The timing of these processes could hardly be more critical. The developing lung must accomplish epithelial differentiation, alveolarization, pulmonary microvascular maturation, establishment of surfactant competence, and adaptation to air breathing within a narrow developmental window. Each of these transitions places enormous demands on intracellular membrane trafficking and organelle quality control. When a premature infant enters the world before alveolar and microvascular maturation is complete, the immature lung becomes acutely vulnerable to hyperoxia, mechanical stress from ventilation, inflammation, and infection. The review emphasizes that lysosomal pathways in this setting should not be viewed as intrinsically protective or pathogenic; their effects depend on cell type, developmental stage, cargo, and the balance between cargo delivery and degradation.

Macroautophagy is the best-characterized lysosome-dependent recycling pathway. Cytoplasmic cargo is enclosed within double-membrane autophagosomes, which subsequently fuse with lysosomes to form autolysosomes in which the cargo is degraded and recycled. Microautophagy and chaperone-mediated autophagy provide additional routes for lysosomal cargo delivery. In the developing lung, these pathways matter because epithelial cells must simultaneously maintain organelle quality, adapt to changing nutrient and oxygen availability, and acquire specialized secretory functions. Mitophagy, the selective delivery of mitochondria to lysosomes for degradation, contributes to mitochondrial quality control, but the review is careful to distinguish its role in normal lung maturation from context-dependent responses observed in pulmonary injury models.

A key methodological warning runs through the entire review: static autophagy markers cannot define functional flux. Increased levels of lipidated microtubule-associated protein 1 light chain 3 (LC3-II) or p62/sequestosome 1 (p62/SQSTM1), or increased autophagosome abundance, may result either from increased autophagosome formation or from impaired downstream degradation. Conclusions about pathway activation or inhibition should therefore be supported by dynamic flux measurements or complementary turnover assays. This distinction is particularly important when lysosomal dysfunction is proposed as a mechanism of pediatric lung disease, where misreading a static marker could lead researchers down entirely the wrong therapeutic path.

Direct pulmonary evidence implicates epithelial autophagy in lung branching and morphogenesis. In alveolar type II (AT-II) cell models, disruption of autophagy-related pathways impairs lamellar-body maturation and surfactant homeostasis. Lamellar bodies are specialized lysosome-related organelles that serve as major intracellular sites for surfactant storage and secretion, and the review insists they must be distinguished from conventional degradative lysosomes. These organelles maintain an acidic lumen with a reported pH of approximately 5.0 to 5.5, and their function depends on vacuolar-type H⁺-ATPase (V-ATPase)-dependent proton transport, ABCA3-dependent lipid transport, EMC3-associated surfactant protein and lipid homeostasis, and mechanosensitive TMEM63A and TMEM63B channels that mediate surfactant secretion during lung inflation. Loss of core autophagy components such as FIP200 or ATG7 disrupts lamellar-body maturation and pulmonary surfactant homeostasis, supporting roles for autophagy in organelle maturation and epithelial secretory competence.

Lysosomal lipid handling provides a particularly vivid example of how lysosomal function can shape pulmonary epithelial phenotype. Lysosomal acid lipase (LAL), encoded by LIPA, hydrolyzes cholesteryl esters and triglycerides within lysosomes and thereby contributes to intracellular neutral-lipid homeostasis. In the lung, respiratory epithelial overexpression of human LAL disrupts surfactant composition, reduces neutral lipid content in bronchoalveolar lavage fluid, depletes lamellar bodies in AT-II cells, and is associated with alveolar simplification and airspace enlargement. These findings indicate that excessive lysosomal lipid catabolism can disturb the lipid environment required for surfactant homeostasis and alveolar structure. The review is careful to note that these data do not establish lysosomal degradation as the principal source of substrate for de novo surfactant synthesis; rather, they demonstrate that the magnitude and compartmentalization of lysosomal lipid catabolism can influence the cellular lipid pool, lamellar-body biology, and alveolar architecture within a distributed lipid-trafficking network that includes the endoplasmic reticulum, Golgi apparatus, lipid transporters, lamellar bodies, and extracellular surfactant recycling.

The mechanistic target of rapamycin (mTOR)–transcription factor EB (TFEB) signaling axis provides the interface between nutrient availability, growth, autophagy, and lysosomal function. During lung morphogenesis, mTOR contributes to airway branching, epithelial differentiation, and coordination between epithelial and vascular development. Amino acids recruit mTOR complex 1 (mTORC1) to the lysosomal surface through the Ragulator–Rag complex, connecting nutrient sensing to autophagy and TFEB-dependent lysosomal gene expression. Lysosomal positioning can also affect autophagosome–lysosome encounters. The review notes that separate neonatal hyperoxia studies report improved structural outcomes after autophagy induction or TFEB-linked intervention, but these injury-model findings do not by themselves establish a TFEB-dependent program in normal lung development. Stage- and cell-specific perturbation with rescue is needed to determine whether TFEB affects AT-II differentiation directly or supports adaptation after developmental stress.

Alveolar macrophage biology intersects with postnatal structural maturation, though the review acknowledges that direct evidence does not yet identify a lysosomal cause. Fetal monocytes acquire an alveolar macrophage phenotype around birth through granulocyte–macrophage colony-stimulating factor (GM-CSF)-dependent maturation. In a mouse model with epithelial β1-integrin deletion, macrophage depletion reduced persistent inflammation and rescued defective secondary septation. In neonatal hyperoxia, depletion experiments implicated the colony-stimulating factor 1 receptor (Csf1r)-expressing monocyte/macrophage lineage in arrested alveolarization. These studies link macrophage state to alveolar structure under developmental perturbation, but none establishes that macrophage lysosomal activity independently directs normal alveolarization. The authors propose that the next test is to perturb a defined lysosomal step specifically in neonatal alveolar macrophages, verify its effect on clearance or signaling, and then measure secondary septation, epithelial differentiation, and vascular development.

The review then turns to pediatric lung diseases, examining how distinct upstream stressors and endolysosomal or autophagic alterations converge on impaired clearance, disturbed surfactant homeostasis, mitochondrial injury, and epithelial dysfunction. Bronchopulmonary dysplasia (BPD), a multifactorial disorder in which prematurity, oxygen exposure, mechanical ventilation, inflammation, nutritional factors, and genetic susceptibility interact to disrupt alveolarization and pulmonary vascular development, shows heterogeneous lysosomal and autophagic phenotypes in experimental models. In murine and baboon models, impaired autophagic activity has been associated with BPD pathogenesis, while autophagy-inducing interventions can improve selected measures of alveolarization in hyperoxia-exposed neonatal animals. Other experimental BPD studies implicate macrophage AMPK-dependent autophagy, METTL3-related suppression of ATG8-mediated autophagy, TFEB-linked mitochondrial clearance, and hyperoxia-induced TMEM106B impairing ULK1-mediated autophagy through TLR3/JNK signaling. The direction of effect depends on cell type, pathway, and injury model; most evidence remains preclinical.

Cystic fibrosis (CF) provides a useful example of why lysosomal function must be interpreted at the level of the specific intracellular compartment. Early studies reported abnormal intracellular organelle acidification, whereas subsequent work identified hyperacidification of selected endocytic compartments and direct measurements showing that lysosomal pH may remain unchanged after CFTR loss or inhibition. Lysosomal, endosomal, Golgi, and airway surface liquid pH should not be treated as interchangeable variables. CFTR dysfunction can also alter autophagy and bacterial clearance independently of bulk lysosomal pH: defective CFTR has been associated with reactive oxygen species-mediated inhibition of autophagy and aggresome formation, while syntaxin-17-dependent pathways can influence autophagosomal clearance under stress. The CF example is valuable not because it establishes a universal lysosomal pH defect, but because it demonstrates the importance of compartment-resolved measurements.

Respiratory viruses remodel endolysosomal trafficking, lipid metabolism, and autophagy, but the direction and consequence depend on the virus, cell type, and stage of infection. Respiratory syncytial virus (RSV) provides a particularly clear example: RSV infection has been reported to reduce LAL activity, impair cholesterol transport from lysosomes to the endoplasmic reticulum, activate the SREBP2–LDLR axis, and promote cholesterol accumulation within lysosomes. Cholesterol enrichment is associated with impaired lysosomal acidification and blocked autophagic flux, resulting in retention of the RSV fusion protein and enhanced viral replication. Other viruses exploit endolysosomal biology differently: betacoronaviruses can use lysosomal trafficking for non-lytic egress, a process associated with lysosomal deacidification and impaired degradation, while SARS-CoV-2 open reading frame 3a (ORF3a) has been reported to inhibit autophagosome–lysosome fusion. These distinct steps should not be generalized across pediatric viral pneumonias or conflated with virus entry.

Therapeutically, the review argues that intervention should begin with a defined defect in autophagosome formation, fusion, lysosomal acidification, or cargo degradation. The clinical success of lysosome-directed therapies in selected lysosomal storage disorders establishes the tractability of the organelle as a therapeutic target, but these successes cannot be directly extrapolated to BPD, CF, or other pediatric lung diseases. Experimental BPD studies provide an initial proof of principle: autophagy-inducing interventions and TFEB-linked modulation have improved selected outcomes in neonatal hyperoxia models. The translational priority is therefore not broad activation of the lysosome–autophagy axis, but identification of the defective step and restoration of appropriate flux. Excessive or misdirected lysosomal activation could alter developmental signaling or compromise cellular viability.

Lysosome-targeted delivery may provide a means to improve cellular specificity and reduce systemic exposure. Experimental nanocarriers can exploit endolysosomal trafficking, luminal pH, or intracellular protease activity to deliver cargo to lysosome-associated compartments. For pediatric pulmonary applications, however, the relevant questions extend beyond delivery efficiency: investigators must establish where the material accumulates, how long it persists, which lung cell types internalize it, whether it reaches conventional lysosomes or lysosome-related organelles, and whether it alters surfactant or macrophage function. Premature lungs provide a particularly demanding translational environment because epithelial, vascular, immune, and surfactant systems are simultaneously undergoing maturation. Future studies should prioritize dynamic autophagic-flux assays, compartment-specific pH measurements, organelle-targeted functional readouts, and causal rescue experiments, tested across developmental time points and evaluated for effects on alveolarization, pulmonary vascular growth, surfactant secretion, epithelial differentiation, immune maturation, and host defense.

The review concludes that lysosomes occupy a central position at the interface of degradation, metabolism, organelle quality control, and inflammatory signaling in the developing lung. Direct pulmonary evidence supports epithelial autophagy in lung morphogenesis, AT-II cell autophagy-related pathways in lamellar-body maturation and surfactant homeostasis, and the effects of experimentally altered lysosomal lipid handling on surfactant and alveolar structure. Disease-model studies identify context-dependent remodeling of autophagic or endolysosomal pathways in hyperoxic injury, BPD, and RSV infection, but these injury-related mechanisms should not be assumed to direct normal lung development. The most promising direction is a developmentally informed, compartment-specific model of lysosomal biology in which lysosomes and lysosome-related organelles integrate metabolic and stress signals to maintain AT-II cell competence, surfactant homeostasis, mitochondrial quality, and immune function. When this adaptive network is disrupted by prematurity, hyperoxia, infection, or other stressors, impaired clearance, lipid imbalance, mitochondrial injury, and inflammatory amplification may contribute to defective alveolar and epithelial maturation. Future work should move from descriptive lysosomal phenotyping toward causal experiments that define the affected compartment and restore its function. If these requirements are met, lysosome-centered biology may provide a tractable framework for understanding and eventually treating selected forms of pediatric lung disease.

Subject of Research: Lysosome–autophagy networks in lung development, maturation, and pediatric lung disease

Article Title: Lysosome–autophagy networks in lung development, maturation, and pediatric lung disease

Article References: Song, Y., Zhang, D., Bao, J., Jiang, G., & Zhang, D. (2026). Lysosome–autophagy networks in lung development, maturation, and pediatric lung disease. Frontiers in Pediatrics, 14, Article 1967172. https://doi.org/10.3389/fped.2026.1967172

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1967172

Keywords: Lysosome, autophagy, networks, lung, development, maturation, pediatric, disease, scientific research