Evaluation des kardiovaskulären Risikos bei Patienten mit Phenylketonurie

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. In order to prevent neurological complications, patients have to keep a lifelong phenylalanine-restricted diet supplemented by synthetic amino acids. Previous studies have suggested diet-associated renal impairment and oxidative stress in PKU patients and described an altered lipoprotein profile, indicating a higher risk for cardiovascular disease. The purpose of this study was to assess the cardiovascular risk in patients with PKU by non- invasive examination of arterial functions and risk-specific serum markers. In 23 adult PKU patients (age: 18-47y; 30,8± 8,4y) and 28 healthy controls (age: 18-47y; 30,1 ± 9,1y) we performed venous occlusion plethysmography (VVP) to assess endothelial function and measured the carotid to femoral pulse wave velocity (PWV), an indicator of arterial stiffness. We further analyzed blood pressure, resting heart rate, BMI, inflammatory markers, oxidative stress markers and the lipoprotein profile. To assess the influence of the diet on vascular parameters we calculated the cumulative intake of synthetic amino acids over the last 5 years. We found increased arterial stiffness and endothelial dysfunction in patients with PKU as well as higher blood pressure and resting heart rate compared to healthy controls . The SAA, CRP and MDA serum levels, markers of inflammation and oxidative stress, respectively, were increased while levels of HDL-C and HDL2C were lower compared to the control group. PKU patients showed no renal impairment and no association of the cumulative intake of synthetic amino acids with arterial function parameters. In conclusion, we found that PKU patients exhibited vascular pathologies, elevated blood pressure and resting heart rate, elevated biomarkers of inflammation, oxidative stress and an atherogenic lipoprotein profile. This indicates a higher risk for cardiovascular disease in these patients. The results of our pilot study call for further investigations and stresses the need for early preventive measures against cardiovascular disease in young patients with PKU.Die Phenylketonurie (PKU) gehört zu den häufigsten angeborenen Stoffwechselerkrankungen. Um neurologische Komplikationen zu vermeiden, müssen Patienten lebenslang eine Phenylalanin-arme Diät einhalten und synthetische Aminosäuremischungen einnehmen. Die Zufuhr dieser synthetischen Aminosäuren wurde in mehreren Studien mit Nierenfunktionsstörungen und oxidativem Stress in Verbindung gebracht. Weiterhin wurde ein verändertes Lipoproteinprofil festgestellt. All das lässt vermuten, dass Patienten mit PKU im Langzeitverlauf ein erhöhtes kardiovaskuläres Risiko aufweisen könnten. Das Ziel dieser Studie war es, das Ausmaß der kardiovaskulären Gefährdung von PKU-Patienten anhand nicht-invasiver Gefäßuntersuchungen zu beurteilen und diese mit verschiedenen etablierten ebenso wie neueren kardiovaskulären Risikomarkern zu korrelieren. Hierfür wurden 23 erwachsene Patienten mit PKU (Alter: 18-47 Jahre; 30,8 ± 8,4 Jahre) und 28 gesunde Kontrollen (Alter: 18-47 Jahre; 30,1 ± 9,1 Jahre) untersucht und Blutdruck, Pulsfrequenz sowie BMI ermittelt. Neben der Beurteilung der Gefäßsteifigkeit (Pulswellengeschwindigkeit) und der Endothelfunktion (Venenverschlussplethysmographie) wurde eine umfassende Analyse von Lipoproteinwerten, Inflammationsparametern und oxidativen Stressmarkern durchgeführt. Des Weiteren wurde die kumulative Zufuhr synthetischer Aminosäuren über 5 Jahre berechnet, um den Einfluss der Diät auf die Gefäßfunktion zu untersuchen. Die Patienten mit PKU wiesen in dieser Studie signifikant erhöhte Pulsfrequenz- und Blutdruckwerte sowie eine signifikant erhöhte Gefäßsteifigkeit und eine endotheliale Dysfunktion auf. Außerdem konnten wir erhöhte SAA- und CRP-Werte als Marker der Inflammation, erhöhte MDA-Werte als oxidativen Stress-Parameter und verminderte HDL-C und HDL2C-Werte nachweisen. PKU-Patienten wiesen keine Nierenfunktionsstörungen auf und wir konnten keinen Zusammenhang zwischen der Zufuhr synthetischer Aminosäuren und der Gefäßfunktion feststellen. Diese Studie zeigt somit, dass Patienten mit PKU eine beeinträchtigte Gefäßfunktion, höhere Blutdruck- und Pulsfrequenzwerte, ein vermehrtes Maß an Inflammation und oxidativem Stress sowie ein proatherogenes Lipoproteinprofil aufweisen. All diese Veränderungen sprechen für ein erhöhtes kardiovaskuläres Risiko bei diesen Patienten. Den Ergebnissen unserer Pilotstudie sollte in umfangreicheren klinischen Studien nachgegangen werden. Sie weisen auf die Notwendigkeit hin, bei Patienten mit PKU schon im jungen Erwachsenenalter Strategien zur Prävention kardiovaskulärer Erkrankungen zu planen

The cardiovascular phenotype of adult patients with phenylketonuria

BACKGROUND: Patients with Phenylketonuria (PKU) are exposed to multiple cardiovascular risk factors, but the clinical significance of these abnormalities is yet unknown. The purpose of this study was to characterize the cardiovascular phenotype in adult patients with PKU by clinical and dietary data, measurements of biochemical markers, and non-invasive examination of vascular functions. RESULTS: Twenty-three adult patients with PKU (age: 18-47 y; 30.8 ± 8.4 y) and 28 healthy controls (age: 18-47 y; 30.1 ± 9.1 y) were included in this study. PKU patients had significantly higher systolic and diastolic blood pressure, increased resting heart rate and a higher body mass index. Total cholesterol and non-HDL cholesterol levels were significantly increased in PKU patients, whereas plasma levels of HDL cholesterol and its subfraction HDL2 (but not HDL3) were significantly decreased. The inflammatory markers C-reactive protein and serum amyloid A protein and the serum oxidative stress marker malondialdehyde were significantly higher in patients with PKU. Venous occlusion plethysmography showed marked reduction in post-ischemic blood flow and the carotid to femoral pulse wave velocity was significantly increased demonstrating endothelial dysfunction and increased vascular stiffness. CONCLUSIONS: This study shows that the cardiovascular phenotype of adult PKU patients is characterized by an accumulation of traditional cardiovascular risk factors, high levels of inflammatory and oxidative stress markers, endothelial dysfunction and vascular stiffness. These data indicate the need for early cardiovascular risk reduction in patients with PKU

Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity

Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.

Peer reviewed: TrueBACKGROUND AND AIMS: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids. METHODS: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors. RESULTS: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids. CONCLUSIONS: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity

Image_3_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p

Image_4_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p

Image_1_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p

Image_5_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p

Image_6_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p

Image_2_Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.tif

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.</p