context [7].

The chronic activation of the immune components, mainly microglia and astrocytes, in the CNS as a result of damage, infection, poisoning, or systemic inflammatory factors leads to neuroinflammation [7]. Temporary inflammation is not dangerous, but if neuroinflammation continues and causes damage to neurons, synaptic dysfunction, and relentless neurodegeneration, it becomes dangerous. At the molecular level, the activated glial cells release ROS, chemokines, and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). These mediated substances cause neuronal death, change the balance of neurotransmitters, and interfere with synaptic plasticity [9]. A significant pathogenic effect that increases neurotoxicity is the release of more systemic inflammatory mediators into the central nervous system due to damage to the BBB [10]. Clinically, neuroinflammation seems to be a common pathogenic mechanism of a variety of psychological and neurological conditions. It is an essential characteristic of multiple sclerosis, depression, Parkinson’s disease, Alzheimer’s disease, and post-stroke cognitive impairment [11]. Particularly, further data suggest that oxidative stress, hypoxia, and chronic systemic inflammatory conditions such as those found in COPD can act as triggers for neuroinflammatory cascades.

Further, neuroinflammation is clinically significant because it can act as a link between peripheral diseases and central nervous system dysfunction. It discusses how systemic conditions like metabolic diseases, autoimmune diseases, and respiratory conditions like COPD may lead to cognitive impairment, disruptions in memory patterns, emotional disorders, and a decreased quality of life [3]. It is important to know that the knowledge of neuroinflammation is not just a mechanistic link between COPD and the brain; it is also a potential pathway for finding a solution that could alleviate systemic problems as well as problems in the CNS.

Being a lung disease, COPD has shown implications on other systems of the body as well, such as the brain, as seen through the manifestations of hypoxia, oxidative stress, and systemic inflammation. There has been talk of the lung-brain axis, seen through the increasing understanding that conditions affecting the lungs may influence the brain through common aspects of inflammatory and metabolic responses [12]. There are a number of mechanisms by which the lung-inflammatory axis and the brain-inflammatory axis interact. First of all, systemic inflammatory responses of COPD may influence the CNS. Circulating cytokines like IL-1β, IL-6, and TNF-α cross or breach the BBB, augmenting neuroinflammatory cascades. Second, severe COPD causes hypoxemia and hypercapnia, which interfere with neuronal metabolism and increase oxidative stress in the brain, leading to mood disorders and memory loss [3]. Third, oxidative stress and mitochondrial impairment in COPD could enhance neurodegenerative processes, extending further the link between respiratory dysfunction and cerebral pathology. Clinical evidence shows that cognitive impairment, depression, anxiety, and possibly dementia are more common in COPD patients than in the general population. Research on neuroimaging shows that patients with COPD have structural changes in their brains, such as hippocampus atrophy and reduced grey matter. These results place the brain at risk as an affected target of chronic lung disease [13].

Researching the lung-brain axis is important for both developing new treatment processes and understanding the mechanisms behind illness. The treatments for COPD that reduce oxidative stress and systemic inflammation may reduce the severity of CNS problems. However, protecting the brain from long-term inflammatory damage may enhance functional results and quality of life for COPD patients [14]. In order to better understand COPD as a multisystem disorder and develop integrated treatment strategies that target both pulmonary and neurological outcomes, it is crucial to look into the interactions between COPD and neuroinflammation. Hence, in this review, an attempt was made to find out the crosslink mechanisms between COPD and neuroinflammation.

Accordingly, this review is clearly defined from the perspective of cigarette smoke-induced lung pathology as the initiating mechanism for the development of COPD. When chronic exposure to cigarette smoke leads to inflammation, oxidative stress, and an immune response in the lungs, it results in a series of systemic inflammatory responses. These systemic responses from the lungs lead to dysfunction of the blood-brain barrier, thereby activating neuroinflammatory responses in the central nervous system, including the roles of microglial and astrocyte cells. Additionally, aspects such as obesity, lack of exercise, and infectious stressors are addressed as secondary modulators of the systemic inflammatory responses mediated by cigarette smoke-induced lung pathology, rather than being independent initiating factors.

Molecular basis of COPD-induced systemic inflammation

The underlying cause of COPD is linked to pulmonary pathology due to cigarette smoke, characterized by chronic airway inflammation, oxidative stress, and immune dysregulation [15]. Cigarette smoke, biomass smoke, and air pollution sources cause prolonged inflammation of the lung, and they cause activation of alveolar macrophages and neutrophils, resulting in the production of increased free radicals and pro-inflammatory cytokines. Oxidative stress and activated immune mediators. To create a change in local lung inflammation to systemic chronic inflammation [16].

Spill over theory

The spill-over theory provides a mechanistic foundation for linking CS induced pulmonary inflammation to systemic and neuroinflammatory results in individuals with COPD. In response to chronic CS exposure, alveolar macrophages, neutrophils, and airway epithelial cells and results in the release of early pro-inflammatory cytokines such as IL-1β and TNF-α, followed by IL-6 as a downstream mediator. These cytokines are associated with a variety of chemokines and oxidised compounds [15]. Continued inflammation of the lungs damages the integrity of both the endothelial and epithelial barriers, promoting the movement of inflammatory mediators and reactive oxidative species from the lungs to systemic circulation, thereby creating a state of chronic low-grade systemic inflammation and dysfunction of the endothelium [17].

In accordance with this concept, the spill-over concept of the spill-over theory recognizes CS-induced pulmonary inflammation as the key mechanism for the onset of systemic and neuroinflammation-related disorders of COPD. For example, research studies have shown that the effects of persistent inflammation, induced by CS exposure, on pulmonary tissue integrity result in the leakage of inflammatory mediators and ROS into the systemic circulation via the disruption of the pulmonary barrier. As such, this initiates neuroinflammation disorders and cognitive impairment in animal models of COPD [17]. Additionally, the activities of CS-exposed activated macrophages and neutrophils result in the release of IL-1β and TNF-α into the local environment of the lungs. Consequently, this leads to the increased synthesis of IL-6 and enhances inflammation-related disorders within the lungs [18]. Moreover, increased vascular permeability and enhanced drainage from the lungs into the bloodstream significantly enhance the systemic spread of inflammation-related mediators into the systemic circulation. As such, the onset of low-grade inflammation is achieved, as evidenced by associated elevated concentrations of circulating cytokines and acute-phase proteins in the bloodstream of both smokers and patients with COPD compared to healthy nonsmokers [17].

Accumulating evidence shows that systemic inflammatory mediators and oxidative stress disturb endothelial function and integrity of the BBB, creating a conduit through which peripheral inflammatory signals impact the CNS. Disruption of the BBB in COPD has been associated with microglial and astrocytic activation, leading to continued neuroinflammation, neuronal dysfunction, and cognitive impairment [18]. While cytokine spill-over and oxidative stress–driven mechanisms are strongly supported, direct migration of peripheral immune cells into the brain remains less clearly established and appears to depend on disease severity and BBB integrity. Nevertheless, CS-induced alterations in glial cell profiles have been linked to cognitive impairment in animal models, reinforcing the mechanistic connection between pulmonary inflammation, systemic spill-over, and neuroinflammatory outcomes [19]. Collectively, this framework distinguishes well-supported inflammatory pathways from emerging or speculative associations in COPD-related neuroinflammation.The various lung-derived systemic inflammatory mechanisms described here are vital in the explanation of the widespread and systemic pathophysiological consequences of COPD [17, 20, 21] (Fig. 1).

Fig. 1.

Molecular basis of COPD induced systemic inflammation. Chronic inhaled irritants lead to COPD, causing systemic inflammation throughout the body. As a result, ROS and cytokines such as IL-1β, IL-6 and TNF-α are released. These substances affect several organs by causing mitochondrial dysfunction, brain inflammation, vascular inflammation, and Cachexia. This figure is created using Biorender.com

The inflammatory cascade in COPD follows a well-defined biological hierarchy that begins with the rapid induction of IL-1β and TNF-α in response to cigarette-smoke–induced epithelial injury. These early-response cytokines are released primarily by activated macrophages, neutrophils, and airway epithelial cells and serve as the main initiators of innate immune signalling through NF-κβ, MAPK, and NLRP3 inflammasome pathways [22, 23].

IL-1β

IL-1β promotes neutrophil recruitment, mucus hypersecretion, and airway remodelling, while TNF-α amplifies downstream chemokine production and enhances epithelial permeability, establishing a persistent inflammatory microenvironment characteristic of COPD. As inflammation becomes chronic, IL-6 emerges as a secondary pleiotropic mediator whose elevation reflects sustained upstream cytokine activation rather than an initial trigger of disease [24, 25].

IL-6

The role of IL-6 in COPD is not extrapolated from other disease contexts but is strongly supported by COPD-specific clinical and experimental evidence. Multiple cohort studies demonstrate that elevated circulating and sputum IL-6 levels are associated with airflow limitation, frequent exacerbations, skeletal muscle catabolism, cachexia, neutrophilic inflammation, Th17 differentiation, cardiovascular disease, and increased all-cause mortality in COPD patients [26]. IL-6 is also related to exercise capacity, systemic metabolic disorders, and the low-grade inflammatory condition of COPD progression [27]. With its role in neuroinflammatory conditions, IL-6 increases the permeability of the BBB, induces microglial activation through the JAK/STAT3 pathway, and is related to synaptic dysfunction and apoptosis, all of which have been recognized in the cognitive disorders of COPD. Therefore, understanding the correct place of IL-6 in the hierarchy of the cytokine network identifies it as a downstream effect that has implications for patient outcome in relation to the progression of pulmonary inflammatory processes and the consequences in the evolution of COPD [28, 29].

TNF- α

TNF-α is an essential early factor in COPD development. It is rapidly induced following CS- induced airway injury. It is produced mainly by alveolar macrophages, neutrophils, and damaged epithelial cells and plays a major role as an amplifier of the inflammatory response by activating NF-κβ and the MAPK signalling pathways [17]. Outside of the lung, TNF-α plays a major role in the systemic effects of COPD, such as endothelial dysfunction and muscle wasting associated with elevated systemic TNF-α levels in COPD patients. Persistent TNF-α action has been related to the generation of oxidative stress and tissue remodelling, thereby relating COPD pathogenesis to the extremes of the innate immune system [18].

Mechanisms of key inflammatory mediators

COPD is a chronic systemic inflammatory disease caused by repeated pulmonary insults. COPD is a chronic and uncontrolled inflammatory process that is perpetuated by continued exposure to cigarette smoke, oxidative stress, impaire/resolution pathways, and activation of immune cells [22]. Although the inflammation seen in COPD may be self-sustaining for extended period, in the setting of continued irritant exposure, it does not become a self-sustaining process. Another important point to be emphasized is that COPD does not result from neuroinflammation. COPD and neuroinflammation are two separate pathologic entities involving different target organs. However, COPD can significantly contribute to neuroinflammatory alterations by several interacting mechanisms. Systemic cytokines, including IL-1β, IL-6, and TNF-α, may cross or disrupt the blood-brain barrier and activate the glial cells [23]. Chronic hypoxemia, commonly seen in the advanced stage of COPD, stabilizes the HIF-1α, which promotes microglial activation, oxidative stress, and cellular injury within the CNS [24]. Moreover, COPD-related systemic oxidative stress and mitochondrial dysfunction are potent to amplify both peripheral and central inflammatory signalling events [25, 26].

Cigarette smoke serves primarily as an inflammatory stimulant in COPD via its capacity to deliver an overwhelming load of reactive oxidative species, free radicals, and toxic substances to airway epithelial cells. These toxic substances directly cause damage to epithelial cells and stimulate pattern-recognition receptors in epithelial cells and macrophages. The oxidative stress induced by CS activates pathways involving NF-κβ, MAPK, and NLRP3 inflammasome activities [17]. These pathways upregulate and promote the rapid transcription and production of IL-1β and TNF-α. The pro-inflammatory signal induced by continued exposure to CS sustains pathways for chronic inflammation that upregulate IL-6 production as an overlapping mediator. The process also enhances chemokine-mediated leukocyte chemotaxis. The pathway ultimately promotes the establishment of chronic inflammation that is responsible for lung damage and systemic inflammatory manifestations [18].

Following this cascade of inflammation in COPD, the levels of cytokines are released in a particular biological order. Starting with the upstream effects, IL-1β, which is activated through the NLRP3 inflammasome pathway due to cigarette smoke-induced stress, acts as the initiating step in airway inflammation. As an early response, IL-1β plays the role of recruiting neutrophils, producing excess mucus, remodelling the respiratory tract, and causing spill-over effects in inflammation [27, 28]. The other early response cytokine, TNF-α, which acts from the outset, is secreted by macrophages, epithelial cells, and neutrophils. It stimulates NF-κB, thereby making the effects of IL-1β more potent, which, in turn, leads to the activation of secondary cytokines [30]. Through these main mediators, IL-6 plays an important role as a pleiotropic cytokine, and there are many studies on IL-6 that have shown significant evidence of this cytokine in COPD pathology, with all COPD patient groups showing correlations between IL-6 levels, disease severity, exacerbations, skeletal muscle depletion, cachexia, cardiovascular disease, and all-cause mortality [31, 32]. Moreover, IL-6 has new potential applications in COPD-related neuroinflammation, as it has been observed that elevated IL-6 can impair BBB integrity, increase the transfer of cytokines into the CNS, and stimulate microglia through JAK2-STAT3 pathways, leading to issues of synaptic function, neuronal apoptosis, and brain damage [23, 33].

While much of the literature focuses on acute inflammatory mediators such as IL-1β, IL-6, and TNF-α, chronic COPD is also driven by long-term activation of endogenous danger signals and persistence of tissue DAMPs, which sustain an exaggerated inflammatory environment over time. In the early stages of disease, exposure to cigarette smoke and other irritants triggers innate immune activation and recruitment of neutrophils and macrophages. If this insult persists, damaged airway epithelial cells release DAMPs such as HMGB1, mitochondrial DNA, ATP, and S100 proteins, which engage pattern recognition receptors (TLRs, NLRs) on resident and infiltrating immune cells and prolong signalling beyond the initial insult [20, 34]. Unlike transient cytokine spikes, DAMPs serve as chronic amplifiers of inflammation that reinforce PRR activation, induce oxidative stress, and promote ongoing tissue injury. Over time, this establishes a self-perpetuating feedback loop in which DAMP release begets further immune activation, protease release, extracellular matrix breakdown, and more DAMP generation. Importantly, this progression from cytokine flux to sustained DAMP-mediated signalling integrates timing and causation in the irreversible progression from a self-limiting inflammatory reaction to irreversible airways remodelling and emphysematous destruction. In addition, sustained DAMP-mediated signalling can sustain NF-κβ and inflammasome activation, sustaining elevated levels of inflammatory cytokines at all times because of elevated levels of basal inflammatory cytokines and their release even in the absence of any initiating cause, effectively relating pulmonary inflammation with systemic effects [35]. The importance of considering a temporal pattern of inflammation from cytokines to sustained DAMP-mediated inflammation lies at the crux of how COPD progresses and why the inflammatory environment is sustained rather than relaxed [35].

Oxidative stress-induced systemic inflammation in COPD

Systemic inflammation and COPD pathogenesis have an important link with oxidative stress. COPD presents with high levels of ROS, and these are due to endogenous as well as exogenous sources. Endogenous sources include intracellular sources of ROS, where mitochondria produce ROS due to leakage of electrons during the transport chain, activated neutrophils, macrophages, epithelial cells, and NADPH oxidases. Endogenous ROS is highly upregulated during chronic airway inflammation [36]. Exogenous sources of ROS include cigarette smoke, biomass fuel, air pollution, and environmental oxidants that directly introduce high levels of ROS into the airway. ROS cause damage to lung epithelial cells by causing lipid peroxidation, protein alteration, and DNA damage. ROS activate the NLRP3 inflammasome, which in turn stimulates IL-1β maturation and neutrophil recruitment, in addition to NF-κβ and AP-1, which produce pro-inflammatory cytokines and adhesion molecules. DAMPs that depend on inflammasomes, such as HMGB1 and extracellular ATP, enhance inflammation [37]. Systemically, oxidative stress increases the risk of cardiovascular disease and vascular inflammation by reducing endothelial function, increasing adhesion molecules, and decreasing NO availability. Mitochondrial dysfunction contributes by generating excess ROS and releasing mitochondrial DNA and peptides as circulating DAMPs, triggering immune activation, muscle wasting, and accelerated cellular senescence [38]. In COPD, osteoporosis, and cachexia are caused by damage to peripheral tissues, like skeletal muscle and bone. COPD is related to cognitive decline because ROS in the CNS cause neuronal apoptosis, activate microglia, and disrupt the BBB [39].

It is documented that COPD compromises antioxidant defences. Glutathione reduction is followed by decreases in enzymes such as glutathione peroxidase, catalase, and superoxide dismutase. A deficient level of Nrf2, a crucial regulator of antioxidant gene production, substantially diminishes cytoprotection. Markers of oxidative stress, such as MDA, 8-isoprostane, and protein carbonyls, are elevated in plasma, sputum, and exhaled breath and are linked to the severity of the disease and treatment resistance. Significantly, oxidative stress damages HDAC2, which mediates corticosteroid response and leads to steroid resistance [40].

Oxidative stress is an important factor in systemic inflammation in COPD.ROS, which damage lung tissues and stimulate inflammatory signalling pathways, are produced more commonly when people are exposed to pollutants and cigarette smoke regularly. Cytokines, including IL-1β, IL-6, and TNF-α, are released into the bloodstream as a result of this activation, which causes inflammation to spread beyond the lungs. Muscle atrophy, endothelial dysfunction, and loss of organ function are all results of the continuous oxidative stress–inflammation process. Ultimately, this systemic inflammation worsens the symptoms of COPD and increases the risk of complications, such as cardiovascular disease, showing the critical role of oxidative stress in the disease development [39].

COPD and neuroinflammation crosstalk

It is commonly believed that hypoxia, which is caused by inadequate airflow in COPD lungs, may affect the activity of enzymes that produce neurotransmitters like serotonin and dopamine [41, 42]. However, COPD is a complicated and extremely varied medical condition that can impact CNS function and maintain inflammation in the brain through a variety of mechanisms. Insufficient oxygen, oxidative stress, and swelling are the causes of this inflammation [39, 43]. Together, these elements impair the brain’s defences, activate immune cells, and eventually disrupt neuronal activity.

Lung-brain axis: concept and evidence

Inflammation plays a crucial part in the deterioration of respiratory system function in COPD, according to recent studies. It is believed that extrapulmonary complications in patients with COPD are caused by inflammatory factors that spill over from the lungs. Inflammatory mediators like CRP, IL-6, IL-8, fibrinogen, and TNF-α are markedly higher in the serum of COPD patients than in that of healthy people [14, 44]. The brain has historically been thought of as a separate system that is protected by the BBB. However, new research has revealed a number of pathways and elements that support immune transmission between the brain and blood [45, 46]. The cholinergic anti-inflammatory pathway represents a critical neuroimmune mechanism through which the central nervous system modulates peripheral inflammation, particularly within the lung. This pathway is primarily mediated by efferent vagus nerve signalling, culminating in the release of acetylcholine, which binds to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages and other immune cells. Activation of α7nAChR inhibits NF-κβ signalling and suppresses the release of key pro-inflammatory cytokines, including IL-1β, Il-6 and TNF-α, thereby exerting a potent anti-inflammatory effect [47].

In COPD, chronic hypoxemia, oxidative stress, and sustained neuroinflammation may deteriorate vagal tone and disturb central autonomic control, leading to a blunted cholinergic anti-inflammatory response in the lung, suggesting a loss of neural constraint on immune activation [48]. Moreover, structural and functional changes in brain areas that contribute to autonomic control, as seen in COPD patients, might further deteriorate vagus nerve output, creating a feed-forward cycle that enhances pulmonary inflammation and systemic immune dysregulation [17, 49]. Collectively, dysfunction of the vagus nerve-mediated cholinergic anti-inflammatory pathway provides a mechanistic link between brain pathology and sustained lung inflammation in COPD, reinforcing the concept of a bidirectional lung-brain axis and highlighting CAP as a potential therapeutic target (Fig. 2).

Fig. 2.

The lung-brain axis: potential connections between neurological dysfunction and COPD. Inflammatory mediators such as IL-6, IL-8, and TNF-α are significantly released when peripheral immune cells are activated by COPD. There is evidence that the integrity of the BBB is compromised by this “spillover” of cytokines into the systemic circulation. These inflammatory mediators can enter the CNS as a result of the ensuing BBB breakdown, which eventually causes neuroinflammation. This figure is created using Biorender.com

Additionally, the BBB can be ruptured by inflammatory cytokines like IL-1β, IL-6, and TNF-α, which can cause neuroinflammation and disrupt the central nervous system. COPD may result from this neuroinflammation since it can weaken neurons and cause structural damage to them [23]. Further, some research suggests a connection between microglia-mediated neuroinflammation and neurocognitive disorders brought on by CS [20]. The brain’s internal immune cells, known as microglia, are essential for controlling neurogenesis, synaptogenesis, and cognition. But long-term microglia activation encourages axonal and neuronal loss, which eventually results in neurocognitive deficits [50, 51]. Additionally, ROS produced by activated microglia can result in oxidative stress in COPD and long-term neurocognitive deficits [52]. Despite these realizations, it is still unknown how to stop this kind of neuroinflammation.

Hypoxia-induced neuroinflammatory signalling

Chronic hypoxia, which is a hallmark of COPD, plays a significant role in initiating neuroinflammatory responses through its effects on glial cell activation, oxidative stress, and cytokine signalling. This starts in the central nervous system mainly through exposure-induced inflammation, mucus plugging, damage to the alveoli, and ventilation/perfusion abnormalities, which compromise gas exchange, thereby causing prolonged hypoxia by continued suppression of arterial oxygen levels [17]. Prolonged exposure to CS results in the development of emphysematous remodelling, loss of functional alveolar surface area, and thickening of the AL Cap. This compromises the efficiency of oxygen dysfunction. In parallel, the oxidative stress and inflammation resulting from CS lead to the development of pulmonary dysfunction. This compromises the ability of the lungs to perform their functions. The narrow airways and the presence of a mucus plug compromise the heterogeneity of the ventilatory process, and the loss of pulmonary microcirculation compromises oxygen uptake [2]. Prolonged low oxygen levels ensure the stability of the transcription factor hypoxia-inducible factor-1α (HIF-1α), which promotes the pro-inflammatory character of activated microglia and increases the production of cytokines such as IL-1β, IL-6, and TNF-α [24, 53]. Hypoxia also increases mitochondrial electron leakage, generating reactive oxygen species that activate NF-κβ and the NLRP3, further amplifying IL-1β maturation and release [26, 54]. Simultaneously, astrocytes respond to chronic hypoxic stress by undergoing reactive astrogliosis, characterized by elevated HIF-1α and HIF-2α signalling and secretion of VEGF-A, which disrupts tight-junction proteins such as occludin and claudin-5. These alterations weaken the blood–brain barrier, allowing systemic inflammatory mediators already elevated in COPD, particularly IL-1β, IL-6, CRP, and TNF-α, to enter the CNS and perpetuate glial activation [33, 55]. Hypoxia-induced astrocytic release of chemokines, including CCL2 and CXCL10, combined with impaired glutamate regulation, further exacerbates oxidative stress and contributes to neuronal vulnerability and excitotoxicity [56, 57]. Evidence from COPD animal models shows that chronic alveolar hypoxia leads to pronounced microglial activation in the hippocampus and cortex, correlating with cognitive deficits and mood alterations [39, 58] (Fig. 3).

Fig. 3.

Potential mechanism linking alveolar destruction induced by chronic hypoxia to chronic inflammation. Chronic hypoxia initiates two parallel pathways. HIF-1α stabilization, which increases ROS and activates cytokines (like IL-1β, TNF-α, and IL-6), upregulates VEGF. Both pathways work together to damage the BBB, which is a crucial step that leads to mitochondrial dysfunction and the continuation of a chronic inflammatory state. This figure is created using Biorender.com

Oxidative stress and mitochondrial dysfunction in COPD

Mitochondrial dysfunction is an essential element in the complex molecular environment and is linked to the development of COPD. Based on the impact of oxidative stress and bioenergetic dysfunction, this section aims to provide a detailed exploration of all aspects of the involvement of mitochondria in COPD. Traditionally regarded as the powerhouse of the cell, the function of the mitochondria in COPD is two-fold: both a cause and consequence of oxidative stress. The major site of ROS production is primarily through the process of the electron transport chain in the mitochondria. The unprecedented level of oxidative stress is caused by an untoward disruption of the fine balance that exists between ROS production and antioxidant defense in COPD. Studies clearly reveal that in COPD patients, there is enhanced production of ROS in the mitochondria upon exposure to environmental stress like cigarette smoke [59]. The signal from increased ROS triggers several downstream events that include, but are not limited to, the continued damage to cellular structures. Furthermore, it has already been established that mtDNA is overwhelmingly susceptible to oxidative stress. Oxidative stress can act to compromise the ability of the respiratory chain to function. The result is that a cycle of excessively produced ROS and dysfunction in the mitochondria is established. To address some of the complexities surrounding the notion of COPD, it is necessary to understand the interaction between oxidative stress and dysfunction in the mitochondria. The newly emerging interventions that may slow the progression of COPD may include interventions aimed at counteracting the production of ROS in the mitochondria. If these types of interventions yield positive results, they may act to break the cycle of oxidative stress. This would ultimately lead to new and better ways to treat individuals who already suffer from COPD. Finding the exact molecular processes causing mitochondrial failure in oxidative stress may open the door to more individualized and focused treatment approaches as research progresses, bringing in an entirely novel method of managing COPD [38].

BBB disruption in COPD

Capillary wall endothelial cells, pericytes, and astrocytes make up the BBB [60]. Under healthy conditions, it is essential for controlling the movement of chemicals into and out of the brain, shielding it from diseases and dangerous substances [61]. BBB permeability is closely linked to microglia, which also have a dual function in preserving BBB integrity during inflammation. In the beginning, microglia interact with cerebral blood vessels to preserve the integrity of the BBB. However, more persistent inflammation changes the phenotype of microglia, making them more active and able to phagocytise astrocyte end-feet and reduce BBB permeability [62]. Activated microglia generate IL-1β during neuroinflammation, which causes astrocytes to release VEGF-A. In turn, VEGF-A inhibits TJ proteins in endothelial cells, including occluding and claudin-5, through processes that are dependent on endothelial cells. As a result, the BBB becomes more permeable, and the TJs are disturbed [53]. A mouse model of COPD caused by CS and LPS was further verified by demonstrating decreased expression of Cldn5 and Ocln in the cerebral microvasculature. Furthermore, harmful CS components can penetrate the circulation and jeopardise the integrity of the BBB [58]. It has been demonstrated that both CS and e-cigarettes decrease important TJ proteins, such as Ocln and ZO-1, which clearly suggests that smoking is linked to a loss of BBB integrity [63, 64]. Pro-inflammatory cytokines such as ROS and CRP can interfere with the control of TJs in brain endothelial cells over the course of COPD illness, increasing BBB permeability, causing brain cell damage, and encouraging atherosclerosis in the anterior and internal cerebral arteries [33]. According to these results, neuroinflammation in brain areas linked to cognitive performance may cause astrocyte damage, activate microglia, and alter the expression of important TJ proteins, all of which increase BBB permeability [39] (Fig. 4).

Fig. 4.

The possible mechanism of systemic inflammation and disruption of the BBB causing chronic inflammation in COPD. Increased systemic cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress (ROS) result from the disease’s promotion of neutrophil and macrophage activation. The breakdown of the BBB is thought to be caused by these peripheral inflammatory conditions. This results in the activation of glial cells in the CNS, particularly astrocytes and microglia, which leads to a persistent inflammatory condition. This figure is created using Biorender.com

Activation of microglia and astrocytes in COPD

Microglial activation is quite common in diverse neuropathologies, including neuropathic pain, neurodegeneration, and traumatic brain injury (TBI). Current research has demonstrated the critical function of chemicals released by activated microglia in triggering reactive astrocytosis and controlling astrocytic immune responses. In the central nervous system, astrocytes have a role in controlling both local innate and adaptive immunological responses [64]. According to reports, astrocytes carry innate immunological PRRs, including complement receptors, mannose receptors, scavenger receptors, NLRs, and TLRs [65, 66]. Astrocytes are involved in innate immune responses and are major producers of inflammatory mediators in the central nervous system, such as cytokines, chemokines, and other complement components, when activated by TLR or NLR ligands [67]. Significant increases in macrophages and neutrophils [68], pro-inflammatory cytokines (TNF-α and IL-1β) and chemokines (CCL2 and CCL3) [69], cell apoptosis [4], oxidative stress (reactive oxygen species and reactive nitrogen species), and the suppression of antioxidant proteins (such as glutathione peroxidase, catalase, and superoxide dismutase) are all frequently linked to COPD-induced airway obstruction [70] in both the airways and lung parenchyma, in response to noxious particles and gases [71]. Chronic low-grade inflammation causes the alveolar wall to be destroyed and mucus to be secreted in excess. This leads to structural damage to the lung parenchyma (emphysema) and small and large airways (bronchitis) [70], which in turn causes a decline in lung function [71]. Furthermore, mediators of lung inflammation and oxidative stress may enter the bloodstream, leading to markedly elevated levels of cytokines, chemokines, oxidative stress, and acute phase proteins, such as fibrinogen and CRP, in people with COPD relative to their healthy counterparts [72].

Clinical evidence of COPD-associated neuroinflammation

Cognitive impairment and behavioural changes

Cognitive difficulties associated with COPD may be explained by a complicated interplay between pulmonary and non-pulmonary risk factors, in addition to decreased oxygen and/or greater carbon dioxide levels in the blood [73]. Neuronal damage caused by hypoxia has been identified as a major explanation for cognitive impairment in COPD, but it has also been claimed that oxygen-dependent enzymes, which are crucial for the production of neurotransmitters like acetylcholine, may be impacted. Cerebral metabolism was significantly changed in individuals with non-hypoxic severe COPD, according to a magnetic resonance spectroscopy research, and the pattern of disruption was different from that observed in heart failure and diabetes. Given that CRP has been linked to cognitive decline through either a direct neurotoxic effect or an impact on cerebral atherosclerosis, inflammation may be a factor. Other inflammatory mediators, such as IL-1β, IL-6, and TNF-α, and α1-antichymotrypsin, have also been connected to cognitive impairment. These investigations, however, point to an association rather than a causal connection [6].

Other significant risk factors that may be linked to cognitive impairment include increased oxidative stress and inflammation [74], decreased physical activity [75], peripheral vascular disease [76], high or low blood pressure (non-normotensive patients) [77], elevated intracranial pressure linked to the narrowing of blood vessels in the brain [78], coexisting comorbidities [79], tobacco use [80], and genetic predisposition [81].

Physical inactivity and increased sedentary behaviour are common in individuals with COPD and are largely driven by airflow limitation, exertional dyspnea, muscle weakness, frequent exacerbations, and the need for long-term oxygen therapy [82]. These behavioural changes substantially reduce quality of life and functional independence. Although reduced physical activity is not a direct neuroinflammatory mechanism, it may indirectly contribute to systemic inflammation and oxidative stress, both of which are known to influence neuroinflammatory processes. However, current evidence primarily supports an associative relationship rather than a causal link between physical inactivity and neuroinflammation in COPD [83]. Therefore, physical inactivity is best considered a behavioural and functional consequence of COPD that may secondarily modulate systemic and neurological outcomes rather than a primary driver of neuroinflammatory pathology (Table 1).

Table 1.

Clinical evidence of behavioural changes related to COPD

Category	Key Concepts and Causes	Specific Effects and Evidence	Consequences And Implications	References
Cognitive Impairment	• Hypoxia (low oxygen) • Systemic Inflammation & Oxidative Stress • Reduced Blood Flow (from high or low BP) • Comorbidities, Smoking, Genetics	Decline in multiple domains: Memory (Hippocampus), Executive Function (planning, decision-making) - Attention - Language & Social Skills	• Accelerated brain ageing and cognitive decline. • Assessment is crucial during initial check-ups, especially for older patients or those with low O₂. • Early detection of Mild Cognitive Impairment (MCI) allows for intervention to slow decline and identify dementia risk.	[6, 73]
Behavioral Changes	• Overwhelming Breathlessness (Dyspnea) • Low Energy & Reduced Fitness • Fear of Activity (to avoid triggering symptoms) • Well-meaning encouragement of rest	• Significant shift to a sedentary lifestyle. • Patients spends nearly 50% less time active and more time sitting/lying down than healthy individuals. • Fatigue after flare-ups solidifies inactivity.	• Severely reduced quality of life. • Creates a vicious cycle where inactivity leads to further physical decline, worsening symptoms.	[83]
Brain Structural Changes (Neuroimaging)	• Chronic stress of struggling for air. • Fear and anxiety related to breathlessness and activity.	• Specific Gray Matter Reduction in: -Anterior Cingulate Cortex (processes breathlessness &fear),  Hippocampus (memory), Amygdala (fear center) • White Matter Damage (disrupts brain communication). • Small Vessel Disease (white matter hyperintensities).	• Shrinkage in fear centers is directly linked to longer illness duration and greater fear of activity. • Provides a biological explanation for emotional and cognitive challenges.	[84]

Neuroimaging evidence of brain structural changes

Neuroimaging studies provide compelling clinical evidence that COPD is associated with early and progressive structural and functional brain alteration, often preceding overt cognitive decline. MRI and voxel-based morphometry analyses have consistently demonstrated reductions in grey matter volume in key cognitive regions, including the hippocampus, prefrontal cortex, anterior cingulate cortex, and insula in patients with COPD. These resulting structural changes have a direct correlation to the severity of the disease, hypoxemia, and cognitive function impairment [13, 85–87]. Additionally, functional brain imaging and resonance spectroscopy have demonstrated alterations in cerebral perfusion and functional brain connectivity in COPD-suffering patients, irrespective of the presence of hypoxemia [79, 88]. Hypoxemia intensifies these alterations by inducing a deficiency in the oxygen-dependent neuronal metabolism and production of neurotransmitters, resulting in accelerated brain atrophy in these patients [13].

In addition, neuroimaging techniques have an essential role in supervising therapeutic interventions in COPD. An example is provided about the role of neuroimaging in examining the effect of long-term oxygen therapy, pulmonary rehabilitation, and cognitive skills training, with partially preserved brain structure and function following long-term oxygen therapy, which confirms the clinical application of neuroimaging techniques, especially in diagnosing and predicting cognitive progression in patients with COPD [13, 89]. Advanced neuroimaging approaches integrating imaging histology and machine learning techniques show promise in predicting molecular alterations and clinical outcomes, offering mechanistic insights into neurotoxicity and brain dysfunction associated with chronic lung disease. Such approaches may support the development of targeted neuroprotective strategies, including pharmacological and non-pharmacological interventions aimed at preserving cognitive function in COPD patients [84, 90] (Table 1).

Biomarkers of neuroinflammation in COPD patients

Any clinical characteristics, imaging quantification, or laboratory-based test indicators that describe disease activity and help diagnose and track disease processes and treatment response are known as biomarkers. Potential biomarkers for identifying COPD, describing COPD characteristics, and tracking therapy response have been compiled in recent outstanding reviews [91–93]. In addition to helping with patient selection based on risk, accurate early prediction of exacerbation and mortality risk may offer suitable early therapy commencement. Recognised studies in patients who meet certain criteria, such as a history of exacerbations within the past year, a decline in FEV1s, an increase in the St. George Questionnaire score (life quality diminution), and elevated levels of certain inflammatory biomarkers, such as neutrophils, CRP, fibrinogen, pro-calcitonin, eosinophils, IL-6, IL-8, CCL-18/PARC, and SP-D [94, 95].

When compared to healthy controls, patients with AECOPD showed significant changes in all evaluated peripheral biomarkers. Serum levels of BDNF were significantly lower in the AECOPD group (median: 0.23 vs. 0.58 ng/mL; p < 0.001; d = − 2.94), suggesting a significant lack of neurotrophic support. On the other hand, levels of MMP-9 and programmed cell death protein 1 were markedly increased (PD-1: 0.87 vs. 0.26 pg./mL, d = + 3.29; MMP-9: 2.38 vs. 0.92 ng/mL, d = + 2.60), indicating extracellular matrix remodelling and immunological fatigue, respectively. The AECOPD group’s inflammatory cytokine profiles showed increased pro-inflammatory activity, with higher levels of TNF-α (12.75 vs. 6.65 pg./mL; d = + 0.80) and IL-1β (IL-1β: 13.75 vs. 4.00 pg./mL; d = + 1.28). On the other hand, the important anti-inflammatory cytokine IL-10 was much lower (1.60 vs. 6.10 pg./mL; d = − 5.64), suggesting reduced compensatory immunomodulatory function. The Hamilton Depression Rating Scale ratings for depression were significantly greater for the AECOPD group (18.5 vs. 4.0, d = + 3.22, p < 0.001), indicating a greater depressed load is experienced, and the individual’s psychological state is also severely compromised. The above individual findings demonstrate a significant immunological neuroendocrine disruption with the presence of chronic inflammation, neurotrophic depletion, and emotional disturbance as seen in AECOPD [96].

While serum and peripheral biomarkers are also increasingly being employed as markers of COPD, they do not provide a direct indication of inflammation or inflammation-related diseases of the CNS. Rather, they suggest peripheral immunological responses and neuroendocrine disorders that, in turn, might affect the CNS by altering blood-brain barrier function, perfusion, and microglia priming [49]. Moreover, systemic inflammation, particularly during acute exacerbations of COPD, can instigate neuroinflammatory signaling and neuronal vulnerability, which can result in cognitive decline [97]. While CRP, IL-6, TNF-alpha, and fibrinogen levels have been associated with brain atrophy, white matter abnormalities, and cognitive decline as markers of chronic inflammatory and cardiopulmonary diseases, they can be used as indirect indicators of neuroinflammatory risk rather than CNS-related diseases [98]. Similarly, reduced circulating BDNF levels may reflect compromised neurotrophic support and have been linked to cognitive impairment and mood disturbances in COPD and related inflammatory conditions [99]. However, these biomarkers have not been formally validated as specific proxies for CNS inflammation in COPD, underscoring the need for integrated biomarker neuroimaging studies (Table 2).

Table 2.

Neuroinflammatory biomarkers in COPD patients

Category	Key Concepts and Causes	Specific Effects and Evidence	Consequences And Implications	References
Systemic Inflammatory Markers	Systemic Inflammation from COPD disrupts the BBB	CRP, Fibrinogen, IL-6, TNF-α, IL-1β, and IL-10	This disrupts the BBB, triggers neuroinflammation, and activates microglia and astrocytes. This contributes to cognitive decline, mood disorders, and white matter damage.	[91]
Potential Neural Injury Markers	Inflammatory mediators enter the brain and activate glial cells.	BDNF, PD-1, and MMP-9	• Linked to neuropsychiatric symptoms: depression, anxiety, cognitive decline, chronic pain. • Future research is needed on CSF analysis and specific biomarker panels to develop targeted therapies.	[96]

Emerging therapeutic strategies

Anti-inflammatory strategies

COPD is characterised by an abnormal inflammatory response, including both innate and adaptive immunity. It is difficult to pinpoint the exact function of particular cell types in the development of COPD, though. Although neutrophils and macrophages are the primary markers of chronic inflammation, 20 to 40% of individuals have elevated eosinophil counts in their blood and lung tissue. Additionally, many individuals have concurrent eosinophilic and neutrophilic inflammation. Additionally implicated in COPD are T cells, B cells, dendritic cells (DCs), and epithelial cells [100]. In the last twenty years, research has concentrated on finding novel targets that can prevent inflammatory cells involved in COPD from being recruited or activated, as well as developing medications that can prevent the inflammatory mediators that these cells produce. The lung’s structural and inflammatory cells create a complex network of inflammatory mediators, including chemokines, growth factors, and lipid mediators, which are linked to COPD and may contribute to its aetiology. Consequently, inhibiting them is a crucial tactic to interfere with the continuous inflammatory process. Regretfully, the outcomes have frequently not lived up to expectations [101] (Table 3).

Table 3.

Emerging therapeutic strategies in COPD-induced neuroinflammation

Therapeutic Target	Key Mechanisms and Challenges	Agents And Strategies	Primary Goal	References
Anti-inflammatory Strategies	Driven by complex immune response (neutrophils, macrophages, T cells). Limited corticosteroid effectiveness due to oxidative stress reducing HDAC2, low glucocorticoid receptor levels, and resistance.	Small Molecule Inhibitors: PDE inhibitors, CXCR2 antagonists, p38 MAPK inhibitors, PI3K inhibitors. Biologics: Anti-IL-5, Anti-IL-4/13, Anti-TSLP, Anti-IL-33. Other: Neutrophil elastase/MMP inhibitors, targeting NETs, alpha-1 antitrypsin replacement.	To precisely target the root causes of inflammation and move towards personalized medicine using patient phenotyping to slow disease progression.	[101]
Oxidative Stress Modulators	An imbalance between reactive oxygen species and the body’s antioxidant defense, fueling inflammation and tissue damage. Challenges include bioavailability and individual oxidative phenotypes.	Thiol-based Antioxidants: N-acetylcysteine (NAC), erdosteine. Nrf2 Activators: Boost natural antioxidant enzymes. Catalytic Antioxidants: SOD mimetics, glutathione peroxidase analogues. Dietary Polyphenols: Resveratrol, curcumin (also anti-inflammatory).	To boost the lungs’ natural antioxidant capacity, reduce oxidative stress, and potentially restore corticosteroid sensitivity to slow progression and reduce exacerbations.	[102]
Immunomodulators with CNS Penetration	Systemic inflammation (e.g., IL-1β, IL-6, TNF-α) crosses the BBB, causing neuroinflammation leading to depression, anxiety, and cognitive decline. Current treatments have limited CNS penetration.	Novel Therapeutics under development: Agents designed to cross the BBB to target neuroinflammation directly.	A dual-effect strategy to reduce both lung and brain inflammation, disrupt the lung-brain axis, improve CNS comorbidities, and enhance overall quality of life.	[103]

Oxidative stress modulators

The pathophysiology of chronic lung illnesses, such as COPD, is implicitly linked to oxidative stress. Therefore, a logical strategy for treating COPD would be to take into account antioxidant intervention in order to both identify the source of oxidants and overwhelm their formation, as well as to counteract the elevated oxidative stress and the ensuing inflammatory response. There are two ways to do this, either boosting the body’s natural antioxidant enzyme defences or strengthen0 the non-enzymatic defences through medication or nutrition. Currently undergoing clinical testing are several tiny molecular weight drugs that target oxidant signalling or quench reactive aldehydes and oxidants resulting from cigarette smoke. Thiol donors and analogues (GSH and mucolytic medications, such as N-acetyl-L-cysteine, nacystelyn, erdosteine, and carbocysteine lysine salt), dietary polyphenols, and flavonoids (curcumin, resveratrol, green tea-catechins, quercetin) have all been shown to scavenge and detoxify free radicals and oxidants, raise intracellular thiol levels, regulate NF-β activation, and ultimately suppress the expression of inflammatory genes [102] (Table 3).

Immunomodulators with CNS penetration

This section lists a few immunomodulatory techniques that have been used thus far to stop the progression of the disease and enhance lung function in patients with COPD. Pro-resolving lipid mediators, PDE2 antagonists, and antibodies that target inflammatory cytokines are some of the other strategies that, although successful in animal models, have not yet shown a significant clinical benefit when tested in clinical trials. This serves to highlight the significant pharmacological challenge posed by chronic inflammation in COPD. Notably, one of the main areas of drug discovery and the treatment of inflammatory diseases is the optimization of low molecular weight medications.

Hopefully, more powerful and effective medications to stimulate anti-inflammatory pathways or block inflammatory ones will be developed as selectivity and pharmacokinetics improve. In addition to lowering expenses and adverse effects, this will enable more complex and customized medication combinations. Furthermore, a new approach to treating lung diseases may be provided by the epigenetic modification of inflammatory genes [29] (Table 3).

Limitations

Research on COPD has advanced remarkably, although there are still important molecular and mechanistic information gaps. It is still unknown which specific signaling mechanisms link chronic lung inflammation to systemic and neuroinflammatory alterations. Although oxidative stress, immune cell activation, and inflammatory cytokines are recognized causative variables, little is known about the inter-organ interaction, especially between the brain and lung [29]. It is not clear, for example, how BBB permeability alterations, mitochondrial damage, or microglial activation led to cognitive impairment in COPD.

NF-κβ, MAPK, and JAK-STAT are well-established classical inflammatory pathways in COPD; however, not enough research has been done on their tissue-specific regulation, temporal dynamics, and regulatory interaction across organs [33]. Interpatient variability resulting from genetic diversity, epigenetic state, and environmental exposure makes combination molecular modelling. It is also unclear how ROS translates into long-term changes in gene expression, epigenetic memory, or immunological “priming”; this complicates the relationship between oxidative stress and immune dysregulation [104].

The second major area of uncertainty is non-coding RNAs and epigenetics. Although their precise functions are unclear, microRNAs, long non-coding RNAs, histone modifications, and DNA methylation most likely regulate the inflammation and neurodegeneration associated with COPD [105]. Although molecular mediators are hypothetical, the novel gut-lung axis and microbiome-immune-brain pathway show promise [106]. For example, how microbiome dysbiosis contributes to CNS dysfunction in COPD, but it may have an impact on Oxidative homeostasis and systemic inflammation.

Single-cell and spatial transcriptomics, longitudinal multi-omics, ncRNA, epigenomic profiling, and biomarker co-localization with disease are all necessary to close these gaps. To create molecularly focused therapies that can change the course of the illness rather than merely manage its symptoms, it is necessary to map the sequential path from airway to damage to systemic and neurological harm [107, 108].

Future perspectives

Precision medicine and multi-omics provide very successful new methods for breaking down the complexity of COPD and customizing treatment. Combining genomic, transcriptomic, and epigenomic data offers the potential to reveal the underlying molecular networks controlling the course of illness, as standard COPD treatment is mostly symptomatic and general [16].

Discovering molecular endotypes, or patient populations recognized by similar pathway abnormalities or biomarker patterns, is made easier by multi-omics. For example, proteomic metabolomic layers can detect circulating biomarkers for aggravation or comorbidity, whereas genomic layers can detect risk variants linked to oxidative stress [109]. By merging these, accurate patient categorization and interventions will be possible.

Large-scale omics data may be processed by precision medicine technologies like AI and machine learning to create a prediction model of the progress of a disease, the risk of comorbidity, and the response to therapy [16]. An integrated approach for individualized treatment is offered by combining environmental factors, imaging, and omics [110].

Single-cell RNA sequencing may break down cell-type-specific expression changes between the lung immunological, brain compartments, and metabolic signatures linking oxidative stress and cerebral inflammation can be found using metabolomic and lipidomic research [111]. Modulators of Nrf2, mitochondrial function, or inflammatory cascade are examples of novel therapeutic discoveries that can be guided by these platforms [112].

Multi-omics biomarkers will facilitate pharmacogenomics-driven therapies, precise phenotyping, and early diagnosis in a clinical context. The shift from a “one-size-fits-all” strategy that addresses both pulmonary and systemic/neuroinflammatory effects will be made easier by omics integration [109].

Conclusion

COPD is identified as a complex multisystem disorder rather than a disease, which is limited to the respiratory system. Chronic airway inflammation, oxidative stress, and systemic “spillover” of inflammatory mediators like IL-1β, IL-6, and TNF-α are all carried by chronic exposure to inhaled irritants, particularly cigarette smoke and pollution. Widespread organ failure can be caused by these circulating cytokines and oxidative neuronal damage, glial cell activation, and disruption of the BBB, which leads to neuroinflammation. Through the concept of the lung-brain axis, hypoxia and mitochondrial dysfunction increase these effects and indicate a molecular connection between COPD and depression, cognitive decline, and other neuropsychiatric illnesses. Patient with COPD have structural and functional alterations in their brains which are correlated with oxidative indicators and systemic inflammation, according to both clinical and neuroimaging evidence. Corticosteroid resistance and insufficient CNS uptake currently restrict the possibilities for therapy that reduce oxidative stress, pulmonary, and systemic inflammation. Meanwhile, several more recent therapeutic approaches indicate the potential, including immunotherapies that can pass the BBB, Nrf2 activators, and antioxidant modulators. To discover genetic endotypes, find new biomarkers, and create specific mechanism-based treatments, future COPD research will need to include multi-omics, targeted therapy, and AI-driven analytics. Identifying the antagonistic relationships between lung and brain pathology would improve COPD patients’ overall quality of life and cognitive function in addition to promoting more effective therapies. 

Abbreviations

COPD

Chronic Obstructive Pulmonary Disease

IL

6-Interleukin-6

TNF

α-Tumor Necrosis Factor-alpha

IL

1β-Interleukin-1beta

NF

κβ-Nuclear Factor-kappa B

AP

1-Activator Protein-1

TLR4

Toll-Like Receptor-4

JAK/STAT3

Janus Kinase/Signal Transducer and Activator of Transcription-3

TNFR1

Tumor Necrosis Factor Receptor-1

TNFR2

Tumor Necrosis Factor Receptor-2

MAPK

Mitogen-Activated Protein Kinase

NLRP3

NOD-like Receptor Family Pyrin Domain Containing-3

MUC5AC

Mucin 5AC

CXCL1

C-X-C Motif Chemokine Ligand-1

HDAC2

Histone Deacetylase-2

MDA

Malondialdehyde

Nrf2

Nuclear Factor Erythroid-2-Related Factor-2

HIF

1α-Hypoxia-Inducible Factor-1 alpha

HIF

2α-Hypoxia-Inducible Factor-2 alpha

HIF

3α-Hypoxia-Inducible Factor-3 alpha

ARNT

Aryl Hydrocarbon Receptor Nuclear Translocator

PHD

Prolyl Hydroxylase Domain protein

mtDNA

Mitochondrial DNA

ATP

Adenosine Triphosphate

HPA Axis

Hypothalamic-Pituitary-Adrenal Axis

Authors’ contributions

S.M.F. was involved in supervision, conceptualisation, reviewing drafted manuscript, and certified the final manuscript. S.M.F., and A.P. were involved in literature search, data extraction, preparation of figures and drafting of manuscript. K.P. and S.L.R. were involved in preparation of figures and drafting of manuscript.

Funding

Not applicable as it is a literature review.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

As this is a review manuscript no ethical approval is applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.