Publicação
The role of GSK-3 inhibition in lung injury
| Resumo: | Acute respiratory distress syndrome (ARDS) is an adult and children life-threatening lung injury. In this disease, alveolar epithelial and endothelial damage leads to severe inflammation. Evidence suggests that inhibition of glycogen synthase kinase 3 (GSK-3), a molecule involved in cell death, proliferation, and differentiation in lung injury attenuates severe inflammation. Interestingly, a recent work demonstrated that CHIR99021, a potent GSK-3 inhibitor, promotes lung progenitor cell proliferation and alveolar epithelial cell (AEC) maturation. In this way, we hypothesized that GSK-3 inhibition by CHIR99021 promotes proliferation of lung progenitors and regeneration of the alveolar epithelial population after acute lung injury (ALI). To this end, CHIR99021 was administered 30 minutes and 18 hours after LPS-induced ALI in mice so that the influence of GSK-3 could be analyzed during the peak of inflammatory cell recruitment or during its attenuation, respectively. Analysis of lung injury score by hematoxylin and eosin staining showed that administration of CHIR99021 reduced the risk of lung injury at 24 hours and 72 hours, respectively. Flow cytometry analysis revealed no differences in the recruitment of the different type of leukocytes in the time points analyzed. CHIR99021-treated animals presented an increase in proliferation of AECII at 24 hours and proliferation of bipotent alveolar progenitor cells at 24 hours and 72 hours. Interestingly, higher protein expression of an AECII to AECI transdifferentiation marker was observed 30 hours after LPS injection when CHIR99021 was administrated at 18 hours. Moreover, protein expression of AECII and AECI markers was also elevated at 30 hours and 72 hours in CHIR99021- treated animals at 18 hours. Taken together, these results suggest that GSK-3 inhibition by CHIR99021 promotes proliferation of AEC and bipotent cells and transdifferentiation of AECII to AECI, mainly in the mitigation period of the inflammatory phase, inducing repopulation of the alveolar epithelium and consequently enhancing lung regeneration and repair. |
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| Autores principais: | Fernandes, Raquel Alexandra Gomes |
| Assunto: | ARDS Acute lung injury GSK-3 inhibition Alveolar epithelial progenitor cell proliferation Lung regeneration / repair SDRA Dano pulmonar agudo Inibição da GSK-3 Proliferação de células progenitoras epiteliais alveolares Regeneração / reparação pulmonar |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Acute respiratory distress syndrome (ARDS) is an adult and children life-threatening lung injury. In this disease, alveolar epithelial and endothelial damage leads to severe inflammation. Evidence suggests that inhibition of glycogen synthase kinase 3 (GSK-3), a molecule involved in cell death, proliferation, and differentiation in lung injury attenuates severe inflammation. Interestingly, a recent work demonstrated that CHIR99021, a potent GSK-3 inhibitor, promotes lung progenitor cell proliferation and alveolar epithelial cell (AEC) maturation. In this way, we hypothesized that GSK-3 inhibition by CHIR99021 promotes proliferation of lung progenitors and regeneration of the alveolar epithelial population after acute lung injury (ALI). To this end, CHIR99021 was administered 30 minutes and 18 hours after LPS-induced ALI in mice so that the influence of GSK-3 could be analyzed during the peak of inflammatory cell recruitment or during its attenuation, respectively. Analysis of lung injury score by hematoxylin and eosin staining showed that administration of CHIR99021 reduced the risk of lung injury at 24 hours and 72 hours, respectively. Flow cytometry analysis revealed no differences in the recruitment of the different type of leukocytes in the time points analyzed. CHIR99021-treated animals presented an increase in proliferation of AECII at 24 hours and proliferation of bipotent alveolar progenitor cells at 24 hours and 72 hours. Interestingly, higher protein expression of an AECII to AECI transdifferentiation marker was observed 30 hours after LPS injection when CHIR99021 was administrated at 18 hours. Moreover, protein expression of AECII and AECI markers was also elevated at 30 hours and 72 hours in CHIR99021- treated animals at 18 hours. Taken together, these results suggest that GSK-3 inhibition by CHIR99021 promotes proliferation of AEC and bipotent cells and transdifferentiation of AECII to AECI, mainly in the mitigation period of the inflammatory phase, inducing repopulation of the alveolar epithelium and consequently enhancing lung regeneration and repair. |
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