Changyun Yang , Lin Fu , Rui Li , Haixiong Tang , Zemin Chen , Sudan Gan , Jiamin Sun , Shiyue Li , Jing Li , Lihong Yao
{"title":"在lps诱导的小鼠急性肺损伤模型中,组织蛋白酶S通过akt依赖途径介导气道上皮Pannexin 1的破坏","authors":"Changyun Yang , Lin Fu , Rui Li , Haixiong Tang , Zemin Chen , Sudan Gan , Jiamin Sun , Shiyue Li , Jing Li , Lihong Yao","doi":"10.1016/j.yexcr.2025.114663","DOIUrl":null,"url":null,"abstract":"<div><div>Airway epithelial dysfunction constitutes a pivotal contributor to the pathogenesis of acute lung injury (ALI). Pannexin 1 (Panx1), a plasma membrane channel activated during epithelial injury, not only helps dampen inflammation but also plays a key role in epithelial repair. Cathepsin S (CTSS) is implicated in ALI pathophysiology. This study investigates the mechanistic link between CTSS and airway epithelial Panx1 dysregulation in ALI pathogenesis. Lipopolysaccharide (LPS) was instilled into the airways of BALB/c mice, followed by intraperitoneal injection of the CTSS inhibitor LY3000328. The effects of recombinant mouse CTSS (rCTSS) were tested in vivo, and Akt inhibition was used to explore the possible mechanism. In vitro, LPS-treated BEAS-2B cells were co-cultured with or without CTSS or Akt inhibitors. LPS exposure significantly increased pulmonary expression of CTSS. Treatment with LY3000328 alleviated the LPS-induced neutrophil accumulation, alveolar permeability and edema. Additionally, we observed decreased expression of Panx1 in the airway epithelium of LPS-exposed mice, accompanied by increased serine phosphorylation of Akt (p-Akt); inhibition of CTSS restored Panx1 and suppressed the p-Akt. Treatment with rCTSS directly downregulated Panx1 expression and induced Akt phosphorylation in the lung, which could be reversed by pharmacological inhibitor of Akt. In BEAS-2B cells, LPS increased CTSS and p-Akt expression alongside decreased levels of junction proteins (E-cadherin and occludin) and Panx1. Blockade of the CTSS/Akt axis restored the disruption of E-cadherin, occludin, and Panx1. Taken together, our data demonstrated that CTSS regulates the dysregulation of airway epithelial Panx1 through the Akt signaling pathway in an LPS-induced ALI model.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"450 2","pages":"Article 114663"},"PeriodicalIF":3.5000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cathepsin S mediates the disruption of airway epithelial Pannexin 1 via an Akt-dependent pathway in an LPS-induced murine model of acute lung injury\",\"authors\":\"Changyun Yang , Lin Fu , Rui Li , Haixiong Tang , Zemin Chen , Sudan Gan , Jiamin Sun , Shiyue Li , Jing Li , Lihong Yao\",\"doi\":\"10.1016/j.yexcr.2025.114663\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Airway epithelial dysfunction constitutes a pivotal contributor to the pathogenesis of acute lung injury (ALI). Pannexin 1 (Panx1), a plasma membrane channel activated during epithelial injury, not only helps dampen inflammation but also plays a key role in epithelial repair. Cathepsin S (CTSS) is implicated in ALI pathophysiology. This study investigates the mechanistic link between CTSS and airway epithelial Panx1 dysregulation in ALI pathogenesis. Lipopolysaccharide (LPS) was instilled into the airways of BALB/c mice, followed by intraperitoneal injection of the CTSS inhibitor LY3000328. The effects of recombinant mouse CTSS (rCTSS) were tested in vivo, and Akt inhibition was used to explore the possible mechanism. In vitro, LPS-treated BEAS-2B cells were co-cultured with or without CTSS or Akt inhibitors. LPS exposure significantly increased pulmonary expression of CTSS. Treatment with LY3000328 alleviated the LPS-induced neutrophil accumulation, alveolar permeability and edema. Additionally, we observed decreased expression of Panx1 in the airway epithelium of LPS-exposed mice, accompanied by increased serine phosphorylation of Akt (p-Akt); inhibition of CTSS restored Panx1 and suppressed the p-Akt. Treatment with rCTSS directly downregulated Panx1 expression and induced Akt phosphorylation in the lung, which could be reversed by pharmacological inhibitor of Akt. In BEAS-2B cells, LPS increased CTSS and p-Akt expression alongside decreased levels of junction proteins (E-cadherin and occludin) and Panx1. Blockade of the CTSS/Akt axis restored the disruption of E-cadherin, occludin, and Panx1. Taken together, our data demonstrated that CTSS regulates the dysregulation of airway epithelial Panx1 through the Akt signaling pathway in an LPS-induced ALI model.</div></div>\",\"PeriodicalId\":12227,\"journal\":{\"name\":\"Experimental cell research\",\"volume\":\"450 2\",\"pages\":\"Article 114663\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental cell research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014482725002630\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014482725002630","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Cathepsin S mediates the disruption of airway epithelial Pannexin 1 via an Akt-dependent pathway in an LPS-induced murine model of acute lung injury
Airway epithelial dysfunction constitutes a pivotal contributor to the pathogenesis of acute lung injury (ALI). Pannexin 1 (Panx1), a plasma membrane channel activated during epithelial injury, not only helps dampen inflammation but also plays a key role in epithelial repair. Cathepsin S (CTSS) is implicated in ALI pathophysiology. This study investigates the mechanistic link between CTSS and airway epithelial Panx1 dysregulation in ALI pathogenesis. Lipopolysaccharide (LPS) was instilled into the airways of BALB/c mice, followed by intraperitoneal injection of the CTSS inhibitor LY3000328. The effects of recombinant mouse CTSS (rCTSS) were tested in vivo, and Akt inhibition was used to explore the possible mechanism. In vitro, LPS-treated BEAS-2B cells were co-cultured with or without CTSS or Akt inhibitors. LPS exposure significantly increased pulmonary expression of CTSS. Treatment with LY3000328 alleviated the LPS-induced neutrophil accumulation, alveolar permeability and edema. Additionally, we observed decreased expression of Panx1 in the airway epithelium of LPS-exposed mice, accompanied by increased serine phosphorylation of Akt (p-Akt); inhibition of CTSS restored Panx1 and suppressed the p-Akt. Treatment with rCTSS directly downregulated Panx1 expression and induced Akt phosphorylation in the lung, which could be reversed by pharmacological inhibitor of Akt. In BEAS-2B cells, LPS increased CTSS and p-Akt expression alongside decreased levels of junction proteins (E-cadherin and occludin) and Panx1. Blockade of the CTSS/Akt axis restored the disruption of E-cadherin, occludin, and Panx1. Taken together, our data demonstrated that CTSS regulates the dysregulation of airway epithelial Panx1 through the Akt signaling pathway in an LPS-induced ALI model.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.