-
1.
Role of inositol to improve surfactant functions and reduce IL-6 levels: A potential adjuvant strategy for SARS-CoV-2 pneumonia?
Laganà, AS, Unfer, V, Garzon, S, Bizzarri, M
Medical hypotheses. 2020;:110262
-
-
Free full text
-
Abstract
To date, the spread of SARS-CoV-2 infection is increasing worldwide and represents a primary healthcare emergency. Although the infection can be asymptomatic, several cases develop severe pneumonia and acute respiratory distress syndrome (ARDS) characterized by high levels of pro-inflammatory cytokines, primarily interleukin (IL)-6. Based on available data, the severity of ARDS and serum levels of IL-6 are key determinants for the prognosis. In this scenario, available in vitro and in vivo data suggested that myo-inositol is able to increase the synthesis and function of the surfactant phosphatidylinositol, acting on the phosphoinositide 3-kinase (PI3K)-regulated signaling, with amelioration of both immune system and oxygenation at the bronchoalveolar level. In addition, myo-inositol has been found able to decrease the levels of IL-6 in several experimental settings, due to an effect on the inositol-requiring enzyme 1 (IRE1)-X-box-binding protein 1 (XBP1) and on the signal transducer and activator of transcription 3 (STAT3) pathways. In this scenario, treatment with myo-inositol may be able to reduce IL-6 dependent inflammatory response and improve oxygenation in patients with severe ARDS by SARS-CoV-2. In addition, the action of myo-inositol on IRE1 endonuclease activity may also inhibit the replication of SARS-CoV-2, as was reported for the respiratory syncytial virus. Since the available data are extremely limited, if this potential therapeutic approach will be considered valid in the clinical practice, the necessary future investigations should aim to identify the best dose, administration route (oral, intravenous and/or aerosol nebulization), and cluster(s) of patients which may get beneficial effects from this treatment.
-
2.
Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells.
Püschel, F, Favaro, F, Redondo-Pedraza, J, Lucendo, E, Iurlaro, R, Marchetti, S, Majem, B, Eldering, E, Nadal, E, Ricci, JE, et al
Proceedings of the National Academy of Sciences of the United States of America. 2020;(18):9932-9941
Abstract
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
-
3.
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, et al
The Journal of allergy and clinical immunology. 2019;(2):577-590
-
-
Free full text
-
Abstract
BACKGROUND Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. CONCLUSIONS Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
-
4.
Surgical Stress Reduction in Elderly Patients Undergoing Elective Colorectal Laparoscopic Surgery within an ERAS Protocol.
Mari, G, Costanzi, A, Crippa, J, Falbo, R, Miranda, A, Rossi, M, Berardi, V, Maggioni, D, ,
Chirurgia (Bucharest, Romania : 1990). 2016;(6):476-480
Abstract
ERAS program applied to colorectal laparoscopic surgery is well known to reduce hospitalization improving short terms outcomes and minimizing the Surgical Stress Response. However its effectiveness in elderly population is yet to be demonstrated. The primary aim of this study is to compare the level of immune and nutritional serum indexes across surgery in patients aged over 70 years old undergoing elective colorectal laparoscopic surgery within an ERAS protocol or according to a Standard program. 83 patients undergoing colorectal laparoscopic surgery were enrolled and randomized in two groups (ERAS Group 40, Standard Group 43) within a larger randomized trial on a general population. Surgical stress parameters were collected preoperatively, 1, 3 and 5 days after surgery. Nutritional parameters were collected preoperatively, 1 and 5 days after surgery. Short Term Outcomes were also prospectively assessed. IL-6 levels were lower in the EG on 1, 3, and 5 days post-operatively (p 0.05). IL-6 levels in the Enhanced group returned to pre operative level 3 days after surgery. C-reactive protein level was lower in the Enhanced group on day 1, 3, and 5 (p 0.05). There was no difference in Cortisol and Prolactin levels between groups. Prealbumin serum level was higher on day 5 (p 0.05) compared to standard group. Postoperative outcomes in terms of normal bowel function and length of hospital stay were significantly improved in the ERAS group. Colorectal laparoscopic surgery within an ERAS prototcol in elderly patients affects Surgical Stress Response, decreasing IL-6 and CRP levels postoperatively and improving Prealbumin post operative synthesis.
-
5.
Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
Staiano, RI, Loffredo, S, Borriello, F, Iannotti, FA, Piscitelli, F, Orlando, P, Secondo, A, Granata, F, Lepore, MT, Fiorelli, A, et al
Journal of leukocyte biology. 2016;(4):531-40
-
-
Free full text
-
Abstract
Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.
-
6.
Biomarkers of necrotising soft tissue infections: aspects of the innate immune response and effects of hyperbaric oxygenation-the protocol of the prospective cohort BIONEC study.
Hansen, MB, Simonsen, U, Garred, P, Hyldegaard, O
BMJ open. 2015;(5):e006995
Abstract
INTRODUCTION The mortality and amputation rates are still high in patients with necrotising soft tissue infections (NSTIs). It would be ideal to have a set of biomarkers that enables the clinician to identify high-risk patients with NSTI on admission. The objectives of this study are to evaluate inflammatory and vasoactive biomarkers as prognostic markers of severity and mortality in patients with NSTI and to investigate whether hyperbaric oxygen treatment (HBOT) is able to modulate these biomarkers. The overall hypothesis is that plasma biomarkers can be used as prognostic markers of severity and mortality in patients with NSTI and that HBOT reduces the inflammatory response. METHODS AND ANALYSIS This is a prospective, observational study being conducted in a tertiary referral centre. Biomarkers will be measured in 114 patients who have been operatively diagnosed with NSTI. On admission, baseline blood values will be obtained. Following surgery and HBOT, daily blood samples for measuring regular inflammatory and vasoactive biomarkers (pentraxin-3, interleukin-6 and nitrite) will be acquired. Samples will be analysed using validated ELISA assays, chemiluminescence and Griess reaction. Clinical data will be obtained during admission in the intensive care unit for a maximum of 7 days. The primary analysis will focus on pentraxin-3, interleukin-6 and nitrite as early markers of disease severity in patients with NSTI. ETHICS AND DISSEMINATION The study has been approved by the Regional Scientific Ethical Committee of Copenhagen (H-2-2014-071) and the Danish Data Protection Agency (J. no. 30-0900 and J. no. 30-1282). Results will be presented at national and international conferences and published in peer-reviewed scientific journals. TRIAL REGISTRATION NCT02180906.
-
7.
Vitamin D3 treatment of Crohn's disease patients increases stimulated T cell IL-6 production and proliferation.
Bendix-Struve, M, Bartels, LE, Agnholt, J, Dige, A, Jørgensen, SP, Dahlerup, JF
Alimentary pharmacology & therapeutics. 2010;(11-12):1364-72
-
-
Free full text
-
Abstract
BACKGROUND Vitamin D3 has shown immune-modulating effects in CD4+ T cells from Crohn's disease patients in vitro. AIM: To investigate the effects of in vivo vitamin D3 treatment on T cells in Crohn's disease patients. METHODS Peripheral blood mononuclear cells (PBMC) were isolated at week 0 and at week 26 from 10 vitamin D3- and 10 placebo-treated Crohn's disease patients participating in a randomized, placebo-controlled, clinical trial study. Monocyte-depleted PBMC were stimulated with anti-CD3 and anti-CD28, and cultured for 7, days, to investigate CD4+ T-cell proliferation and T-cell cytokine production. RESULTS In vitamin D3-treated patients, the median 25-hydroxyvitamin D3 levels increased 70 nmol/L compared with -5 nmol/L in the placebo group. Vitamin D3 treatment increased interleukin-6 production (delta = 188 pg/mL, range: -444 to 4071) compared with a decrease in the placebo group (delta = -896 pg/mL, range: -3841 to 1323) (P < 0.02, Wilcoxon rank sum test). Interestingly, vitamin D3 increased the amount of proliferating stimulated CD4+ T cells from median 41% (range: 10-75%) to 56% (range: 26-77%) (P = 0.02, Wilcoxon rank sum test). CONCLUSIONS Vitamin D3 treatment of Crohn's disease patients increased the IL-6 levels. Interestingly, vitamin D3 treatment enhanced the CD4+ T cell proliferation.