• Matthew A Sherman, Madathilparambil V Suresh, Vladislav A Dolgachev, Lane K McCandless, Xiang Xue, Li Ziru, David Machado-Aranda, Yatrik M Shah, and Krishnan Raghavendran.
• Department of Surgery, University of Michigan, Ann Arbor, MI.
• Ann. Surg. 2018 Feb 1; 267 (2): 382-391.

ObjectiveTo understand the fate and regulation of hypoxic type II alveolar epithelial cells (AECs) after lung contusion (LC).BackgroundLC 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-1α is a major driver of acute inflammation after LC through type II AEC.MethodsLC was induced in wild-type mice (C57BL/6), luciferase-based hypoxia reporter mice (ODD-Luc), and HIF-1α 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.ResultsGlobal 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-1α conditional knockout mice. The expression of proteins involved in HIF-related pathways and inflammasome activation were significantly increased in hypoxic AECs.ConclusionsThese are the first in vivo data to identify, isolate, and characterize hypoxic AECs. HIF-1α regulation through hypoxic AECs is critical to the initiation of acute inflammation after LC.

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