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Hypoxia-Inducible Factor 1? Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.

ABSTRACT: 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)1? 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 HIF1? target gene GLUT1. ATII cell proliferation during repair was attenuated in ATII cell-specific HIF1? knockout (SftpcCreERT2+/-;HIF1?f/f) mice. The HIF target vascular endothelial growth factor promoted ATII cell proliferation in vitro and after lung injury in vivo. In the scratch wound assay of cell spreading, HIF stabilization accelerated, whereas HIF1? shRNA delayed wound closure. SDF1 and its receptor, CXCR4, were found to be HIF1?-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 HIF1? is activated in ATII cells after lung injury and promotes proliferation and spreading during repair.

SUBMITTER: McClendon J

PROVIDER: S-EPMC5530913 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.

McClendon Jazalle J Jansing Nicole L NL Redente Elizabeth F EF Gandjeva Aneta A Ito Yoko Y Colgan Sean P SP Ahmad Aftab A Riches David W H DWH Chapman Harold A HA Mason Robert J RJ Tuder Rubin M RM Zemans Rachel L RL

The American journal of pathology 20170612 8

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 spre ...[more]

PMID: 28618253

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Project description:BackgroundWhile acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection.Methods and findingsTo examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A.ConclusionsThese studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation.

Project description:OBJECTIVE:Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1? is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1? plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion. DESIGN:Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia-inducible factor-1? conditional knockout mice. The mice were killed at 5-, 24-, 48-, and 72-hour time points, and the extent of systemic and tissue hypoxia was assessed. In addition, injury and inflammation were assessed by measuring bronchoalveolar lavage cells (flow cytometry and cytospin), albumin (permeability injury), and cytokines (inflammation). Isolated type 2 cells from the hypoxia-inducible factor-1? conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-?B and interleukin-1? as intermediates in this interaction was studied. RESULTS:Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1? from lung samples was observed as early as 60 minutes, following the insult. The extent of lung injury following lung contusion was significantly reduced in conditional knockout mice at all the time points, when compared with the wild-type littermate mice. Release of proinflammatory cytokines, such as interleukin-1?, interleukin-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant, was significantly lower in conditional knockout mice. These actions are in part mediated through nuclear factor-?B. Hypoxia-inducible factor-1? in lung epithelial cells was shown to regulate interleukin-1? promoter activity. CONCLUSION:Activation of hypoxia-inducible factor-1? in type 2 cell is a major driver of acute inflammation following lung contusion.

Dataset Information

Hypoxia-Inducible Factor 1? Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.

Publications

Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.

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