Role of hypoxia-inducible factor 1α in modulating cobalt-induced lung inflammation

Hypoxia plays an important role in development, cellular homeostasis, and pathological conditions, such as cancer and stroke. There is also growing evidence that hypoxia is an important modulator of the inflammatory process. Hypoxia-inducible factors (HIFs) are a family of proteins that regulate the cellular response to oxygen deficit, and loss of HIFs impairs inflammatory cell function. There is little known, however, about the role of epithelial-derived HIF signaling in modulating inflammation. Cobalt is capable of eliciting an allergic response and promoting HIF signaling. To characterize the inflammatory function of epithelial-derived HIF in response to inhaled cobalt, a conditional lung-specific HIF1α, the most ubiquitously expressed HIF, deletion mouse, was created. Control mice showed classic signs of metal-induced injury following cobalt exposure, including fibrosis and neutrophil infiltration. In contrast, HIF1α-deficient mice displayed a Th2 response that resembled asthma, including increased eosinophilic infiltration, mucus cell metaplasia, and chitinase-like protein expression. The results suggest that epithelial-derived HIF signaling has a critical role in establishing a tissue's inflammatory response, and compromised HIF1α signaling biases the tissue towards a Th2-mediated reaction.

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The critical role of mast cell-derived hypoxia-inducible factor-1α in regulating mast cell function

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12622 ◽

2016 ◽

Vol 68 (11) ◽

pp. 1409-1416 ◽

Cited By ~ 7

Author(s):

Xin Liang ◽

Guifang Yin ◽

Yuanyuan Ma ◽

Ke Xu ◽

Jianwen Liu ◽

...

Keyword(s):

Mast Cell ◽

Cell Function ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1Α

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The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

The Journal of Cell Biology ◽

10.1083/jcb.200903030 ◽

2009 ◽

Vol 187 (7) ◽

pp. 1101-1116 ◽

Cited By ~ 78

Author(s):

Chiara Francavilla ◽

Paola Cattaneo ◽

Vladimir Berezin ◽

Elisabeth Bock ◽

Diletta Ami ◽

...

Keyword(s):

Cell Migration ◽

Cellular Response ◽

Critical Role ◽

Biological Significance ◽

Receptor Activation ◽

Dependent Manner ◽

Fgf Receptor ◽

Neural Cell Adhesion ◽

Sustained Activation

Neural cell adhesion molecule (NCAM) associates with fibroblast growth factor (FGF) receptor-1 (FGFR1). However, the biological significance of this interaction remains largely elusive. In this study, we show that NCAM induces a specific, FGFR1-mediated cellular response that is remarkably different from that elicited by FGF-2. In contrast to FGF-induced degradation of endocytic FGFR1, NCAM promotes the stabilization of the receptor, which is recycled to the cell surface in a Rab11- and Src-dependent manner. In turn, FGFR1 recycling is required for NCAM-induced sustained activation of various effectors. Furthermore, NCAM, but not FGF-2, promotes cell migration, and this response depends on FGFR1 recycling and sustained Src activation. Our results implicate NCAM as a nonconventional ligand for FGFR1 that exerts a peculiar control on the intracellular trafficking of the receptor, resulting in a specific cellular response. Besides introducing a further level of complexity in the regulation of FGFR1 function, our findings highlight the link of FGFR recycling with sustained signaling and cell migration and the critical role of these events in dictating the cellular response evoked by receptor activation.

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Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Neurosurgical FOCUS ◽

10.3171/2014.9.focus14496 ◽

2014 ◽

Vol 37 (6) ◽

pp. E8 ◽

Cited By ~ 18

Author(s):

Matthew Womeldorff ◽

David Gillespie ◽

Randy L. Jensen

Keyword(s):

Cellular Response ◽

Treatment Options ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Poor Patient ◽

Growth Development ◽

The Relationship ◽

Insight Into ◽

Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽

10.1161/hyp.60.suppl_1.a396 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Toshihiro Ichiki

Keyword(s):

Cellular Response ◽

Target Genes ◽

Interstitial Fibrosis ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Renin Angiotensin System ◽

Prolyl Hydroxylase ◽

Ang Ii ◽

Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

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Hypoxia and HIF Signaling: One Axis with Divergent Effects

International Journal of Molecular Sciences ◽

10.3390/ijms21165611 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5611 ◽

Cited By ~ 2

Author(s):

Chiara Corrado ◽

Simona Fontana

Keyword(s):

Cellular Response ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Biological Processes ◽

Oxygen Homeostasis ◽

Tissue Responses ◽

Liver And Kidney ◽

Heterodimeric Complex ◽

Complex Activities

The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation of multiple genes involved in many biological processes. Among them, hypoxia-inducible factor (HIF) represents the master regulator of the hypoxia response. The active heterodimeric complex HIF α/β, binding to hypoxia-responsive elements (HREs), determines the induction of at least 100 target genes to restore tissue homeostasis. A growing body of evidence demonstrates that hypoxia signaling can act by generating contrasting responses in cells and tissues. Here, this dual and controversial role of hypoxia and the HIF signaling pathway is discussed, with particular reference to the effects induced on the complex activities of the immune system and on mechanisms determining cell and tissue responses after an injury in both acute and chronic human diseases related to the heart, lung, liver, and kidney.

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Perturbations to Homeostasis in Experimental Models Revealed Innate Pathways Driving Food Allergy

Frontiers in Immunology ◽

10.3389/fimmu.2020.603272 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kelly Bruton ◽

Joshua F. E. Koenig ◽

Allyssa Phelps ◽

Manel Jordana

Keyword(s):

Food Allergy ◽

Critical Role ◽

Allergic Sensitization ◽

Experimental Models ◽

Innate Immune ◽

Th2 Response ◽

Type 2 Immune Response ◽

Physical And Chemical

While type 2 immunity has been conventionally viewed as beneficial against helminths, venoms, and poisons, and harmful in allergy, contemporary research has uncovered its critical role in the maintenance of homeostasis. The initiation of a type 2 immune response involves an intricate crosstalk between structural and immune cells. Structural cells react to physical and chemical tissue perturbations by secreting alarmins, which signal the innate immune system to restore homeostasis. This pathway acts autonomously in the context of sterile injury and in the presence of foreign antigen initiates an adaptive Th2 response that is beneficial in the context of venoms, toxins, and helminths, but not food allergens. The investigation of the triggers and mechanisms underlying food allergic sensitization in humans is elusive because sensitization is a silent process. Therefore, the central construct driving food allergy modeling is based on introducing perturbations of tissue homeostasis along with an allergen which will result in an immunological and clinical phenotype that is consistent with that observed in humans. The collective evidence from multiple models has revealed the pre-eminent role of innate cells and molecules in the elicitation of allergic sensitization. We posit that, with the expanding use of technologies capable of producing formidable datasets, models of food allergy will continue to have an indispensable role to delineate mechanisms and establish causal relationships.

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The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal

Genes ◽

10.3390/genes11101163 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1163

Author(s):

Sebastian L. Wild ◽

Aya Elghajiji ◽

Carmen Grimaldos Rodriguez ◽

Stephen D. Weston ◽

Zoë D. Burke ◽

...

Keyword(s):

Critical Role ◽

Hypoxia Inducible Factor ◽

Signalling Pathway ◽

Fate Specification ◽

Cellular Processes ◽

Recent Developments ◽

Body Patterning ◽

Important Regulator ◽

Canonical Wnt

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine.

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Hypoxia-inducible factor (HIF1alpha) inhibition modulates cumulus cell function and affects bovine oocyte maturation in vitro†

Biology of Reproduction ◽

10.1093/biolre/ioaa196 ◽

2020 ◽

Author(s):

Aslihan Turhan ◽

Miguel Tavares Pereira ◽

Gerhard Schuler ◽

Ulrich Bleul ◽

Mariusz P Kowalewski

Keyword(s):

Oocyte Maturation ◽

Cell Function ◽

Hypoxia Inducible Factor ◽

Cumulus Cell ◽

Cumulus Cells ◽

Negative Effects ◽

Protein Levels ◽

Maturation In Vitro

Abstract Various metabolic and hormonal factors expressed in cumulus cells are positively correlated with the in vitro maturation (IVM) of oocytes. However, the role of hypoxia sensing both during maturation of cumulus–oocyte complexes (COCs) as well as during the resumption of meiosis remains uncertain. HIF1alpha plays major roles in cellular responses to hypoxia, and here we investigated its role during bovine COC maturation by assessing the expression of related genes in cumulus cells. COCs were divided into the following groups: immature (control), in vitro matured (IVM/control), or matured in the presence of a blocker of HIF1alpha activity (echinomycin, IVM/E). We found an inhibition of cumulus cell expansion in IVM/E, compared with the IVM/control. Transcript levels of several factors (n = 13) were assessed in cumulus cells. Decreased expression of HAS2, TNFAIP6, TMSB4, TMSB10, GATM, GLUT1, CX43, COX2, PTGES, and STAR was found in IVM/E (P < 0.05). Additionally, decreased protein levels were detected for STAR, HAS2, and PCNA (P < 0.05), while activated-Caspase 3 remained unaffected in IVM/E. Progesterone output decreased in IVM/E. The application of PX-478, another blocker of HIF1alpha expression, yielded identical results. Negative effects of HIF1alpha suppression were further observed in the significantly decreased oocyte maturation and blastocyst rates from COCs matured with echinomycin (P < 0.05) or PX-478 (P < 0.05). These results support the importance of HIF1alpha for COC maturation and subsequent embryo development. HIF1alpha is a multidirectional factor controlling intercellular communication within COCs, steroidogenic activity, and oocyte development rates, and exerting effects on blastocyst rates.

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55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

Journal of Applied Physiology ◽

10.1152/japplphysiol.00843.2012 ◽

2012 ◽

Vol 113 (9) ◽

pp. 1343-1352 ◽

Cited By ~ 17

Author(s):

Larissa A. Shimoda

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Circulation ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Arterial ◽

Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

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