Endoplasmic reticulum stress-mediated disruption of mitochondrial homeostasis drives airway epithelial barrier fragility and enhances susceptibility to recurrent respiratory tract infections in children

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Background: Recurrent respiratory tract infections (RRTIs) are among the most common pediatric health problems and impose substantial healthcare burden. Airway epithelial fragility is increasingly recognized as an important contributor to RRTIs in children, although the upstream molecular mechanisms remain incompletely understood. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been implicated in epithelial injury in chronic airway diseases, yet their interplay in pediatric RRTIs is unclear. This study aimed to investigate whether ER stress-mediated disruption of mitochondrial homeostasis drives airway epithelial barrier fragility and enhances inflammatory susceptibility in children with RRTIs. Methods: Nasal swab samples from healthy children and RRTI patients were analyzed for ER stress-, barrier-, and mitochondrial-related markers. Tunicamycin-induced ER stress and polyinosinic-polycytidylic acid [Poly(I:C)]-stimulated inflammatory amplification models were established in 16HBE cells, followed by rescue treatment with 4-phenylbutyric acid (4-PBA) or MitoTEMPO. Results: Compared with healthy controls, RRTI children exhibited significantly increased HSPA5 and DDIT3 mRNA expression and elevated IL-6, IL-8, and CXCL10 protein levels (all P<0.001), whereas TJP1, OCLN, and TFAM expression was markedly reduced (all P<0.001). In 16HBE cells, tunicamycin induced ER stress activation, mitochondrial dysfunction, transepithelial electrical resistance (TEER) reduction, and epithelial permeability elevation. Under ER stress preconditioning, Poly(I:C)-induced inflammatory responses, mitochondrial reactive oxygen species (mtROS) accumulation, mitochondrial membrane potential collapse, and barrier leakage were further aggravated (all P<0.001). Both 4-PBA and MitoTEMPO partially reversed these pathological alterations. Conclusions: ER stress-mediated mitochondrial homeostasis disruption promotes airway epithelial barrier fragility and enhances inflammatory susceptibility in pediatric RRTIs.

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