Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

Evans, Colin E.

doi:10.3390/cells11020183

Cited by 23 publications

(19 citation statements)

References 82 publications

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“…Key transcription factors such as HIFs and NRF2 modulate SELPLG transcription which strongly support promoter regulation. Hypoxemia is a critical pathological hallmark of ARDS/ALI and via HIFs, HIF‐1α and HIF‐2α, hypoxia is a potent stimulus for amplification of ARDS inflammatory cascades 37–39 . Both HIF‐1α and HIF‐2α are multifunctional and have been implicated as contributing to ARDS severity.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxemia is a critical pathological hallmark of ARDS/ALI and via HIFs, HIF-1α and HIF-2α, hypoxia is a potent stimulus for amplification of ARDS inflammatory cascades. [37][38][39] Both HIF-1α and HIF-2α are multifunctional and have been implicated as contributing to ARDS severity. HIF-1α drives LPSinduced IL-1β, 40 tumor necrosis factor, IL-12, and VEGF expression 41 and nmMLCK expression.…”

Section: Discussionmentioning

confidence: 99%

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Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

et al. 2023

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We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene (SELPLG), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)-and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS-and VILI-induced lung injury.In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPSmediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed.These findings indicate SELPLG transcriptional regulation by clinicallyrelevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

et al. 2023

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“…Moreover, IL‐6 played a strong roles in promoting inflammation in the pathogenesis of MODS secondary to heat stroke 36 . vWF and ET‐1 were associated with the function of promoting coagulation 37 . Endothelium was effective in constricting blood vessels via releasing ET‐1 37 .…”

Section: Discussionmentioning

confidence: 99%

Heat stress combined with lipopolysaccharide induces pulmonary microvascular endothelial cell glycocalyx inflammatory damage in vitro

Chen,

Ding,

Cao

et al. 2023

Immunity Inflam & Disease

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Heat stroke is a life‐threatening disease with high mortality and complications. Endothelial glycocalyx (EGCX) is essential for maintaining endothelial cell structure and function as well as preventing the adhesion of inflammatory cells. Potential relationship that underlies the imbalance in inflammation and coagulation remains elusive. Moreover, the role of EGCX in heat stroke‐induced organ injury remained unclear. Therefore, the current study aimed to illustrate if EGCX aggravates apoptosis, inflammation, and oxidative damage in human pulmonary microvascular endothelial cells (HPMEC). Heat stress and lipopolysaccharide (LPS) were employed to construct in vitro models to study the changes of glycocalyx structure and function, as well as levels of heparansulfate proteoglycan (HSPG), syndecan‐1 (SDC‐1), heparansulfate (HS), tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐6, Von Willebrand factor (vWF), endothelin‐1 (ET‐1), occludin, E‐selectin, vascular cell adhesion molecule‐1 (VCAM‐1), and reactive oxygen species (ROS). Here, we showed that heat stress and LPS devastated EGCX structure, activated EGCX degradation, and triggered oxidative damage and apoptosis in HPMEC. Stimulation of heat stress and LPS decreased expression of HSPG, increased levels of SDC‐1 and HS in culture supernatant, promoted the production and release of proinflammation cytokines (TNF‐α and IL‐6,) and coagulative factors (vWF and ET‐1) in HPMEC. Furthermore, Expressions of E‐selection, VCAM‐1, and ROS were upregulated, while that of occludin was downregulated. These changes could be deteriorated by heparanase, whereas they meliorated by unfractionated heparin. This study indicated that EGCX may contribute to apoptosis and heat stroke‐induced coagulopathy, and these effects may have been due to the decrease in the shedding of EGCX.

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“…In turn, HIF pathways in multiple immune cell types are context-specific and can significantly affect inflammatory process [ 91 , 92 ]. The role of leukocyte-specific HIF isoforms in pulmonary inflammation has been investigated [ 93 , 94 ], suggesting that HIF-2α regulates essential inflammatory functions of immune cells [ 95 ].…”

Section: Hif As a Key Molecular “Hub” In Lung Physiology And Copdmentioning

confidence: 99%

Endotyping COPD: hypoxia-inducible factor-2 as a molecular “switch” between the vascular and airway phenotypes?

et al. 2023

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COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelialHif-2α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular “switch” between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidasesviairon- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets.

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Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

Cited by 23 publications

References 82 publications

Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

Heat stress combined with lipopolysaccharide induces pulmonary microvascular endothelial cell glycocalyx inflammatory damage in vitro

Endotyping COPD: hypoxia-inducible factor-2 as a molecular “switch” between the vascular and airway phenotypes?

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