Role of succinate in airway epithelial cell regulation following traumatic lung injury
Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelia...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-09-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.166860 |
| _version_ | 1797634242653454336 |
|---|---|
| author | Madathilparambil V. Suresh Sinan Aktay George Yalamanchili Sumeet Solanki Dily Thazhath Sathyarajan Manikanta Swamy Arnipalli Subramaniam Pennathur Krishnan Raghavendran |
| author_facet | Madathilparambil V. Suresh Sinan Aktay George Yalamanchili Sumeet Solanki Dily Thazhath Sathyarajan Manikanta Swamy Arnipalli Subramaniam Pennathur Krishnan Raghavendran |
| author_sort | Madathilparambil V. Suresh |
| collection | DOAJ |
| description | Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α–mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models. |
| first_indexed | 2024-03-11T12:05:57Z |
| format | Article |
| id | doaj.art-b1cbcd3d962e4bd2b5919772d23ec69e |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:57Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b1cbcd3d962e4bd2b5919772d23ec69e2023-11-07T16:26:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-09-01818Role of succinate in airway epithelial cell regulation following traumatic lung injuryMadathilparambil V. SureshSinan AktayGeorge YalamanchiliSumeet SolankiDily Thazhath SathyarajanManikanta Swamy ArnipalliSubramaniam PennathurKrishnan RaghavendranLung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α–mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.https://doi.org/10.1172/jci.insight.166860InflammationPulmonology |
| spellingShingle | Madathilparambil V. Suresh Sinan Aktay George Yalamanchili Sumeet Solanki Dily Thazhath Sathyarajan Manikanta Swamy Arnipalli Subramaniam Pennathur Krishnan Raghavendran Role of succinate in airway epithelial cell regulation following traumatic lung injury JCI Insight Inflammation Pulmonology |
| title | Role of succinate in airway epithelial cell regulation following traumatic lung injury |
| title_full | Role of succinate in airway epithelial cell regulation following traumatic lung injury |
| title_fullStr | Role of succinate in airway epithelial cell regulation following traumatic lung injury |
| title_full_unstemmed | Role of succinate in airway epithelial cell regulation following traumatic lung injury |
| title_short | Role of succinate in airway epithelial cell regulation following traumatic lung injury |
| title_sort | role of succinate in airway epithelial cell regulation following traumatic lung injury |
| topic | Inflammation Pulmonology |
| url | https://doi.org/10.1172/jci.insight.166860 |
| work_keys_str_mv | AT madathilparambilvsuresh roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT sinanaktay roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT georgeyalamanchili roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT sumeetsolanki roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT dilythazhathsathyarajan roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT manikantaswamyarnipalli roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT subramaniampennathur roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury AT krishnanraghavendran roleofsuccinateinairwayepithelialcellregulationfollowingtraumaticlunginjury |