A developmentally informed narrative review of Toll-like receptors in adult and pediatric acute respiratory distress syndrome

Background and Objective: Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung syndrome associated with high mortality and morbidity. Toll-like receptors (TLRs), key pattern-recognition receptors of innate immunity, mediate inflammatory responses to both infectious and sterile lung injury. Although TLR signaling has been increasingly implicated in ARDS pathogenesis, significant developmental and translational gaps remain, particularly in pediatric ARDS (PARDS). This review summarizes current evidence on TLR-mediated mechanisms in ARDS and PARDS, with emphasis on developmental regulation and translational relevance.

Methods: A narrative review was conducted using English-language studies identified from PubMed/MEDLINE and Google Scholar databases. Experimental, translational, and clinical studies investigating TLR signaling in ARDS and PARDS were reviewed, including studies involving cell-surface and endosomal TLRs, developmental immunology, animal models, genetic and transcriptomic analyses, and therapeutic modulation of TLR pathways or their key effector cytokines.

Key Content and Findings: TLR4 is an extensively studied receptor in ARDS, mediating inflammatory responses to endotoxins, sterile injury, sepsis, and ventilator-induced lung injury (VILI) through MyD88- and TRIF-dependent pathways. Endosomal TLRs, including TLR3, TLR7, and TLR9, contribute predominantly to viral-induced lung injury and antiviral immunity. Experimental studies demonstrate that TLR activation drives cytokine amplification, neutrophil recruitment, endothelial dysfunction, and alveolar-capillary barrier disruption. Human studies identify TLR-associated polymorphisms and transcriptomic alterations linked to ARDS susceptibility and outcomes. Importantly, pediatric immune responses exhibit developmental regulation of TLR signaling, with age-dependent variation in receptor expression and cytokine production, suggesting PARDS pathogenesis involving TLR activation cannot be directly inferred from adult disease models. However, direct TLR-focused studies in PARDS remain limited.

Conclusions: TLR signaling pathways are central to ARDS and PARDS pathogenesis and represent potential therapeutic targets. However, direct evidence in PARDS remains limited. Future research should prioritize age-stratified pediatric studies to define developmental differences in TLR signaling and guide therapeutic development.