The effectiveness of Corticosteroids on mortality in patients with acute respiratory distress syndrome or acute lung injury: a secondary analysis

Zhang, Zhongheng; Chen, Lin; Ni, Hongying

doi:10.1038/srep17654

Cited by 43 publications

(39 citation statements)

References 29 publications

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“…These data suggest that, despite unchanged basal IL-10 levels among the elderly, chronic inflammation may render elderly individuals more susceptible to death by sepsis and indicate the importance of investigating mechanisms that lower inflammation. While corticosteroid treatment was found to have no effect on mortality outcome in ARDS, whether prophylactic or chronic corticosteroid use affects mortality in the context of sepsis and ARDS is unknown [48]. In concordance with many of our group’s previous studies, in this study, exercise induced IL-10 expression in the BAL as well as parenchymal and epithelial lung cells, and remained elevated for at least 24 h following inoculation [17, 18, 20, 37, 43, 49].…”

Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Protects from Pseudomonas aeruginosa-Induced Pneumonia in Elderly Mice

et al. 2018

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Background: Pseudomonas aeruginosa (PS) infection results in severe morbidity and mortality, especially in immune-deficient populations. Aerobic exercise (AE) modulates the immune system, but its effects on the outcomes of pulmonary PS infection in elderly mice are unknown. Methods: BALB/c mice (24 weeks old) were randomized to sedentary, exercise (EX), PS, and PS + EX groups for the acute experimental setting, and PS and PS + EX groups for the chronic setting. Low-intensity AE was performed for 5 weeks, 60 min/day; 24 h after the final AE session, mice were inoculated with 5 × 10⁴ colony-forming units (CFU) of PS, and 24 h and 14 days after PS inoculation, mice were studied. Results: AE inhibited PS colonization (p < 0.001) and lung inflammation (total cells, neutrophils, lymphocytes [p < 0.01] in bronchoalveolar lavage [BAL]), with significant differences in BAL levels of IL-1β (p < 0.001), IL-6 (p < 0.01), CXCL1 (p < 0.001), and TNF-α (p < 0.001), as well as parenchymal neutrophils (p < 0.001). AE increased BAL levels of IL-10 and parenchymal (p < 0.001) and epithelial (p < 0.001) IL-10 expression, while epithelial (p < 0.001) and parenchymal (p < 0.001) NF-κB expression was decreased. AE diminished pulmonary lipid peroxidation (p < 0.001) and increased glutathione peroxidase (p < 0.01). Pre-incubation of BEAS-2B with IL-10 inhibited PS-induced epithelial cell expression of TNF-α (p < 0.05), CD40 (p < 0.01), and dichlorodihydrofluorescein diacetate (p < 0.05). Conclusions: AE inhibits PS-induced lung inflammation and bacterial colonization in elderly mice, involving IL-10/NF-κB, and redox signaling.

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Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Protects from Pseudomonas aeruginosa-Induced Pneumonia in Elderly Mice

et al. 2018

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“…Notable is that the dexamethasone study by Villar et al excluded patients that were already receiving steroids at enrollment. Other possible explanations for all these inconsistent findings may lay on the origin of ARDS (viral vs. other) [20][21][22][23], genetic factors, or the use of different corticosteroids. The use of IFN All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung

Jalkanen

Pettilä

Karvonen

et al. 2020

Preprint

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Running head: Glucocorticoids abolish beneficial effects of IFNAbbreviations: Acute Physiology and Chronic Health Evaluation (APACHE) II, interferon (IFN(, Sequential Organ Failure Assessment (SOFA) Take home message: Glucocorticoids inhibit type I interferon beta signaling and the upregulation of CD73 that is a key molecule preventing vascular leakage and harmful leukocyte infiltration into the lungs. This work provides the mechanistic basis for the need to avoid glucocorticoids in viralinduced ARDS, in which endogenous interferon is needed to combat the infection and its consequences. AbstractPurpose: Glucocorticoids are widely used to treat acute respiratory distress syndrome (ARDS) despite its use is highly controversial based on randomized controlled trials and meta-analyses. As type I interferons (IFNs) are our first line of defense against severe viral respiratory infections, we explored whether glucocorticoids interfere with IFN signaling and whether their use associates to outcome of IFN beta treatment of ARDS. Methods:We performed a propensity-matched post-hoc-analysis using data from the recent randomized INTEREST-trial comparing IFN beta-1a to placebo in ARDS patients. Based on the results of these analyses we utilized human lung tissue and human pulmonary endothelial cell cultures to investigate the effect of hydrocortisone on IFN nuclear signaling and the protein transcription of CD73, a molecule responsible for vascular integrity. Results:We found that hydrocortisone reduces the production, and prevents the nuclear translocation of IRF9, that is required for IFN beta-dependent signaling of multiple IFN-induced genes. In addition, hydrocortisone inhibits IFN beta-dependent upregulation of CD73 in human lung tissue. Additionally, we found that use of glucocorticoids with IFN beta-1a was independently associated with increased mortality (OR 5.4, 95% CI 2.1-13.9, P< 0.001) in the INTEREST-trial. Conclusions:Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. This provides the mechanistic basis for the harmful association of glucocorticoids in IFN beta treated patients in the INTEREST-trial. Most importantly, it strongly speaks against the use of glucocorticoids in viral-induced ARDS such as in the current corona virus pandemia.

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“…The typical pathological changes of lung injury are heterogeneous lung edema due to increased endothelial permeability and uncontrolled inflammation cascade. Many approaches have been tested before, such as Prostaglandin E2 (PGE2), activated protein C (APC), corticosteroid, etc., [13][14][15][16]. Unfortunately, none of them showed confirmed benefit in clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of Robo4 Ameliorates LPS Induced Acute Lung Injury in Mice through Binding to Rhoa

Wu¹,

Sun²,

Liu³

et al. 2018

Immunome Res

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Robo4 maintains the barrier function of the mature vascular network by inhibiting endothelial permeability induced by pro-angiogenic factor and the function of Robo4 was tissue specific. The aim of this study was to investigate the role and signaling pathways of Robo4 in pulmonary endothelial permeability in Lipopolysaccharides (LPS) induced acute lung injury (ALI) in mice. Mice were challenged by intra-peritoneal (IP) injection of LPS (15 mg/kg) 48 h after gene transfer of Retro-hRobo4. Protein in bronchoalveolar lavage fluid (BALF), lung wet/dry ratio, lung injury score, MPO activity, secondary cytokine and survival rate was recorded. Co-immunoprecipitation (Co-ip) was used to detect the binding of Robo4 and RhoA. Robo4 mRNA and protein concentration in mice lungs were significantly increased after retrovirus-mediated gene delivery. Up-regulation of Robo4 significantly decreased protein in BALF, lung wet/dry ratio, lung injury score and MPO activity while intercellular tight junction protein ZO-1 was significantly increased. However, up-regulation of Robo4 didn't change the concentration of TNF-a, vWF and VEGF in serum of mice. In addition, administration of Retro-hRobo4 significantly improved the survival of mice. Robo4 was bind to RhoA confirmed by Co-ip. These findings suggest that up-regulation of Robo4 enhanced pulmonary micro-vascular integrity and reduced lung edema in LPS induced ALI partially through binding to RhoA.

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The effectiveness of Corticosteroids on mortality in patients with acute respiratory distress syndrome or acute lung injury: a secondary analysis

Cited by 43 publications

References 29 publications

Aerobic Exercise Protects from Pseudomonas aeruginosa-Induced Pneumonia in Elderly Mice

Aerobic Exercise Protects from Pseudomonas aeruginosa-Induced Pneumonia in Elderly Mice

Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung

Enhanced Expression of Robo4 Ameliorates LPS Induced Acute Lung Injury in Mice through Binding to Rhoa

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