Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury
| Autor: | Rubin M. Tuder, Yoko Ito, Nicole L. Jansing, Robert J. Mason, Rachel L. Zemans, Jazalle McClendon, Sean P. Colgan, Aneta Gandjeva, David W. H. Riches, Harold A. Chapman, Elizabeth F. Redente, Aftab Ahmad |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Pathology Regenerative Medicine Medical and Health Sciences chemistry.chemical_compound Mice Receptors 2.1 Biological and endogenous factors Aetiology Lung Acute Respiratory Distress Syndrome Regular Article respiratory system Cell biology Vascular endothelial growth factor medicine.anatomical_structure Hypoxia-inducible factors Respiratory Hypoxia-Inducible Factor 1 Signal Transduction Receptors CXCR4 medicine.medical_specialty Stromal cell Alveolar Epithelium Acute Lung Injury Biology Lung injury alpha Subunit Permeability Pathology and Forensic Medicine Cell Line 03 medical and health sciences Rare Diseases medicine Animals Cell Proliferation Basement membrane CXCR4 Wound Healing Cell growth Animal Hypoxia-Inducible Factor 1 alpha Subunit Chemokine CXCL12 Rats Pulmonary Alveoli Disease Models Animal 030104 developmental biology chemistry Cell culture Alveolar Epithelial Cells Disease Models |
| Zdroj: | The American journal of pathology, vol 187, iss 8 |
| Popis: | During the acute respiratory distress syndrome, epithelial cells, primarily alveolar type (AT) I cells, die and slough off, resulting in enhanced permeability. ATII cells proliferate and spread onto the denuded basement membrane to reseal the barrier. Repair of the alveolar epithelium is critical for clinical recovery; however, mechanisms underlying ATII cell proliferation and spreading are not well understood. We hypothesized that hypoxia-inducible factor (HIF)1α promotes proliferation and spreading of ATII cells during repair after lung injury. Mice were treated with lipopolysaccharide or hydrochloric acid. HIF activation in ATII cells after injury was demonstrated by increased luciferase activity in oxygen degradation domain-Luc (HIF reporter) mice and expression of the HIF1α target gene GLUT1. ATII cell proliferation during repair was attenuated in ATII cell-specific HIF1α knockout (SftpcCreERT2+/-;HIF1αf/f) mice. The HIF target vascular endothelial growth factor promoted ATII cell proliferation invitro and after lung injury invivo. In the scratch wound assay of cell spreading, HIF stabilization accelerated, whereas HIF1α shRNA delayed wound closure. SDF1 and its receptor, CXCR4, were found to be HIF1α-regulated genes in ATII cells and were up-regulated during lung injury. Stromal cell-derived factor 1/CXCR4 inhibition impaired cell spreading and delayed the resolution of permeability after lung injury. We conclude that HIF1α is activated in ATII cells after lung injury and promotes proliferation and spreading during repair. |
| Databáze: | OpenAIRE |
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