Chronic <i>Pseudomonas aeruginosa</i> Pneumonia Triggers Inflammation-Driven Oncogenic Signaling in Juvenile Mice: Implications for Pharmacological Intervention

Abstract

Background: Chronic pulmonary infections pose a significant health burden, with accumulating evidence suggesting their potential to trigger oncogenic transformation. However, the link between chronic bacterial pneumonia and early neoplastic changes remains poorly understood, particularly in juvenile lungs. Objectives: The present study investigates how repeated Pseudomonas aeruginosa infection induces inflammation, oxidative stress, DNA damage, and oncogenic signaling in juvenile mice, and explores potential pharmacological targets to prevent long-term oncogenic consequences. Methods: Juvenile BALB/c mice received intranasal challenges with P. aeruginosa on days 0, 5, and 10. Lung tissues were collected at baseline (day 0) and after the establishment of chronic infection (day 21) for all downstream analyses. Lung tissues were analyzed for inflammatory [factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α)], oxidative [nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1)], and DNA damage (γH2AX) markers using Western blotting, quantitative real-time PCR (qPCR), and immunofluorescence microscopy. Cell viability was assessed using MTT assays, and wound healing capacity was evaluated through scratch assays. Oncogenic markers (Myc, Kras) were quantified by qPCR. Results: Chronic P. aeruginosa infection led to persistent upregulation of inflammatory proteins (NF-κB, COX-2, TNF-α) and oxidative stress markers (Nrf2, HO-1) in lung tissues on day 21 compared to day 0. Increased γH2AX expression indicated DNA damage, although no significant DNA fragmentation was detected, suggesting sublethal, localized damage. Functionally, chronic infection resulted in a 35% reduction in cell viability and significantly delayed wound healing (60% closure compared to 90% in controls). Importantly, infected tissues displayed a 2.8-fold increase in Myc and a 2.5-fold increase in Kras mRNA levels, indicating early oncogenic signaling. Conclusions: Chronic P. aeruginosa infection in juvenile mice induces a sustained inflammatory and oxidative response, leading to epithelial cell dysfunction and activation of oncogenic pathways. These findings highlight the need for early therapeutic intervention targeting inflammation and oxidative stress to mitigate malignant transformation risks associated with recurrent pediatric lung infections. Agents modulating NF-κB activity or enhancing antioxidant defenses, such as Nrf2 activators, may represent promising pharmacological strategies. Early intervention and monitoring of chronic lung infections in pediatric populations are essential to mitigate potential oncogenic risks.