IL-22 promotes liver regeneration after portal vein ligation.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Fetal lung growth predicts the risk for early-life respiratory infections and childhood asthma.

BACKGROUND: Early-life respiratory infections and asthma are major health burdens during childhood. Markers predicting an increased risk for early-life respiratory diseases are sparse. Here, we identified the predictive value of ultrasound-monitored fetal lung growth for the risk of early-life respiratory infections and asthma. METHODS: Fetal lung size was serially assessed at standardized time points by transabdominal ultrasound in pregnant women participating in a pregnancy cohort. Correlations between fetal lung growth and respiratory infections in infancy or early-onset asthma at five years were examined. Machine-learning models relying on extreme gradient boosting regressor or classifier algorithms were developed to predict respiratory infection or asthma risk based on fetal lung growth. For model development and validation, study participants were randomly divided into a training and a testing group, respectively, by the employed algorithm. RESULTS: Enhanced fetal lung growth throughout pregnancy predicted a lower early-life respiratory infection risk. Male sex was associated with a higher risk for respiratory infections in infancy. Fetal lung growth could also predict the risk of asthma at five years of age. We designed three machine-learning models to predict the risk and number of infections in infancy as well as the risk of early-onset asthma. The models' R2 values were 0.92, 0.90 and 0.93, respectively, underscoring a high accuracy and agreement between the actual and predicted values. Influential variables included known risk factors and novel predictors, such as ultrasound-monitored fetal lung growth. CONCLUSION: Sonographic monitoring of fetal lung growth allows to predict the risk for early-life respiratory infections and asthma.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

Tissue-resident immunity in the lung: a first-line defense at the environmental interface.

The lung is a vital organ that incessantly faces external environmental challenges. Its homeostasis and unimpeded vital function are ensured by the respiratory epithelium working hand in hand with an intricate fine-tuned tissue-resident immune cell network. Lung tissue-resident immune cells span across the innate and adaptive immunity and protect from infectious agents but can also prove to be pathogenic if dysregulated. Here, we review the innate and adaptive immune cell subtypes comprising lung-resident immunity and discuss their ontogeny and role in distinct respiratory diseases. An improved understanding of the role of lung-resident immunity and how its function is dysregulated under pathological conditions can shed light on the pathogenesis of respiratory diseases.

The Use of Antenatal Dexamethasone in Late Preterm and Term Pregnancies to Improve Neonatal Morbidity and Mortality: A Systematic Review and Meta-Analysis.

There are no acceptable worldwide recommendations regarding the use of dexamethasone in late-preterm newborns delivered either vaginally or via cesarean section and term gestation that are performed via cesarean section. The present study aims to compare the effectiveness of antenatal intramuscular dexamethasone versus placebo/no-treatment in reducing neonatal respiratory complications in high-risk for imminent preterm birth in late preterm pregnancies and term pregnancies undergoing elective cesarean section. The PubMed, Scopus, and Cochrane Library databases were searched to assess the effectiveness of dexamethasone during late preterm and term gestation. The last literature search was performed on March 20th, 2022. Randomized controlled trials compared antenatal dexamethasone administration with placebo or no treatment. The outcomes of interest were: the incidence of Respiratory Distress Syndrome; Transient Tachypnea of the Newborn, Neonatal Intensive Care Unit admissions; and the need for ventilatory support or mechanical ventilation. A standardized data form and three independent investigators performed the data extraction. Ten RCTs fulfilled our inclusion criteria. No statistically significant difference was found regarding all of the outcomes in the 34th-36th gestational week group. In the >37th gestational week group, a statistically significant difference was found regarding the incidence of RDS [RR (95% CI); p-value: 0.56 (0.36, 0.87); 0.01], TTN [RR (95% CI); p-value: 0.54 (0.42, 0.71); <0.00001], need for ventilatory support [RR (95% CI); p-value: 0.71 (0.52, 0.96); 0.03] and need for mechanical ventilation [RR (95% CI); p-value: 0.56 (0.33, 0.95); 0.03]. To conclude, the antenatal administration of dexamethasone can be considered to prevent neonatal complications and reduce perinatal morbidity in term pregnancies.

Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials.

OBJECTIVE: To assess the efficacy of IL-6 inhibitors compared to standard of care (SOC) in COVID-19 patients. DATA SOURCES: A systematic review of the MEDLINE and Scopus databases (last search: October 8th, 2021) was performed according to the PRISMA statement. STUDY SELECTION: Randomized control trials (RCTs) comparing IL-6 inhibitors to SOC in hospitalized COVID-19 patients were deemed eligible. DATA EXTRACTION AND SYNTHESIS: Individual patient data were extracted from the Kaplan-Meier curves or were obtained from authors of included studies. Additionally, the reviewers independently abstracted data and assessed study quality of each eligible report. RESULTS: Eleven studies were identified, incorporating 7467 patients (IL-6 inhibitors: 4103, SOC: 3364). IL-6 inhibitors were associated with decreased risk for death compared to SOC at the one-stage meta-analysis (Hazard Ratio [HR]: 0.75, 95% Confidence interval [CI]: 0.69-0.82, p<0.0001) and the two-stage meta-analysis (HR: 0.85, 95%CI: 0.77-0.93, p<0.001, I2 = 0.0%). Meta-regression analysis revealed that the difference in OS between the two groups was not influenced by the mean age of patients. At secondary meta-analyses, IL-6 inhibitors were associated with decreased odds for intubation OR:0.74, 95%CI:0.65-0.85, p<0.001, I2=0.0%). IL-6 inhibitors were associated with increased odds for discharge compared to SOC (OR:1.28, 95% CI:1.15-1.42, p<0.001, I2=0.0%). CONCLUSIONS AND RELEVANCE: This meta-analysis of individual patient data from randomized trials shows that IL-6 inhibitors significantly reduce the risk of death compared to SOC. IL-6 inhibitors are also associated with better outcomes in terms of intubation and discharge rates compared to SOC.

Self-reported risk of obstructive sleep apnea syndrome, and awareness about it in the community of 4 insular complexes comprising 41 Greek Islands.

Obstructive Sleep Apnea Syndrome (OSAS) is a chronic disease that significantly increases morbidity and mortality of the affected population. There is lack of data concerning the OSAS prevalence in the insular part of Greece. The purpose of this study was to investigate the self-reported prevalence of OSAS in 4 Greek insular complexes comprising 41 islands, and to assess the awareness of the population regarding OSAS and its diagnosis. Our study comprised 700 participants from 41 islands of the Ionian, Cyclades, Dodecanese and Northeast Aegean island complexes that were studied by means of questionnaires via a telephone randomized survey (responsiveness rate of 25.74%). Participants were assessed by the Berlin Questionnaire (BQ) for evaluation of OSA risk, by the Epworth Sleepiness Scale (ESS) for evaluation of excessive daytime sleepiness, and by 3 questions regarding the knowledge and diagnosis of OSAS. The percentage of participants at high risk according to BQ was 27.29% and the percentage of people who were at high risk according to ESS was 15.43%. A percentage of 6.29% of the population was at high risk for OSAS (high risk both in BQ and ESS). A high percentage of 73.43%, were aware of OSAS as a syndrome however a significantly less percentage (28.00%) was aware of how a diagnosis of OSAS is established. The community prevalence of OSAS in Greek islands in combination with the low-level awareness of the OSAS diagnostic methods highlights the need for development of health promotion programs aiming at increasing the detection of patients at risk while increasing the awareness of OSAS.