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Abstract
Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC–LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC–LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.
Highlights
Despite being generally well oxygenated, multiple pathological scenarios exist in which lung tissue becomes hypoxic [1]
Other features of Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) include apoptosis of alveolar epithelial cells (AECs) and lung endothelial cells (LECs) along with LEC–LEC junction weakening and leukocyte infiltration, which together result in vascular leakage and lung edema [2] (Figure 1A)
These results indicate that hypoxia-inducible transcription factors (HIFs)-1α is induced during inflammatory EC injury and that inflammatory LEC injury occurs via HIF-1α [44]
Summary
Despite being generally well oxygenated, multiple pathological scenarios exist in which lung tissue becomes hypoxic [1]. Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19) are examples of inflammatory lung conditions characterized by pulmonary hypoxia at the level of the tissue and cell. Other features of ALI/ARDS include apoptosis of alveolar epithelial cells (AECs) and lung endothelial cells (LECs) along with LEC–LEC junction weakening and leukocyte infiltration, which together result in vascular leakage and lung edema [2] (Figure 1A). In the reparative phase following pulmonary hypoxia and inflammatory lung injury, the lung repairs and regenerates via increases in AEC proliferation and LEC proliferation and junction re-annealing [3] (Figure 1B). HIF-2 include anti-inflammatory and pro-inflammatory cytokines, the latter of which exacerbate matory lung injury, creating a positive feedback loop.
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