Early-life lung injury and the developing brain: a lung-brain axis perspective on neurodevelopmental disorders

Abstract

Emerging evidence indicates that early-life lung injuries—including bronchopulmonary dysplasia, childhood asthma, recurrent respiratory infections, and environmental tobacco smoke exposure—are significantly associated with an increased risk of neurodevelopmental disorders such as cognitive impairment, autism spectrum disorder, attention-deficit/hyperactivity disorder, and emotional or behavioral affections. The developing brain is particularly vulnerable during infancy and childhood, and pulmonary insults during this critical window may disrupt normal neurodevelopment through multiple interconnected mechanisms along the lung-brain axis. These mechanisms include the hypoxia-oxidative stress axis, which impairs oligodendrocyte maturation and myelination; pulmonary microvascular injury leading to neuronal energy metabolism dysregulation; systemic inflammation-mediated disruption of the blood–brain barrier; and a cascade from pulmonary inflammation to neuroinflammation, characterized by microglial activation, synaptic dysfunction, and impaired myelination. Together, these pathways converge to produce long-lasting neurodevelopmental consequences. Understanding the lung-brain axis provides a novel theoretical framework for explaining this comorbidity and highlights the need to integrate neurodevelopmental risk assessment and early intervention into the clinical management of early-life lung diseases. Future research should focus on longitudinal cohorts, identification of critical developmental windows, and targeted therapeutic strategies that address both pulmonary and neurological health.

Introduction

The developing brain undergoes a highly ordered sequence of events, including neurogenesis, neuronal migration, synaptogenesis, gliogenesis, and myelination [1]. The precise execution of these processes depends critically on a stable internal environment and an adequate supply of energy [2–4]. Early-life stages represent critical phases of brain maturation, and the central nervous system (CNS) is particularly vulnerable to adverse external influences during this period of enhanced neuroplasticity [5–8]. Any pathophysiological disruption occurring within this developmental window can reshape neurodevelopmental trajectories through "programming effects", leading to functional impairments and potentially long-term neuropsychiatric consequences in adolescence or adulthood [6, 9, 10].

In recent years, emerging epidemiological evidence showed that early-life pulmonary injuries—such as bronchopulmonary dysplasia (BPD), childhood asthma, respiratory tract infections, and environmental tobacco smoke (ETS) exposure—not only compromise respiratory health but are also significantly associated with later neurodevelopmental disorders, including cognitive, behavioral, and emotional disorders [11–15].

Relevant research largely focused on individual organ systems, with limited attention to the mechanistic interactions between the lung and brain. Consequently, a comprehensive theoretical framework has yet to be fully established. The recent conceptualization of the lung-brain axis offers a novel perspective for interpreting these findings. Growing evidence supports the existence of this bidirectional communication pathway [16]. As an organ that interacts directly with the external environment, the lung may exert a "remote" influence on the CNS through various mechanisms via inflammation, hypoxia, and neuroendocrine changes. Applying the framework of the lung-brain axis to the study of early lung injury and subsequent neurodevelopmental disorders may therefore provide a crucial theoretical foundation for resolving this scientific problem.

Against this backdrop, this review aims to address the following key question: Early-life lung injury (such as BPD, asthma, recurrent respiratory infection, and ETS exposure) is not merely a respiratory disease but may also affect the development of the CNS. This perspective suggests that clinical practice should incorporate the assessment of neurodevelopmental risks and early intervention into the management of early-life lung injuries. This review will summarize the epidemiological evidence regarding four typical types of early-life lung injuries and their association with neurodevelopmental disorders, introduce the "lung-brain axis" theoretical framework to explain the underlying mechanisms, and explore future research directions and targeted intervention strategies, with the aim of providing theoretical support for this neglected field.

Overview and classification of early-life injury

Normal lung development continues after birth and extends throughout the early stages of life, including infancy and childhood. During this period, the developing lungs are highly susceptible to various factors that can lead to structural abnormalities and functional impairments [17]. Abnormal lung development during early life, along with environmental exposures such as allergens, air pollutants, tobacco smoke, and recurrent respiratory tract infections, may trigger the release of pro-inflammatory cytokines, disrupt the alveolar-capillary barrier, or induce neuroinflammation, ultimately leading to brain tissue remodeling, cognitive dysfunction, and neurodevelopmental disorders [18, 19] (Fig. 1).

Fig. 1.

Schematic illustration of the lung–brain axis in early-life and lung injury contributing to neurodevelopmental disorders. This diagram summarizes the key pathological processes linking pulmonary damage during early life (infancy and childhood) to adverse neurological outcomes. Lung insults—including environmental smoke exposure, epithelial injury, alveolar interstitial thickening, capillary endothelial dysfunction, respiratory tract infections, and inflammatory cell infiltration—impair gas exchange and induce systemic inflammation. These pulmonary abnormalities are associated with disrupted lung–brain signaling, ultimately leading to cognitive impairment, learning difficulties, and neuropsychiatric conditions such as ADHD, ASD, and BPD-related neurodevelopmental sequelae. The lung–brain axis thus represents a crucial pathway through which early respiratory injury predisposes to long-term brain dysfunction. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BPD, bronchopulmonary dysplasia

BPD is a disease caused by premature birth that leads to lung developmental disorders [20]. The conventional treatment methods for BPD include oxygen inhalation and mechanical ventilation, etc. [21]. Among them, the incidence of BPD in very low birth weight (VLBW) premature infants is as high as 43% [22]. BPD involves the interaction of multiple pathological mechanisms, such as interstitial thickening and infiltration of inflammatory cells [23], disruption of the alveolar-capillary barrier leading to pulmonary edema and increased vascular permeability [24]. Clinically, BPD primarily manifests as abnormal lung function [25] or even respiratory distress syndrome [26]; in severe cases, it may progress to respiratory failure [27]. This may cause irreversible harm to the growth and development of premature infants [28]. More notably, BPD during the neonatal period leads to recurrent hypoxia, hypercapnia, and respiratory acidosis, which may predispose these infants to hypoxia-related brain injuries, including neurosensory disorders, language delay, and visual perception impairment [29].

Asthma is one of the most common chronic diseases in childhood [30]. The latest data shows that the global prevalence of childhood asthma ranges from 5 to 20% [31], with respiratory symptoms primarily including shortness of breath, wheezing, and coughing [32]. The pathophysiological mechanism of asthma mainly involves chronic airway inflammation, which leads to airway hyperresponsiveness and subsequently results in reversible airflow limitation and airway remodeling in patients [33, 34]. Notably, new research indicates that chronic respiratory inflammation may lead to the emergence of neuroinflammation, thereby affecting the development of the nervous system [33–35]. Studies have explored the risk of brain development impairment associated with childhood asthma. Researchers observed that children with asthma scored lower in episodic memory, processing speed, and attention compared to a group of children without asthma [13].

Respiratory tract infections refer to localized inflammatory diseases caused by pathogens such as bacteria, viruses, and mycoplasma invading the nasal cavity, throat, trachea, bronchi, or lungs [36]. The primary pathophysiological mechanism involves the release of pro-inflammatory factors triggered by respiratory infections, which exacerbates inflammatory responses and compromises the integrity of the airway and air-blood barrier [34]. In severe cases, this may lead to deterioration of pulmonary function or even systemic infection [36]. Pneumonia, as an acute respiratory infection affecting the lungs, constitutes a leading cause of mortality among children [37]. According to the World Health Organization, pneumonia was estimated to account for 14% of all deaths in children under the age of five. Choi et al. identified a statistically significant association between the COVID-19 pandemic and neurodevelopmental delays in young children, particularly affecting their communication and social interaction skills [38].

Extensive studies have confirmed that ETS exposure adversely affects the health of infants and children [39]. ETS is one of the most prevalent environmental risk factors [40]. Its long-term effects primarily manifest as chronic pulmonary inflammation and immune dysfunction, which contribute to lung tissue remodeling and fibrosis, exacerbate respiratory system damage [41], and may subsequently compromise cardiovascular health [42, 43]. In addition, recent literature has confirmed a link between exposure to ETS and attention deficit hyperactivity disorder (ADHD) in preschool-aged children; the higher the level of exposure, the greater the risk of ADHD [11, 44, 45].

Epidemiological evidence on association between early-life lung injuries and neurodevelopmental disorders

Epidemiological evidence indicates that early-life lung injury is significantly associated with neurodevelopmental disorders later in life. These outcomes generally manifest in three primary domains: cognitive impairment and learning difficulties, elevated risk of autism spectrum disorder (ASD), and emotional or behavioral affections (Table 1).

Table 1.

Summary of neurodevelopmental disorders associated with different types of early-life lung injuries

Early-life lung injury type	Cognitive impairment and learning difficulties	ASD	Emotional and behavioral affections
BPD	• ↓verbal, performance, total IQ • ↑special education needs • ↓reading & academic achievement	Controversial	• ↑internalizing problems • ↑attention and social problems • ↑withdrawn behavior and pervasive developmental problems
Childhood asthma	• ↓episodic memory, speed, inhibition, and attention	↑ASD risk	• Bidirectional association with ADHD • ↑risk of depression and anxiety
Respiratory infections	• ↓psychomotor development • ↓intelligence, attention, and verbal memory	Limited evidence, risk factor?	↑internalizing and externalizing problems
ETS exposure	• ↓reading, math, block design, vocabulary, IQ • ↓cognitive flexibility, episodic memory, receptive language development	↑ASD risk	• ↑ ADHD risk • ↑ externalizing symptoms

Abbreviations: ADHD Attention deficit hyperactivity disorder, ASD Autism spectrum disorder, BPD Bronchopulmonary dysplasia, ETS Environmental tobacco smoke, IQ Intelligence quotient, ↑ = increased; ↓ = decreased

Cognitive impairment and learning difficulties

BPD is strongly associated with deficits in cognitive function and academic achievement. A meta-analysis by Twilhaar et al., which included 71 studies comprising 7,752 extremely or very preterm infants and 5,155 full-term children, found that the mean intelligence quotient (IQ) of extremely preterm children was 0.86 standard deviations (approximately 12.9 points) lower than that of term controls. Notably, BPD accounted for 65% of the between-study variance in IQ scores, and a diagnosis of BPD was associated with an IQ reduction of roughly 15 points compared to children without BPD [46]. A prospective cohort study tracking VLBW infants and term controls up to age 8 similarly reported that children with BPD had significantly lower verbal, performance, and full-scale IQ scores. Among children with BPD, 54% received special education services and 20% had full-scale IQ scores below 70, rates substantially higher than those observed in VLBW children without BPD (11%) and term-born children (3%). Furthermore, a greater proportion of children with BPD performed below average in reading and mathematics [47].

The relationship between asthma and cognitive function in children has garnered considerable attention. A longitudinal analysis demonstrated that children with asthma scored lower on measures of episodic memory, processing speed, inhibition, and attention. Notably, those with earlier asthma onset exhibited slower improvement in episodic memory over time compared to their peers [13].

The impact of respiratory infections on cognitive development is also noteworthy. A prospective cohort study of neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection found that affected infants had lower Psychomotor Development Index (PDI) scores and a higher proportion of mild developmental delay at 18–24 months of age, indicating an adverse effect of viral respiratory infection on the developing brain [48]. Similarly, a study of children aged 6 to 12 years who had been hospitalized and mechanically ventilated for bronchiolitis revealed lower intelligence scores and poorer performance in neurocognitive domains such as speed, attention, and verbal memory compared to controls [49].

Studies have also confirmed the association between ETS exposure and cognitive impairment in children. An analysis of 4,399 children aged 6–16 years found that serum cotinine levels—a biomarker of ETS exposure—were inversely associated with scores in reading, mathematics, and block design, even at very low exposure levels [50]. Additional research has demonstrated that urinary cotinine concentrations correlate negatively with full-scale IQ, verbal IQ, performance IQ, vocabulary, math, and block design scores; the association with verbal IQ persisted after adjusting for maternal intelligence [51]. Childhood cotinine levels have also been linked to poorer performance on tasks assessing cognitive flexibility, episodic memory, and receptive language development [44].

Risk of ASD

Using data from 66,790 children and adolescents aged 0–17 years in the 2007–2012 U.S. National Health Interview Survey, Patel et al. reported a weighted ASD prevalence of 1.5% among children with asthma, significantly higher than the 0.9% observed in those without asthma. After adjusting for age, sex, race, and socioeconomic status (SES), asthma was associated with a prevalence ratio (PR) of 1.4 for ASD (95% confidence interval [CI]: 1.2–1.7), indicating a notable comorbidity [52]. A study that followed 2,134 children newly diagnosed with asthma before age 3, along with 8,536 age- and sex-matched controls, found that the cumulative incidence of ASD after eight years was 1.3% in the asthma group compared to 0.7% in the control group. After adjusting for age, sex, urbanization level, and allergic comorbidities, children with asthma faced a twofold higher risk of subsequently developing ASD (hazard ratio [HR] = 2.01; 95% CI: 1.19–3.40) [53].

The relationship between BPD and ASD remains controversial, with studies reporting conflicting findings. One case–control study of extremely preterm infants found no significant association between BPD and the risk of ASD, as the prevalence of BPD was nearly identical in the ASD and non-ASD groups (56% in both groups, P = 1.00) [54]. In contrast, a prospective study reported a positive association, with a relative risk of 1.69 for suspected ASD in very preterm infants with BPD [55]. A 2026 meta-analysis integrating the available evidence suggested an association between BPD—defined as requiring oxygen or respiratory support at 36 weeks postmenstrual age—and ASD risk. However, the high heterogeneity (I² = 71.2%) limits confidence in this finding [56]. Notably, a large cohort study of 4,963 VLBW children found that in the multivariable analyses BPD was not significantly associated with ASD (odds ratio [OR] = 1.44; 95% CI: 0.84–2.45); however, postnatal steroid therapy for BPD prevention/treatment was significantly associated with ASD (OR = 1.97; 95% CI: 1.18–3.29) [57]. This suggests that the corticosteroid for the prevention or treatment of BPD may be a potential factor in the reported association of an increased risk for ASD in preterm and VLBW infants. Future studies evaluating the association between BPD and ASD should take factors such as glucocorticoids into consideration.

Studies have confirmed that ETS exposure during various developmental windows—including the infancy (birth to 1 year), and early childhood (1 to 3 years)—increases the risk of childhood ASD [58–60]. Respiratory infections have also been implicated as a significant risk factor for ASD in a cross-sectional case–control study [61]; however, prospective cohort studies are required to establish causality.

Emotional and behavioral affections

Emotional and behavioral affections are important manifestations of neurodevelopmental outcomes related to early-life lung injuries. According to the performance characteristics, it can be divided into internalizing problems (anxiety, depression) and externalizing problems (ADHD, conduct problems).

Research indicates that school-aged children with BPD exhibit more internalizing behaviors, as well as difficulties with attention and social, compared to classroom controls [62]. A study of children born at 22–26 weeks of gestation assessed behavior using the Child Behavior Checklist at 22–26 months of corrected age. After adjusting for confounders, children with grade 3 BPD scored 2.4 points higher (worse) on the pervasive developmental problems (95% CI: 0.76–3.98) and 2.2 points higher on the withdrawn behavior (95% CI: 0.67–3.78) than those without BPD. Interestingly, they exhibited comparatively better scores on measures of externalizing problems, sleep problems, and aggressive behavior, indicating that the relationship between BPD and behavior is complex, and the effects of BPD on behavior may be mediated by multiple factors, such as the definition of BPD severity, age at assessment, and family environment [63].

The association between asthma and emotional or behavioral affections has received the most attention. A 2021 meta-analysis confirmed a significant association between childhood asthma and ADHD (OR = 1.52). However, as most of the included studies were cross-sectional, the temporal relationship between the two conditions remains uncertain [64]. Prospective studies of children with asthma provide support for a temporal sequence, showing that early asthma increases the subsequent risk of developing ADHD [65, 66]. Notably, a 12-year large-scale cohort study examining the bidirectional relationship between asthma and ADHD found that the incidence of ADHD in the asthma group was 1.17 times that of the control group, while the incidence of asthma in the ADHD group was 1.10 times that of controls [67]. The bidirectional interaction of the lung-brain axis may explain this phenomenon. Furthermore, children and adolescents with asthma are also at significantly increased risk for depression and anxiety [68].

An association between recurrent respiratory infections (RRI) and behavioral affections in children has also been documented. A study of school-aged children found that those with RRI scored significantly higher on scales measuring withdrawal/depression, somatic complaints, social problems, and rule-breaking behavior, reflecting elevations in both internalizing and externalizing behavioral issues [69].

ETS is significantly associated with an elevated risk of ADHD in children. A U.S. population-based survey of over 6,000 children aged 4–15 years revealed a strong association between secondhand smoke exposure and ADHD (OR = 1.5; 95% CI: 1.1–2.0) [70]. Specifically, a large cross-sectional study of 45,562 Chinese children aged 6–18 years reported that after adjusting for potential confounders, early postnatal second hand smoke exposure (during the first 2 years of life) was associated with a 47% increased odds of ADHD symptoms (OR = 1.47; 95% CI: 1.29–1.68), and current second hand smoke exposure (at school age) was associated with a 20% increased odds of ADHD symptoms (OR = 1.20; 95% CI: 1.09–1.31) [45]. Additionally, ETS exposure during the first four years of life has been shown to predict later externalizing symptoms, even among children whose mothers did not smoke during pregnancy. This underscores the critical importance of minimizing children's exposure to environmental smoke from all sources, including those beyond parental smoking [71]. Table 2 lists the effect sizes of key studies on early-life lung injuries and neurodevelopmental disorders.

Table 2.

Effect sizes of key studies on early-life lung injuries and neurodevelopmental disorders

Exposure	Neurodevelopmental outcome	Effect size (95% CI or Mean ± SD)	Sample/population
BPD	IQ reduction [46]	− 15 points (1 SD)	Meta-analysis (71 studies, 12,907 children)
	IQ reduction [47]	• FSIQ: BPD: 82.8 ± 20.0; VLBW: 91.7 ± 16.0; Term: 101.9 ± 15.0 • Verbal IQ: BPD: 87.4 ± 20.0; VLBW: 95.0 ± 16.0; Term: 102.3 ± 15.0 • Performance IQ: BPD: 81.4 ± 19.0; VLBW: 89.9 ± 17.0; Term: 101.5 ± 15.0 • Mental retardation: BPD: 20%; VLBW: 11%; Term: 3% • Special educational needs rate: BPD: 54%; VLBW: 37%; Term: 25%	98 BPD; 75 VLBW; 99 term infants
	ASD [54]	NS (ASD 56% vs control 56%, p = 1.00)	16 ASD, 48 controls
	ASD [56]	OR = 1.73 (1.03–2.90)	Meta-analysis (6 studies)
	ASD [55]	RR = 1.69 (1.08–2.64)	133 very preterm/VLBW infants
	ASD [57]	BPD: OR = 1.44 (0.84–2.45) Postnatal steroid therapy: OR = 1.97 (1.18–3.29)	4,963 VLBW children
	Internalizing behaviors [62]	BPD:10.4 ± 8.1 vs control:7.4 ± 5.1	66 BPD; 60 preterm controls
	Behavioral Problems [63]	Grade 3 BPD vs. no BPD: • Pervasive developmental problems: + 2.4 points (worse) (0.76–3.98) • Withdrawn behavior: + 2.2 points (worse) (0.67–3.78) • Externalizing problems: –2.4 points (better) (–4.66 to –0.14) • Aggressive behavior: –1.8 points (better) (–3.27 to –0.27) • Sleep problems: –2.1 points (better) (–3.58 to –0.53)	2,310 children born at 22–26 weeks’ gestation; 1,208 no BPD; 806 grade 1; 177 grade 2; 119 grade 3
Childhood asthma	Memory Function [13]	• Episodic memory: β = –0.09 (–0.18 to –0.01) • Processing speed: β = –0.13 (–0.22 to –0.03) • Inhibition and attention: β = –0.11 (–0.21 to –0.02)	1031 asthma; 1031 comparison
	ASD [52]	PR = 1.4 (1.2–1.7)	66,790 children (age 0–17 years)
	ASD [53]	HR = 2.01 (1.19–3.40)	2,134 children with asthma diagnosed at age 0–3 years vs. 8,536 controls
	ADHD [64]	OR = 1.52 (1.42–1.63)	Meta-analysis (23 studies, total sample size not reported)
	ADHD [67]	• Asthma → ADHD: HR = 1.17 (1.11–1.23) • ADHD → asthma: HR = 1.10 (1.03–1.17)	131,937
	ADHD [66]	HR = 1.31 (1.07–1.59)	2,294 children with asthma vs. 9,176 controls
	ADHD [65]	• HI symptoms (≥ 3 symptoms): OR = 2.73 (1.49–5.00) • HI symptoms (≥ 1 symptoms): OR = 1.88 (1.18–3.00) • IN symptoms: no significant association	1,812
	Depression and anxiety [68]	• Depression: pooled OR = 2.09 (1.65–2.64); • Anxiety: pooled OR = 1.83 (1.63–2.07)	Meta-analysis (8 studies involving 3,546 asthma; 24,884 controls)
Respiratory tract infection	Impaired intelligence, attention, verbal memory [49]	• FSIQ: d = –0.59 • Speed and attention: d = –0.41 • Verbal memory: d = –0.60	65 patients with bronchiolitis requiring mechanical ventilation vs. 76 controls (aged 6–12 years)
	Cognitive impairment [48]	• PDI: Study group: 89.13 ± 7.49; Control: 92.30 ± 7.22; • MDP: Study group: 43.3%; Control: 10%;	30 SARS-CoV-2 positive neonates; 60 controls
	ASD [61]	aOR = 22.2 (2.5–191.03)	50 children with ASD (age 3–12 years) vs. 51 controls
	Behavioral Problems [69]	• Internalizing problems: RRI: 6.70 ± 6.6; Control: 3.79 ± 4.3; P = 0.049 • Externalizing problems: RRI: 6.10 ± 5.5; Control: 2.83 ± 6.5; P = 0.043	30 children with RRI, 30 healthy controls
ETS exposure	IQ reduction [51]	• Verbal IQ reduction: B = –0.31 (–0.60 to –0.03)	996 children (age 8–11 years)
	Cognitive impairment [50]	• Reading score: β = –2.69 • Math score: β = –1.93 • Block design score: β = –0.55	4,399 children (age 6–16 years)
	Cognitive impairment [44]	• Cognitive composite: B = − 2.34 (− 3.69 to − 0.98) • Cognitive flexibility: B = –1.29 (− 2.43 to − 0.14) • Episodic memory: B = –0.97 (− 1.77 to − 0.17) • Language development: B = –0.58 (− 1.05 to − 0.11) • Inhibitory control and attention: B = –1.59 (95% CI: − 2.71 to − 0.47)	386 mother–child dyads
	Autistic-like behaviors [58]	Exposed to ETS from birth to one year old: AOR = 1.42 (1.19 to 1.69)	65,243 preschoolers
	ASD [60]	OR = 1.89 (1.12–3.21)	520 children (200 ADHD, 67 ASD, 253 controls), age 6–12 years
	ASD symptoms [59]	OR = 4.03 (1.65–9.84)	676 children
	ADHD [70]	aOR = 1.5 (1.1–2.0)	6,283 children
	ADHD [45]	Exposed to smoke: • During early postnatal period: OR = 1.47 (1.29–1.68) • Current period: OR = 1.20 (1.09–1.31)	45,562 children aged 6–18 years
	HI and conduct problems [71]	• HI: β = 0.20 (0.10–0.30) • Conduct problems: β = 0.16 (0.06–0.26)	1,096 children

Abbreviations: ADHD Attention deficit hyperactivity disorder, AOR/aOR Adjusted odds ratio, ASD Autism spectrum disorder, B B coefficient, BPD Bronchopulmonary dysplasia, CI Confidence interval, d Cohen’s d, FSIQ Full scale intelligence quotient, HI Hyperactivity impulsivity, HR Hazard ratio, IN Inattention, IQ Intelligence quotient, MDP Mildly delayed performance, OR Odds ratio, PDI Psychomotor Development Index, PR Prevalence ratio, RRI Recurrent respiratory infections, RR Relative risk, SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2, SD Standard deviation, VLBW Very low birth weight, β Standardized regression coefficient

Mechanisms underlying lung injury-induced impaired brain development in children (Fig. 2)

Fig. 2.

Through the lung-brain axis, reveal the molecular and cellular mechanism correlations between the early-life lung injuries. This diagram illustrates the pathogenic cascade from local pulmonary insults (e.g., BPD, childhood asthma, pneumonia, tobacco smoke exposure) to systemic inflammation and subsequent brain injury. Local lung inflammation triggers the release of pro-inflammatory cytokines (IL-1β, TNF-α) and ROS, activating transcription factors such as HIF-1α and NF-κB. These mediators enter the systemic circulation, inducing systemic inflammation and calcium overload (Ca²⁺ overload). The resulting endothelial cell dysfunction, mitochondrial damage, and energy depletion compromise BBB integrity. In the brain, increased neuroinflammation, ER stress, and reduced BDNF lead to oligodendrocyte delayed maturation and remyelination disorder. These white matter abnormalities contribute to cognitive impairment, learning difficulties, and neurodevelopmental disorders (e.g., ADHD, ASD). This figure highlights the critical role of the lung–brain axis in translating early respiratory injury into long-term neurological sequelae. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; BPD, bronchopulmonary dysplasia; ER, endoplasmic reticulum; HIF-1α, hypoxia-inducible factor-1α; IL-1β, interleukin-1 beta; NF-κB, nuclear factor-kappa B; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha

The role of the hypoxia-oxidative stress axis in pediatric lung injury and neurodevelopment

Common pathological states of lung injury in children, such as BPD, asthma, pneumonia, and ETS exposure, are universally accompanied by the occurrence of hypoxemia and the activation of oxidative stress. These two factors mutually reinforce each other, forming a vicious cycle that constitutes a core pathological mechanism in the progression of these diseases. In the pathogenesis of BPD, preterm infants are abruptly transferred from a relatively hypoxic intrauterine environment to a hyperoxic extrauterine environment. This triggers the generation of reactive oxygen species (ROS) and inflammatory responses in the lungs, subsequently inducing the sequential activation of endoplasmic reticulum (ER) stress and mitochondrial damage, ultimately leading to impaired alveolar development and aberrant pulmonary vascular remodeling [72, 73]. Studies have shown that myeloperoxidase (MPO)-mediated oxidative stress plays a critical role in BPD lung injury, where activated alveolar myeloid cells release ROS, exacerbating ER stress and promoting cellular senescence [74]. In children with asthma, airway inflammation is accompanied by elevated oxidative stress levels. Inflammatory cells generate substantial amounts of ROS and reactive nitrogen species (RNS), which regulate the release of inflammatory factors through the activation of related signaling pathways, thereby aggravating airway inflammation [75]. Oxidative stress also drives airway structural remodeling: ROS promote the recruitment of eosinophils and neutrophils by activating transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1, amplifying type 2 cytokine responses. Concurrently, glutathione, catalase, superoxide dismutase, and nuclear factor erythroid 2-related factor 2 (Nrf2) play regulatory roles in maintaining redox balance [76].

Pneumonia, a typical manifestation of acute severe infection, has its pathological basis in pathogen invasion that induces massive infiltration of neutrophils and macrophages. These cells overproduce ROS via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and MPO pathways, leading to alveolar epithelial damage and capillary leakage, further exacerbating ventilation/perfusion (V/Q) mismatch and worsening hypoxemia [77, 78]. ETS exposure primarily causes multi-system damage through oxidative stress pathways mediated by NADPH oxidase 2 (NOX2). Clinical studies demonstrate that passively smoking children exhibit significantly elevated serum levels of soluble NOX2-derived peptide, isoprostanes, and hydrogen peroxide. Among these, sNOX2 and hydrogen peroxide are independent predictors of endothelial dysfunction (reduced flow-mediated dilation) [79]. Chronic hypoxia can lead to delayed maturation of oligodendrocyte precursor cells (OPCs) in the immature cerebral white matter and downregulate myelin basic protein (MBP) expression, thereby delaying the myelination process in neural circuits such as the central auditory pathway. Simultaneously, hypoxia can induce oxidative stress responses through mitochondrial dysfunction and ROS bursts [80, 81]. Furthermore, the frequency of early hypoxemia and intermittent hypoxic events is significantly correlated with the extent of white matter injury detected by magnetic resonance imaging (MRI) at term and subsequent neurodevelopmental disorders [82], suggesting a crucial role for early hypoxia and oxidative stress in neurodevelopmental abnormalities.

Mechanisms of pulmonary microvascular injury-mediated neuronal energy metabolism dysregulation

Pulmonary microvascular endothelial cells constitute the core structure of the air-blood barrier and can be categorized into two heterogeneous subpopulations based on spatial localization and functional characteristics: capillary 1 cells located on the arterial side with reparative potential, and capillary 2 cells situated on the venous side forming tight junctions with alveolar epithelial cells [83]. Recent studies indicate that pulmonary microvascular injury can disrupt the oxygen-sensing function of mitochondrial electron transport chain complex I subunit NADH dehydrogenase (ubiquinone) iron-sulfur protein 2, reduce mitochondrial ROS generation, alter the activity of voltage-gated potassium channels (Kv1.5/Kv2.1), and induce calcium homeostasis dysregulation. These events subsequently inhibit hypoxic pulmonary vasoconstriction (HPV). This disruption of pulmonary V/Q matching leads to systemic hypoxemia, ultimately precipitating neuronal energy metabolism disorders [84]. In the pathological progression of BPD, impaired microvascular development is considered an initiating event that triggers disrupted alveolarization. Mouse models of hyperoxia exposure demonstrate that pulmonary microvascular dysregulation precedes impaired alveolarization [85]. Hyperoxia-induced oxidative stress selectively damages the capillary 2 cell subpopulation, leading to increased apoptosis and reduced gas exchange surface area. Concurrently, internalization of vascular endothelial cadherin and disruption of tight junction structures further increase pulmonary microvascular permeability, causing V/Q mismatch and systemic hypoxemia.

Hypoxemia subsequently leads to delayed maturation of OPCs and downregulation of MBP expression in the immature cerebral white matter, ultimately resulting in decompensated neuronal metabolic reprogramming, energy depletion, and irreversible neuronal injury [86]. Interventional studies targeting pulmonary microvascular injury offer potential therapeutic targets. Hyperoxic injury contributes to BPD pathogenesis by reducing tropomyosin receptor kinase B (TrkB) receptor expression in pulmonary gCap cells, whereas activation of the brain-derived neurotrophic factor (BDNF)/TrkB/mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway can promote gCap cell proliferation and angiogenesis, thereby alleviating pulmonary microvascular damage [87]. Additionally, inhibiting lncRNA-VSIG2-1:1 expression stimulates pulmonary angiogenesis via induction of the vascular endothelial growth factor (VEGF)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, representing a significant therapeutic strategy for BPD [88]. In pneumonia-associated acute lung injury, deficiency of epithelial sodium channel (ENaC) in pulmonary endothelial cells exacerbates pneumococcal infection-induced oxidative stress and capillary leakage by upregulating NOX2 activity. Activation of ENaC by TIP peptide inhibits NOX2 activity, repairing vascular barrier function without compromising host defense, highlighting the critical role of the ENaC/NOX2 axis in mediating pulmonary microvascular injury and reducing vascular leakage and oxidative stress [89]. Short-term exposure to nicotine aerosol can also induce pulmonary microvascular inflammation, characterized by increased neutrophil sequestration in the lungs and enhanced neutrophil-platelet interactions, accompanied by decreased plasma MPO levels and altered cytokine profiles, suggesting impaired vascular immune function leading to pulmonary microvascular injury [90]. Cerebral microvascular endothelial cells participate in local energy metabolism regulation through their unique hypoxia-sensing capacity, with mitochondria serving as the core organelle linking pulmonary microvascular injury and neuronal energy metabolism dysregulation [91]. At the neuronal level, mitochondrial dysfunction manifests as multiple energy metabolic abnormalities: inhibition of electron transport chain activity directly reduces adenosine triphosphate (ATP) synthesis, rendering neurons unable to maintain Na⁺/K⁺ ATPase-dependent ion gradients, leading to membrane potential instability and increased susceptibility to excitotoxicity; opening of the mitochondrial permeability transition pore (mPTP) is a key injury event following hypoxia-reperfusion, terminating ATP synthesis; and aberrant mitochondrial proton leak is exacerbated under systemic oxidative stress conditions, imposing a significant metabolic burden on highly energy-demanding neurons [91, 92]. In summary, pulmonary microvascular injury, by inducing hypoxemia, releasing circulating oxidative mediators, and impairing cerebral microvascular hypoxia sensing, ultimately converges on neuronal mitochondrial dysfunction, leading to energy failure and irreversible damage.

Mechanisms of blood–brain barrier (BBB) disruption and impaired brain development mediated by early-life lung injury

The BBB is a neurovascular unit composed of cerebral microvascular endothelial cells, tight junction proteins, basement membrane, pericytes, and astrocytic end-feet. It constitutes the structural foundation for maintaining CNS microenvironmental homeostasis. The BBB in early life is functionally immature, rendering the developing brain highly vulnerable to lung‑derived systemic insults [93]. Pediatric lung injury can induce structural and functional damage to the BBB through multiple mechanisms, thereby mediating impaired brain development. Research indicates that lung injury triggers systemic inflammatory responses, releasing substantial amounts of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) into the circulation. These inflammatory mediators act on the CNS via a "spillover" effect, downregulating the expression of tight junction proteins (Occludin, Claudin-1, Zonula Occludens-1) and increasing barrier permeability, subsequently inducing hippocampal neuroinflammation and synaptic damage [94]. In preterm infants with BPD, extracellular vesicles-adipose derived stem cell (EV-ASC) speck-containing extracellular vesicles derived from alveolar macrophages mediate lung-brain crosstalk. Plasma EV-ASC levels are elevated in hyperoxia-exposed infants; these vesicles can traverse the BBB via the bloodstream, inducing neuroinflammation and cell death in the hippocampus while concurrently exacerbating lung injury. This suggests that EV-ASC acts as a key messenger connecting lung injury and neurodevelopmental disorders [29].

ETS exposure damages the BBB through NOX2-mediated oxidative stress pathways. Inhaled pollutants trigger systemic oxidative stress, and elevated circulating ROS levels can directly attack the lipids and proteins of cerebral microvascular endothelial cell membranes, increasing barrier permeability [95]. Studies confirm that tobacco exposure impairs BBB function by inducing oxidative stress, inflammatory responses, and disruption of tight junction proteins, thereby leading to neurodevelopmental disorders [96]. Furthermore, systemic hypoxemia resulting from lung injury exacerbates BBB damage through multiple pathways: stabilization of hypoxia-inducible factor (HIF-1α) upregulates VEGF expression, increasing vascular permeability; energy metabolism disorders impair endothelial cell Na⁺/K⁺ ATPase function, disrupting ion homeostasis; and hypoxia/reoxygenation cycles trigger mPTP opening and oxidative bursts, further compromising barrier structure and function [97]. In conclusion, pediatric lung injury compromises BBB structure and function through multiple pathways, including inflammatory mediator attack, EV-ASC-mediated cross-barrier delivery, oxidative stress, and hypoxemia, ultimately resulting in impaired brain development.

The inflammatory cascade from pulmonary inflammation to neuroinflammation: mechanisms of lung injury-related impaired neurodevelopment

The developing brain is inherently more susceptible to external insults than the adult brain. Neurodevelopmental processes (neurogenesis, synaptogenesis, myelination) and heightened sensitivity of oligodendrocyte precursors to inflammation and oxidative stress render the immature brain easily damaged by lung‑derived systemic inflammation and hypoxia [98]. The initial events in lung injury are invariably accompanied by the initiation of a local inflammatory response. This response can progressively amplify into a systemic inflammatory state and ultimately trigger CNS neuroinflammation, thereby impacting neurodevelopment [99]. In the pathological progression of BPD, hyperoxia exposure induces oxidative stress, activating alveolar macrophages and epithelial cells, prompting the release of pro-inflammatory cytokines such as IL-1β, IL-6, interleukin-18 (IL-18), and TNF-α. Studies confirm that inflammation is a central component of BPD pathogenesis, closely linked to the depletion of alveolar epithelial type II cells and arrested alveolarization [100]. Asthma, a chronic airway inflammatory disease, is characterized by a T helper type 2 (TH2) cytokine-dominant (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13)) inflammatory response. Recent research indicates that neonatal IL-4 overexposure can induce delayed neuroinflammatory injury, suggesting long-term effects of early pulmonary TH2 inflammation on the CNS [101]. ETS exposure induces pulmonary inflammation and oxidative damage through NOX2-mediated oxidative stress pathways [41].

Circulating systemic inflammatory factors (e.g., TNF-α, IL-1β) can directly act on cerebral microvascular endothelial cells, downregulating tight junction protein expression, increasing BBB permeability, and subsequently crossing the barrier to enter the hippocampus, inducing local inflammatory responses and cell death [102]. Non-neuronal sources of histamine and other inflammatory mediators can indirectly influence brain development processes by modulating microglia-mediated neuroinflammation [103]. Neuroinflammation impairs neuronal function through multiple mechanisms: First, inflammatory cytokines inhibit astrocytic glutamate transporter function, leading to extracellular glutamate accumulation and overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in increased calcium influx [104]. Second, activated microglia release ROS and RNS, damaging the mitochondrial electron transport chain and inducing lipid peroxidation and protein oxidation [105]. Third, inflammatory cytokines directly impair the expression and function of BDNF, a molecule critical for synaptic plasticity [106, 107]. Fourth, IL-1β and TNF-α can inhibit the differentiation and maturation of OPCs, leading to downregulation of MBP expression and hindering myelination [108]. These mechanisms collectively mediate neuronal dysfunction, ultimately resulting in impaired neurodevelopment. In summary, pediatric lung injury initiates a cascade of "pulmonary inflammation → systemic inflammation → neuroinflammation," wherein circulating mediators compromise the BBB and trigger CNS neuroinflammation, ultimately mediating neuronal dysfunction and impaired brain development.

Discussion

This article reviews the associations between BPD, childhood asthma, respiratory tract infections, ETS exposure, and children's cognitive, emotional, and behavioral affections, establishing the clinical basis for the "lung-brain axis" [11, 12, 16], and further explores its underlying mechanisms. The hypoxia-oxidative stress axis is the core starting point: lung injury leads to an imbalance between oxidation and antioxidation [72, 79], accompanied by recurrent or persistent hypoxia. These two conditions exacerbate each other, directly inhibiting oligodendrocyte precursor cell maturation and hindering myelination [80, 82]. Pulmonary microvascular injury and energy metabolism dysregulation constitute an important link, disrupting the V/Q matching [84], which in turn leads to mitochondrial dysfunction and neuronal energy depletion [86]. Meanwhile, BBB disruption is a key step through which lung injury causes brain developmental impairment, allowing peripheral inflammatory factors to enter the brain [95], ultimately triggering an inflammatory cascade and leading to neuronal dysfunction [103, 106, 108]. In summary, early-life lung injury can interfere with brain development through four pathways—hypoxia, oxidative stress, energy dysregulation, and inflammation—ultimately affecting long-term neurological outcomes. Notably, the lung-brain axis does not operate in isolation. It is increasingly recognized to interact with other axes, particularly the gut-brain axis. Through the "gut-lung axis," gut microbiota dysbiosis—driven by early-life factors such as antibiotic exposure, mode of delivery, and nutrition [109]—could influence both pulmonary immunity and neurodevelopmental processes including microglial maturation, myelination, and behavior [110]. Thus, the lung-brain and gut-brain axes may function in concert as an integrated "gut-lung-brain axis" that mediates the impact of early-life lung injury on neurodevelopmental outcomes, a concept that warrants further investigation.

Although current studies have revealed the association between early-life lung injury and developmental disorders, there are still many limitations. Firstly, several confounding factors, including SES, genetic predisposition, and comorbid conditions, may significantly influence the observed associations through multiple pathways. For instance, low SES is often associated with both increased risk of ETS exposure and reduced access to early developmental interventions [111], thereby independently contributing to adverse neurodevelopmental outcomes. Meanwhile, certain genetic factors, such as polymorphisms in inflammatory genes including IL-6, IL-1β, and TNF-α, are associated with both more severe asthma phenotypes and increased susceptibility to neuroinflammation as well as elevated risk of ASD [112]. Preterm infants with BPD often suffer from multiple concurrent insults, including sepsis and necrotizing enterocolitis [113]. Infections themselves can induce systemic inflammation, directly damaging the BBB and neurons. Similarly, children with asthma frequently experience sleep disturbances and psychological stress [114]. Sleep insufficiency could exacerbate daytime attention deficits and executive dysfunction, while anxiety and depression impair cognitive test performance and undermine treatment adherence, further leading to poor asthma control. These intertwined confounding factors make it difficult to isolate the direct neurotoxic effects of lung injury from the indirect influences of coexisting conditions. The dynamic evolution of the developmental time window has not been clarified. Most existing studies are cross-sectional designs, lacking long-term follow-up from infancy to school age [115], making it difficult to identify critical windows of injury. There is a gap between animal models and clinical reality. For example, the timing of brain development differs between rats and humans [116], the neonatal rodent brain roughly corresponds to a late-gestation human fetus, and key developmental processes such as myelination and synaptogenesis occur within a significantly compressed time window in rodents [117]. This discrepancy makes it difficult to directly translate findings regarding "critical windows of vulnerability" from animal models to human clinical settings. Furthermore, animal models simulating lung injury struggle to replicate the complex infections, medication use, and nutritional fluctuations seen in human patients [118]. Moreover, clinical epidemiological data show that the incidence of BPD and asthma in boys is significantly higher than that in girls [119], suggesting that sex may be an important modifier of susceptibility to early-life lung injury. However, existing studies have not fully explored the potential regulatory role of sex in the lung-brain axis. Sex differences may influence lung-brain axis regulation through several interconnected pathways. Sex hormones play a critical modulatory role, as estrogen generally exhibits anti-inflammatory and neuroprotective properties whereas testosterone may enhance pro-inflammatory responses [120]. Microglial also exhibits sexual dimorphism, with male microglia displaying a more pro-inflammatory phenotype and greater sensitivity to activation by peripheral insults, potentially amplifying the inflammatory cascade from the lung to the brain [121]. In terms of the developmental time window, as the male brain follows a slower early maturation trajectory, rendering it vulnerable to injury over a longer period [122]. Collectively, these sex-specific differences suggest that the lung-brain axis is not a uniform pathway. Boys may face a double disadvantage—higher susceptibility to lung injury coupled with greater vulnerability to its neurodevelopmental consequences. Future research should focus on the following directions for breakthroughs. Establish a large longitudinal cohort covering the prenatal, neonatal, and school-age periods, integrating basic characteristics of the population (lung function, medication status, environmental exposure, nutritional status), and regularly collecting neurodevelopmental assessment data and brain imaging data (MRI, functional near-infrared spectroscopy) [123, 124], identifying key biomarkers and time windows with predictive value [125], and providing targets for precise intervention. Utilizing multi-omics technologies to explore the molecular mechanisms of lung and immune cells and microglia phagocytosis of synapses during development [126], as well as the specific pathways through which different pathogens (respiratory syncytial virus vs. pertussis) induce nerve injury. To reduce the gap between animal models and clinical reality, future research can introduce human brain organoid tools [127, 128], using induced pluripotent stem cells to construct individualized hippocampal and cortical organoids [129], directly exposed to patient serum or specific drugs, and monitoring neuronal survival, synapse formation, and microglial responses in real time.

In terms of potential pharmacological interventions, glucocorticoids and bronchodilators are commonly used clinical drugs for preventing BPD and controlling severe asthma [130]. However, there is still a lack of sufficient data to support their impact on the neuro-safety of the developing brain. In contrast, caffeine, inhaled nitric oxide (iNO), and erythropoietin are drugs that can improve lung injury and have been proven to exert direct neuroprotective effects through mechanisms such as antioxidant stress and promoting myelin formation [130, 131]. With the in-depth exploration of the lung-brain axis mechanism, biological agents targeting key inflammatory factors (such as IL-4, IL-6, and IL-1β) are expected to cut off the secondary damage to the brain caused by the inflammatory cascade at its source [132], providing new theoretical possibilities for simultaneously blocking inflammatory damage in the lungs and the CNS. However, their potential impact on the development of the child's overall immune system needs to be carefully evaluated to avoid interfering with normal immune function due to excessive immune regulation [133]. Reparative treatments represented by mesenchymal stem cells and their exosomes (such as EV-ASC) are promising intervention methods for repairing multiple organ injuries [134]. Theoretically, stem cells can alleviate lung inflammation through paracrine action, repair alveolar structure, and thereby improve systemic oxygenation status, indirectly protecting the brain, some exosomes may also directly cross the BBB and exert neurotrophic effects [29]. However, this field is still in the early exploration stage. In the future, large animal models simulating human developmental processes and other preclinical studies are needed to clarify the optimal treatment plan (including drug dosage, intervention timing, and administration route), and to systematically evaluate the long-term neuro-safety of the above-mentioned therapeutic drugs through large-scale randomized controlled trials and long-term follow-up data. Non-pharmacological interventions should serve as the cornerstone of all treatment plans. Specific strategies include the following four points. First, strengthen environmental control and exposure prevention, including protecting air quality during pregnancy, strict smoking control policies, and standardized vaccination [135]. These measures aim to reduce the inducing factors of lung injury from the source. Second, implement precise nutrition and metabolic support, fully leveraging the dual roles of docosahexaenoic acid, immunoglobulin A (IgA), and trace nutrients (vitamin D, iron supplements) in breast milk in lung and brain protection [136], providing a material basis for the coordinated development of the lung and the brain. Third, optimize oxygen therapy plans, through precise setting of oxygen saturation targets for children with BPD [137], to seek a balance between avoiding hypoxic injury and preventing hyperoxic toxicity. Fourth, establish a multidisciplinary joint follow-up system to identify early cognitive and emotional problems in children and combine lung rehabilitation training to improve children's outdoor social activities and learning abilities [138], thereby maximizing the long-term neurodevelopmental potential of the child (Fig. 3).

Fig. 3.

Potential pharmacological and non-pharmacological interventions targeting the lung–brain axis to mitigate neurodevelopmental disorders following early-life lung injury. This schematic categorizes potential therapeutic approaches that interrupt the pathological cascade from pulmonary damage to brain dysfunction. Potential pharmacological interventions include caffeine, iNO, EPO, reparative treatment (EV-ASC), and targeted anti-inflammatory drugs (such as drugs that inhibit IL-4, IL-6, and IL-1β). Non-pharmacological interventions focus on supportive care and environmental modulation: optimizing oxygen therapy (avoiding hyperoxic toxicity and hypoxic injury, precise SpO₂ targeting), reducing pulmonary triggers (smoking cessation, vaccination, air quality protection), promoting breastfeeding (providing DHA/IgA, vitamin D, iron), encouraging outdoor activities, and ensuring regular follow-up. By preserving lung integrity and reducing systemic inflammation, these interventions aim to maintain glial cell function, promote myelin formation, and provide neurotrophic effects, thereby lowering the risk of cognitive impairment, learning difficulties, ADHD, ASD, and BPD related neurological sequelae. This figure highlights the translational potential of lung-brain axis targeted strategies for early neuroprotection. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BPD, bronchopulmonary dysplasia; DHA, docosahexaenoic acid; EPO, erythropoietin; EV-ASC, extracellular vesicles-adipose derived stem cell; iNO, inhaled nitric oxide; IgA, immunoglobulin A; IL-1β, interleukin-1beta; IL-4, interleukin-4; IL-6, interleukin-6; SpO₂, peripheral oxygen saturation

Conclusion

Early-life lung injury is often associated with neurodevelopmental disorders. Unlike adults, children are in a critical window of brain development, during which the nervous system has high plasticity but is also more vulnerable. The underlying mechanisms involve multiple pathways, including hypoxia-oxidative stress, pulmonary microvascular injury and energy metabolism dysregulation, BBB disruption, and inflammatory responses. The deepening of the lung-brain axis concept has improved our understanding of the mechanisms behind this developmental lung-brain co-morbidity and has opened new directions for early identification and intervention of this clinical issue in children. Clinically, traditional lung intervention measures should be combined with targeted strategies for protecting the developing nervous system. This approach ensures lung function while maximizing the maintenance of children's neurodevelopmental potential. In the future, efforts should be made to establish a longitudinal cohort specific to children, identify age-specific biomarkers, and conduct in-depth research on the mechanisms related to the developmental stage, thereby achieving early intervention for neurodevelopmental disorders caused by early-life lung injury.

Abbreviations

ADHD

Attention deficit hyperactivity disorder

AOR/aOR

Adjusted odds ratio

ASD

Autism spectrum disorder

ATP

Adenosine triphosphate

BBB

Blood-brain barrier

BDNF

Brain-derived neurotrophic factor

BPD

Bronchopulmonary dysplasia

CI

Confidence interval

CNS

Central nervous system

DHA

Docosahexaenoic acid

ENaC

Epithelial sodium channel

EPO

Erythropoietin

ER

Endoplasmic reticulum

ETS

Environmental tobacco smoke

EV-ASC

Extracellular vesicles-adipose derived stem cell

FSIQ

Full scale intelligence quotient

HIF-1α

Hypoxia-inducible factor-1α

HR

Hazard ratio

IgA

Immunoglobulin A

IL-1β

Interleukin‑1beta

IL-4

Interleukin‑4

IL-5

Interleukin‑5

IL-6

Interleukin‑6

IL-13

Interleukin‑13

IL-18

Interleukin‑18

iNO

Inhaled nitric oxide

IQ

Intelligence quotient

MBP

Myelin basic protein

MDI

Mental Development Index

MDP

Mildly delayed performance

MPO

Myeloperoxidase

mPTP

Mitochondrial permeability transition pore

MRI

Magnetic resonance imaging

NADPH

Nicotinamide adenine dinucleotide phosphate

NF-κB

Nuclear factor-kappa B

NMDA

N‑methyl‑D‑aspartate

NOX2

NADPH oxidase 2

Nrf2

Nuclear factor erythroid 2-related factor 2

OPCs

Oligodendrocyte precursor cells

OR

Odds ratio

PDI

Psychomotor Development Index

PI3K

Phosphoinositide 3‑kinase

PR

Prevalence ratio

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

RRI

Recurrent respiratory infections

RR

Relative risk

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

SD

Standard deviation

SES

Socioeconomic status

SpO₂

Peripheral oxygen saturation

TH2

T helper type 2

TNF-α

Tumor necrosis factor-alpha

TrkB

Tropomyosin receptor kinase B

VEGF

Vascular endothelial growth factor

VLBW

Very low birth weight

V/Q

Ventilation/perfusion

Authors’ contributions

Author contributions PW, XK, JL, and DL supervised, reviewed, and edited the project. CL, FW, XT, LW, CL and WL summarized the literature, wrote the initial manuscript, and drew the figures. PW, XK, JL, and DL proofread the structures and revised the manuscript. XC and JL 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 (82571352), Shandong Excellent Young Scientists Fund Program (Overseas, 2026HWYQ-013), China Postdoctoral Science Foundation (2024M761822), Qingdao Natural Science Foundation(25–1-1–231-zyyd-jch); 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, QDKY2025QN07), Medical and Health Scientific Research Project of Qingdao (2024-WJKY155).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.