Rewiring the Lung&ndash;CNS Axis After Spinal Cord Injury

HaiRong Wu; Xiaolong Li; Wenjun Zhao; Yihan Li; Hang Zhang; Heng Yin; Xiaofeng Gu

doi:10.2147/JIR.S542308

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Review

Rewiring the Lung–CNS Axis After Spinal Cord Injury

Authors Wu H , Li X, Zhao W , Li Y, Zhang H, Yin H, Gu X

Received 23 May 2025

Accepted for publication 6 November 2025

Published 8 January 2026 Volume 2026:19 542308

DOI https://doi.org/10.2147/JIR.S542308

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Cynthia Koziol-White

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HaiRong Wu,¹ Xiaolong Li,¹ Wenjun Zhao,¹ Yihan Li,¹ Hang Zhang,¹ Heng Yin,^1,² Xiaofeng Gu³

¹Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine., Wuxi, 214071, People’s Republic of China; ²Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi, 210046, People’s Republic of China; ³Department of Orthopedics, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China

Correspondence: Xiaofeng Gu, Email [email protected]

Abstract: Spinal cord injury (SCI) is a catastrophic disorder of the central nervous system, most commonly resulting from traumatic events such as motor vehicle collisions or falls, but it can also arise from non-traumatic causes including neoplastic, infectious, or degenerative diseases. Respiratory complications are among the most frequent and life-threatening sequelae of SCI. In the acute phase, up to 80% of patients experience respiratory dysfunction, including pneumonia, atelectasis, and respiratory failure. These issues are particularly pronounced in individuals with high cervical injuries, where diaphragmatic and intercostal muscle paralysis impairs effective ventilation and clearance of secretions, substantially increasing the risk of infection. Emerging evidence underscores the bidirectional interplay between pulmonary pathology and central nervous system injury. SCI-induced autonomic dysfunction alters immune regulation, heightening susceptibility to pulmonary infections. Conversely, pulmonary complications can amplify systemic inflammatory responses, which may exacerbate neurological deterioration. Understanding the complex interactions between respiratory complications and SCI pathophysiology is essential for improving patient outcomes. This review therefore focuses on elucidating the mechanisms of pulmonary complications post-SCI and exploring therapeutic strategies to mitigate their impact on neurological recovery.

Keywords: spinal cord injury, neuroimmune interaction, pulmonary microenvironment, lung–CNS axis

Introduction

Spinal cord injury (SCI) is a devastating neurological condition that can result from traumatic events—such as traffic accidents or falls—or non-traumatic causes, including vascular malformations, tumors, infections, transverse myelitis, and syringomyelia.^1,2 Although traumatic SCI (tSCI) accounts for the majority of cases, non-traumatic SCI (ntSCI) also constitutes a significant proportion, particularly among elderly populations.³ According to the Global Burden of Disease Study 2019, the annual incidence of SCI is estimated at 900,000 [95% uncertainty interval (UI), 700,000 to 1200,000] cases worldwide, with a global prevalence reaching 20.6 million (95% UI: 18.9–23.6 million).⁴ Due to its high burden of disability, SCI is currently the sixth leading neurological cause of disability worldwide and ranks seventh in Asia, severely impacting quality of life and imposing substantial socioeconomic costs.⁵

Beyond motor impairment, SCI frequently leads to multi-organ complications involving neurological, cardiovascular, urological, gastrointestinal, and particularly respiratory systems.^6,7 Respiratory complications—such as pneumonia, atelectasis, and respiratory failure—remain leading contributors to morbidity and mortality, especially in individuals with cervical and upper thoracic SCI.^6,8 Reports indicate that these complications occur in 40–80% of SCI patients, underscoring their clinical importance.^9,10

Recent research has increasingly focused on the lung-brain axis, highlighting bidirectional interactions between the pulmonary microenvironment and the central nervous system (CNS).^11,12 After SCI, disruptions in respiratory muscle function and autonomic regulation not only predispose patients to infections and inadequate ventilation but also profoundly alter immune homeostasis, vascular permeability, and local inflammatory responses within the lung.¹³ In turn, pulmonary complications may exacerbate systemic inflammation and immune dysregulation, worsening neurological damage and impeding repair processes.^14,15 Mechanistic studies have identified neural reflex circuits, circulating cytokines, extracellular vesicles, and the pulmonary microbiome as crucial mediators in this intricate interplay.^16–19

Despite advances in acute respiratory care, current interventions mainly rely on mechanical ventilation and infection management, with limited strategies directly targeting modulation of the pulmonary microenvironment.^20,21 Growing evidence suggests that optimizing lung health is critical not only for preventing respiratory failure but also for facilitating neurological recovery following SCI.^14,15,22 This review synthesizes current understanding of pulmonary microenvironment remodeling after SCI, elucidates its regulatory role in CNS repair, and explores emerging therapeutic approaches. By advancing our understanding of the lung-CNS axis, this review aims to guide the development of integrated clinical strategies to enhance pulmonary and neurological outcomes in SCI patients.

Survey Methodology

Literature searches were conducted in the PubMed, Web of Science, and Embase databases. In addition to articles published since 2015, earlier seminal studies were also considered. The keywords used were as follows: spinal cord injury, respiratory complications, pneumonia, atelectasis, respiratory failure, pulmonary embolism, sleep-disordered breathing, lung–CNS axis, lung–brain axis, neuroimmune interaction, vagus nerve stimulation, respiratory muscle training, diaphragm pacing, extracellular vesicles, and pulmonary microbiota. As our work gradually unfolded, we then searched literature by combined keywords such as spinal cord injury and pneumonia, spinal cord injury and respiratory muscle training, lung–CNS axis and neuroinflammation, vagus nerve stimulation and spinal cord injury, extracellular vesicles and lung injury, microbiota and spinal cord injury. After removing duplicate and irrelevant records, 186 articles were finally selected for this review.

Spinal Cord Injury and Respiratory Complications

Respiratory Complications

Respiratory complications are among the most critical challenges in SCI and are strongly influenced by injury level and severity.²³ Patients may develop respiratory muscle weakness, diaphragmatic dysfunction, impaired ventilation, secretion retention, and recurrent infections, substantially increasing the risk of pneumonia, respiratory failure, and chronic pulmonary dysfunction²⁴ (Table 1).^8,9,25–41 Incidence rates reach 40–70% in cervical or upper thoracic SCI⁴² and are higher in complete versus incomplete injuries.^43,44 According to the ASIA scale, grade A lesions carry the greatest risk.^29,45 These complications peak within the first year but may persist long-term, leading to acute decompensation and impaired quality of life.^46,47

Table 1 Incidence and Spectrum of Respiratory Complications After Spinal Cord Injury Across Representative Cohorts

Respiratory Failure

Respiratory failure is a major cause of morbidity and mortality, particularly in cervical or high thoracic SCI.^26,48 It reflects inadequate gas exchange with hypoxemia and/or hypercapnia,⁴⁹ and is classified as type I (V/Q mismatch, eg, pneumonia or edema)⁵⁰ or type II (reduced ventilation, eg, muscle fatigue),^45,51 and injuries at C3 or higher usually abolish spontaneous breathing, necessitating continuous mechanical ventilatory support. Lesions above C5 often cause diaphragmatic paralysis.¹⁰

Pneumonia

Pneumonia is a leading cause of death after SCI,⁵² with mortality risk markedly increased in the first year.⁵³ Its incidence is highest in cervical and upper thoracic injuries,⁵⁴ largely due to impaired cough and mucociliary clearance.^55,56 These deficits promote secretion retention, bacterial colonization, and infection. Beyond mortality, pneumonia prolongs hospitalization and increases healthcare costs.⁴⁹

Atelectasis

Atelectasis occurs in up to 36% of acute SCI,¹⁰ driven by impaired inspiration, weak cough, and secretion retention.^23,57 Its severity correlates with neurological level, with vital capacity (VC) decreasing by 20–50% in high cervical injuries49 and by 30–50% in C5–C6 lesions.^10,49,58 Chronic SCI is further complicated by chest-wall stiffness, abdominal muscle laxity, and spasticity, contributing to persistent ventilatory impairment.²⁰ Longitudinal studies confirm progressive declines in FEV₁, reductions in functional residual capacity, and stabilization of VC at ~60% of predicted values.^49,59

Pulmonary Embolism

PE is the second leading cause of death within the first year after SCI,⁶⁰ with an incidence of ~4.5% and mortality of ~3.5%.³¹ Risk factors include immobility, impaired venous return, hypercoagulability, and autonomic dysfunction.^61,62 Prophylactic anticoagulation and close monitoring are therefore essential.

Pulmonary Edema

Pulmonary edema is underrecognized in SCI and arises from venous congestion, immobility, and autonomic dysregulation.^23,63,64 Case reports illustrate its association with autonomic dysreflexia and acute permeability edema.⁶⁵ Experimental data suggest VEGF upregulation after SCI enhances vascular permeability and fluid leakage.⁶⁶

Sleep-Disordered Breathing

OSA develops in 64–83% of tetraplegic patients within months of injury.⁶⁷ Mechanisms include reduced ventilatory drive, diaphragmatic overload during REM sleep, and upper airway instability.^68,69 Clinical features range from nocturnal awakenings and night sweats to excessive daytime sleepiness and impaired cognition. Daytime PaO₂ <45 mmHg or base excess <4 mEq indicates nocturnal hypoventilation.⁷⁰

Mechanisms of Respiratory Complications

Respiratory complications following SCI arise from complex interactions among multiple pathophysiological mechanisms (Figure 1). At their core lies respiratory muscle dysfunction due to disrupted neural pathways controlling the diaphragm, intercostal, and accessory muscles, resulting in impaired ventilation and ineffective airway clearance.^23,49 Autonomic dysfunction further exacerbates respiratory impairment by altering bronchial muscle tone, mucociliary clearance, and vascular permeability.^23,71 Concurrently, immune dysregulation—characterized by impaired innate and adaptive immune responses—increases susceptibility to pulmonary infections.¹⁴ Additionally, disruptions in circulatory regulation, including venous congestion and altered pulmonary blood flow, lead to ventilation-perfusion mismatch and elevate risks for pulmonary edema and embolism.^23,71 Collectively, these interrelated mechanisms highlight the multifaceted nature of respiratory disorders following SCI.

Figure 1 Pathophysiological Mechanisms Linking SCI to Pulmonary Complications. SCI can induce a pulmonary inflammatory response, characterized by the accumulation of interstitial macrophages and the infiltration of immune cells, including neutrophils and CD8⁺ T cells. Concurrently, SCI leads to (a) motor nerve loss, which subsequently causes reduced respiratory effort and an impaired cough reflex combined with increased alveolar mucus. (b) Autonomic nerve loss, also induced by SCI, leads to vascular dysregulation and immune dysregulation, involving α7 nicotinic acetylcholine receptor (α7 nAChR) and β-adrenergic receptor (β-AR) signaling pathways.

Motor Nerves Loss

Respiratory muscle dysfunction is a significant complication following SCI, primarily caused by paralysis associated with spinal shock below the level of injury.²³ The diaphragm, innervated by the phrenic nerve originating from spinal segments C3–C5, is the primary inspiratory muscle and contributes approximately 65% of tidal volume. Intercostal muscles, essential for efficient breathing, are innervated by segments T1–T11, while abdominal muscles, critical for effective expiration and coughing, are innervated by T6–L1.^72,73 SCI at levels C1–C3 typically results in complete diaphragmatic paralysis, rendering patients fully dependent on mechanical ventilation.⁷⁴ Injuries at C4–C5 levels usually cause partial diaphragmatic dysfunction, significantly reducing vital capacity to approximately 20–50% of predicted values.⁴⁹ Patients with lower cervical injuries (C6–C8) generally retain diaphragm function but experience paralysis of intercostal and abdominal muscles, often presenting with paradoxical breathing, characterized by inward chest wall movement during inspiration due to rib cage instability.⁵⁹ Thoracic-level SCI (T1–L1) patients typically exhibit impaired respiratory function secondary to compromised innervation of intercostal and abdominal muscles.

Mechanical respiratory dysfunction after SCI involves paradoxical breathing patterns and reduced chest wall compliance, promoting distal airway collapse and micro-atelectasis.^23,55 Inspiratory muscle weakness limits deep breathing, resulting in impaired gas exchange, reduced lung compliance, and atelectasis.^23,75 Similarly, expiratory muscle weakness reduces coughing effectiveness, exacerbating mucus retention and persistent airway obstruction.^76,77 Consequently, mucus accumulation within airways creates a favorable environment for bacterial colonization, increasing susceptibility to respiratory infections such as pneumonia.⁵³

Autonomic Dysfunction

In addition to motor innervation of respiratory muscles, integrity of the autonomic nervous system (ANS) is critical for maintaining respiratory function and airway protection after SCI. The ANS comprises sympathetic and parasympathetic branches, each with distinct anatomical origins and functional roles. Sympathetic preganglionic neurons originate from the intermediolateral cell column of spinal segments T1 to L2/L3 and synapse with postganglionic neurons in paravertebral ganglia.⁶² In contrast, parasympathetic neurons primarily arise from the brainstem (cranial nerves III, VII, IX, and particularly X—the vagus nerve), as well as sacral spinal segments S2–S4. Notably, parasympathetic innervation from the vagus nerve significantly influences pulmonary function by regulating bronchial smooth muscle tone and mucus secretion.⁷⁸ Disruption of ANS control after SCI leads to profound autonomic imbalance, manifesting clinically as vasodilation, bradycardia, and systemic hypotension—a condition collectively termed neurogenic shock.⁷⁹ The resultant hypotension reduces perfusion to vital organs, including the lungs, compromising tissue oxygenation and metabolism. Concurrent respiratory muscle paralysis further diminishes venous return and cardiac output, exacerbating systemic hypoperfusion.⁷⁹ Enhanced functional connectivity between the nucleus tractus solitarius and the rostral ventrolateral medulla following SCI may potentiate sympathetic activation, increasing pulmonary vascular permeability.⁸⁰ Moreover, the loss of sympathetic vasomotor control results in persistent hypotension, complicating fluid management in approximately 50% of acute tetraplegic patients and increasing pulmonary edema risk.⁸¹

In acute cervical and high thoracic SCI, disruption of sympathetic output (originating from segments T1–L2) severely shifts autonomic balance.⁶² Loss of sympathetic control results in unopposed parasympathetic (vagal) activity, markedly elevating airway resistance through bronchoconstriction and excessive mucus production.⁸² Such autonomic imbalance leads to airway obstruction, impaired gas exchange, hypoxemia, and hypercapnia, frequently necessitating tracheal intubation for ventilation support and mucus clearance during acute management.⁸³

Additionally, patients with SCI at or above the T6 level may experience episodes of autonomic dysreflexia (AD), characterized by exaggerated sympathetic responses triggered by noxious stimuli below the injury level (eg, bladder distension or constipation). During AD episodes, massive catecholamine release—including norepinephrine and epinephrine—can precipitate acute severe hypertension, with systolic pressures often surpassing 200 mmHg.⁸⁴ These hypertensive crises may induce permeability pulmonary edema, severely compromising respiratory function and exacerbating respiratory distress. Sympathetic activation during AD also causes pulmonary venous constriction, further elevating pulmonary capillary pressure. Elevated capillary pressure and endothelial shear stress disrupt endothelial tight junctions, increasing vascular permeability and facilitating protein-rich fluid leakage into alveolar spaces.⁸⁵ Furthermore, excessive catecholamine release activates the NF-κB signaling pathway in alveolar macrophages, stimulating pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines upregulate intercellular adhesion molecule-1 (ICAM-1) expression on endothelial cells, promoting leukocyte adhesion, infiltration, and subsequent protease release, further impairing pulmonary vascular integrity.⁸⁶ Moreover, increased pulmonary capillary hydrostatic pressure mechanically stretches endothelial cells, activating mechanosensitive ion channels such as TRPV4. This mechanical stress induces cytoskeletal rearrangements in endothelial cells, while aquaporin-1 (AQP1) channel dysfunction further aggravates fluid leakage into alveoli.⁸⁷ Collectively, these mechanisms lead to severe, permeability-driven pulmonary edema, characterized by marked proteinaceous exudation.

Thus, autonomic dysfunction after SCI significantly contributes to respiratory complications via multiple mechanisms, including altered airway physiology, excessive mucus secretion, and severe vascular responses.

Immune Dysfunction

Immune dysfunction is a prominent yet frequently overlooked consequence of SCI. Several mechanisms contribute to impaired immune responses, including disruptions in sympathetic and vagal cholinergic pathways innervating lymphoid organs and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.^88,89 Collectively, these alterations significantly increase susceptibility to infections.

SCI-induced dysregulation of the HPA axis results in abnormal cortisol secretion.⁹⁰ Elevated cortisol levels suppress immune cell function, notably reducing the activity of critical immune effector cells such as T lymphocytes and natural killer (NK) cells.⁹¹ Additionally, SCI is associated with early impairment of hematopoiesis, leading to bone marrow dysfunction and diminished immune cell production, further compromising host defenses.⁸⁸ The vagus nerve plays a crucial role in regulating pulmonary inflammation via the cholinergic anti-inflammatory pathway (CAP). Efferent vagal fibers release acetylcholine (ACh), inhibiting nuclear factor κB (NF-κB) activation in alveolar macrophages, thereby reducing pro-inflammatory cytokine (eg, TNF-α, IL-6) production by up to 40%.^92–94 Proper vagal stimulation facilitates resolution of inflammation, whereas vagotomy or deficiency of α7-nicotinic acetylcholine receptors (α7nAChR) exacerbates pulmonary infection, inflammation, tissue injury, and systemic cytokine release.⁹⁵ Thus, either excessive or inadequate vagal responses following SCI can worsen pulmonary infections or chronic inflammatory lung conditions.⁹² Specifically, vagal efferent fibers release ACh, which suppresses NF-κB signaling via α7nAChR, effectively reducing the secretion of pro-inflammatory mediators such as TNF-α.⁹³

Following SCI, sympathetic innervation to lymphoid organs, particularly the spleen, is disrupted. This disruption results in splenic atrophy and impaired lymphocyte function, thereby diminishing the host’s capacity to mount effective immune responses.^96,97 Moreover, norepinephrine (NE), a key neurotransmitter of the sympathetic nervous system (SNS), significantly modulates immune responses in the context of SCI. Elevated NE levels inhibit maturation and activation of type 1 helper T cells (Th1), suppressing immune reactivity and increasing vulnerability to infections.^89,98 Experimental evidence indicates that excessive SNS activation—characterized by increased catecholamine release—reduces TNF-α production and increases interleukin-10 (IL-10) via β-adrenergic receptors on immune cells.⁹⁹ Conversely, blockade of β-adrenergic receptors can mitigate infection risks, including pneumonia.^99,100

Intervention Strategies

Mechanical Ventilation and Tracheostomy

Patients with complete cervical SCI at or above the C3 level frequently require long-term mechanical ventilation support.¹⁰¹ In the acute phase, tracheostomy reduces airway resistance, lowers aspiration risk, and facilitates mucus clearance.¹⁰² However, prolonged use of tracheostomy tubes may lead to speech difficulties, swallowing impairments, increased infection risk, and diminished quality of life.¹⁰³ For patients with high-level SCI (particularly cervical injuries), respiratory dysfunction can be severe enough to necessitate mechanical ventilation.^104,105 Intubation and mechanical ventilation are critical for patients with complete cervical SCI above the C5 level, who experience diaphragmatic paralysis and require ventilatory support.^102,104 Early tracheostomy is generally recommended, as it reduces mechanical ventilation duration, shortens ICU stays, and enhances patient comfort and tolerance.¹⁰⁶ Early tracheostomy has also been associated with lower mortality and reduced respiratory complications in severe cervical SCI.^74,104

Respiratory Muscle Training (RMT)

Respiratory muscle training (RMT) represents an active rehabilitation strategy aimed at improving inspiratory and expiratory muscle strength in individuals with SCI. Unlike passive interventions such as mechanical ventilation, RMT seeks to restore voluntary respiratory capacity by targeting diaphragmatic, intercostal, and accessory respiratory muscles.

Several randomized controlled trials and systematic reviews have demonstrated that inspiratory muscle training (IMT) significantly enhances maximal inspiratory pressure (MIP), vital capacity (VC), and forced expiratory volume in one second (FEV₁) in both acute and chronic SCI patients.^107,108 Similarly, expiratory muscle training (EMT) improves maximal expiratory pressure (MEP) and cough efficiency, thereby facilitating airway clearance and reducing the risk of atelectasis and recurrent pneumonia.¹⁰⁹ When combined with mechanically assisted coughing techniques, RMT further augments mucus clearance and decreases pulmonary infection rates.¹¹⁰

The clinical benefits of RMT extend beyond pulmonary mechanics. By enhancing respiratory strength and endurance, RMT contributes to earlier weaning from mechanical ventilation, shortens intensive care unit stays, and improves long-term quality of life.^111–113 In chronic SCI, regular RMT also alleviates sleep-disordered breathing and enhances exercise tolerance, underscoring its role in long-term rehabilitation.^107,108,114

Despite these promising findings, RMT remains underutilized in clinical practice. Variability in training protocols, duration, and intensity across studies limits standardization and widespread adoption. Future work should focus on defining optimal RMT regimens and integrating them with multimodal respiratory care frameworks to maximize clinical outcomes in SCI patients.

Non-Invasive Ventilation (NIV)

Non-invasive ventilation (NIV) delivers positive-pressure ventilation via interfaces such as mouthpieces, nasal masks, or oronasal masks, and is suitable for conscious patients who maintain spontaneous breathing.¹¹⁵ Studies indicate that NIV serves as a viable alternative to long-term invasive ventilation, reducing the need for tracheostomy, lowering infection risks, and enhancing speech and swallowing functions.^116,117 Intermittent positive-pressure breathing (IPPB), delivered through mouthpieces, masks, or tracheostomy connectors, helps increase inspiratory volume before assisted coughing, preventing atelectasis and improving ventilation.¹¹⁸ Furthermore, combining NIV with mechanically assisted coughing techniques, such as mechanical insufflation-exsufflation, effectively clears airway secretions and reduces pneumonia risk.^119,120 Although tracheostomy remains common in patients requiring long-term ventilatory support, various non-invasive approaches—including mouthpiece and mask ventilation—offer effective alternatives.¹²¹

Diaphragm Pacing Systems (DPS)

Patients with high cervical SCI may be candidates for diaphragm pacing systems (DPS).¹²² In individuals with preserved phrenic nerve function, DPS provides an alternative ventilatory strategy by electrically stimulating the phrenic nerves to induce diaphragmatic contractions, facilitating autonomous breathing.¹²³ Early DPS implantation significantly improves the likelihood of weaning from mechanical ventilation and enhances respiratory mechanics and quality of life.¹²⁴ However, long-term outcomes and precise indications for DPS still require further research.¹²⁴ DPS can be implemented through direct intrathoracic phrenic nerve pacing (traditional approach) or via laparoscopic insertion of electrodes at the diaphragm’s insertion points of the phrenic nerve.¹²⁵ In carefully selected patients with restored diaphragm function, tidal volumes can increase sufficiently to allow tracheostomy removal.¹²⁶ Nevertheless, current evidence regarding long-term DPS efficacy in SCI patients remains limited.

Assisted Breathing Techniques

During the acute phase of SCI, employing abdominal binders or adjusting body positioning (eg, supine position) can enhance diaphragm function and increase vital capacity, especially following acute high cervical injury.¹²⁷ For patients with lower cervical or thoracic SCI, NIV combined with assisted coughing methods (such as the quad-cough technique) effectively improves respiratory function.¹²⁸ The use of abdominal binders and supine positioning optimizes diaphragmatic mechanics, increasing lung volumes in patients immediately following SCI.^127,129 Similarly, in lower cervical and thoracic injuries, integrating NIV and assisted coughing techniques significantly benefits respiratory management.^23,128

Respiratory Complications and CNS Interactions

Emerging research has revealed an important and intricate bidirectional communication network between the lungs and the CNS.¹³⁰ Strong evidence indicates that pulmonary injury can trigger neuroinflammation, which in turn worsens neurological function.^131,132 For instance, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are closely associated with cognitive impairment in survivors, suggesting lung dysfunction significantly affects CNS function.^131–133 The biological basis of this lung–CNS interaction primarily involves three mechanisms: neural signaling pathways, inflammatory mediators, and microbial factors.^130,133 Recent studies further highlight extracellular vesicles, including exosomes, as potential mediators that drive neuroinflammation following pulmonary injury.^134,135 (Figure 2).

Figure 2 Multimodal lung-to-CNS signalling after respiratory complications. Pulmonary injury induces four principal classes of mediators that interact with the central nervous system: (a) Neural—sympathetic efferents, vagal afferent/efferent fibres, and spinal pulmonary afferents; (b) Inflammatory—systemic cytokines released by activated macrophages, neutrophils, and monocytes; (c) Microbial—pathogen-associated molecular patterns (eg, LPS, peptidoglycan) and bacterial metabolites; (d) Exosomal—extracellular vesicles conveying nucleic acids and proteins. These mediators act in parallel rather than sequentially, collectively contributing to neuroinflammation and secondary neurological damage.

Neural Pathways

The vagus nerve (the tenth cranial nerve), composed of approximately 80% afferent and 20% efferent fibers, constitutes the primary neural pathway of the lung-brain axis.¹³⁰ Recent findings suggest that pulmonary vagal afferent fibers transmit signals from the pulmonary microenvironment to the nucleus tractus solitarius (NTS) in the medulla, subsequently activating serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) of the midbrain.^136,137 Sensory nerve terminals of vagal afferents are widely distributed in alveoli and bronchial epithelium, transmitting peripheral signals via the nodose ganglion to the NTS, which forms synaptic connections with brainstem nuclei, including the DRN.¹³⁸ Experimental data have demonstrated that intravenously administered mesenchymal stem cells (MSCs) primarily localize to the lungs, where they activate VGLUT2-positive vagal afferent fibers.¹³⁷ This activation induces increased c-Fos expression in the NTS and subsequently activates serotonergic neurons in the DRN, significantly improving depressive-like behaviors. Lung injury similarly activates pulmonary sensory receptors (eg, stretch and chemoreceptors), which transmit signals via vagal afferents to the brainstem.^136,139 For example, ALI triggers vagus nerve-mediated activation of the hypothalamic-pituitary-adrenal (HPA) axis, thereby amplifying systemic inflammation.¹³⁹

Additionally, sensory nerves from the lungs directly communicate with the brain, akin to nociceptive signaling.¹⁴⁰ Such direct neural communication allows rapid CNS detection of pulmonary infections, triggering sickness behaviors such as fatigue and anorexia.¹⁴¹ This pathway might explain why severe lung injuries can occur with minimal subjective symptoms, potentially due to bacterial biofilms evading immune detection.¹⁴²

Immune Pathways

Pulmonary disorders such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause extensive release of inflammatory cytokines (eg, TNF-α, IL-1β, IL-6).^143,144 Lung inflammation facilitates the entry of cytokines into systemic circulation. Persistent systemic inflammation can downregulate tight junction proteins (such as Claudin-5 and ZO-1) in blood-brain barrier (BBB) endothelial cells, enhancing BBB permeability.^131,145 Increased permeability enables inflammatory cytokines to infiltrate brain parenchyma, leading to neuroinflammation and cognitive dysfunction.¹⁹ Animal studies show that lipopolysaccharide (LPS)-induced ALI causes a threefold increase in microglial activation in the hippocampus, accompanied by a 50% decline in spatial memory performance. The strong association between ALI/ARDS, neuroinflammation, and cognitive dysfunction in survivors provides new avenues for targeted neuromodulatory therapies addressing neuropsychiatric complications following spinal cord injury.^131,146

Lung Flora

Emerging evidence highlights a critical role of the lung microbiota in regulating CNS health, analogous to the well-established gut-brain axis.¹⁴⁷ For example, mouse infection with Bordetella pertussis is associated with inflammation and β-amyloid deposition, whereas colonization by Klebsiella pneumoniae correlates with increased Alzheimer’s disease risk. In healthy individuals, the lung microbiota predominantly comprises Firmicutes (38%), Bacteroidetes (29%), and Proteobacteria (18%).¹⁴⁸ Following SCI, conditions such as neurogenic pulmonary edema and ventilator-associated pneumonia facilitate colonization by Gram-negative bacteria.¹⁴⁹ Lipopolysaccharide (LPS) released by these bacteria may enter the CNS through a compromised blood-spinal cord barrier, triggering neuroinflammation via Toll-like receptor 4 (TLR4) signaling pathways and serving as a direct mediator of lung-brain communication.^150,151 Interestingly, experimental autoimmune encephalomyelitis (EAE) models demonstrated that antibiotic-induced lung microbiome dysbiosis (eg, via neomycin) reduced CNS T-cell infiltration by approximately 70% and downregulated MHC-II expression on microglia by about 50%. This immunomodulatory effect was mediated by LPS from Prevotella species, activating type I interferon responses via TLR4 in microglia, consequently suppressing pro-inflammatory cytokine production.^151,152 Similarly, respiratory infections with aerosolized Bordetella pertussis alleviated EAE severity through IL-10-mediated regulatory T-cell responses and downregulation of VLA-4 and LFA-1 on CD4⁺ T cells.^153,154

Metabolites from lung microbiota also contribute to lung-brain interactions.¹⁵⁵ Short-chain fatty acids (SCFAs) produced by pulmonary bacteria can cross the blood-brain barrier via monocarboxylate transporters.¹⁵⁵ For example, systemic propionate administration increased brain-derived neurotrophic factor (BDNF) expression by 30% in the prefrontal cortex, improving cognitive performance.¹⁵⁶ Conversely, kynurenine—a tryptophan metabolite generated by lung macrophage indoleamine 2,3-dioxygenase-1 (IDO1)—is linked to depressive behaviors due to elevated CNS levels.^157–159

Pulmonary microbiota dysbiosis may also predispose the CNS to direct infections. Cryptococcus neoformans, an inhaled fungal pathogen, initially causes pneumonia and subsequently disseminates to the CNS, resulting in meningoencephalitis. This pathogen accesses the CNS via transmigration of infected macrophages.¹⁶⁰ Additionally, certain respiratory viruses may invade the CNS through retrograde axonal transport along the vagus nerve, reaching brainstem respiratory centers and exacerbating respiratory symptoms such as respiratory distress.^161,162

Extracellular Vesicles Mediators

Exosomes and other extracellular vesicles (EVs) released by pulmonary cells during inflammation carry bioactive molecules, such as microRNAs and proteins.¹⁶³ These EVs can cross the blood-brain barrier, influencing cellular functions within the CNS and promoting neuroinflammation.^163,164 Recent studies have identified EVs as potential mediators of lung-brain communication, capable of transmitting signals that induce neuroinflammation following pulmonary injury. For instance, ventilator-induced lung injury (VILI) activates pyroptosis pathways in spinal cord microglia via circulating exosomes.^165,166 Experimental research demonstrated that lung-derived exosomes released during VILI carry activated caspase-1, causing a three-fold increase in Gasdermin-D (GSDMD) expression within the spinal cord, subsequently promoting neuronal apoptosis.^148,167

Challenges and Prospects

Current Limitations

Respiratory complications—rather than the neurological level alone—largely determine length of stay and cost during the index admission for cervical and high‑thoracic SCI, underscoring the need for proactive pulmonary management.¹⁶⁸ Contemporary care is mainly supportive: endotracheal intubation, tracheostomy, bronchodilators, airway‑clearance devices and empirical antibiotics. Although life‑saving, conventional mechanical ventilation (MV) is neuromuscularly uncoupled; prolonged passive inflation precipitates ventilator‑induced diaphragmatic dysfunction (VIDD) through disuse atrophy, oxidative stress and proteolysis.¹⁶⁹ VIDD, together with baro‑/volutrauma and ventilator‑associated pneumonia, prolongs weaning, reduces survival and degrades quality of life. Extended MV also perturbs the central nervous system: deep sedation and immobility promote ICU‑acquired weakness, and the loss of afferent feedback from paralysed respiratory muscles may impair neuroplasticity in medullary and pontine networks.⁹⁵ Indeed, the ability to wean from MV is one of the strongest predictors of long‑term survival after cervical SCI.^170–172 Repeated antibiotic courses foster dysbiosis and resistance, while chronic infection perpetuates lung injury, leaving many patients ventilator‑dependent with recurrent pneumonia. These shortcomings highlight the urgent need to reactivate or replace central respiratory circuits and to rebalance post‑injury immune dysfunction; without addressing the neurogenic basis of ventilatory failure and its immunological sequelae, durable improvements in pulmonary and neurological outcomes will remain elusive.

A major limitation in managing respiratory complications after SCI is the absence of reliable biomarkers for guiding and monitoring therapeutic interventions.¹⁷³ Patients with SCI exhibit substantial heterogeneity in neurological deficits, immune status, and susceptibility to pulmonary complications.¹⁷⁴ Identifying biomarkers to stratify patients and predict therapeutic responses is therefore essential for effective personalized medicine.^175,176 I Pro-inflammatory cytokines (such as IL-6 and TNF-α) and anti-inflammatory cytokines (such as IL-10), stress hormones (eg, cortisol), and microbial metabolites are candidate biomarkers that can help define a patient’s immune status and predict vulnerability to complications like pneumonia or SCI-induced immune depression (SCI-IDS).^{15,175,177,178} Similarly, biomarkers of neural damage or repair—including neurofilament proteins and growth factors—might indicate the efficacy of systemic treatments in promoting central nervous system (CNS) recovery.¹⁷⁹ However, currently there are no validated biomarkers specifically reflecting lung-spinal cord crosstalk.¹⁵ For instance, the ratio of pro-inflammatory to anti-inflammatory cytokines in cerebrospinal fluid (CSF) or bronchoalveolar lavage fluid (BALF) could serve as indicators of neuroimmune interactions after SCI.^15,177 The development of these biomarkers could enable clinicians to quickly identify patients at heightened risk for SCI-IDS or severe pulmonary complications, thus allowing early initiation and tailored dosing of interventions.¹⁵ Identifying these critical therapeutic windows through biomarker monitoring or advanced imaging is an ongoing research priority.¹⁸⁰

Future Prospects

Immune‑stimulation Pre‑conditioning

Immune-stimulation pre-conditioning (IS-PC) utilizes sub-clinical doses of immune activators, such as Toll-like receptor (TLR) agonists, to induce protective immune tolerance and limit subsequent inflammatory responses following spinal cord injury (SCI). Recent preclinical studies demonstrate that systemic administration of ultra-low, non-pyrogenic doses of TLR ligands—including lipopolysaccharide (LPS; TLR4 agonist), CpG oligodeoxynucleotide (TLR9 agonist), or polyinosinic:polycytidylic acid (poly-I:C; TLR3 agonist)—24 to 72 hours before or shortly after SCI can significantly attenuate neuronal apoptosis and improve functional outcomes.¹⁸¹ The underlying mechanisms involve initial transient activation of NF-κB signaling, followed by induction of negative regulatory factors (A20, SOCS1, IRAK-M), enhanced expression of antioxidant transcription factors (Nrf2–HO-1 pathway), and promotion of protective autophagy.¹⁸² In rodent SCI models, pre-conditioning with low-dose LPS (eg, 0.1–0.2 mg/kg intraperitoneally) effectively reduces inflammatory cytokines and neuronal death, translating into meaningful improvements in locomotor function.¹⁸³ Parallel research in acute lung injury models supports the concept, showing that intravenous administration of ultra-low-dose LPS (approximately 10 µg/kg) prior to lung ischemia–reperfusion injury significantly reduces pulmonary edema, cytokine release, neutrophil infiltration, and alveolar-capillary barrier disruption. These data collectively indicate a narrow therapeutic window: carefully controlled doses confer protection, whereas slightly higher doses exacerbate lung injury and inflammation.¹⁸⁴

From a translational perspective, aerosolized delivery of low-dose immune stimulants is particularly appealing, given rapid pulmonary uptake with minimal systemic effects.¹⁸⁵ Although aerosolized ultra-low-dose LPS inhalation has been used safely in healthy volunteers to model inflammation for drug testing, no clinical trials to date have evaluated IS-PC as a therapeutic strategy in SCI or ARDS patients.¹⁸⁶ Importantly, the dysregulated immune environment post-SCI could alter responses to such immunostimulatory approaches, necessitating careful titration and monitoring.¹⁸⁷

Emerging non-invasive transcutaneous VNS devices, feasible even in acute intensive care settings, are currently under investigation.¹⁸⁸ Although further clinical validation is required, these preliminary findings underscore VNS as an attractive therapeutic option for addressing the neuroimmune dysfunction that links pulmonary complications and neurological injury after SCI.^189,190

Vagus-Nerve Stimulation (VNS)

VNS acts via both cholinergic and adrenergic pathways to modulate inflammation, offering a promising adjunctive approach for SCI-associated respiratory complications.^191,192 Physiologically, VNS activates the cholinergic anti-inflammatory pathway through α7 α7nAChR, thereby reducing pro-inflammatory cytokines such as IL-6 and TNF-α.^192,193 Concurrently, VNS promotes adrenal epinephrine release, which exerts anti-inflammatory effects via β2-adrenergic receptors, further inhibiting NF-κB-mediated inflammatory signaling in alveolar macrophages.^139,194

Clinical studies in ARDS patients have shown that VNS significantly decreases systemic IL-6 levels (by approximately 40%) and concurrently improves cognitive outcomes.¹⁹⁵ Preclinical studies using a T9-level SCI rodent model demonstrated that VNS effectively reduces lipopolysaccharide-induced acute lung injury, indicating its critical role in modulating pulmonary inflammation after SCI.^196,197 Thus, VNS potentially confers dual benefits in SCI: peripheral suppression of pulmonary inflammation, which may mitigate complications such as pneumonia or ARDS, and central modulation of neuroinflammation, potentially facilitating spinal cord repair.¹⁵

Conclusions

Pulmonary interventions after SCI are shifting from passive respiratory support toward targeted therapies that address the neuroimmune dysfunction central to SCI-related complications. As mounting evidence supports the bidirectional crosstalk between the lung and CNS, novel therapeutic strategies are emerging to modulate this interaction. These include VNS, immune-stimulation pre-conditioning with toll-like receptor agonists. Each aims not only to reduce respiratory morbidity and mortality but also to promote neurological recovery by rebalancing systemic immunity and enhancing CNS plasticity. However, several challenges remain—most notably, patient heterogeneity, a lack of robust biomarkers for patient stratification, and uncertainties in optimal intervention timing. Translating these experimental insights into clinical standards will require multimodal therapeutic frameworks, individualized protocols, and rigorous trials. Ultimately, this paradigm shift—from stabilizing respiration alone to therapeutically leveraging pulmonary-CNS interactions—offers the potential to improve both survival and neurological function in patients with SCI.

Data Sharing Statement

No datasets were generated or analyzed during the current study. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The National Natural Science Foundation (81973878),Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2023069); Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease (Jiangsu science and education of traditional Chinese medicine(2021)No. 4).

Disclosure

The authors declare that they have no competing interests.

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