Blocking AGEs Reduces Viral Susceptibility in COPD

Researchers at Guangzhou Medical University have identified a specific molecular pathway linking diabetic hyperglycemia to increased susceptibility to viral infections in patients with chronic obstructive pulmonary disease (COPD). The study, published in EMBO Molecular Medicine, demonstrates that advanced glycation end products (AGEs) accumulate in the airway epithelium of COPD patients with diabetes, activating pro-inflammatory signaling that compromises the tissue’s natural defense against viruses. By pharmacologically inhibiting the formation of these compounds, the team significantly reduced viral loads in both human cell cultures and mouse models, suggesting that targeting AGEs could offer a new therapeutic strategy for this comorbid condition.

The clinical motivation for this work stems from the well-documented but poorly understood interaction between diabetes and COPD. Epidemiological data indicate that approximately 20% of COPD patients also have diabetes, and these individuals face a higher risk of adverse outcomes, including frequent acute exacerbations. While diabetes is known to cause complications in classical target organs such as the kidneys, eyes, and cardiovascular system, its impact on respiratory biology has remained largely unexplored. The research team sought to elucidate how chronic hyperglycemia might impair the airway epithelium, which serves as the first line of defense against respiratory viruses like influenza A, a key driver of COPD exacerbations.

To investigate this link, the researchers conducted a retrospective analysis of clinical data from 123 COPD patients at the First Affiliated Hospital of Guangzhou Medical University. The cohort was stratified into two groups: 60 patients with comorbid type 2 diabetes and 63 patients without diabetes. The study found that COPD patients with diabetes experienced a significantly higher incidence of frequent acute exacerbations, defined as two or more events within a year, compared to their non-diabetic counterparts. Specifically, 86.7% of the diabetic group suffered frequent exacerbations, compared to 58.7% in the non-diabetic group. Furthermore, glycated hemoglobin (HbA1c) levels, a standard biomarker for diabetes severity, were positively correlated with the frequency of these exacerbations in both the diabetic subgroup and the overall COPD cohort.

Single-cell RNA sequencing of bronchial brushing samples from five COPD patients, three without diabetes and two with diabetes, revealed distinct transcriptional alterations in the airway epithelium of those with diabetes. The analysis identified seven distinct cell populations, including secretory, basal, and ciliated epithelial cells, as well as immune cells such as macrophages and T cells. In patients with diabetes, there was a notable increase in epithelial cell proportions and a decrease in immune cell presence. Enrichment analysis of differentially expressed genes showed significant upregulation of pathways associated with viral infection responses, particularly in airway epithelial cells. These findings suggested that diabetic comorbidity exerts a stronger influence on viral defense mechanisms in the epithelium than in the immune cells, pointing to a localized impairment of antiviral capacity.

Functional experiments using air-liquid interface (ALI) cultures of primary airway epithelial cells derived from COPD patients confirmed that hyperglycemia directly enhances viral susceptibility. When these cells were treated with high glucose concentrations for varying durations, they exhibited a dose- and time-dependent increase in influenza A virus (IAV) loads following infection. Immunofluorescence imaging further validated the presence of higher viral protein levels in the hyperglycemic epithelium. Notably, while high glucose treatment upregulated pro-inflammatory cytokines such as TNF-α and IL-6, it did not alter the expression of interferon-stimulated genes, which are typically driven by viral infection. This suggests that the increased viral load is a primary effect of the metabolic environment, leading to a secondary compensatory host response.

The study identified AGEs as the central mediators of this process. Western blotting and histological staining of airway biopsies showed that COPD patients with diabetes had significantly higher levels of AGEs in their airway tissues compared to those without diabetes. Detailed histopathological assessment revealed that areas with high AGEs accumulation displayed characteristic ciliary abnormalities, including reduced density and shortened length, whereas low-AGEs regions preserved ciliary integrity. In vitro, high glucose treatment of ALI-cultured cells led to a marked elevation of AGEs in both the cellular lysate and the supernatant, consistent with the findings in human tissue. Exogenous exposure of these cells to AGEs induced epithelial cytotoxicity and further increased viral loads, establishing a direct causal link between AGEs accumulation and compromised antiviral defense.

To determine the therapeutic potential of targeting this pathway, the researchers used aminoguanidine, a pharmacological inhibitor of AGEs formation. In the ALI culture model, administration of aminoguanidine to high-glucose-treated cells prior to viral challenge significantly decreased viral loads. To validate these findings in vivo, the team established a mouse model of comorbid COPD and diabetes by combining intranasal porcine pancreatic elastase administration for emphysema induction with intraperitoneal streptozotocin injection for hyperglycemia. Mice treated with aminoguanidine showed reduced AGEs levels in tracheal and lung tissues and significantly lower viral loads after influenza infection compared to untreated comorbid mice. These results indicate that inhibiting AGEs production can effectively mitigate hyperglycemia-driven viral susceptibility in a living organism.

Mechanistically, the study demonstrated that AGEs exert their pathological effects by binding to two specific receptors: the receptor for AGEs (RAGE) and myeloid differentiation protein 2 (MD2). Biotinylated protein pull-down and co-immunoprecipitation assays confirmed the physical interaction between AGEs and both receptors in airway epithelial cells. Upon binding, these receptors activate the p38, ERK, and IKK pro-inflammatory signaling pathways. The researchers found that AGEs treatment significantly enhanced the phosphorylation of these kinases and upregulated the expression of inflammatory cytokines. In contrast, other downstream pathways such as AKT and TGFβ/Smad were not activated, highlighting the specificity of the RAGE/MD2-mediated inflammatory response in this context.

Further experiments using pharmacological inhibitors and genetic knockdown of RAGE and MD2 revealed that both receptors contribute to the AGEs-induced pathology. Individual inhibition of either receptor partially attenuated the activation of pro-inflammatory signaling and reduced epithelial injury and viral susceptibility. However, combined inhibition of both RAGE and MD2 provided a greater protective effect, suggesting a cooperative interaction between the two pathways. The protective effect of RAGE inhibition appeared somewhat greater than that of MD2, indicating that RAGE may play a more dominant role in mediating AGE-induced damage. In vivo validation in the mouse model confirmed that treatment with RAGE or MD2 inhibitors reduced viral loads and downregulated pro-inflammatory signaling, supporting the potential for targeting these receptors in clinical settings.

The study acknowledges several limitations that must be considered when interpreting the results. The animal models used, involving streptozotocin-induced diabetes and elastase-induced emphysema, do not fully replicate the complexity of human type 2 diabetes, particularly regarding insulin resistance and the heterogeneous phenotypes of COPD. Additionally, all diabetic patients in the human cohort had type 2 diabetes, so the findings may not directly apply to type 1 diabetes, although both types share chronic hyperglycemia as a key driver of AGEs formation. The researchers also lacked a control group of diabetic patients without COPD, as bronchial biopsies are not routinely obtained from asymptomatic individuals for ethical reasons. This gap prevents a direct determination of whether the observed antiviral defects are driven by diabetes alone or by the combination of diabetes and COPD.

Despite these limitations, the study provides a comprehensive mechanistic framework for understanding how diabetes exacerbates COPD through viral susceptibility. By identifying the hyperglycemia-AGEs-RAGE/MD2 axis, the research highlights a previously unrecognized target organ for AGEs-induced damage: the airway epithelium. The findings suggest that monitoring airway AGEs levels could serve as a biomarker for predicting exacerbation risk in high-risk COPD patients. Furthermore, the successful reduction of viral loads through AGEs inhibition in both in vitro and in vivo models supports the development of pharmacological therapies aimed at breaking the cycle of diabetes-COPD comorbidity. Future directions include optimizing inhaled delivery of AGEs inhibitors and conducting multi-ethnic clinical trials to validate these therapeutic concepts.

Subject of Research: Blocking AGEs reduces airway epithelial viral susceptibility in diabetes-exacerbated COPD

Article Title: Blocking AGEs reduces airway epithelial viral susceptibility in diabetes-exacerbated COPD

Article References: Chen, Z., Qin, Y., Lin, B., Jiang, L., Feng, Z., Chen, S., Ye, Z., Zhou, M., Li, J., Wang, D. Y., Zhong, N., Hou, P., Zhou, Z., Wang, L., & Peng, Y. (2026). Blocking AGEs reduces airway epithelial viral susceptibility in diabetes-exacerbated COPD. EMBO Molecular Medicine, 18(9), 3745-3766. https://doi.org/10.1038/s44321-026-00502-9

Image Credits: AI Generated

DOI: 10.1038/s44321-026-00502-9

Keywords: Blocking, AGEs, reduces, airway, epithelial, viral, susceptibility, diabetes-exacerbated, COPD, scientific research