Jiahui Li1, Kai Wang2, Bo Huang2, Rui Li1, Xilong Wang1, Hailing Zhang1, Haixiong Tang3, Xin Chen4. 1. Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, Guangdong 510280, China. 2. Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, Guangdong 510280, China. 3. Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, Guangdong 510280, China. Electronic address: thx20060303@126.com. 4. Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, Guangdong 510280, China. Electronic address: chen_xin1020@163.com.
Abstract
BACKGROUND: Airway epithelial cells (AECs) act as the first barrier protecting against invasion of environment agents and maintain integrity of lung structure and function. Dysfunction of airway epithelial barrier has been shown to be involved in ALI/ARDS pathogenesis. Yet, the exact mechanism is still obscure. Our study evaluated whether the receptor for advanced glycation end products (RAGE) mediates impaired airway epithelial barrier in LPS-induced murine ALI model. METHODS: Male BALB/c mice were subjected to intratracheal instillation of LPS to generate an ALI model. Inhibitors of RAGE, FPS-ZM1 and Azeliragon were respectively given to the mice through intraperitoneal injection. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected for further analysis. RESULTS: LPS exposure led to markedly increased expression of RAGE and its ligands HMGB1, HSP70, S100b. Treatment of FPS-ZM1 or Azeliragon not only effectively descended the expression of RAGE and its ligands but also attenuated LPS-induced neutrophil-predominant airway inflammation and injury, decreased levels of IL-6, IL-1β and TNF-α in BALF, alleviated increased alveolar-capillary permeability and pulmonary edema. LPS stimulation significantly impaired the integrity of airway epithelium, paralleled with dislocation of adheren junction (AJ) protein E-cadherin at cell-cell contacts and down-expression of both AJ and tight junction (TJ) proteins Claudin-2 and occludin, all of which were dramatically rescued by RAGE inhibition. CONCLUSION: RAGE signaling mediates airway epithelial barrier dysfunction in a LPS-induced ALI murine model.
BACKGROUND: Airway epithelial cells (AECs) act as the first barrier protecting against invasion of environment agents and maintain integrity of lung structure and function. Dysfunction of airway epithelial barrier has been shown to be involved in ALI/ARDS pathogenesis. Yet, the exact mechanism is still obscure. Our study evaluated whether the receptor for advanced glycation end products (RAGE) mediates impaired airway epithelial barrier in LPS-induced murine ALI model. METHODS: Male BALB/c mice were subjected to intratracheal instillation of LPS to generate an ALI model. Inhibitors of RAGE, FPS-ZM1 and Azeliragon were respectively given to the mice through intraperitoneal injection. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected for further analysis. RESULTS:LPS exposure led to markedly increased expression of RAGE and its ligands HMGB1, HSP70, S100b. Treatment of FPS-ZM1 or Azeliragon not only effectively descended the expression of RAGE and its ligands but also attenuated LPS-induced neutrophil-predominant airway inflammation and injury, decreased levels of IL-6, IL-1β and TNF-α in BALF, alleviated increased alveolar-capillary permeability and pulmonary edema. LPS stimulation significantly impaired the integrity of airway epithelium, paralleled with dislocation of adheren junction (AJ) protein E-cadherin at cell-cell contacts and down-expression of both AJ and tight junction (TJ) proteins Claudin-2 and occludin, all of which were dramatically rescued by RAGE inhibition. CONCLUSION:RAGE signaling mediates airway epithelial barrier dysfunction in a LPS-induced ALI murine model.
Authors: Seigmund Wai Tsuen Lai; Edwin De Jesus Lopez Gonzalez; Tala Zoukari; Priscilla Ki; Sarah C Shuck Journal: Chem Res Toxicol Date: 2022-10-05 Impact factor: 3.973