Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD.

BACKGROUND & AIMS: Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH). METHODS: The effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis. RESULTS: The THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH. CONCLUSIONS: Antagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD. LAY SUMMARY: In non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity.

Systemic lupus erythematosus presenting as non-resolving pneumonia: a case report.

BackgroundSystemic lupus erythematosus (SLE) is a rheumatological disorder with a heterogeneous clinical presentation and disease course. Case presentationWe report a case concerning a young woman with pleuropneumonia, non-responsive to conventional antibiotic therapy, who was, upon further inquiry and passage of time, diagnosed with SLE. Key pointsBy means of this case, we would like to emphasize the clinical implications and prognostic significance of lymphopenia in patients with SLE. Moreover, we attempt to make the reader aware of some of the protean manifestations of SLE and we would like to raise suspicion of acute lupus pneumonitis by demonstrating a case of a young female with non-resolving pneumonia.

Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases in the Western society and its prevalence is likely to rise even further. An increasing body of evidence shows that NAFLD is not only a potentially progressive liver disease, but also has systemic consequences. More specifically, evidence points out that NAFLD has to be considered as a significant independent risk factor for subclinical and clinical cardiovascular disease (CVD). Long-term follow-up studies demonstrate cardiovascular mortality to be the most important cause of death in NAFLD patients. Moreover, ample evidence associates NAFLD with endothelial dysfunction, increased pulse wave velocity, increased coronary arterial calcifications and increased carotid intima media thickness, all established markers for CVD. Despite of all this evidence, the mechanisms by which NAFLD causally contributes to CVD are not fully elucidated. Furthermore, an extensive overview of all potential pathophysiological mechanisms and the corresponding current data are lacking. In this review we summarise current knowledge, originating from fundamental and clinical research, that mechanistically links NAFLD to CVD. Subsequently, the impact of CVD on current clinical practice and future research in the area of NALFD are discussed.