The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway
Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disru...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-11-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222010939 |
| _version_ | 1798030971682947072 |
|---|---|
| author | Na Zhang Sihui Tang Jinjin Zhang Biwei Pei Tingting Pang Gengyun Sun |
| author_facet | Na Zhang Sihui Tang Jinjin Zhang Biwei Pei Tingting Pang Gengyun Sun |
| author_sort | Na Zhang |
| collection | DOAJ |
| description | Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, β-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI. |
| first_indexed | 2024-04-11T19:49:50Z |
| format | Article |
| id | doaj.art-fd5c5dc35fb34b779b8e90de46d9b309 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T19:49:50Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-fd5c5dc35fb34b779b8e90de46d9b3092022-12-22T04:06:21ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-11-01155113704The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathwayNa Zhang0Sihui Tang1Jinjin Zhang2Biwei Pei3Tingting Pang4Gengyun Sun5Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, ChinaDepartment of Respiratory and Critical Care Medicine, The Second People’s Hospital of Hefei, Hefei, Anhui 230011, China; Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Hefei Affiliated to Bengbu Medical University, Bengbu, Anhui 230030, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Corresponding author.Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, β-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI.http://www.sciencedirect.com/science/article/pii/S0753332222010939LinagliptinAcute lung injuryMicrovascular endotheliumBarrier functionEpac1 |
| spellingShingle | Na Zhang Sihui Tang Jinjin Zhang Biwei Pei Tingting Pang Gengyun Sun The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway Biomedicine & Pharmacotherapy Linagliptin Acute lung injury Microvascular endothelium Barrier function Epac1 |
| title | The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway |
| title_full | The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway |
| title_fullStr | The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway |
| title_full_unstemmed | The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway |
| title_short | The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway |
| title_sort | dipeptidyl peptidase 4 inhibitor linagliptin ameliorates lps induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the epac1 akt pathway |
| topic | Linagliptin Acute lung injury Microvascular endothelium Barrier function Epac1 |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222010939 |
| work_keys_str_mv | AT nazhang thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT sihuitang thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT jinjinzhang thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT biweipei thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT tingtingpang thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT gengyunsun thedipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT nazhang dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT sihuitang dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT jinjinzhang dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT biweipei dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT tingtingpang dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway AT gengyunsun dipeptidylpeptidase4inhibitorlinagliptinameliorateslpsinducedacutelunginjurybymaintenanceofpulmonarymicrovascularbarrierviaactivatingtheepac1aktpathway |