The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders

Abstract

The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.

Introduction

In recent years, the lung–brain axis has garnered significant attention in the field of neurological diseases as a critical bidirectional communication network linking the respiratory and central nervous systems (CNS) [1, 2]. This conceptual framework originated from in-depth investigations into the interactions between the lung microbiome and the nervous system, revealing a complex regulatory mechanism between the lungs and the brain, mediated by neural, immune, endocrine, and microbial metabolic pathways [3–5]. The traditional view of the lungs as a relatively sterile environment has been fundamentally overturned by advances in next-generation sequencing (NGS) studies [6]. Resident microbial communities in the lungs are now understood to influence brain function through multiple mechanisms. Beyond microbial dysbiosis or direct translocation, microbial metabolites can modulate neuronal activity and subsequently impact brain function via various circulatory pathways, including immune regulation, vagus nerve signaling, hypoxic metabolic effects, and dysregulation of endocrine axes [1, 7, 8]. While these mechanisms are highly similar to those of the gut-brain axis, the lung-brain axis has unique research significance because of the direct exposure of the lungs to the respiratory environment and their primary role in gas exchange [9]. These findings not only elucidate the distinct nature of lung-brain interactions but also highlight the pivotal roles of these regulatory mechanisms in the pathogenesis and progression of neurological disorders.

A substantial body of clinical evidence substantiates the close association between the lung-brain axis and the pathogenesis of these neurological conditions. In individuals with Alzheimer’s disease (AD), pulmonary infections (e.g., with Bordetella pertussis) can promote cerebral β-amyloid (Aβ) deposition and accelerate neuropathological progression via the olfactory pathway [10–12]. Patients with Parkinson’s disease (PD) exhibit significant correlations between an altered lung microbiota and inflammation in the substantia nigra pars compacta, suggesting that systemic inflammation may compromise dopaminergic neurons through the blood-brain barrier (BBB) permeation [7, 13]. Recent research has further demonstrated that the lung microbiome directly modulates susceptibility to autoimmune diseases, such as multiple sclerosis (MS), by regulating immune responses within the CNS [14]. Moreover, studies of ischemic stroke have indicated that the translocation of lung-derived immune cells and the release of inflammatory factors exacerbate postischemic brain injury. In contrast, stroke-induced autonomic dysfunction can concurrently precipitate pulmonary impairment, establishing a detrimental bidirectional cycle [15, 16]. This reciprocal interplay manifests both as pulmonary inflammation influencing brain function via humoral and neural pathways, and as cerebral pathologies triggering feedback loops that induce pulmonary dysfunction. Collectively, these findings illuminate the pathophysiological links between neurodegenerative diseases and alterations in the pulmonary microenvironment, in which the systemic dissemination of inflammation and disruption of the BBB emerge as central processes ultimately driving neurological pathology [13, 17, 18]. Importantly, this bidirectional regulation is not confined to acute infections such as Coronavirus Disease 2019 (COVID-19) [8] but persists in chronic inflammatory states such as asthma and chronic obstructive pulmonary disease (COPD), providing novel insights into the sustained mechanisms of the lung-brain axis and the long-term progression of neurodegenerative disorders [13, 19].

The discovery of the lung-brain axis has also revealed new therapeutic targets for the prevention and treatment of neurological diseases. The existing evidence indicates that interventions aimed at modulating the lung microbiota composition, such as probiotic administration, or targeting specific inflammatory pathways (e.g., inhibiting IL-6 transcytosis across the BBB) may constitute effective strategies [20–24]. These innovative approaches not only broaden our understanding of neurological diseases but also hold promise for developing more precise treatment regimens. However, the mechanisms underlying neurological diseases via the lung-brain axis remain insufficiently systematized, particularly the role of airborne environmental exposures in this axis. Beyond recapitulating established pathways, we dedicate considerable attention to translational implications, systematically evaluating potential therapeutic avenues such as anti-inflammatory modulation, oxidative stress mitigation, and lung microbiota remodeling. More importantly, the review aims to bridge mechanistic understanding with therapeutic prospects, offering a cohesive perspective that supports the development of targeted interventions for lung-brain axis related neurological diseases.

Pulmonary diseases and neurological disorders

Pulmonary diseases extensively influence the structure and function of the nervous system through pathways such as inflammation, hypoxia, and microbiome dysbiosis. These effects span cognitive, affective, and motor dysfunctions, underscoring the regulatory role of pulmonary-cerebral interactions in neurological integrity [7, 8, 13] (Fig. 1).

Fig. 1.

Effects of pulmonary diseases on neurological disorders. 1 Lung diseases can be broadly categorized into types such as acute and chronic pulmonary diseases, primary lung disorders, COVID-19, lung cancer, tuberculosis, and iatrogenic conditions like those associated with mechanical ventilation. 2 Systemic Effects: They exert multi-system influence, affecting the vascular system, microbiota, and critical pathways (immunological, neural, metabolic, and hormonal). 3 Brain Communication: Cytokines secreted from the lungs and activated immune cells can translocate to the brain, modifying its immune environment. 4 Neurological Impact: These pulmonary-derived cytokines contribute to the pathogenesis of various neurological disorders

Pneumonia

Bacterial pneumonia, such as that caused by Pseudomonas aeruginosa, can impair synaptic plasticity in hippocampal neurons via Tau-dependent mechanisms, leading to cognitive deficits [3, 25, 26]. Hospitalized patients with pneumonia exhibit a markedly increased incidence of cognitive impairment, with mild cognitive impairment observed in 22.8% of patients and severe cognitive impairment in 10% of patients [27, 28]. Animal studies involving intratracheal inoculation of Pseudomonas aeruginosa have confirmed that the pathogen compromises BBB integrity, as indicated by reduced expression of VE-cadherin and claudin-5, and induces anxiety-like behaviors [29]. Viral pneumonia, including respiratory syncytial virus (RSV) infection, can lead to severe neurological complications, such as encephalitis and acute encephalopathy, which occur in approximately 2% of RSV-positive patients [30]. Notably, infection models with Klebsiella pneumoniae show aggravated neurofunctional deficits and increased neuroinflammation following intracerebral hemorrhage, indicating a clear association between pulmonary infection and adverse cerebrovascular outcomes [31].

Influenza

Influenza virus infection is significantly associated with an increased risk of PD. Postmortem studies have detected influenza virus antigens within the substantia nigra of PD patients [32], confirming that the virus can cross the BBB and trigger inflammation in dopaminergic neurons [33–37]. Furthermore, postviral manifestations such as myoclonus and encephalopathy are closely linked to vascular damage in the pontine-mesencephalic brainstem region, with neuroimaging revealing vascular occlusion, microthrombi, hemorrhage, and edema around vessels in this area [38–40]. These findings suggest that the virus may induce dysfunction in specific brain regions through selective neurotropic damage. Additionally, influenza infection can activate microglia and astrocytes, promoting the release of proinflammatory cytokines (e.g., IL-1β and TNF-α), thereby exacerbating neuroinflammatory responses [41, 42].

Acute lung Injury/Acute respiratory distress syndrome

Up to 78% of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) experience long-term cognitive impairment, primarily characterized by memory deficits and executive dysfunction [43, 44]. Animal models demonstrate that ARDS induces atrophy of hippocampal CA1 neurons and a significant increase in S-100β expression, a brain injury marker [45]. The core mechanism involves activation of the inflammasome pathway, whereby the release of proinflammatory factors disrupts BBB integrity [46, 47]. Psychological impairments can persist for up to five years in ARDS survivors [48], and the duration of in-hospital delirium predicts long-term cognitive decline [49, 50]. Secondary pulmonary infections in these patients can further amplify neurological deficits, underscoring the pivotal role of inflammatory mediators in neural injury [5, 45].

COPD

COPD is significantly associated with cognitive impairment, with approximately 60% of patients exhibiting neurocognitive deficits and a 2–3 times higher risk of dementia [51–55]. Magnetic resonance imaging (MRI) studies show reduced gray matter density in prefrontal, limbic, and thalamic regions in COPD patients, along with increased cerebral small vessel disease manifestations such as white matter hyperintensities, lacunar infarcts, and cerebral microbleeds [56, 57]. Serological analyses have shown markedly elevated levels of Aβ40 and Aβ42 in COPD patients, resembling the pathological features of AD [58–60]. Notably, COPD patients with comorbid AD exhibit more pronounced frontal lobe deficits, suggesting that COPD may accelerate AD-like pathological progression [60]. Genetic studies indicate smoking, a primary cause of COPD, synergizes with the APOE ε4 genotype to increase dementia risk [61]. An altered respiratory microbiome in COPD patients (e.g., decreased Firmicutes and Bifidobacterium abundances) is also associated with increased risk of PD [5, 7, 62, 63].

Asthma

Asthma patients exhibit a high prevalence of cognitive impairment (45%), anxiety disorders (22.7%), and a doubled risk of depression [19, 64–68]. Neuroimaging shows abnormal functional activity in the cerebellum, frontal, and temporal lobes in asthma patients, with insular activity changes correlated with lung function decline and eosinophil infiltration [69–71]. Elevated neurogranin and phosphorylated Tau-protein in the cerebrospinal fluid of children with asthma indicate an AD-like pathological basis [72]. Animal models exhibit reduced hippocampal synaptic plasticity and impaired long-term potentiation (LTP) maintenance, accompanied by upregulation of hypoxia-inducible factors (HIF)-1α expression and downregulation of c-FOS protein expression [73–75]. Inhaled corticosteroids can alleviate early anxiety symptoms, but long-term use may suppress the hypothalamic-pituitary-adrenal (HPA) axis and reduce hippocampal volume, potentially worsening cognitive impairment [76, 77].

Silicosis

Silicosis, a classic occupational lung disease, results from silica exposure that not only causes alveolar collapse and pulmonary inflammation but also induces significant neurodegenerative changes. Silica-induced pulmonary inflammation upregulates hippocampal proinflammatory cytokines (e.g., IL-1β and TNF-α) in animal models. It promotes AD-like pathology, including aberrant Aβ deposition, Tau-protein hyperphosphorylation, and synaptic damage, leading to memory deficits. These effects may be mediated by inflammatory factors released from activated alveolar macrophages, which subsequently affect the CNS via the circulation [78, 79]. Furthermore, neuroimaging has revealed the development of progressive multifocal leukoencephalopathy in silicosis patients without long-term immunosuppressive treatment, suggesting extensive CNS involvement [80].

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) shows a significant pathological association with neurodegenerative disorders like AD and PD [81–83]. Genetic variants in the DEPTOR gene on chromosome 8 are linked to both IPF susceptibility and cortical thinning in the anterior cingulate cortex [84], providing a genetic basis for the cognitive impairment frequently observed in IPF patients. Pirfenidone, a Food and Drug Administration (FDA)-approved medication for IPF, attenuates pulmonary function decline by targeting the TGF-β signaling pathway and exhibits neuroprotective effects by mitigating neuroinflammation and neurodegeneration following traumatic brain injury (TBI) [85, 86]. These insights not only elucidate the comorbid mechanisms between IPF and neurological diseases but also identify novel molecular targets for combined therapeutic strategies.

Pulmonary hypertension

Patients with pulmonary hypertension (PH) frequently present with neuropsychiatric symptoms, including cognitive impairment, autonomic dysfunction, depression, and anxiety [87, 88]. High-resolution MRI has revealed significant reductions in gray matter volume, which are directly associated with deficits in cognition, autonomic regulation, and emotional processing [89]. Pathophysiological investigations have indicated impaired cerebral oxygenation and carbon dioxide (CO₂) reactivity, with symptoms exacerbated by exercise [90]. Animal studies confirm white matter injury, microvascular alterations, hypothalamic inflammation, and increased sympathetic drive in PH [91, 92]. Increased BBB permeability mediated by elevated endothelin-1 (ET-1) is a key mechanism of PH [92–94], and ET-1 receptor antagonists like bosentan not only alleviate PH symptoms but also exert neuroprotective effects by modulating BBB function [95, 96].

COVID-19

COVID-19, as a novel respiratory infectious disease, has emerged as one of the most severe public health crises of the 21st century. Its distinctiveness lies not only in acute respiratory symptoms but also in its pronounced multisystem involvement. Substantial clinical evidence indicates that COVID-19 can affect multiple vital organ systems, including the heart, kidneys, digestive tract, and nervous system [97–99]. Clinical data have shown that neurological symptoms occur in 30–80% of patients [100–102], with olfactory loss and dysgeusia frequently preceding typical pulmonary manifestations [103–106]. Furthermore, a proportion of patients experience persistent symptoms after recovery, termed “long COVID” [107–109]. This biphasic pattern—neurological symptoms heralding the acute phase, followed by long-term neurological sequelae during recovery distinguishes COVID-19 from other respiratory infections. The most common neurological manifestations are olfactory loss (53%) and taste disturbances (44%); cognitive impairment, seizures, and encephalopathy occur less frequently [8, 110–112]. Acute encephalopathy affects up to 70% of severe cases and correlates with in-hospital mortality. Even in recovered individuals, approximately 20–45% experience persistent cognitive deficits, including impaired attention, executive dysfunction, language deficits, slowed processing speed, and memory loss—a constellation often referred to as “brain fog”. These symptoms can persist for months and are classified as long COVID syndrome [49, 113–115].

Neuroimaging in acute COVID-19 has revealed microhemorrhages in the corpus callosum, thalamic infarcts, intracranial hematomas, and increased diffusivity in white matter tracts, suggesting acute neuroinflammation and vascular injury [116–121]. Long-term follow-up of previously infected individuals revealed progressive gray matter atrophy, widespread functional connectivity abnormalities, and hypoperfusion in multiple regions, such as the prefrontal and parietal cortices; these structural changes correlated significantly with persistent cognitive dysfunction [103, 122–125]. Autopsy studies confirmed viral replication predominantly in the brainstem, with potential invasion via neurotropic pathways (e.g., olfactory or trigeminal nerves) or ACE2-mediated transcellular entry across the BBB [126, 127]. Indirect mechanisms involve systemic inflammatory responses exemplified by a “cytokine storm”, which disrupts BBB integrity, activates microglia, and induces neuroinflammation [128, 129]. Metabolomic studies have indicated that infection with the Delta variant leads to significantly reduced postsynaptic protein expression, along with elevated α-synuclein and Tau-protein levels, resembling AD and PD pathology [130–133]. Hypoxemia-induced oxidative stress and impaired cerebrovascular autoregulation are additional contributing factors [134, 135] (Fig. 1).

Other pulmonary conditions

Lung cancer

Lung cancer, a common malignancy, metastasizes to the brain in approximately one-third of patients, with brain metastases sometimes detected even before the primary lung cancer is diagnosed [1]. The composition of the lung microbiome in lung cancer patients differs significantly from that in individuals without cancer, and this dysbiosis may indirectly affect neurological function via the release of proinflammatory cytokines and signaling molecules that promote tumor cell proliferation [136, 137]. Patients with small cell lung cancer—known for its high degree of malignancy and invasiveness—often receive chemotherapy and prophylactic cranial irradiation, which are frequently followed by cognitive deterioration; nearly half of these patients meet the criteria for cognitive impairment [117, 138, 139]. Neuroimaging provides objective evidence that treated patients show significant reductions in gray matter volume in the right subcortical regions, bilateral insular cortex, and superior temporal gyrus, accompanied by microstructural white matter alterations in the corpus callosum. These structural abnormalities are closely associated with cognitive deficits such as reduced verbal fluency [138, 140–142]. Thus, unlike other respiratory diseases, the cerebral changes in lung cancer patients are attributable primarily to the neurotoxic effects of radiotherapy and chemotherapy.

Tuberculosis

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis.Beyond pulmonary inflammation, Mycobacterium tuberculosis can lead to CNS infection. Mechanistically, the bacterium activates microglia via the Toll-like receptor 4 (TLR4) signaling pathway, promoting the release of inflammatory factors (e.g., TNF-α) and the formation of secretory vesicles that damage cerebral microvascular endothelial cells and ultimately disrupt the BBB [143–146]. Animal studies confirm elevated inflammatory cytokines in specific brain regions, including the hypothalamus, hippocampal formation, and cerebellum, along with marked alterations in neurotransmitter synthesis. As the infection progresses, histopathological changes such as the spread of neuroinflammation, neurodegeneration, and even neuronal death are observed, which explains some neuropsychiatric abnormalities in tuberculosis patients [147]. Notably, even pulmonary tuberculosis patients without cerebral infection can develop cognitive deficits or behavioral changes, manifested as clear episodes of depression and anxiety-like behavior, phenomena that are likely linked to the chronic inflammatory state characteristic of tuberculosis [147–152].

Mechanical ventilation

Mechanical ventilation (MV) is a critical life-support intervention in the intensive care unit (ICU). Clinical studies have indicated that up to 80% of ICU patients develop neurological dysfunction or delirium, with MV identified as a significant contributing factor. This phenomenon was particularly evident during the COVID-19 pandemic [153, 154]. The underlying pathology involves multiple synergistic mechanisms. On the one hand, MV induces the release of inflammatory cytokines (e.g., IL-6) from lung tissue, damages the BBB, and triggers neuronal apoptosis in the frontal cortex and hippocampus. On the other hand, ventilatory pressure stimulates pulmonary mechanoreceptors, which modulate TLR4 immune receptors via vagal afferents, initiating a neuroinflammatory cascade [23, 155, 156]. Elevated IL-6 correlates with poor outcomes even under protective ventilation (tidal volume of 6 mL/kg), and anti-IL-6 therapy may mitigate injury, which underscores the key role of inflammatory mediators in lung-brain axis signaling [157]. In vulnerable populations such as extremely preterm infants, MV—even in the absence of overt brain injury—is associated with white matter abnormalities and neurodevelopmental delay. Moreover, bronchopulmonary dysplasia (BPD), a common complication of MV, is an independent predictor of adverse neurodevelopment in extremely preterm infants [158–161]. These findings collectively indicate that MV-related neurological effects are not only acute but also may lead to profound long-term neurodevelopmental consequences.

Airborne environmental exposures and neurological disorders

Airborne environmental exposures encompass a broad range of factors encountered continuously through respiration. Various inhaled pollutants, whether organic or inorganic, can exert profound effects on neurological health through shared mechanistic pathways, including oxidative stress, systemic inflammation, and BBB disruption. Furthermore, significant variations in susceptibility across populations, based on genetics, sex, and developmental stage, highlight the complexity and pervasiveness of the neurological hazards posed by air pollutants (Fig. 2).

Fig. 2.

Effects of air pollutants on neurological disorders. A The impact of air pollutants on neurological disorders involves both organic components (e.g., cigarette smoke, dioxins, burn pit emissions, and organic solvents) and inorganic components (e.g., PM₂.₅, ozone, nitrogen oxides, and sulfur dioxide). B Air pollutants activate immune cells, leading to the release of various inflammatory molecules. These inflammation-related molecules can cross the Blood-brain barrier (BBB), activate glial cells, and promote the development of neuroinflammation

Organic pollutants

The association between organic inhaled pollutants and neurological diseases is supported by substantial clinical evidence. Cigarette smoke, a typical form of organic exposure, accelerates neurodegenerative processes, including increased AD-associated Aβ deposition and PD-characteristic α-synuclein aggregation in the substantia nigra [162]. Moreover, smoking is a well-established risk factor for MS exacerbation [163]. Neuroimaging studies have confirmed that reduced gray matter volume in the dorsolateral prefrontal cortex (DLPFC) of long-term smokers directly correlates with a decline in executive function, whereas compromised cingulum bundle integrity affects emotional regulation [164, 165]. Persistent organic pollutants (POPs), which are byproducts of industrial and chemical processes, constitute another critical category of organic inhalants and exhibit significant neurotoxicity. Polycyclic aromatic hydrocarbons (PAHs) activate the aryl hydrocarbon receptor (AhR) pathway, promoting atherosclerotic plaque formation and local inflammation [166–168], and are directly linked to an increased risk of ischemic stroke [169]. Combined exposure to military burn pit emissions, such as naphthalene (NA) and carbon black nanoparticles (CBNs), activates the NF-κB signaling pathway in brain tissue, leading to PD-like motor impairments and memory deficits in veterans [170–173]. Despite the 1978 ban on the production of polychlorinated biphenyl (PCB), its legacy from industrial manufacturing remains a public health concern, with exposure increasing the risk of ischemic stroke in a serum level-dependent manner [174–176]. Organophosphorus pesticides disrupt neurotransmitter balance by inhibiting cholinesterase, with the incidence of PD in U.S. Midwest agricultural regions reaching 2–10 times the national average [177]. The ubiquitous use of per- and polyfluoroalkyl substances (PFAS) in household and industrial products, combined with their environmental persistence, results in unique health risks, as evidenced by the increased stroke risk in residents near chemical plants reported in epidemiology studies [178], and high PFAS levels also increase the risks of cardiovascular and cerebrovascular events in males [179]. Phthalates impair executive function by interfering with the dopaminergic system [180–183]. Among air pollutants, volatile organic compounds (VOCs) and carbon black particles exhibit notable synergistic effects [172]. Diesel exhaust particles (DEPs) increase IL-6 and TNF-α levels, activate microglia and NADPH oxidase activity, perpetuate neuronal apoptosis [162, 184, 185], and induce cognitive deficits. As emerging pollutants, nano/microplastics (NPs/MPs), specifically 5 μm polystyrene microplastics (PS-MPs), do not accumulate in the brain but significantly impair cognitive function in animal experiments. Mechanistic studies have indicated that PS-MPs alter lung microbiota composition, increase lipopolysaccharide (LPS) release, and activate M1 microglial polarization, leading to spatial memory impairments [186]. Organic dust (OD) exposure triggers microglial activation via the High mobility group box-1/Receptor for advanced glycation end products (HMGB1/RAGE) signaling pathway, as confirmed by behavioral tests in animal models, confirming sensorimotor integration deficits [187]. Importantly, these pollutants often exist as mixtures, resulting in synergistic toxicity; for instance, co-exposure to tobacco smoke and asbestos synergistically increases the risk of lung cancer by 80-fold [162], suggesting that the neurological risks of mixed exposures may be underestimated.

The development of the nervous system represents a period of heightened vulnerability, during which time exposure to inhaled organic pollutants can cause profound neurological toxicity. Prenatal tobacco exposure reduces the fetal hippocampal volume [188, 189] and increases the lifelong attention deficit hyperactivity disorder (ADHD) risk. Similarly, prenatal phthalate exposure decreases attention and inhibitory control in children [190–193], with boys being more susceptible to attention deficits [194–196]. Childhood pesticide exposure also has sex-specific effects, primarily impairing inhibitory control among boys [197–199]. Adolescent e-cigarette use increases the risk of adult mood dysregulation [200]. Among occupational groups, farmers who are chronically exposed to OD exhibit a higher prevalence of neurodegenerative diseases such as PD and AD [177, 187]. Veterans exposed to military burn pits exhibit altered KCNQ3 and TGFBR1 gene expression in brain tissue, which is significantly correlated with the rate of cognitive decline [172]. Genetically susceptible individuals display specific responses; HLA-DRB1*15:01 carriers who smoke experience a drastically increased MS risk, demonstrating a dose‒response relationship [201, 202]. Compared with the general population, COPD patients, as a typical comorbidity among smokers, show a positive correlation between hippocampal atrophy and serum IL-6 levels and a significantly increased dementia risk [61, 162].

Inorganic pollutants

Airborne delicate PM is extensively correlated with a high incidence and mortality of ischemic stroke [203–206]. Multiple studies have indicated that long-term exposure leads to changes in the brain structure on MRI and neurobehavioral abnormalities, which are particularly significant in children and elderly individuals [207–214]. PM₂.₅ is classified as a carcinogen, and systematic analyses have identified it as the second leading risk factor for stroke after hypertension [215, 216]. Animal studies have further demonstrated that PM₂.₅ enters the bloodstream and promotes cerebral inflammation and microglial activation, ultimately causing neuronal damage and motor/cognitive dysfunction [170, 217–220]. Ozone (O₃), a highly reactive gas, cannot directly cross the BBB but can induce systemic inflammation and peripheral immune responses via the lung-brain axis, exacerbating neurodegeneration and neuronal injury. Epidemiological studies have shown that O₃ exposure increases the risk of cognitive impairment by 10.4%, with increased amyloid plaques and aberrant astrocyte activation observed in AD mouse models [59, 114]. Gaseous pollutants such as nitrogen oxides and sulfur dioxide are also significantly associated with the development and relapse of neurological diseases, including MS [6, 221]. Metal pollutants (lead, mercury, and manganese) in occupational settings (welding and mining) cause peripheral neurotoxicity and are correlated with PD and executive dysfunction [222–224]. In addition to causing pleural mesothelioma, asbestos, a classic inorganic fiber, can translocate to the brain tissue, which is correlated with Aβ deposition and reduced acetylcholine [225, 226], thereby contributing to AD pathology [227]. Follow-up data from occupationally exposed populations revealed a significantly increased incidence of brain tumors and neurodegenerative diseases [228]. Nanoscale inorganic materials such as carbon nanotubes (CNTs) and carbon quantum dots (CQDs) exhibit asbestos-like pathogenicity in animal studies; respiratory exposure not only induces pulmonary inflammation but also causes systemic inflammation and neuronal ferroptosis by altering the lung microbiome structure, ultimately leading to motor and cognitive deficits and indicating nonnegligible neurotoxicity [229–233]. Special populations exhibit increased susceptibility to and adverse neurological outcomes from exposure to inorganic pollutants. Children are particularly vulnerable to neurodevelopmental disorders because of an immature BBB, underdeveloped detoxification mechanisms, and increased exposure per unit body weight [234–236]. Prenatal and postnatal exposure to PM₂.₅, heavy metals, and other environmental toxins are closely associated with impaired executive function, autism spectrum disorders, and reduced cognitive flexibility [208, 211–213, 237–240], with sex-specific effects, as exposure to certain chemicals specifically impairs cognitive inhibition in boys [211, 241]. Due to age-related BBB degeneration, attenuated antioxidant defenses, and cumulative exposure, older adults are more susceptible to cognitive decline and neurodegenerative diseases caused by air pollution [207]. Studies have shown a significantly increased incidence of AD and vascular dementia among elderly residents in highly polluted areas, accompanied by increased cerebral Aβ-PET signals [59, 210, 214, 242–245]. Chronic PM₂.₅ exposure reduces the hippocampal expression of brain-derived neurotrophic factor (BDNF), inducing depression-like behaviors [246, 247]. Concurrently, aged animals exhibit more severe neuroinflammatory responses to O₃ and mixed vehicle emissions, with increased microglial activation [248]. Occupationally exposed groups (construction workers, miners, and urban laborers) that are consistently exposed to asbestos, welding fumes, and heavy metals not only have higher lung cancer and mesothelioma rates but also have increased incidences of AD, PD, and brain metastases. Asbestos-exposed individuals may experience occupational/environmental legacy effects decades later, underscoring the long-term and latent health effects [249–259]. Additionally, groups with a lower socioeconomic status often reside in highly polluted areas with limited protective resources, and epidemiological data show higher neurological disease incidence and mortality rates in these populations [252, 260]. Collectively, this evidence indicates substantial differences in neurological susceptibility to inhaled pollutants across life stages and exposure backgrounds.

Potential pathways of the Lung-to-brain influence

The lung-brain axis constitutes a complex interactive network that links pulmonary diseases and the CNS, collectively promoting the onset and progression of neurological disorders [261]. The process may be mediated by microbial, immune, neural, metabolic, and hormonal pathways [262–265]. When the lungs are exposed to infection, chronic inflammation, or environmental toxins, they produce a wide array of inflammatory mediators, cytokines, pathogen-associated molecular patterns, and aberrant endogenous metabolites [266, 267]. These signals can breach local barriers, enter the systemic circulation, and exert remote effects on the brain. Through multiple pathways, including the direct disruption of BBB integrity and activation of resident immune cells in the brain, they will have a significant impact on the functions of neurons, and even cause programmed cell death, thereby triggering or exacerbating a series of neurological disorders [268] (Fig. 3).

Fig. 3.

Potential mechanisms and effectors of the lung–brain axis. Communication along the lung-brain axis is mediated through microbial, immune, neural, metabolic, and hormonal pathways. Signals originating from the lung—such as its microbiota, pathogens, activated immune cells (e.g., Th1, Th2, Treg, Th17, and B cells), metabolites, neurotransmitters, and hormones—can reach the brain via key routes. These include direct microbial translocation, vagus nerve signaling, HPA axis activation, and systemic immune modulation. Upon reaching the brain, these factors may disrupt the blood-brain barrier, activate resident immune cells, and impair neuronal function, thereby contributing to the pathogenesis of neurological disorders

Microbial pathway

The impact of lung microbiota on the CNS homeostasis and neurological disease progression can be categorized into two interconnected mechanisms: direct translocation and indirect modulation.

Direct translocation represents the most straightforward pathway. Microorganisms or their products, such as LPS, can directly cross the alveolar‒capillary barrier to enter the systemic circulation, subsequently traversing the BBB to invade the CNS. Critically, the integrity of this initial pulmonary barrier can be compromised by inhaled toxic substances (e.g., PM₂.₅, O₃, cigarette smoke), which downregulate tight junction proteins and increase epithelial permeability. This pollutant-induced damage facilitates the translocation of both airborne pathogens and resident lung microbes, lowering the threshold for systemic invasion [269, 270]. This direct breach triggers neuroinflammation and contributes to cognitive impairment [1, 271]. Evidence supporting this route includes the detection of bacteria in brain tissue that are identical to strains found in the lungs in severe pneumonia models indicating a direct translocation mechanism which disrupts cerebral homeostasis [262]. This pathway is not limited to bacteria; neurotropic viruses, such as Nipah virus, can penetrate the BBB via cranial nerve axons or hematogenous routes. After initial replication in the respiratory tract, they directly invade the CNS, causing acute encephalitic syndrome, with a mortality rate of up to 40% [272]. Similarly, human metapneumovirus (HMPV) can persist in neurons and be reactivated following glucocorticoid treatment, leading to infection of epithelial cells [273]. The recent SARS-CoV-2 pandemic has provided a salient example, where the virus invades neurons via the ACE2 receptor and undergoes retrograde axonal transport to the brainstem. This direct invasion induces amyloid deposition and neuroinflammation, explaining the frequent neurological complications observed in COVID-19 patients [103, 274–281]. Furthermore, fungal and mycobacterial pathogens utilize specialized strategies; Cryptococcus neoformans employs a “Trojan horse” strategy to cross the cerebral vasculature within macrophages, while Mycobacterium tuberculosis invades the CNS via hematogenous spread, both leading to severe neurotoxicity [114, 282–284].

Critically, these direct invasion events often serve as the initiating trigger for broader, indirect modulation of the CNS. Beyond the direct translocation of pathogens, the lung microbiota can indirectly modulate CNS disease progression through complex immune and metabolic pathways, frequently in response to or in conjunction with signals from direct translocation. The immunologic axis of this indirect modulation is pivotal. Lung dysbiosis – induced by factors such as antibiotic treatment or environmental exposures like inhaled PM₂.₅—indirectly regulates microglial activation states. For instance, Exposure to PM₂.₅ alters the lung microbiome by reducing Proteobacteria and enriching Gram-negative bacteria, thereby increasing local levels of their product, LPS [285, 286]. This microbial LPS can directly translocate to the brain, where it activates microglia through the TLR4/NF-κB pathway, promoting type I interferon signaling while suppressing type II interferon-driven autoimmune responses, thereby influencing susceptibility to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) [1, 287]. This concept is experimentally supported by models in which neomycin treatment increased the abundance of Bacteroidetes in rat lungs by 2.5-fold and elevated LPS levels, which in turn alleviated EAE by promoting microglial type I interferon production [14]. Concurrently, lung-resident Th17 cells, which are regulated by the microbiome, can delay disease onset when retained, and intranasal LPS administration can induce this protective inflammation [288].

In parallel to immune mechanisms, metabolic pathways constitute a second major pillar of indirect modulation. Microbial metabolites (e.g., short-chain fatty acids, SCFAs) can indirectly modulate neuroinflammation by altering the gut-lung-brain axis [289–292]. Lung microbiome disruption promotes LPS release, exacerbating neuronal apoptosis via oxidative stress and neuroinflammatory cascades [232, 293]. Clinical translational studies have indicated that interventions targeting the lung microbiota, such as probiotics that modulate the Bacteroides balance or targeted antibiotics that inhibit neurotoxic metabolite production, can regulate microglial activation states, offering potential therapeutic options for neurological disorders [271, 294]. The interplay between direct invasion and indirect immunometabolic consequences, as evidenced by these findings, collectively underscores the therapeutic relevance of targeting microbial pathways.

Immune pathway

Inflammatory responses originating in the lungs can propagate to the CNS through a multifaceted interplay of humoral and cellular immune mechanisms [263].

The initial step involves the dissemination of local pulmonary inflammation. In pathological states such as asthma, COPD, or pulmonary infections, large amounts of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-17, are released from the lung tissue. These cytokines not only exacerbate local pulmonary inflammation but also enter the systemic circulation, triggering a systemic inflammatory response that can culminate in a “cytokine storm” affecting the CNS. For instance, in patients with COVID-19, the intensity of the cytokine storm directly correlates with the severity of encephalopathy [295]. Inhaled toxic substances, such as DEPs, represent important exogenous triggers of this process. They activate alveolar macrophages, leading to a substantial release of pro-inflammatory cytokines, including IL-6 and TNF-α [266, 296, 297]. Concurrently, key inflammatory alarmins—the high-mobility group box 1 protein (HMGB1) and acute-phase serum amyloid A (A-SAA)—are released into the circulation, amplifying the systemic inflammatory cascade [59, 187, 298]. Notably, certain A-SAA isoforms can cross the BBB and directly mediate the transmission of lung-derived inflammatory signals to the CNS [299].

These circulating inflammatory cytokines can access the brain directly through regions lacking a complete BBB, such as the circumventricular organs, activating microglia and astrocytes and inducing neuroinflammation [19, 300–302]. Additionally, they can bind receptors on cerebral vascular endothelial cells, causing the release of mediators such as prostaglandins and nitric oxide (NO), which disrupt the BBB structure and increase its permeability, facilitating the invasion of circulating inflammatory cells and molecules into the brain parenchyma [13, 19, 303], particularly in cognition-critical regions such as the hippocampus and prefrontal cortex [19, 304, 305]. Sustained neuroinflammation further leads to neuronal atrophy, decreased synaptic plasticity, and inhibited neurogenesis in these key brain areas, resulting in cognitive impairment and mood disorders [306–308]. Concurrently, oxidative stress is significantly increased during inflammation, and upregulated NOX1 expression in microglia increases reactive oxygen species (ROS) levels, thereby exacerbating glutamate neurotoxicity and ultimately worsening neuronal damage [300, 301, 309].

Beyond this humoral pathway, activated immune cells themselves can traffic from the lungs to the brain, creating a direct cellular link that amplifies and sustains neuroinflammation. For instance, T cells primed in the lung microenvironment can acquire migratory competence and infiltrate the CNS, as observed in experimental models [288, 310]. Similarly, B cells may travel to the brain [311, 312] and modulate CNS autoimmune responses. In addition, B cells present antigens to T cells, triggering the differentiation of CD4 + or CD8 + T cells. Eosinophils release mediators, such as CCL11, which cross the BBB to activate microglia [309, 313]. During pulmonary inflammation, neutrophils and macrophages contribute by secreting IL-17 A, which further activates central pathways (e.g., SAA1-TLR2/NF-κB) to promote immune cell infiltration and TNF-α expression in the hippocampus [267, 278, 314–317]. Once inside the CNS or upon receiving peripheral signals, resident microglia transform into a pro-inflammatory M1 phenotype, releasing damaging mediators such as ROS and cytokines [303, 318, 319]. Furthermore, cytokines from Th2 cells can weaken BBB integrity by affecting tight junction proteins, thereby facilitating immune cell infiltration into brain tissue [317, 320].

Therefore, the pathway from lung inflammation to neuroinflammation is a synergistic process: the systemic spread of inflammatory signals that compromise the BBB and ignite neuroinflammation, coupled with the direct migration and action of specialized immune cells that exacerbate and sustain the inflammatory response within the CNS.

In addition to cytokine-mediated and cellular routes, extracellular vesicles (EVs) have emerged as a novel and potent vehicle for lung-to-brain signal transduction. Following the inhalation of asbestos or PM₂.₅, lung-derived EVs can carry misfolded proteins, miRNAs (e.g., miR-155), and inflammatory factors into the brain via the bloodstream, suppressing the expression of neuronal repair genes and promoting Aβ aggregation [321, 322]. This EV-mediated interorgan communication not only amplifies neuroinflammation but may also induce chromosomal aberrations and epigenetic changes, such as DNA methylation-mediated silencing of the neuroprotective gene PTEN [323], thereby systematically linking pulmonary inflammation to CNS pathology.

This combined assault ultimately disrupts neuronal homeostasis, contributing to the structural and functional impairments underlying the observed cognitive and neuropsychiatric sequelae.

Neural pathway

The vagus nerve serves as the primary channel for lung-brain communication. Its sensory neurons extensively innervate lung tissue and airways, forming the anatomical basis for the pulmonary parasympathetic inflammatory reflex [264]. Vagus nerve and pulmonary TRPV1 + nociceptors are core conduits of the lung-brain axis, detecting a broad spectrum of pulmonary insults. These include classic pulmonary inflammation signals such as LPS or prostaglandin E2, as well as inhaled irritants like O₃. Upon activation by lung infection, inflammation, or environmental exposure, these afferent signals are relayed via integrative centers such as the nucleus tractus solitarius (NTS) to the hypothalamus, thereby activating central stress response circuits [324–326]. This neural signaling underlies the generation of sickness behaviors (e.g., fatigue and anorexia) [324] and can further initiate neuroimmune changes, including microglial activation [325, 326]. Ultimately, this signaling regulates both lung and brain function through efferent mechanisms, including the release of neurotransmitters like acetylcholine [327]. Beyond humoral signaling, this neural pathway also facilitates the spread of neurotropic pathogens. For example, RSV infection induces vagus nerve activation, with potential anterograde transport along the olfactory nerve into the CNS, triggering neural remodeling and suggesting that pathogen transmission from the lung to the brain occurs via specific cranial nerve pathways potentially linked to CNS injury [328–330]. The aforementioned Nipah virus and SARS-CoV-2 also possess neurotropic properties, utilizing peripheral nerve pathways to invade the CNS.

In chronic inflammatory diseases, the sustained activation of the lung-brain axis contributes to long-term symptoms, as exemplified in asthma, where airway inflammation—which may be initiated or exacerbated by pollutant exposure—drives persistent vagal signaling through the NTS to functional regions such as the insula and prefrontal cortex, ultimately fostering neural phenotypes associated with dyspnea and mood disorders [331, 332]. Conversely, external interventions or brain injury can acutely dysregulate this axis. MV can activate the vagus nerve and exacerbate hippocampal inflammation and neuronal apoptosis via the TRPV4-ATP-P2X signaling pathway [333, 334], whereas vagotomy exerts protective effects [334]. Furthermore, brain injuries such as stroke can damage vagus nerve structure or function, impairing swallowing and weakening anti-inflammatory pathways, leading to pulmonary immunosuppression and an increased risk of bacterial pneumonia [283].

Beyond these long-range pathways, intrapulmonary neurons—including sensory and adrenergic subtypes—exert direct, localized immunomodulatory effects within the lung parenchyma through the release of neuropeptides and neurotransmitters, forming spatially organized “neuro-immune units.” These units respond not only to local tissue injury and infection but also to inhaled irritants, which can activate sensory nerve terminals and modulate ensuing neuroimmune crosstalk [325, 326]. Generally, intrapulmonary sensory neurons play a protective role in inflammation and tissue repair. In bleomycin-induced pulmonary fibrosis, TRPV1 + nociceptors release calcitonin gene-related peptide (CGRP), which inhibits aberrant vasoactive intestinal peptide (VIP) production by alveolar macrophages, thereby suppressing TGF-β1-mediated recruitment of Siglec-F+ neutrophils and neutrophil extracellular trap (NET) formation, ultimately slowing fibrosis progression [335]. In allergic airway inflammation, sensory neurons similarly suppress type 2 innate lymphoid cell (ILC2) activity via the JAK1-Calcb/CGRPb axis, mitigating allergic responses [336]. However, this local neuroimmune regulation can also exacerbate pathology. During severe pneumonia caused by carbapenem-resistant Klebsiella pneumoniae, activated TRPV1 + nociceptors release CGRP, which acts on Ly6Chi monocytes, suppressing their bactericidal activity and ROS production, thereby impairing early pulmonary clearance and promoting systemic bacterial dissemination [337]. Similarly, pulmonary sympathetic nerves release norepinephrine (NE), which acts on local immune cells, including a subset of ADRB2 + interstitial macrophages surrounding sympathetic nerve terminals. NE exerts pro-inflammatory effects via the MAPK pathway [338] and modulates pneumonia and ALI through β2-adrenergic receptors (ADRB2) on immune cells. This anatomical and functional coupling between nerve endings and specific immune populations illustrates a spatially precise mode of neuro-immune crosstalk within the lung.

Consistent with this local interplay, sympathetic nervous system activation can amplify pulmonary inflammation and promote a systemic inflammatory environment via catecholamine release, affecting cerebral blood flow and exacerbating immune cell migration, thereby increasing lung and brain susceptibility to secondary injury and worsening complications such as poststroke pneumonia [339, 340].

In summary, dysfunction of these neural circuits—whether driven by infection, endogenous inflammation, or inhaled toxicants—not only directly causes neuropathological symptoms but also creates a deleterious feedback loop that perpetuates lung-brain comorbidity [5, 340].

Metabolic and hormonal pathway

Brain injury through the lung-brain axis is driven by interconnected metabolic and hormonal dysregulation. Core metabolic disturbances—oxidative stress, mitochondrial dysfunction, and hypoxia—initiate neurological damage, while the hormonal system, centered on the HPA axis, amplifies and coordinates these effects.

Oxidative stress, a central metabolic pathway that links pulmonary disease and neurological injury, induces neurocognitive dysfunction in patients with chronic respiratory diseases such as asthma and COPD through multiple mechanisms. In individuals with asthma, oxidative stress modulates the balance of Th1/Th2-mediated immune-inflammatory responses, activates microglia, promotes NF-κB signaling, increases inflammatory cytokine release in cognition-related brain regions such as the hippocampus, reduces N-acetylaspartate levels, and ultimately leads to learning and memory impairments [304, 305]. In COPD, systemic effects include lung inflammation and the generation of excess ROS by NADPH oxidase (NOX4). These ROS, reach the brain via the circulation, disrupting neuronal antioxidant defenses, inducing lipid peroxidation and protein modification, and promoting the accumulation of the lipid peroxidation end product 4-HNE to cause astrocytic ferroptosis and ultimately lead to synaptic structural degeneration and memory deficits [341–343]. Critically, such oxidant burden on the CNS is not exclusive to chronic respiratory diseases but can also be directly initiated by environmental insults. Beyond endogenous metabolic derangements, inhaled ultrafine particles (e.g., PM₀.₁ and asbestos fibers) can translocate to the brain via systemic circulation. Once in the CNS, these particles induce local oxidative stress and endothelial activation. Moreover, surface-adsorbed PAHs or heavy metals may trigger endoplasmic reticulum stress and mitochondrial dysfunction in astrocytes, thereby creating a neuronal metabolic crisis through pathways convergent with those seen in COPD and asthma [230, 344–347]. At the cellular level, neurons, which are postmitotic cells that are highly dependent on mitochondrial respiration, are susceptible to oxidative stress. High intracellular ROS levels promote the persistent accumulation of toxic lipid peroxides, causing long-lasting oxidative damage and contributing to COPD-associated neurocognitive impairment [348, 349]. Molecularly, a key consequence of this sustained oxidant burden, whether from disease or environment, is glutathione depletion. This exacerbates oxidative damage, leading to dendritic injury, neuronal death, and cognitive impairment [350]. Neuronal glutathione depletion is closely associated with the downregulation of excitatory amino acid transporter 3 (EAAT3), which is mediated by lipid peroxidation-induced neuronal membrane dysfunction [351]. Furthermore, during COPD progression, elevated levels of pulmonary inflammation and oxidative stress markers can extend beyond locally confined regions, triggering systemic inflammation and causing brain damage [352, 353]. The neuronal energy supply relies heavily on proper mitochondrial respiratory chain function, making neurons particularly vulnerable to mitochondrial dysfunction [354]. Acute hypoxia can exacerbate hippocampal injury by inducing mitochondrial dysfunction [355], and the interplay between oxidative stress and mitochondrial dysfunction further disrupts the balance of neuronal energy metabolism.

Hypoxia, a common feature in chronic respiratory diseases, upregulates HIFs in the brain. HIF-1α, in particular, exerts dual effects: while its activation can provide anti-inflammatory and neuroprotective benefits, as observed in stroke models [356], its sustained upregulation correlates with impaired synaptic plasticity and memory deficits [74, 75]. This duality is exemplified in COPD patients, where chronic hypoxia leads to concurrent HIF-1α upregulation and c-FOS (a key memory formation regulator) downregulation in the hippocampus, directly linking these molecular changes to spatial memory formation deficits [73]. In contrast, acute hypoxia, such as during ALI, drives hippocampal injury through immediate metabolic crisis. Mechanisms include disrupted glycolysis, increased adenosine levels, activated cardiopulmonary compensatory responses, exacerbated oxidative stress, and mitochondrial dysfunction [355]. The close association between reduced cerebral glucose metabolism and cognitive impairment [357] highlights the critical role of the energy metabolic balance in maintaining neurological function. Furthermore, hypoxia activates peripheral chemoreceptors, causing hyperventilation, hypercapnia, cerebral vasoconstriction, and hypoperfusion, thereby worsening cognitive impairment [358, 359]. This is reflected in the particular vulnerability of hypoxia-sensitive hippocampal CA1 pyramidal neurons in ARDS patients, whose damage correlates with long-term cognitive decline [360]. Thus, metabolic disturbances initiate a direct path to neurological dysfunction. Importantly, their impact is further modulated by the body’s integrated stress response, most notably through the HPA axis.

As a central hormonal pathway, the HPA axis establishes bidirectional communication between the lungs and the brain. Upon activation by stress or inflammation, it releases neuroendocrine factors such as corticotropin-releasing hormone (CRH) and glucocorticoids. These hormones not only regulate glucose metabolism but also modulate pulmonary and cerebral inflammation through immunosuppressive functions [361–367]. Glucocorticoids regulate downstream inflammatory gene expression by interacting with the transcription factors NF-κB and AP-1 and exert dual concentration-dependent immunomodulatory effects: immune-permissive effects at low concentrations and immunosuppressive effects at high concentrations [361, 362, 368]. This axis forms a complete regulatory circuit: pulmonary inflammation activates the HPA axis via widely distributed lung CRH receptors [369], while brain injury-induced glucocorticoid secretion in turn supports lung development and regulates key processes such as type II epithelial cell differentiation and surfactant synthesis [370, 371]. In asthma pathology, airway inflammation activates brain regions such as the amygdala and prefrontal cortex, stimulating the release of glucocorticoids from the HPA axis. These hormones bind glucocorticoid receptors on airway epithelial cells, regulating the expression of inflammatory cytokines such as IL-4, IL-5, and IL-13, and exerting central regulation of peripheral inflammation [265, 372]. Pollutants also act as potent environmental stressors that can activate the HPA axis directly or via induced inflammation (e.g., through IL-6 and TNF-α release), thereby amplifying the neuroendocrine response [266, 296, 297, 361–367, 373].

However, chronic or excessive activation of this regulatory circuit can become maladaptive, contributing to neuropsychiatric complications. Under sustained stress, NLRP3 inflammasome activation promotes increased serum levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), further activating the HPA axis and causing increased glucocorticoid release. Chronically high glucocorticoid levels induce neuronal atrophy and inhibit neurogenesis and synaptic plasticity in the hippocampus and prefrontal cortex, whereas excess IL-1β reduces BDNF production, collectively contributing to a depressed mood [306–308]. This mechanism explains the increased depression risk in asthma patients [68]. This dysregulation is amplified through synergy with the sympathetic nervous system, wherein catecholamine release primes a pro-inflammatory environment and increases susceptibility to secondary insults [340]. Clinical evidence suggests that reduced lung microbial diversity leads to abnormally elevated alveolar catecholamine concentrations; these substances and their metabolites exert neurotoxic effects via the systemic circulation and are closely associated with the development of neurological disorders such as PD and depression [373]. Dysregulation of this neuroendocrine system is evident in conditions such as COPD and in severe infections, such as COVID-19. In COPD, persistent pulmonary inflammation leads to HPA axis overactivation, resulting in significantly reduced basal serum corticosterone levels [374]. Following acute brain injury, HPA axis activation by inflammatory mediators such as IL-6 triggers a systemic compensatory anti-inflammatory response to protect peripheral organ function; however, this compensatory mechanism may induce long-term neuroendocrine imbalance [375]. Particularly during viral infections such as COVID-19, aberrant HPA axis activation significantly exacerbates neurological complications, involving complex interactions among multiple factors: cytokine storm-induced HPA axis hyperactivation, hypercoagulability, and MV-associated bacteremia [376–378]. These mechanisms collectively reveal the bridging role of the HPA axis in lung-brain interactions.

Altered BBB permeability

The BBB is a highly selective semipermeable barrier composed of vascular endothelial cells and supporting cells. It protects the CNS from neurotoxins and pathogens by regulating the exchange of substances between the blood and brain tissue [379], playing a pivotal role in maintaining CNS homeostasis [380]. BBB disruption allows peripheral immune cells, cytokines, and toxic molecules to enter the brain, serving as a significant trigger for subsequent neuronal and glial cell damage, and forming a vicious cycle that ultimately exacerbates neurodegenerative processes [380].

Recent studies suggest that BBB disruption is a potential mechanism underlying brain injury associated with respiratory diseases [381]. Pulmonary inflammation and injury can increase peripheral levels of inflammatory cytokines. These peripherally derived cytokines can damage cerebral capillary endothelial cells, thereby altering BBB permeability [382]. For instance, TNF-α signaling through TNFR-1 disrupts tight junction structure and induces necrosis in brain microvascular endothelial cells, facilitating the entry of toxins and pathogens into the CNS. Furthermore, TNF-α can downregulate the expression of the tight junction protein Cldn5 via activation of the NF-κB signaling pathway, exacerbating tight junction disruption [383]. In addition, IL-1β affects the BBB through two mechanisms. First, it induces the expression of HIF-1 and its downstream target VEGF-A in human astrocytes, promoting BBB degradation and accelerating CNS degeneration [384]. Second, IL-1β promotes the secretion of other proinflammatory cytokines (e.g., IL-6 and TNF-α), thereby disrupting BBB integrity via paracellular pathways. Beyond direct BBB injury, studies using asthma models have shown that increased acetylcholinesterase activity and decreased Na+, K+-ATPase activity contribute to a proinflammatory microenvironment, indirectly affecting BBB function and leading to anxiety-like behaviors in mice [385, 386]. Additionally, the release of LPS by gram-negative bacteria can lead to inflammatory disruption of the BBB through activation of the caspase-4/11-GSDMD signaling pathway in brain endothelial cells [387]. This mechanism provides further support for patients infected with SARS-CoV-2 who present with neurological symptoms [388, 389]. For example, MRI examinations of the brains of deceased COVID-19 patients by Lee et al. revealed punctate hyperintensities in some patients, suggesting cerebral microvascular damage and fibrinogen leakage [329]. Specific pathological states also exacerbate barrier damage. In patients with COVID-19, systemic hypercoagulability and endothelial dysfunction promote microangiopathy, while type III interferon released by lung dendritic cells not only disrupts the pulmonary epithelial barrier but also may impair BBB integrity, leading to neuroinflammation and brain injury [103, 390]. An animal study showed that when Pseudomonas aeruginosa (PA) was dripped into the trachea of mice to induce lung infection, 7 days later, the mice’s anxiety-like behavior increased. Further research found that PA lung infection increased circulating cytokine levels, but PA did not directly penetrate the brain. Immunostaining revealed that the integrity of the endothelial cell layer was severely damaged, suggesting that cytokines directly acted on the brain microvascular endothelium, disrupted cell junctions, reduced the resistance of the intercellular adhesion barrier, and increased the permeability of the BBB. The data from the study support the mechanism linking the lungs and the brain [29]. Inhaling substances also has a negative impact on the integrity of the BBB. Studies have shown that nicotine may upregulate matrix metalloproteinases (MMPs) expression by activating α4β2 nAChRs; these MMPs degrade tight junction proteins (e.g., claudin-5 and occludin) and increase BBB permeability [391]. Combined exposure to cigarette smoke and silver/copper oxide nanoparticles exacerbates BBB leakage, with nanoparticles penetrating the brain via endocytosis, further aggravating cellular stress [347] (Fig. 4).

Fig. 4.

Potential mechanisms of neuronal injury induced by pulmonary diseases or airborne environmental exposure. 1 Pulmonary diseases or air pollutants can directly promote the production of inflammatory factors that damage the BBB, thereby inducing the onset and progression of neurological disorders. 2 Pulmonary diseases or air pollutants promote microglial activation. Under the influence of HMGB1, microglia transition to the M1 phenotype, which is characterized by an enlarged process diameter, the secretion of various inflammatory factors, and the inhibition of the shift to the M2 phenotype. These cells promote neuroinflammation and oxidative stress, leading to neuronal injury. 3 Pulmonary diseases or air pollutants act on astrocytes and microglia, exacerbating neurotoxicity by releasing NO and glutamate or inhibiting the uptake of extracellular neurotransmitters. They also inhibit oligodendrocyte recruitment or promote oligodendrocyte death, resulting in neuronal loss and aggravated neurological dysfunction. 4 Pulmonary diseases or air pollutants can increase the degree of crosstalk between astrocytes and microglia, thereby amplifying neuroinflammation and accelerating the progression of neurological disorders

Neuroglial cell activation

Neuroglial cells are the primary nonneuronal cells in the CNS. They are central hubs connecting the peripheral environment to brain health, with the discovery of the “lung-brain axis” being particularly pivotal [14].

Pulmonary microbiota dysbiosis is a core factor in respiratory pathologies such as asthma and COPD [392]. Studies indicate that lung dysbiosis and inhaled pollutants can induce CNS pathology through shared mechanisms [186, 393]. This mechanism has been confirmed in a rat model of asthma, in which significant microglial activation and proliferation were detected in the prefrontal cortex and amygdala [394–396]. Specifically, these pulmonary insults lead to increased levels of LPS and DAMPs (e.g., HMGB1), which, upon binding to and activating TLR4, promote proinflammatory cytokine expression via the NF-κB and MAPK pathways. The released cytokines enter the CNS via the circulation, driving microglial polarization from a homeostatic state toward a proinflammatory M1 phenotype. This phenotypic switch promotes the synthesis of inflammatory mediators (e.g., TNF-α, IL-1β, and IL-6) and cytotoxic substances (e.g., glutamate, NO, peroxides, and reactive radicals), initiating inflammatory responses, causing apoptosis and secondary damage, and causing significant neurotoxicity. This activation not only directly triggers neuroinflammation but also, more critically, impairs the core phagocytic function of microglia [59, 397, 398]. For example, in models of prolonged MV, O₃ exposure, or chronic smoking, hippocampal microglia can be activated by HMGB1 via the TLR4-NLRP3 axis, thereby interfering with TREM2 expression and subsequently severely compromising microglial ability to clear Aβ plaques, exacerbating AD-related pathology [59, 187, 399]. Activated microglia can also induce astrocytes to transform into a neurotoxic A1 phenotype by secreting IL-1α, C1q, and TNF [400]. Under normal conditions, astrocytes clear excess glutamate from the synaptic cleft via high-affinity glutamate transporters (EAAT1/2) to prevent excitotoxicity and efficiently remove K+ ions from the extracellular fluid by expressing various potassium channels, regulating neuronal excitability [401]. Furthermore, astrocytes provide energy support to neurons through the “lactate shuttle” [402]. However, once their function is impaired, which is manifested as reduced glutamate uptake, dysfunctional K+ buffering, or dysregulated lactate metabolism, increased neuronal excitotoxicity, metabolic disturbance, and aggravated injury occur, thereby promoting the progression of neurodegenerative diseases such as MS, AD, PD, and Huntington’s disease [403, 404]. A1 astrocytes not only highly express inflammatory mediators, inducing apoptosis in neurons and oligodendrocytes, but may also release excessive amounts of GABA and glutamate, causing memory impairment and synaptic loss, and contributing to microcirculatory disturbances and BBB disruption, further promoting Aβ deposition and exacerbating the AD disease [405] (Fig. 4).

Clinical findings reveal that the brains of most patients with severe acute pneumonia who subsequently develop neurological syndromes exhibit hyperactivation of microglia and astrocytes, accompanied by axonal injury and Aβ deposition [406, 407]. Researchers used LPS to establish a severe pneumonia mouse model, and genomic analysis confirmed that pulmonary endogenous bacteria can translocate to the brain and drive the transition of microglia and astrocytes from a resting state to an activated state via infection-associated pathways, thereby disrupting brain homeostasis [262]. Sustained microglial activation not only drives a chronic neuroinflammatory state but is also closely associated with impaired synaptic function and neuronal death, serving as a common pathological basis for various neuropsychiatric disorders, including depression and cognitive impairment [408, 409]. During the process of lung cancer brain metastasis, inflammatory factors (e.g., TNF-α and IL-6) released by tumors can modulate microglial polarization toward the protumor M2 phenotype, influencing patient prognosis [410–412].

Cerebrovascular dysfunction

Cerebral blood vessels are key structures for maintaining brain function. Studies have shown that compared with the general population, patients with COPD or impaired lung function face a higher risk of stroke and more significant cognitive decline [413–416]. The underlying mechanisms are closely related to systemic inflammation and oxidative stress [417]. Research has indicated that airway infections and systemic inflammation can exacerbate arterial stiffness through multiple pathways, including sympathetic overexcitation, altered NO bioavailability, and arterial endothelial dysfunction [418], thereby promoting the occurrence of lacunar infarcts and white matter lesions in the brain [419].

Chronic hypoxia and inflammatory signals triggered by pulmonary diseases activate the sympathetic nervous system, leading to increased NE release. NE can act directly on blood vessels, inducing endothelial cell dysfunction, increasing endothelin secretion, and reducing NO synthesis, thereby promoting increased vascular tone and arteriosclerosis [420]. Furthermore, peripheral inflammatory cytokines can directly damage vascular endothelial cells, while the damaged areas highly express adhesion molecules, promoting leukocyte aggregation and further exacerbating local inflammation [421]. Under persistent inflammatory stimulation, the vascular wall gradually thickens and hardens, leading to the formation of arteriosclerotic plaques. In diseases such as asthma and COPD, oxidative stress can lead to abnormal local NO metabolism [422]. NO dysfunction not only causes arterial contraction but also promotes smooth muscle proliferation, increases the adhesion of macrophages to endothelial cells, induces foam cell formation, and exacerbates platelet aggregation. This leads to atherosclerosis, increases the risk of thrombosis, and may cause myocardial infarction or stroke [423].

Numerous clinical studies have confirmed that elevated levels of inflammatory markers (e.g., C-reactive protein and white blood cell count) in COPD patients can serve as predictors of ischemic stroke risk [424, 425]. Concurrently, these patients often exhibit increased carotid‒femoral pulse wave velocity, indicating systemic arterial stiffness [426]. Animal experiments further revealed that cerebral hypoperfusion triggers a series of molecular and cellular events: insufficient brain perfusion first leads to dysfunctional mitochondrial energy metabolism, subsequently inducing excitotoxicity (primarily mediated by the overactivation of NMDA/AMPA receptors), and ultimately resulting in neuronal dysfunction and death [427]. In this process, multiple mechanisms, such as oxidative stress, mitochondrial dysfunction, and neuroinflammation, act synergistically, forming a vicious cycle. This complete pathological cascade driven by cerebral hypoperfusion has been clearly observed in individuals with chronic conditions such as vascular cognitive impairment [428]. Animal studies have also confirmed the central role of hypoxia in this process. Chronic intermittent hypoxia can enhance the spread and accumulation of pathological tau proteins, and exacerbate AD-like memory and synaptic plasticity deficits [429]. Clinical intervention studies further support the central roles of inflammation and oxidative stress: anti-inflammatory treatment can prevent vaccine-induced endothelial dysfunction and arterial stiffness [430], whereas its combination with antioxidant therapy can improve the vasodilatory capacity in COPD patients [431], thereby exerting a protective effect on the nervous system.

The lung-brain axis and neurological disorders(Fig. 5)

Fig. 5.

Role of the lung–brain axis in the pathogenesis of neurological diseases. The lung–brain axis may play a critical role in the pathogenesis of neurological disorders. Through various molecular signals, including microglial transition from a resting state to an active state, T-cell activation, thrombus formation, the release of neuroinflammation-related factors, and vagus nerve activation, the lung–brain axis influences the progression of multiple neurological conditions, such as PD, AD, epilepsy, migraine, anxiety/depression, stroke, and MS

AD

AD, the most common neurodegenerative disorder worldwide, is characterized by typical neuropathological features, including extracellular Aβ plaques and intracellular neurofibrillary tangles composed of the hyperphosphorylated Tau-protein [432]. These pathologies lead to widespread neuronal loss and synaptic dysfunction, which clinically manifest as progressive memory decline, cognitive impairment, and neuropsychiatric symptoms.

Notably, studies have revealed a new role for the lung-brain axis in the pathogenesis of AD [59, 114, 312]. AD-related pathological Aβ can reach the lungs via the meningeal lymphatic vessels, activate pulmonary B cells via the TLR4/NF-κB signaling pathway, and pulmonary memory B cells can infiltrate the frontal cortex of the brain via the CXCL12-CXCR4 axis. Animal experiments further confirmed that pulmonary memory B cells can inhibit Aβ production in the frontal cortex of mice, thereby alleviating AD-like pathological changes [312]. These findings not only expand our understanding of the interaction between the lungs and the brain but also highlight the critical role of peripheral immune cells in the pathogenesis of AD.

Recent research has further revealed associations between increased AD risk and air pollution and various pulmonary diseases [433]. O₃, an air pollutant, is considered a potential promoter of AD-related neurodegeneration [434]. Ozonation can enhance the toxicity of air pollutants to mitochondria, reduce cell vitality, damage neurons, and provide a pathological basis for cognitive impairment [435]. Simultaneously, O₃ triggers chronic neuroinflammation, exacerbating CNS injury. Recent research has also indicated that O₃ may impair the microglial clearance of Aβ plaques by downregulating HMGB1 expression in bronchoalveolar lavage immune cells, thus providing a new immune-mediated mechanism for AD pathology [436, 437]. A study using brain imaging and biochemical analysis confirmed that residents who were chronically exposed to high PM pollution had more Aβ42 deposits and phosphorylated Tau-protein tangles in the olfactory bulb, hippocampus, and cortical regions [244, 438]. In addition, pulmonary infections are closely linked to AD. Meta-analyses have shown that Chlamydia pneumoniae infection can increase the incidence of AD approximately fivefold, whereas spirochete infection can increase the risk of AD more than tenfold [439]. Pathogens such as Mycobacterium tuberculosis can cause CNS infections and release TNF-α [143, 283], which promotes AD progression through the following mechanisms: promoting Aβ generation and accumulation; impairing the phagocytic function of immune cells; exacerbating neuronal loss; and disrupting BBB integrity by activating Toll-like receptor signaling pathways, remodeling the cytoskeleton, and damaging brain microvascular endothelial cells. Furthermore, the long-term cognitive effects of SARS-CoV-2 infection are attracting attention. A 2.5-year follow-up study of elderly COVID-19 survivors revealed an overall incidence of cognitive impairment of 19.1% [113], further supporting the potential link between pulmonary microbial infection and AD-related cognitive dysfunction.

PD

The pathogenesis of PD is closely associated with the degeneration and death of dopaminergic neurons in the substantia nigra [440]. Recent studies have indicated that the neurodegenerative process in PD may be linked to pulmonary diseases [441]. Inflammation-related signaling molecules play a key role in the link between the two diseases. When the lungs are stimulated by infection or oxidative stress, immune cells (e.g., alveolar macrophages and dendritic cells) release inflammatory cytokines such as TNF-α and IL-6 [442], which enter the brain via the bloodstream. TNF-α can activate brain microglia, prompting their transition from a resting to an activated state, leading to the release of inflammatory mediators and ROS, exacerbating neuroinflammation, accelerating the degeneration of the substantia nigra region, and ultimately damaging dopaminergic neurons to drive PD progression [33, 443]. In vitro, specific inhibition of TNF-α reduced the loss of dopaminergic precursors and the alterations in morphology, and had a positive impact on its survival and differentiation [444]. Microglia in a chronic inflammatory state can also promote the aggregation of α-syn to form Lewy bodies, which are mainly distributed in neurons throughout the brain. This is a neuropathological marker of PD [445]. Concurrently, elevated IL-6 levels in individuals with pulmonary inflammation can modulate the neuroendocrine system, disrupt HPA axis function, alter hormone levels, and affect neuronal activity and neurotransmitter metabolism [446, 447]. Additionally, IL-6 can impair cerebrovascular endothelial cell function, disrupt BBB integrity, and facilitate the entry of harmful substances from peripheral tissues into brain tissue, thereby exacerbating intracerebral pathology in PD patients.

Oxidative stress has also been confirmed to be the core pathogenic factor of dopaminergic neuron damage. Due to continuous gas exchange, lung tissue is exposed to high oxygen concentrations and is prone to generating ROS. The resulting sharp decline in dopamine levels in the brain selectively affects the striatum and the substantia nigra pars compacta - these two key nuclei in the substantia nigra-striatum system that regulate motor function. When the degeneration of dopaminergic neurons reaches a critical threshold, it triggers the characteristic motor dysfunction of PD [448]. When the balance between the oxidative and antioxidant systems is disrupted, a large amount of ROS enters the circulatory system and is transported to the brain. Mitochondria, as the core source and main target of ROS [449], their functional damage will further form a positive feedback loop of “ROS generation - mitochondrial damage”, causing energy metabolism disorders and inducing mitochondria to release pro-apoptotic factors such as cytochrome C, ultimately leading to neuronal apoptosis [450]. This mechanism is highly correlated with the characteristic progressive neuronal loss observed in PD patients.

MS

MS is a chronic, inflammatory, demyelinating disease of the CNS. Its core pathological features include immune cell infiltration into the CNS, immune-mediated myelin sheath destruction, and subsequent axonal injury [451].

Although research on the role of the “lung-brain axis” in MS is still in its early stages, substantial evidence indicates that the immune system plays a crucial role. Factors such as pulmonary infections, COPD, and smoking [202, 452–454] are not only associated with an increased risk of developing MS but also may exacerbate disease progression and severity, potentially through mechanisms involving pulmonary inflammatory responses and their downstream immunomodulatory effects [455]. For instance, a study indicated that upon external stimulation, pathogenic immune T cells in the lungs can be “programmed” into myelin-reactive T-cell blasts, which then cross the BBB, initiating the autoimmune tissue destruction characteristic of MS [310]. Furthermore, neurotoxic substances introduced by smoke exposure (e.g., free radicals, cyanate, and carbon monoxide) can exacerbate inflammatory damage to neurons and glial cells in the CNS via the circulatory system [456]. Notably, an imbalance in the lung microbiome can also significantly influence an individual’s susceptibility to CNS autoimmune diseases. A recent study found that the lung microbiota can modulate microglial activity—key immune cells in the CNS—thereby altering susceptibility to MS [14]. In an EAE model, neomycin-treated rats exhibited lower levels of microglial activation markers and cytokine release. In contrast, their microglia shifted toward a type I interferon response with enhanced phagocytic function and exerted neuroprotective effects. Further research revealed that neomycin treatment significantly increased lung LPS levels and that LPS plays a key role in suppressing EAE onset. Thus, changes in lung microbiota composition can indirectly affect microglial activation status and the brain’s immune microenvironment by regulating LPS levels, ultimately modulating disease progression.

Other neurological disorders

Delirium in ICU patients is associated with MV [153]. The associated brain injury is mediated primarily via the “lung-brain axis”: on the one hand, mechanical stretch activates specific pulmonary mechanosensors (e.g., TRPV4 channels), transmitting signals via vagal afferents that alter hippocampal dopaminergic activity, directly leading to neuronal dysfunction and apoptosis and thereby triggering delirium [334, 457]. On the other hand, lung injury caused by MV results in the release of many inflammatory cytokines (e.g., IL-6), which can enter the circulation, cross the BBB, or induce central neuroinflammation, further damaging cognition-related brain areas such as the hippocampus and collectively contributing to delirium onset [156, 458].

Studies have shown that dyspnea in asthma patients can trigger abnormal activity in brain regions involved in emotional regulation (e.g., the insula), leading to a reduced emotional control capacity and a predisposition to anxiety and depression [71, 459]. The core mechanism involves systemic inflammation causing disruption of the BBB; the activation of microglia and astrocytes in the amygdala and prefrontal cortex; and disrupted synthesis and release of neurotransmitters such as dopamine, serotonin, and NE, directly promoting anxiety-like behaviors [460]. Concurrently, abnormalities in synaptic plasticity-related proteins in patients’ brains further provide a pathological basis for comorbid cognitive and mood disorders, confirming that asthma is a significant somatic trigger for psychiatric conditions [461].

The core pathology of migraine involves dysregulation of the trigeminovascular system and brainstem descending pain pathways (e.g., 5-HT neurons in the periaqueductal gray) [462–464]. Clinical observations showed an increased risk of migraine in patients with asthma, bronchitis, and even lung cancer [465–467]. Notably, recent animal experiments revealed that changes in the lung microbiome can activate vagal sensory fibers, relay signals to the NTS, and subsequently promote the release of serotonin in the brain, ultimately alleviating migraine-like pain [468].

Furthermore, pulmonary diseases may directly induce or exacerbate neurological damage: hypoxemia and metabolic disturbances caused by pneumonia can lower the seizure threshold, and pathogen toxins or secondary autoimmune responses can lead to abnormal neuronal discharges; chronic hypoxia from lung disease can even result in the formation of permanent epileptic foci [469, 470]. On the other hand, the lung‒brain axis also plays a regulatory role in neurodegenerative diseases; for instance, ALI and COPD may influence the progression of Huntington’s disease by affecting cellular autophagy activity [471], which is involved in the clearance of mutant proteins [472]. One hypothesis suggests that air pollutants (e.g., PFAS) may increase stroke risk by activating platelets and promoting thrombus formation [473]. These mechanisms collectively reveal the significant effect of respiratory system health on CNS function.

Discussion and perspectives

The lung-brain axis represents a complex communication network that links the respiratory system and the CNS [261]. This interconnected network, in which signaling is mediated by neural, inflammatory, and immunomodulatory pathways, plays crucial roles in the pathogenesis and progression of various diseases [262, 263]. A growing body of fundamental and clinical research underscores the intricate relationship between pulmonary and CNS pathologies.

Foremost, the inflammatory response is paramount. Pulmonary inflammation, triggered by factors such as bacterial infections and air pollution, activates peripheral immune responses, leading to sustained increases in proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in the systemic circulation [474]. These molecules can access the CNS via specific transporters or by compromising BBB integrity, subsequently activating microglia and inducing neuroinflammation [393]. Neuroinflammation is not only is a hallmark of neurodegenerative diseases such as AD but also directly exacerbates Aβ and Tau pathology and impairs synaptic plasticity [475]. Furthermore, chronic pulmonary diseases, such as COPD, are often associated with a significant oxidative/antioxidant imbalance [476]. ROS can directly assault cerebrovascular endothelial cells, worsening BBB dysfunction. More critically, upon penetrating the BBB, ROS directly damage neurons and glial cells. Concurrently, ROS can activate key inflammatory signaling pathways such as NF-κB [477]. In contrast, inflammatory cytokines released by cells can further promote ROS production, creating a vicious cycle between oxidative stress and inflammation that exacerbates neural injury. This cycle represents one potential mechanism underlying dopaminergic neuronal damage in patients with PD [478]. Both inflammatory responses and oxidative stress also impair cerebrovascular function and integrity [479], affecting cerebral blood flow perfusion by reducing the vasodilatory capacity and potentially promoting plaque deposition. This process can lead to dysfunctional mitochondrial energy metabolism. Hypoxia, directly or indirectly via HIF-1-induced neuronal apoptosis, can disrupt neural cell integrity [480], thereby increasing the risks of epilepsy and cognitive impairment.

The elucidation of the lung-brain axis has profoundly transformed our understanding of the etiology of neurological disorders and opened promising new avenues for the development of cross-system intervention strategies. Future therapeutic directions targeting lung-brain axis-related pathologies could focus on three core aspects: anti-inflammatory modulation, oxidative stress defense, and pulmonary microbiota remodeling.

Regarding anti-inflammatory strategies, targeting the inflammatory response—a key node in lung-brain injury—calls for the development of precise therapeutics [263]. Priorities include the design of specific neutralizing antibodies or receptor antagonists that can efficiently cross the BBB or act in the peripheral system to block signaling by critical cytokines such as TNF-α, IL-1β, and IL-6 [382]. Simultaneously, modulating microglial polarization from a proinflammatory M1 phenotype to a neuroprotective M2 phenotype is a vital strategy for treating related diseases such as AD [398]. Oxidative stress, another critical link connecting pulmonary injury and neurological disorders, underscores the importance of increasing the endogenous antioxidant capacity [481]. The development of novel mitochondria-targeted antioxidants can effectively counteract disrupted energy metabolism induced by lung-derived ROS [482]. Furthermore, increasing the body’s intrinsic antioxidant defenses by activating signaling pathways such as Nrf2 represents a broad-spectrum and sustainable neuroprotective strategy for treating neurodegenerative diseases such as PD [483].

The lung microbiome, which acts as an “upstream regulator” of the lung-brain pathway, is an attractive intervention target [1]. Restoring lung microbiota homeostasis via inhaled probiotics or specific antibiotics can reduce the generation of proinflammatory signals at their source [484], thereby indirectly modulating microglial function and achieving early control of central neuroinflammation. Such personalized therapies based on microecological modulation hold promise as cutting-edge approaches for preventing and alleviating lung-brain axis-related diseases. Notably, research on key protein markers such as TLR4, ACE2, and IL-6 is advancing rapidly: anti-IL-6 receptor antibodies have been tested in COVID-19 patients [485]; TLR4 knockout models have been used to confirm the protective role of TLR4 in MV-associated neuroinflammation [486]; and ACE2 modulators have been shown to mitigate the pulmonary and neurological complications of COVID-19 [487].

Given the complexity of lung-brain axis mechanisms, future clinical practice may increasingly rely on combination therapies. Concurrently, the active identification of biomarkers that reflect the state of lung-brain communication, such as specific inflammatory cytokine profiles in peripheral blood or characteristic features of the lung microbiota, is crucial for identifying high-risk individuals before the onset of neurological symptoms and enabling early intervention [290, 382]. Future efforts should employ longitudinal studies to definitively establish the causal relationship between respiratory and neurological diseases, delve deeper into key mediators related to inflammatory factors and oxidative stress, and explore interventions targeting these pathways. Identifying high-risk individuals before the onset of neurological symptoms and achieving early intervention are vital.

Conclusions

In summary, the lung-brain axis represents a complex, bidirectional network through which pulmonary dysfunction contributes to neurological disorders via integrated microbial, immune, neural, metabolic, and hormonal pathways. These mechanisms collectively drive neuroinflammation, BBB disruption, and neuroglial activation, ultimately leading to neuronal injury and cognitive or behavioral deficits. The axis operates reciprocally, with CNS pathology also predisposing to pulmonary complications. Environmental exposures further amplify this crosstalk, extending neurological risk. Elucidating this interconnected framework transcends conventional organ-specific paradigms and offers a transformative perspective for early diagnosis, prevention, and therapeutic strategies that jointly target respiratory and neurological health.

Authors’ contributions

PW, XK, ZX, and GW supervised, reviewed, and edited the project. LW, FW, XW, XC and CL summarized the literature, wrote the initial manuscript, and drew the figures. PW, XK, ZX, GW proofread the structures and revised the manuscript. KS and HZ have completed the manuscript revision and the figure preparation. All authors have read and agreed to the published version of the manuscript.

Funding

The work was supported by National Natural Science Foundation of China (Nos.82571352; 22201164), China Postdoctoral Science Foundation (2024M761822), the Qingdao Key Health Discipline Development Fund (QDZDZK-2025064), the Natural Science Foundation of Shandong Province (ZR2024QH041), the Scientific Research Foundation of Qilu Hospital of Shandong University (QDKY2023ZD02), Medical and Health Scientific Research Project of Qingdao (2024-WJKY155), Qingdao Municipal Natural Science Foundation (25-1-1-231-zyyd-jch).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.