Dual Roles of Hypoxia-Inducible Factor 1 in Acute Lung Injury: Tissue-Specific Mechanisms and Therapeutic Modulation

Abstract

Acute lung injury (ALI), a life-threatening clinical syndrome with multifactorial origins, is characterized by uncontrolled pulmonary inflammation and disrupted alveolar-capillary barrier integrity, leading to progressive hypoxemia and respiratory failure. In this hypoxic setting, hypoxia-inducible factor (HIF)-1 is activated, acting as a central regulator of the inflammatory response and reparative processes in injured lung tissue during ALI. The role of HIF-1 is distinctly dualistic; it promotes both anti-inflammatory and reparative mechanisms to a certain extent, while potentially exacerbating inflammation, thus having a complex impact on disease progression. We explore the latest understanding of the role of hypoxia/HIF-mediated inflammatory and reparative pathways in ALI and consider the potential therapeutic applications of drugs targeting these pathways for the development of innovative treatment strategies. Therefore, this review aims to guide future research and clinical applications by emphasizing HIF-1 as a key therapeutic target for ALI.

Keywords: acute lung injury; hypoxia; hypoxia-inducible factors; inflammation; regulation; tissue repair.

Figure 1

Pathophysiology of ALI. Direct and indirect factors such as pneumonia and concussion lead to ALI, causing impairment of the pulmonary epithelial-endothelial barrier and infiltration of inflammatory cells, such as neutrophils, into the alveoli, which promotes the progression of ALI. Created in BioRender. https://BioRender.com.

Figure 2

The structure of HIF-1 is depicted in the figure. HIF-1 is a heterodimer consisting of the functional subunit HIF-1α and the structural subunit HIF-1β, with two transcriptionally activated structural domains (TADs), N-TAD, which is a regulator that stabilizes HIF-1α, and C-TAD, which regulates HIF-1α transcription under hypoxic conditions. Created in BioRender. https://BioRender.com.

Figure 3

Regulation of HIF-1α under normoxic and hypoxic conditions. Under normal oxygen conditions, HIF-1 is ubiquitinated by PHD and VHL, and under hypoxic conditions, PHD is inactive, HIF-1α stabilizes and migrates from the cytoplasm into the nucleus, subsequently dimerizing with HIF-1β localized in the nucleus to assemble a functional HIF-1 transcriptional complex, which ultimately binds to the HRE in the HIF-1-promoter region to regulate gene expression. Created in BioRender. https://BioRender.com.

Figure 4

Regulation of inflammation by HIF-1α in ALI. HIF-1α, which is expressed in the alveolar epithelium, exerts anti-inflammatory effects by promoting adenosine production and competing with NF-κB for co-activation, and pro-inflammatory effects by regulating VEGF and HO-1 target genes and co-acting with NF-κB, which increases vascular permeability, leading to the exudation of inflammatory factors as well as the induction of iron death and oxidative stress. Created in BioRender. https://BioRender.com.

Figure 5

Regulation of ALI by HIF-1. HIF-1 plays a dual role in ALI by regulating different target genes. The left part of the figure shows that HIF-1α contributes to the development of inflammation and oxidative stress and exacerbates ALI by regulating HO-1 and VEGF, and cooperatively interacts with NF-κB, whereas the right part of the figure shows that HIF-1α contributes to the development of ALI through the regulation of glycolysis, adenosine, the FOXM1 signaling pathway, and the angiogenic factor VEGF, as well as alveolar proliferation and SDF1, and promotes angiogenesis and tissue repair through the regulation of receptor CXCR4 expression, which is important for the alleviation of ALI. Created in BioRender. https://BioRender.com.