Exendin-4 blockade of T1R2/T1R3 activation improves Pseudomonas aeruginosa-related pneumonia in an animal model of chemically induced diabetes

Shanjun Yu; Chaoqun Xu; Xiang Tang; Lijun Wang; Lihua Hu; Liang Li; Xiangdong Zhou; Qi Li

doi:10.1007/s00011-024-01891-8

Exendin-4 blockade of T1R2/T1R3 activation improves Pseudomonas aeruginosa-related pneumonia in an animal model of chemically induced diabetes

Inflamm Res. 2024 May 15. doi: 10.1007/s00011-024-01891-8. Online ahead of print.

Authors

Shanjun Yu^#^{1

2}, Chaoqun Xu^#^{1

3}, Xiang Tang^{1

2}, Lijun Wang^{1

2}, Lihua Hu^{1

2}, Liang Li^{1

2}, Xiangdong Zhou^{4

5}, Qi Li^{6

7}

Affiliations

¹ Department of Respiratory Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570102, China.
² Hainan Province Clinical Medical Center of Respiratory Disease, Haikou, Hainan, 570102, China.
³ Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, 579199, China.
⁴ Department of Respiratory Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570102, China. zxd999@263.net.
⁵ Hainan Province Clinical Medical Center of Respiratory Disease, Haikou, Hainan, 570102, China. zxd999@263.net.
⁶ Department of Respiratory Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570102, China. liqi82@hainmc.edu.cn.
⁷ Hainan Province Clinical Medical Center of Respiratory Disease, Haikou, Hainan, 570102, China. liqi82@hainmc.edu.cn.

^# Contributed equally.

PMID: 38748233
DOI: 10.1007/s00011-024-01891-8

Abstract

Objective: Poorly controlled diabetes frequently exacerbates lung infection, thereby complicating treatment strategies. Recent studies have shown that exendin-4 exhibits not only hypoglycemic but also anti-inflammatory properties. This study aimed to explore the role of exendin-4 in lung infection with diabetes, as well as its association with NOD1/NF-κB and the T1R2/T1R3 sweet taste receptor.

Methods: 16HBE human bronchial epithelial cells cultured with 20 mM glucose were stimulated with lipopolysaccharide (LPS) isolated from Pseudomonas aeruginosa (PA). Furthermore, Sprague‒Dawley rats were fed a high-fat diet, followed by intraperitoneal injection of streptozotocin and intratracheal instillation of PA. The levels of TNF-α, IL-1β and IL-6 were evaluated using ELISAs and RT‒qPCR. The expression of T1R2, T1R3, NOD1 and NF-κB p65 was assayed using western blotting and immunofluorescence staining. Pathological changes in the lungs of the rats were observed using hematoxylin and eosin (H&E) staining.

Results: At the same dose of LPS, the 20 mM glucose group produced more proinflammatory cytokines (TNF-α, IL-1β and IL-6) and had higher levels of T1R2, T1R3, NOD1 and NF-κB p65 than the normal control group (with 5.6 mM glucose). However, preintervention with exendin-4 significantly reduced the levels of the aforementioned proinflammatory cytokines and signaling molecules. Similarly, diabetic rats infected with PA exhibited increased levels of proinflammatory cytokines in their lungs and increased expression of T1R2, T1R3, NOD1 and NF-κB p65, and these effects were reversed by exendin-4.

Conclusions: Diabetic hyperglycemia can exacerbate inflammation during lung infection, promote the increase in NOD1/NF-κB, and promote T1R2/T1R3. Exendin-4 can ameliorate PA-related pneumonia with diabetes and overexpression of NOD1/NF-κB. Additionally, exendin-4 suppresses T1R2/T1R3, potentially through its hypoglycemic effect or through a direct mechanism. The correlation between heightened expression of T1R2/T1R3 and an intensified inflammatory response in lung infection with diabetes requires further investigation.

Keywords: Pseudomonas aeruginosa; Diabetes; Exendin-4; Pneumonia; Sweet taste receptor.

Abstract

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