| First Author | Sherman MA | Year | 2018 |
| Journal | Ann Surg | Volume | 267 |
| Issue | 2 | Pages | 382-391 |
| PubMed ID | 27811509 | Mgi Jnum | J:326331 |
| Mgi Id | MGI:6869472 | Doi | 10.1097/SLA.0000000000002070 |
| Citation | Sherman MA, et al. (2018) Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1alpha. Ann Surg 267(2):382-391 |
| abstractText | OBJECTIVE: To understand the fate and regulation of hypoxic type II alveolar epithelial cells (AECs) after lung contusion (LC). BACKGROUND: LC due to thoracic trauma is a major risk factor for the development of acute respiratory distress syndrome. AECs have recently been implicated as a primary driver of inflammation in LC. The main pathological consequence of LC is hypoxia, and a key mediator of adaptation to hypoxia is hypoxia-inducible factor (HIF)-1. We have recently published that HIF-1alpha is a major driver of acute inflammation after LC through type II AEC. METHODS: LC was induced in wild-type mice (C57BL/6), luciferase-based hypoxia reporter mice (ODD-Luc), and HIF-1alpha conditional knockout mice. The degree of hypoxia was assessed using hypoxyprobe and in vivo imaging system. The fate of hypoxic AEC was evaluated by luciferase dual staining with caspases-3 and Ki-67, terminal deoxynucleotidyl transferase dUTP nick end labeling, and flow cytometry with ApoStat. NLRP-3 expression was determined by western blot. Laser capture microdissection was used to isolate AECs in vivo, and collected RNA was analyzed by Q-PCR for HIF-related pathways. RESULTS: Global hypoxia was present after LC, but hypoxic foci were not uniform. Hypoxic AECs preferentially undergo apoptosis. There were significant reductions in NLRP-3 in HIF-1alpha conditional knockout mice. The expression of proteins involved in HIF-related pathways and inflammasome activation were significantly increased in hypoxic AECs. CONCLUSIONS: These are the first in vivo data to identify, isolate, and characterize hypoxic AECs. HIF-1alpha regulation through hypoxic AECs is critical to the initiation of acute inflammation after LC. |
