Dexamethasone Attenuates VEGF Expression and Inflammation but Not Barrier Dysfunction in a Murine Model of Ventilator–Induced Lung Injury

Hegeman, Maria A.; Hennus, Marije P.; Cobelens, Pieter M.; Kavelaars, Annemieke; Jansen, Nicolaas J. G.; Schultz, Marcus J.; Vught, A. J. van; Heijnen, Cobi J.

doi:10.1371/journal.pone.0057374

Cited by 28 publications

(29 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a simpler explanation is that, in addition to stabilizing HIF protein, GR binds a subset of promoters to regulate transcription. A complex interplay is suggested by other reports: for example, while HIF up-regulates VEGF expression and promotes angiogenesis, GCs are generally angiostatic (31) and negatively regulate VEGF expression (32)(33)(34). Similarly, during high altitude sickness, GC and HIF may have apparently opposing effects (35,36).…”

Section: Discussionmentioning

confidence: 90%

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Vettori

Greenald

Wilson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.hypoxia-inducible factor | glucocorticoid signaling | Von Hippel Lindau | metabolism | liver G lucocorticoids (GCs) are steroid hormones secreted from the adrenal glands that regulate carbohydrate, lipid, and protein metabolism. GCs are widely used as anti-inflammatory agents for treating pathological conditions where hypoxia plays a role in disease progression such as rheumatoid arthritis and chronic obstructive pulmonary disease. GCs and hypoxia pathways have a close interplay in physiology and disease (1-3); however, recent studies report conflicting results on the cross-talk between GC action and hypoxia (4, 5). Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcriptional complexes constituted by α-and β-subunits that activate diverse pathways regulating cellular glucose and lipid metabolism and proliferation (6, 7). Under normoxic conditions, the HIF-1α transcriptional subunit is recognized by prolyl hydroxylases and targeted for degradation via the Von Hippel Lindau (VHL)-mediated ubiquitin proteasome pathway; however, under hypoxic conditions HIF-1α is stabilized and translocates to the nucleus to exert its transcriptional activity. HIFs play a central role in many disease processes and provide a therapeutic target for treating pathological conditions including cancer, ischemia, stroke, inflammation, and chronic anemia (8-11). Screens to identify agents that stabilize HIFs have identified numerous agents, with the majority acting either via iron chelation or as 2-oxyglutarate analogs (12). In vitro HIFreporter screening methods, although extremely valuable, do not provide physiological information and may overlook tissue-s...

show abstract

Section: Discussionmentioning

confidence: 90%

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Vettori

Greenald

Wilson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…One of the underlying mechanisms of VILI is the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and macrophage inflammatory protein (MIP)-2, in response to MV associated mechanical stretch [13], [14]. In clinical practice, treatment aimed to limit the initial inflammatory state has not proven successful [15].…”

Section: Introductionmentioning

confidence: 99%

Mechanical Ventilation Enhances HMGB1 Expression in an LPS-Induced Lung Injury Model

et al. 2013

View full text Add to dashboard Cite

BackgroundMechanical ventilation (MV) can augment inflammatory response in lipopolysaccharide (LPS) challenged lungs. High mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury, but its mechanisms are not well defined. This study investigated the role of HMGB1 in lung inflammation in response to the combination of MV and LPS treatment.MethodsForty-eight male Sprague-Dawley rats were randomized to one of four groups: sham control; LPS treatment; mechanical ventilation; mechanical ventilation with LPS treatment. Mechanically ventilated animals received 10 ml/kg tidal volumes at a rate of 40 breaths/min for 4 h. In the HMGB1-blockade study, sixteen rats were randomly assigned to HMGB1 antibody group or control antibody group and animals were subjected to MV+LPS as described above. A549 cells were pre-incubated with different signal inhibitors before subjected to 4 h of cyclic stretch. Lung wet/dry weight (W/D) ratio, total protein and IgG concentration, number of neutrophils in bronchoalveolar lavage fluid (BALF), and lung histological changes were examined. The levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in BALF were measured using ELISA. Real-time quantitative PCR and Western blot were used to analyze mRNA and protein expression of HMGB1. Western blot were employed to analyze the activation of IκB-α, NF-κB, JNK, ERK, and p38.ResultsMV significantly augmented LPS-induced lung injury and HMGB1 expression, which was correlated with the increase in IL-1β, IL-6 and MIP-2 levels in BALF. In vivo, intratracheally administration of HMGB1 antibody significantly attenuated pulmonary inflammatory injury. In vitro experiments showed cyclic stretch induced HMGB1 expression through signaling pathways including p38 and NF-κB.ConclusionsThe findings indicated that moderate tidal volume MV augmented LPS induced lung injury by up-regulating HMGB1. The mechanism of HMGB1-mediated lung injury is likely to be signaling through p38 and NF-κB pathways.

show abstract

“…The role of GC in VEGF expression, however, is somewhat contradictory. Highly concentrated DEX suppressed VEGF expression in the developing lung and plays an essential role in the growth of epithelial and endothelial cells in rats . In other studies, antenatal DEX and triamcinolone decreased VEGF expression and reduced alveolarization, while antenatal BET had a tendency to induce VEGF expression in animals and did not decrease alveolarization .…”

Section: Discussionmentioning

confidence: 76%

“…Highly concentrated DEX suppressed VEGF expression in the developing lung and plays an essential role in the growth of epithelial and endothelial cells in rats. 35 In other studies, antenatal DEX 36,37 and triamcinolone 38 decreased VEGF expression and reduced alveolarization, while antenatal BET had a tendency to induce VEGF expression in animals and did not decrease alveolarization. 36,37 In contrast, the activation of glucocortiocoid receptor (GR) leads to slight proliferation of lung epithelial cells, 39 and the deletion of GR results in arrested alveolar development.…”

Section: Discussionmentioning

confidence: 86%