Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

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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.

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HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

M Ivan, K Kondo, H. Yang … (2001)

HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.

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Acute respiratory distress syndrome

Michael Matthay, Rachel L. Zemans, Guy Zimmerman … (2019)

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30–40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

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A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

G. L. Semenza, G. L. Wang (1992)

We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.