Abstract
Acute brain injury (ABI) frequently precipitates severe extracranial target-organ complications, with the lungs being the most directly and fatally affected distant organs. Traditionally, the rapid onset of pulmonary dysfunction following brain injury has been attributed to the “massive catecholamine release”—a massive, dysregulated release of catecholamines leading to intense systemic vasoconstriction, elevated pulmonary capillary hydrostatic pressure, and subsequent neurogenic pulmonary edema. However, this purely neuro-hemodynamic model falls short of explaining the delayed onset and highly inflammatory nature of acute respiratory distress syndrome that persists during the later stages of injury. Recently, the discovery of the glymphatic system has provided a groundbreaking molecular and anatomical framework for understanding the pathological crosstalk within the “brain-lung axis.” As a macroscopic waste clearance network within the central nervous system highly dependent on the polarized expression of aquaporin-4 (AQP4), the glymphatic system undergoes structural and functional severe impairment following ABI. The loss of AQP4 polarization, coupled with reactive astrogliosis, halts cerebrospinal fluid-interstitial fluid exchange. This drainage failure not only forces the massive accumulation of damage-associated molecular patterns and pro-inflammatory cytokines within the brain parenchyma but also drives the systemic “spillover” of high-concentration neurogenic toxins through enzymatic disruption of the blood–brain barrier and the hijacked meningeal lymphatics. These brain-derived mediators—whether circulating freely or encapsulated within extracellular vesicles—travel via the systemic circulation to the pulmonary capillary bed. Upon reaching the lungs, they specifically target pulmonary microvascular endothelial cells by binding to TLR4 and RAGE receptors, triggering the phosphorylation and internalization of vascular endothelial cadherin, and thus completely dismantling the endothelial barrier. Concurrently, these signals drive the M1 polarization of alveolar macrophages, eliciting destructive neutrophil infiltration and parenchymal damage. Crucially, this pulmonary dysfunction generates severe hypoxemia and releases lung-derived inflammatory mediators that feed back to the central nervous system, establishing a fatal bidirectional vicious cycle. This narrative conceptual review aims to comprehensively dissect the bidirectional immune-inflammatory cascade network of the brain-lung axis triggered by glymphatic collapse and systematically evaluate the latest therapeutic prospects, considering the impact of pre-morbid systemic stressors and mechanical ventilation, while targeting AQP4 modulation, lymphangiogenesis, and systemic inflammation blockade.
1 Introduction
1.1 Evolution of the “brain-lung axis” concept: from massive catecholamine release to glymphatic breakdown
An intricate and bidirectional communication network exists between the CNS and the respiratory system, a trans-organ physiological and pathological interface widely termed the “brain-lung axis” (1, 2). For decades, the understanding of acute lung injury (ALI) secondary to severe brain injury within intensive care and neurosurgical settings was largely confined to the theory of autonomic hyperactivation (3). The classical paradigm postulated that severe cranial trauma or sudden spikes in intracranial pressure (ICP) trigger uncontrolled discharges in the hypothalamic and brainstem sympathetic centers, releasing massive quantities of epinephrine and norepinephrine (4, 5). This endocrine cataclysm, known as a “massive catecholamine release,” induces intense systemic vasoconstriction, shifting massive blood volumes into the lower-resistance pulmonary circulation (6). This abrupt surge overwhelms the hydrostatic pressure threshold of pulmonary capillaries, forcing protein-rich fluid into the alveolar space via mechanical “stress failure,” culminating in classic NPE (7, 8).
While the hydrostatic and massive catecholamine release theory elucidates the hyperacute pulmonary edema erupting within minutes to hours post-injury, it fails to explain the ARDS characterized by profound immune-inflammatory features that typically emerges 3 to 7 days post-ABI (9). Recent neurobiological breakthroughs have bridged this theoretical gap: the discovery of the glymphatic system and its functional impairment following brain injury marks a new era where molecular immunology intersects with neuroanatomy in brain-lung axis research (10, 11). The glymphatic system is not merely a physical clearance network maintaining the internal microenvironment of the brain; it serves as the central “floodgate” regulating the outward diffusion of central inflammation (12, 13). Recent reviews highlight that glymphatic dysfunction exerts systemic effects beyond the CNS, contributing directly to the breakdown of the brain-lung axis (14). When this system collapses post-injury, it metamorphoses from a protective clearance conduit into a focal source that amplifies and broadcasts neuroinflammation systemically, profoundly rewriting our fundamental understanding of brain-lung axis disruption.
1.2 High incidence and poor prognosis of ALI following ABI
In the clinical practice of the neurocritical care unit (NICU), pulmonary complications triggered by ABI (including severe TBI, high-grade aneurysmal SAH, and massive ischemic stroke) exhibit a striking incidence and exceptionally high mortality (15). Recent epidemiological meta-analyses and prospective cohort studies indicate that the incidence of ALI, progressing to severe ARDS, reaches 15 to 22% in patients with isolated severe TBI or high-grade SAH (16, 17). This secondary lung injury does not occur concurrently with the initial brain trauma; the median time to clinical diagnosis is typically around day 3 post-primary injury, which precisely coincides with the peak of intracerebral inflammatory cytokines and the most severe phase of glymphatic drainage stagnation.
Once an ABI patient develops ARDS, a fatal bidirectional vicious cycle is rapidly initiated. On one hand, extensive destruction of lung parenchyma and hyaline membrane formation lead to severe, refractory hypoxemia and hypercapnia, directly exacerbating the brain’s secondary metabolic crisis and inducing hypoxic–ischemic encephalopathy. Furthermore, the severely injured lungs no longer act merely as a passive target; they become an active secondary reservoir of systemic inflammation. Activated alveolar macrophages and injured pulmonary endothelium release massive lung-derived pro-inflammatory cytokines (such as IL-6 and TNF-α) and extracellular vesicles back into the systemic circulation. These lung-derived mediators travel back to the brain, infiltrating the already compromised blood–brain barrier to further aggravate neuroinflammation, exacerbate astrogliosis, and worsen glymphatic stagnation (18–20). On the other hand, mechanical ventilation strategies required to correct hypoxemia (e.g., high positive end-expiratory pressure, PEEP) impede jugular venous return. This elevated intrathoracic pressure not only further elevates ICP and causes a precipitous drop in cerebral perfusion pressure (CPP) (21), but critically, it mechanically suppresses normal CSF flow and glymphatic drainage, severely compounding the brain’s inability to clear neurotoxic waste.
1.3 Objective of the review
Given these critical clinical challenges, the primary objective of this review is to systematically delineate a network mechanism model based on the latest molecular and anatomical evidence, elucidating how the failure of the glymphatic system as the central “clearance pipeline” mediates targeted damage to the distal lung parenchyma. We will deeply deconstruct the microscopic dynamics of AQP4 polarization loss, trace the specific routes by which brain-derived toxic substances (especially DAMPs and extracellular vesicles) breach the BBB and utilize meningeal lymphatics to “spill over” into the systemic circulation, and uncover the molecular targets through which these mediators precisely attack the pulmonary vascular endothelial barrier and remodel the alveolar immune microenvironment. By bridging the mechanistic link from intracranial glial cells to pulmonary microvascular endothelial cells, this article aims to provide a panoramic cognitive framework for researchers and establish a robust theoretical foundation for future precision medicine strategies that salvage the “brain-lung axis” via targeted glymphatic protection. It is important to note that post-ABI ARDS is highly multifactorial; the glymphatic hypothesis operates in parallel with established clinical contributors such as ventilator-associated lung injury (VALI), secondary aspiration pneumonitis, and systemic fluid overload (22).
1.4 Literature search strategy
To comprehensively gather the latest evidence on the glymphatic system’s role in the brain-lung axis, a systematic literature search was conducted in PubMed and the Web of Science Core Collection, primarily targeting publications from the past decade. The search strategy utilized a combination of Medical Subject Headings (MeSH) and free-text keywords, employing Boolean operators (AND, OR) to intersect three core concept pools: central nervous system injury and drainage mechanisms (e.g., “Glymphatic System,” “Aquaporin 4,” “Meningeal lymphatics,” “Brain Injuries,” “Subarachnoid Hemorrhage”), distal pulmonary damage (e.g., “Acute Lung Injury,” “Respiratory Distress Syndrome,” “Neurogenic Pulmonary Edema”), and mediating molecular pathways (e.g., “DAMPs,” “HMGB1,” “Systemic Inflammation”). Crucially, during the literature selection process, original research was strictly prioritized.
2 Physiology and pathophysiology of the glymphatic system: microenvironmental catastrophe within the brain parenchyma
From a neuroanatomical and neurophysiological perspective, the brain is the most metabolically active organ in the human body, yet it lacks a traditional intraparenchymal lymphatic vessel network (23). In its place is a highly specialized fluid convection and waste clearance network dependent on astrocytes and their perivascular endfeet—the glymphatic system (Figure 1).
Figure 1
2.1 AQP4-mediated CSF-ISF exchange under physiological conditions
In a healthy physiological state, the glymphatic system maintains fluid balance, nutrient distribution, and macroscopic metabolic waste clearance within the CNS (24). The anatomical basis of this system is the perivascular space (Virchow-Robin space), a continuous channel formed between the vascular smooth muscle layer of penetrating cerebral arteries and the overlying astrocytic endfeet (25). Cerebrospinal fluid (CSF) flows from the subarachnoid space down these periarterial spaces, penetrating deep into the brain parenchyma (26). The downward driving force for this fluid is primarily derived from the mechanical arterial pulsation generated by the cardiac cycle (27).
The core molecular cornerstone facilitating efficient exchange between CSF and interstitial fluid (ISF) is aquaporin-4 (AQP4). AQP4 is a specific channel protein mediating rapid transmembrane water transport. Under physiological conditions, its distribution in the brain exhibits high structural asymmetry, termed “polarization.” Over 80% of AQP4 is densely clustered on astrocytic endfeet directly abutting cerebral microvessels and the pia mater, forming orthogonal arrays of particles (OAPs), which are primarily mediated by the M1 and M23 isoforms of AQP4. This polarized distribution relies on the dystrophin-associated protein complex (DAPC), specifically α-syntrophin, which firmly anchors AQP4 to the perivascular basal lamina (28).
As arterial pulsation drives CSF into the periarterial space, assisted by low-resistance transmembrane water flow mediated by AQP4, CSF efficiently crosses the astrocytic endfeet, enters the brain parenchyma, and mixes with ISF. This mixed fluid creates a microscopic convective flow within the parenchyma, flushing toxic waste products generated by neuronal and glial metabolism (e.g., amyloid-β, p-Tau protein, and various cytokines) toward deep perivenous spaces (29, 30). Ultimately, this waste-laden fluid exits the brain parenchyma along the perivenous spaces, draining into meningeal lymphatics or the cervical lymphatic network. Notably, this physiological “washing” process is highly state-dependent; during deep non-rapid eye movement (NREM) sleep, a decline in central noradrenergic tone expands the extracellular space volume by approximately 60%, boosting CSF-ISF convective exchange efficiency to several times that of the awake state.
2.2 After ABI: loss of AQP4 polarization, astrogliosis, and drainage stagnation
Following ABI (such as severe TBI or SAH, primarily as a secondary cause of parenchymal ABI), this precise fluid dynamic and molecular anchoring system suffers devastating disruption, plunging the glymphatic drainage into complete stagnation. This systemic collapse originates from multidimensional pathophysiological cascades (31).
First, acute mechanical trauma (e.g., shear stress in TBI) or subarachnoid blood degradation products (e.g., fibrinogen and microthrombi in SAH) cause direct physical tearing of astrocytic endfeet and microcirculatory dysfunction (32–34). This severe physical and chemical stress triggers the disassembly of the DAPC anchoring complex (35). Stripped of its underlying molecular tether, AQP4 detaches from the perivascular endfeet and redistributes uniformly across the entire astrocytic soma (36). This critical mislocalization is termed “loss of AQP4 polarization” or AQP4 depolarization. The loss of AQP4 polarization severs the fluidic coupling between arterial pulsation and CSF parenchymal entry, severely reducing or completely halting directional trans-astrocytic water flow.
Second, ABI incites a robust neuroinflammatory response, inducing reactive astrogliosis. During the early to subacute phases of injury, astrocyte somas become markedly hypertrophic, accompanied by a sharp upregulation of marker proteins like glial fibrillary acidic protein (GFAP). The hypertrophic and proliferating astrocytes interweave to form a dense glial scar. While this structural remodeling partially isolates the injury core, its direct side effect is the physical compression and occlusion of the already narrow perivascular spaces. Consequently, molecular AQP4 depolarization and anatomical spatial occlusion caused by astrogliosis synergistically seal off the brain’s clearance pipeline, severely impairing the glymphatic system’s convective and clearance functions (37).
2.3 The consequences of drainage stagnation: cascade accumulation of DAMPs and cytokines
The most direct and destructive consequence of glymphatic stagnation is the entrapment of massive amounts of brain-derived toxic substances within the extracellular space (ECS). During ischemia, hypoxia, or physical tearing, necrotic or secondarily apoptotic neurons and glial cells release intracellular structural proteins, nucleic acids, and metabolites into the microenvironment, collectively known as DAMPs.
Key DAMPs driving the breakdown of the “brain-lung axis” include:
High mobility group box 1 (HMGB1): Normally a non-histone protein residing in the nucleus involved in DNA folding, HMGB1 transforms into a highly destructive pro-inflammatory alarmin once released extracellularly. It binds with high affinity to various pattern recognition receptors (PRRs, predominantly TLR4 and RAGE), initiating fierce inflammatory transcriptional cascades (38–40).
S100B protein: A calcium-binding protein primarily secreted by astrocytes. Post-ABI, its local concentration rises exponentially. As a potent ligand for RAGE, it amplifies glial stress responses (41–43).
Neuron-specific enolase (NSE) and other metabolites: These macromolecules continually accumulate in the undrained brain parenchyma (42, 44).
Due to the halted glymphatic flow, these high-concentration DAMPs cannot be transported to cervical lymph nodes for immune tolerization; instead, they continuously ferment within local brain tissues. By binding to TLR4 and RAGE receptors on microglia and astrocytes, they activate the MyD88 and NF-κB pathways, compelling resting microglia to rapidly polarize into the highly cytotoxic M1 (classically activated) phenotype (45, 46). M1 microglia subsequently unleash a deluge of primary pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (47, 48). This forms an uncontrollable death spiral: DAMP accumulation triggers an inflammatory storm, which further disrupts AQP4 polarization and exacerbates perivascular edema, ultimately turning the brain microenvironment into a highly invasive “pro-inflammatory microenvironment “capable of attacking the periphery.
3 “Spillover” and systemic propagation of brain-derived toxic substances: from cranial disaster to systemic alarm
Within the closed, un-drained cranial vault, accumulating DAMPs and pro-inflammatory cytokines act as a rapidly pressurizing time bomb. The brain typically enjoys “immune privilege,” maintained by the strict filtration of the BBB and the organized drainage of meningeal lymphatics (49, 50). However, when severe neuroinflammation dismantles and remodels these anatomical defenses, intracranial toxins begin an uncontrolled “spillover” into the systemic circulation, initiating the systemic propagation phase of brain-lung axis collapse (Figure 2). The stagnation of glymphatic convective flow generates an extreme interstitial concentration gradient, physically driving these accumulated DAMPs across the enzymatically compromised BBB into the systemic circulation.
Figure 2
3.1 Enzymatic disruption of the BBB and the dual role of meningeal lymphatics
The mechanical and enzymatic degradation of the BBB serves as the primary gateway for brain-derived toxic substances to flood into the peripheral blood. M1 microglia and reactive astrocytes, activated by DAMPs and local cytokines (like IL-1β and TNF-α), synthesize and secrete massive quantities of matrix metalloproteinases (MMPs, especially MMP-3 and MMP-9). Acting as molecular scissors, these proteolytic enzymes specifically degrade key structural proteins maintaining endothelial tight junctions, such as Claudin-5, Occludin, and Zonula Occludens-1 (ZO-1). Accompanied by endothelial cytoskeletal contraction and pathological widening of intercellular gaps, BBB permeability increases drastically. Previously confined gigatons of HMGB1, S100B, and free cytokines leak directly down their concentration gradients into capillary and venule networks, rapidly merging into the systemic venous circulation.
Concurrently, recent advances in neuroimmunology have uncovered the complex “dual role” played by meningeal lymphatic vessels (mLVs) located in the dura mater during this pathological process (51). Under physiological conditions or mild trauma, mLVs exert protective clearance and immune surveillance functions, absorbing antigen-laden CSF and draining it orderly toward the skull base to eventually reach deep cervical lymph nodes (dCLNs) (52). However, during severe ABI and glymphatic dysfunction, the extreme burden of inflammatory mediators and tissue debris can physically obstruct or paralyze mLVs due to lymphatic endothelial damage, plunging immune surveillance efficiency. More lethally, the lymphatic vessels that remain patent transform from benign antigen-presenting channels into a high-capacity “toxin highway.” Ultra-high concentrations of brain-derived cytokines and DAMPs march straight through the mLVs to the dCLNs, causing aggressive priming of the peripheral immune system. Here, antigen-presenting cells present brain-derived antigens to peripheral T cells and monocytes, inducing systemic immune dysregulation. This mobilizes peripheral immune cells to be released masse into the systemic circulation, providing ample “ammunition” for the impending inflammatory storm in the lungs.
3.2 Tracking systemic propagation and “stealth delivery” via EVs
After breaching anatomical barriers, these concentrated brain-derived toxic mediators must traverse the systemic circulation to reach the lungs. From an anatomical-dynamic perspective, toxic substances entering capillaries via the damaged BBB or joining the venous angles via cervical lymph nodes directly converge into the internal jugular vein, subsequently entering the superior vena cava. Because the pulmonary circulation is the first—and the most expansive (over 100 square meters of surface area)—microvascular bed encountered by all returning venous blood, the lungs inevitably become the “first filter” and the most direct target organ for brain-derived toxins.
Notably, recent molecular investigations reveal that this propagation is not solely reliant on the free diffusion of molecules in the blood. A significant proportion of highly pathogenic mediators are encapsulated within brain-derived EVs for targeted delivery (53). EVs are nanoscale lipid-bilayer vesicles (typically 30–150 nm in diameter) secreted by damaged neurons, astrocytes, and microglia (54). Owing to their lipid bilayer structure, EVs possess formidable penetrating ability, easily crossing the disrupted BBB while shielding vulnerable encapsulated macromolecules (e.g., proteins, RNAs) from degradation by abundant blood proteases and nucleases (55).
Post-ABI, not only does the quantity of brain-derived EVs explode, but their “cargo” also undergoes significant pathological alteration. Studies demonstrate that EVs are a crucial, stealthy vehicle for the release and systemic dissemination of DAMPs like HMGB1 and inflammasome components. Crucially, these EVs are enriched with pathological microRNAs (miRNAs) wielding epigenetic regulatory functions, such as miR-362 (56). When these EVs, carrying the “codes of neural injury, “reach the pulmonary circulation, they are directly taken up by pulmonary microvascular endothelial cells and alveolar macrophages via membrane fusion or receptor-mediated endocytosis. This precisely unleashes the brain’s “destruction directives” into the cytoplasm of lung cells, triggering deep gene expression reprogramming and targeted attacks.
4 Targeted attack on the lungs: from endothelial barrier disruption to immune microenvironment remodeling
As free serum proteins laden with HMGB1 and S100B, primed peripheral immune cells, and brain-derived EVs carrying pathological miRNAs surge into the pulmonary capillary bed, the structural devastation of the lungs officially commences (57). This process exhibits astonishing molecular specificity, progressing via two main pathways: the direct destruction of the vascular endothelial physical barrier, and the malignant remodeling of the alveolar immune microenvironment (Figure 3). Because the intracranial glymphatic clearance remains severely impaired, the brain acts as a continuous upstream generator of EVs and DAMPs, actively preventing the resolution of pulmonary inflammation. However, it is crucial to recognize that this communication is not a unidirectional downstream cascade. Once the pulmonary immune microenvironment is mal-remodelled, the lungs transition from a ‘victim’ organ to a potent secondary driver of pathology. The intense oxidative stress, trapped neutrophils, and alveolar damage generate a massive influx of retrograde inflammatory signals (hypoxemia, lung-derived DAMPs) back to the central nervous system. This bidirectional feedback severely compounds neural vulnerability, creating an interdependent cycle of neuro-pulmonary deterioration where neither organ can resolve its inflammation without the other.
Figure 3
4.1 Brain-derived DAMPs/cytokines bind TLR4, dismantling the VE-cadherin endothelial barrier
The integrity of the alveolar-capillary barrier is a prerequisite for maintaining normal gas exchange and preventing fluid extravasation. The core stability of this physical barrier relies on the adherens junctions (AJs) between pulmonary microvascular endothelial cells, with Vascular Endothelial Cadherin (VE-cadherin) acting as the most critical transmembrane structural protein (58).
The luminal surface of pulmonary vascular endothelial cells constitutively expresses high levels of various pattern recognition receptors (PRRs), particularly TLR4 and RAGE. When brain-derived DAMPs (such as HMGB1) arrive at the pulmonary capillaries, they exhibit extremely high affinity for TLR4 and RAGE, executing specific binding. The activation of the HMGB1-TLR4/RAGE axis not only triggers classical MyD88-dependent pathways—leading to NF-κB nuclear translocation and localized secondary inflammatory cascades—but critically, it rapidly initiates rapid kinase signaling pathways that dismantle endothelial junctions.
Upon receptor activation, intracellular pro-permeability signaling molecules, such as c-Src kinase and RhoA-associated coiled-coil forming protein kinase (ROCK), are swiftly activated, simultaneously inhibiting vascular endothelial protein tyrosine phosphatase (VE-PTP), which normally maintains barrier tightness (59). This signaling imbalance leads to hyperphosphorylation of key tyrosine residues in the intracellular domain of VE-cadherin. Phosphorylated VE-cadherin not only loses physical binding affinity with its intracellular anchoring proteins (like p120-catenin and plakoglobin) but also undergoes rapid internalization from the cell membrane, entering intracellular degradation pathways. The downregulation and internalization of VE-cadherin forcefully “unzip” the adherens junctions between adjacent endothelial cells, forming paracellular gaps. This total collapse of endothelial connectivity causes pulmonary capillary permeability to skyrocket exponentially, allowing protein-rich fluid, red blood cells, and activated immune cells to pour unrestrictedly into the pulmonary interstitium and alveolar spaces, yielding the hallmark protein-rich exudate and severe pulmonary edema of ARDS.
4.2 M1 polarization of alveolar macrophages and destructive neutrophil infiltration
Beyond the collapse of physical barriers, the pulmonary immune microenvironment undergoes profound rearrangement. Under physiological conditions, alveolar macrophages (AMs) residing on the alveolar surface maintain a resting (M0) or reparative (M2) polarization state, possessing high phagocytic capacity without inciting severe inflammation to preserve immune tolerance. However, when exposed to the barrage of brain-derived EVs and DAMPs (e.g., high levels of HMGB1, ATP) that flood the lungs secondary to BBB disruption, these macrophages are forced to undergo abrupt phenotypic switching, polarizing towards the classically activated, pro-inflammatory M1 phenotype.
Once polarized to M1, alveolar macrophages act like highly reactive effector cells. NADPH oxidases (such as the NOX2 system) on their cell membranes are strongly activated, sparking an explosive generation of reactive oxygen species (ROS) and creating an environment of intense oxidative stress. Simultaneously, these M1 cells unleash floods of chemokines (e.g., CXCL1, IL-8) and primary pro-inflammatory cytokines (IL-1β, TNF-α) (60). Furthermore, bone marrow-derived monocytes and neutrophils—mobilized by brain injury inflammatory signals—massively roll, adhere, and transmigrate across the already VE-cadherin-depleted endothelial gaps, surging aggressively into the lung interstitium and alveolar spaces under the guidance of CXCL1 chemotactic gradients.
Upon entering the alveolar space, neutrophils degranulate under extreme inflammatory stimulation, releasing neutrophil elastase and matrix metalloproteinases that further degrade alveolar epithelial cells. More, driven by HMGB1 and severe oxidative stress, large numbers of neutrophils undergo NETosis, extruding neutrophil extracellular traps (NETs) composed of web-like DNA structures and microbicidal proteins (61). Although NETs originally evolved to ensnare invading pathogens, in this scenario of sterile neuroinflammation, widespread NETs directly inflict lethal damage on fragile type I alveolar epithelial cells and surfactant-secreting type II alveolar epithelial cells, resulting in alveolar collapse and the blockade of normal gas exchange.
4.3 Molecular distinction between NPE and typical ARDS
While NPE and brain-injury-associated ARDS both present with diffuse bilateral pulmonary infiltrates and severe hypoxemia on clinical imaging, their underlying pathobiology and molecular drivers are fundamentally distinct. To delineate this temporal and pathological transition, the table below systematically contrasts classic sympathetic-driven NPE with ARDS driven by glymphatic dysfunction (Table 1).
Table 1
| Clinical and molecular features | Neurogenic pulmonary edema (NPE) | ABI-associated ARDS (glymphatic dysfunction-driven) |
|---|---|---|
| Time of onset | Hyperacute phase (minutes to hours post-primary injury) | Delayed/Subacute phase (median onset generally 3 to 7 days post-injury) |
| Core driving mechanism | Central sympathetic storm, massive catecholamine release | Glymphatic clearance failure, DAMP spillover, and systemic inflammatory amplification |
| Hemodynamic changes | Intense systemic and pulmonary vasoconstriction; transient spike in pulmonary capillary hydrostatic pressure | Inflammatory vasodilation; progressive, catastrophic increase in pulmonary vascular endothelial permeability |
| Capillary pathology | Predominantly mechanical “Stress failure” | VE-cadherin internalization/degradation; enzymatic cleavage of tight and adherens junctions |
| Plasma/lung fluid markers | Rapid elevation of epinephrine, norepinephrine, neuropeptide Y | High levels of DAMPs (HMGB1, S100B, NSE), elevated IL-6, TNF-α, vWF |
| Extracellular vesicles (EVs) | Lack of specific pro-inflammatory EV enrichment | Massive influx of pathological brain-derived EVs carrying miR-210, miR-338-3p, and ACE+ EVs |
| Alveolar immune response | Mild early stress changes; lack of significant parenchymal destruction | Widespread M1 macrophage polarization; massive neutrophil infiltration, degranulation, and NETosis |
| Edema fluid nature | Transudate: low protein content, few cellular components | Exudate: High protein content, rich in cellular debris, fibrin, and inflammatory cells |
Comparison of mechanistic and molecular features between neurogenic pulmonary edema (NPE) and brain-derived ARDS mediated by glymphatic dysfunction.
4.4 The afferent loop: pulmonary dysfunction exacerbates neural vulnerability
Crucially, the brain-lung crosstalk is not unidirectional but constitutes a pathological bidirectional vicious cycle. As pulmonary pathologies such as ARDS develop, they profoundly impact neural vulnerability. The resulting refractory hypoxemia and hypercapnia directly induce cerebral vasodilation, elevating intracranial pressure (ICP) and compounding the brain’s metabolic crisis (62, 63). Furthermore, the injured lungs act as a secondary inflammatory reservoir. Activated alveolar macrophages and injured pulmonary endothelium release massive quantities of systemic cytokines (e.g., IL-6, TNF-α) and lung-derived EVs. These peripheral inflammatory signals breach the already compromised BBB, triggering autonomic neuro-dysregulation and an intensified immune feedback loop within the CNS. This secondary hit exacerbates reactive astrogliosis, further polarizing microglial activation, and continuously suppresses glymphatic outflow, thereby trapping the patient in a lethal feedback loop of interdependent organ failure (16, 64, 65).
5 Therapeutic prospects targeting the glymphatic system to protect the “brain-lung axis”
Given that pulmonary complications following ABI are deeply rooted in the physical severe impairment of the intracranial glymphatic system and the subsequent systemic “spillover” of immune-inflammation, the focus of modern neurocritical intervention is undergoing an unprecedented paradigm shift. The frontier of clinical treatment is pivoting from isolated pulmonary support (e.g., mechanical ventilation adjustments) to disrupting the malignant axis of trans-organ communication at its source. Strategies to protect the “brain-lung axis” primarily focus on two core dimensions: repairing glymphatic clearance physically or pharmacologically within the cranium, and precisely intercepting the spread of neurogenic inflammatory cascades in the systemic circulation.
5.1 Pre-morbid vulnerabilities and mechanical ventilation as modulators
When evaluating therapeutic potential, it is imperative to recognize that therapeutic frameworks cannot treat the organs merely as isolated “sources” or “victims,” but rather as interdependent victims within a bidirectional crosstalk. Furthermore, the efficacy of any intervention is heavily influenced by pre-morbid systemic stressors and environmental modulators. Patients with pre-morbid obstructive sleep apnoea (OSA) suffer from chronic intermittent hypoxia, which severely disrupts the circadian control of the glymphatic system. Similarly, environmental factors like cigarette smoke and ozone in chronic obstructive pulmonary disease (COPD) chronically exacerbate oxidative stress and influence DAMPs. These pre-morbid conditions induce chronic glymphatic outflow dysfunction, alter lung-to-brain EV signaling, and disrupt the peri-plaque microenvironment, often leading to amyloid-beta accumulation and astrocyte dysfunction even prior to the acute ABI (66–68). Consequently, when ABI occurs, these patients possess a highly vulnerable neuro-immune-pulmonary network. Additionally, the inevitable clinical use of mechanical ventilation limits therapeutic efficacy by artificially increasing ICP and physically suppressing CSF flow, necessitating highly personalized ventilation strategies that balance oxygenation with glymphatic patency.
5.2 Pharmacological and physiological interventions to improve glymphatic function
The key to reversing glymphatic stagnation lies in restoring the fluid dynamics of the brain interstitial space and repairing AQP4 spatial polarization, thereby unblocking the macromolecular “clearance pipeline.”
5.2.1 Sleep regulation and the neuroprotective role of dexmedetomidine
The fluid convection efficiency of the glymphatic system is profoundly regulated by the sleep–wake cycle. During slow-wave sleep in the deep NREM phase, central noradrenergic tone drops significantly, expanding perivascular space volume and minimizing interstitial fluid drainage resistance, thereby maximizing the clearance efficiency of amyloid proteins and DAMPs. In states of severe brain trauma or postoperative stress, patients often experience profound sleep deprivation and neurotransmitter disruption, further exacerbating the severe impairment of the clearance system.
Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated remarkable therapeutic potential in this context. At the molecular and network level, Dex specifically inhibits locus coeruleus-mediated norepinephrine release, inducing an electrophysiological pattern highly analogous to natural slow-wave sleep (69). By simulating deep sleep, Dex effectively expands the physical spaces between astrocytes, boosting CSF flow. Critically, preclinical studies confirm that Dex significantly stabilizes BBB tight junction proteins (including Claudin-5 and Occludin) and effectively prevents AQP4 dislocation from astrocytic endfeet caused by surgical stress or trauma (70). By suppressing local neuroinflammation and restoring AQP4 polarization, Dex reignites the glymphatic convection mechanism, promptly flushing harmful metabolites from damaged brain regions, thereby cutting off the accumulation and peripheral spillover of inflammatory factors at the source (71).
5.2.2 Phased intervention strategies using AQP4 modulators
Given the central role of AQP4 in brain fluid transport and water balance and convective transport, direct pharmacological regulation via AQP4 Modulators has emerged as a highly attractive target. Representative drugs such as TGN-020 and AER-271 (and its prodrug AER-270) are currently the most extensively studied selective AQP4 inhibitors (72, 73).
During the hyperacute phase (within hours) of ischemic stroke or TBI, astrocytes rapidly absorb water via AQP4, leading to cytotoxic edema that mechanically compresses and occludes perivascular spaces. Administering AQP4 inhibitors like TGN-020 or AER-271 at this stage effectively blocks water influx, significantly alleviating cerebral edema, preventing the irreversible expansion of the ischemic core, and maintaining initial BBB integrity. However, because AQP4-mediated transmembrane water transport is equally vital for maintaining glymphatic convection and waste clearance during the middle-to-late injury stages, prolonged blanket inhibition can paradoxically result in protein waste accumulation (74). Thus, future applications of AQP4 modulators will trend toward precise “phased therapies”: utilizing small-molecule inhibitors to resist edema in the acute phase, while employing gene therapies or nanoparticle drugs in the subacute phase to target the DAPC complex (e.g., α-syntrophin), chemically re-anchoring AQP4 channels to restore polarized perivascular expression and re-initiate robust CSF-ISF convective flushing.
5.2.3 Pro-lymphangiogenic therapy for mLVs
To address congestion at the downstream exit of the glymphatic system, enhancing the drainage capacity of meningeal lymphatics toward cervical lymph nodes represents another cutting-edge approach. Recent studies demonstrate that adeno-associated virus (AAV)-mediated delivery or local hydrogel administration of Vascular Endothelial Growth Factor C (VEGF-C) post-injury robustly stimulates the proliferation and dilation of dural lymphatic vessels (lymphangiogenesis) (75). The application of VEGF-C significantly increases the number of lymphatic branches and vessel diameters, vastly improving the drainage efficiency of CSF and DAMP-rich interstitial fluid (76, 77). This “sewer-widening” strategy accelerates CCL2-dependent macrophage debris clearance and lowers intracranial pressure, simultaneously alleviating the burden of dumping toxic substances directly into the blood circulation. This dual effect protects the brain while effectively shielding the lungs from distal injury.
5.3 Blocking systemic inflammatory cascades: intercepting brain-derived “inflammatory mediators “
When glymphatic severe impairment is established and brain-derived toxins have breached the BBB in large quantities into the systemic circulation, the final line of defense for the lungs is to intercept these lethal signals directly within the peripheral blood or the local pulmonary microvasculature.
Among all brain-derived DAMPs, HMGB1 stands as the primary therapeutic target due to its extreme destructive potency and broad receptor-binding capacity. The systemic administration of anti-HMGB1 neutralizing monoclonal antibodies (Anti-HMGB1 mAbs) has demonstrated game-changing efficacy in various in vivo animal models of severe TBI and stroke complicated by lung injury. Once injected into the bloodstream, these antibodies rapidly bind and neutralize freely circulating HMGB1 as well as HMGB1 complexes released via EVs. By establishing a blockade at the ligand level, the antibodies effectively prevent HMGB1 from contacting TLR4 and RAGE receptors on the surface of pulmonary capillary endothelial cells.
This precise targeted blockade directly short-circuits the secondary MyD88 and NF-κB-mediated inflammatory cascades within the lungs, successfully averting the phosphorylation and subsequent internalization and degradation of VE-cadherin by ROCK and c-Src kinases. Consequently, adherens junctions between endothelial cells remain structurally intact, vascular permeability is normalized, and the exudation of protein-rich fluid is fundamentally prevented. Furthermore, intercepting HMGB1 deprives alveolar macrophages of their core driver for M1 polarization, significantly reducing the secretion of neutrophil chemokines and halting the occurrence of interstitial NETosis and extensive epithelial necrosis. Similarly, pharmacological inhibitors of HMGB1 like Glycyrrhizin, or specific TLR4 blockers like TAK-242, can interrupt this lethal network axis at either the receptor or ligand level, effectively mitigating the severity of neurogenic ARDS and substantially increasing the overall survival rate of subjects with severe brain injury.
5.4 Holistic and non-invasive integrative modalities
Moving beyond acute pharmacological interventions, a holistic approach is essential for comprehensive brain-lung axis management. Emerging evidence highlights the relevance of the gut-lung-brain axis, where microbiome modulation through probiotics or targeted dietary interventions may offer systemic immunoregulatory benefits, attenuating both neuroinflammation and pulmonary immune hyper-reactivity (78–80). For patients with structural pre-morbid vulnerabilities, pulmonary-specific interventions can directly benefit glymphatic function. For instance, the use of continuous positive airway pressure (CPAP) in patients with pre-morbid OSA can restore normal sleep architecture and alleviate intermittent hypoxia, thereby rescuing circadian glymphatic clearance (81–83). Similarly, the application of senolytic therapy in COPD models has shown promise in clearing senescent cells, reducing systemic oxidative stress, and thereby ameliorating baseline neurovascular vulnerability (84–86). Furthermore, non-invasive integrative modalities present significant adjunct therapeutic value. Addressing the diaphragmatic role to improve inspiratory muscle function can optimize negative intrathoracic pressure mechanics, facilitating venous return and indirectly promoting CSF drainage. Additionally, alternative modalities such as acupuncture are gaining recognition for their potential to modulate neuroinflammation and balance autonomic dysregulation, offering a truly integrative pathway to stabilizing the bidirectional brain-lung axis (87–89).
5.5 Limitations and unresolved questions
Currently, most evidence is derived from murine models. Translating these findings to humans requires caution, as non-invasive, high-resolution imaging of the human glymphatic system remains technically challenging.
6 Conclusion and future directions
In summary, the pathological foundation of ARDS emerging as a fatal distal complication following acute brain injury is far deeper and more complex than the traditional concepts of “massive catecholamine release” and hydrostatic alterations. The latest molecular and anatomical evidence illustrates that the comprehensive severe impairment of the glymphatic system—the brain’s dedicated metabolic waste clearance network—is the keystone event triggering the collapse of the “brain-lung axis.” Mechanical stress and inflammatory responses cause the loss of AQP4 polarization, which, coupled with the anatomical spatial occlusion caused by astrogliosis, completely obstructs CSF-ISF convective exchange. This “pipeline failure” directly leads to a local accumulation of DAMPs (including HMGB1 and S100B) and pro-inflammatory cytokines within the brain parenchyma. Subsequently, these highly concentrated neurotoxins act like a breached dam, surging through the enzymatically degraded BBB or hijacking the inflammation-compromised meningeal lymphatics to flood the systemic circulation, either as free molecules or hidden within EVs. Upon reaching the pulmonary circulation, these mediators specifically bind and activate TLR4/RAGE receptors on endothelial cells, inducing downstream kinase cascades that cause the phosphorylation and internalization of VE-cadherin, completely obliterating the physical alveolar-capillary barrier. Simultaneously, they remodel the pulmonary immune microenvironment, driving alveolar macrophages toward M1 polarization and recruiting neutrophils to execute destructive NETosis, ultimately causing irreversible lung parenchymal damage and respiratory failure.
This precise mapping of network mechanisms offers revolutionary intervention targets for neurocritical care medicine. Looking ahead, translating these major laboratory findings into clinical life-saving capabilities will first require the use of high-resolution in vivo imaging technologies (such as Diffusion Tensor Image Analysis along the Perivascular Space, dynamic contrast-enhanced MRI, and PET tracers) to dynamically monitor glymphatic stagnation and its temporal correlation with pulmonary functional deterioration in both live models and humans (10). Moreover, deep profiling of the specific molecular cargo (e.g., miRNA transcriptomes) of brain-derived EVs in plasma holds promise for providing exquisitely sensitive liquid biopsy biomarkers for early warning of brain-lung injury (10). Therapeutically, a multidimensional combination strategy aimed at disrupting the bidirectional vicious cycle of the brain-lung axis—integrating Dexmedetomidine to simulate sleep and protect AQP4 polarization, gene modification with VEGF-C to selectively promote meningeal lymphatic drainage, and anti-HMGB1 antibodies to cast an immunological safety net in the peripheral circulation—will undoubtedly offer the most promising medical breakthrough to shatter the malignant pathological loop of the “brain-lung axis” and save the lives of patients with severe brain injuries.
Statements
Author contributions
LM: Conceptualization, Writing – original draft. ZY: Writing – original draft. FJ: Conceptualization, Supervision, Visualization, Writing – original draft, Writing – review & editing.
Funding
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Acknowledgments
We would like to express our gratitude to all those who helped us.
Conflict of interest
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Supplementary material
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Summary
Keywords
acute brain injury, acute lung injury, AQP4, brain-lung axis, glymphatic system
Citation
Mao L, Yang Z and Jiang F (2026) Network mechanisms of glymphatic system dysfunction in the disruption of the “brain-lung axis”. Front. Neurol. 17:1844527. doi: 10.3389/fneur.2026.1844527
Received
01 April 2026
Revised
08 July 2026
Accepted
31 July 2026
Published
18 August 2026
Volume
17 - 2026
Edited by
Giuseppe Barisano, Stanford University, United States
Reviewed by
Mustapha Muzaimi, Universiti Sains Malaysia Health Campus, Malaysia
Anwar Zahran, An-Najah National University, Palestine
Updates
Copyright
© 2026 Mao, Yang and Jiang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Feijun Jiang, jiangfeijun@yeah.net
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.