Plasma hydrogen sulphide does not predict severity of acute pancreatitis in humans.

The primary aim of this study was to assess the usefulness of plasma hydrogen sulphide (H2S) level at admission as a predictor of severity of acute pancreatitis. The secondary aims were to examine whether the level of H2S after 48 h correlated with severity and whether level of H2S correlated with pulmonary, renal or infectious complications. Plasma hydrogen sulphide was measured within 24 h of admission and 48 h later, in patients with acute pancreatitis. Patients were classified as having mild or severe pancreatitis, and H2S levels in the two groups were compared. A total of 55 patients had H2S estimation carried out within 24 h of admission. H2S levels were similar in patients with mild (mean 31.8 ± 18.8, range 7.1 to 81.4 µmol/L) and severe pancreatitis (mean 28.2 ± 21.6, range 6.1 to 74.4 µmol/L; p = 0.339). There was no difference found between the groups after 48 h (mild n = 28, mean 26.8 ± 19.4 µmol/L, and severe n = 20, mean 34.6 ± 21.0 µmol/L; p = 0.127). There was also no difference in the levels between patients with or without lung injury, kidney injury or sepsis. Performing H2S estimation to predict severity in acute pancreatitis is not beneficial.

Aberrant Niche Signaling in the Etiopathogenesis of Ulcerative Colitis.

BACKGROUND: Primary colonic epithelial defects leading to inflammatory responses are considered central to the development of ulcerative colitis (UC). However, a systematic analysis of various colonic subcompartments in the pathogenesis of UC before inflammation remains elusive. Here, we explored changes in colonic subcompartments and their associated niche signals in patient mucosal biopsies and in an animal model of colitis. METHODS: Analysis of mucosal biopsies obtained from uninvolved and involved regions of patients with UC and Crohn's disease was performed and compared with normal subjects. Temporal analysis of colonic subcompartments was performed in mice administered with 5% dextran sodium sulphate. Phenotypic enumeration of the crypt subcompartment was complemented with flow cytometric analysis. Members of Notch and Wnt signaling pathways were analyzed by molecular, biochemical, and colocalization studies. RESULTS: Phenotypic enumeration of colonocytes' subcompartments from patients revealed significant alterations of the lower crypt, enriched in stem cell and progenitors, independent of inflammation. These changes, unique to UC, were confirmed by immunohistochemistry and molecular analysis. In parallel, a defect in proliferation and Muc2 synthesis was observed. Animal data before inflammation recapitulated human studies. Mechanistic studies revealed that changes in signaling through Wnt primarily affected colonic stem cells, whereas Notch affected progenitor function. CONCLUSIONS: Our results thus provide new insights into the development of inflammation and relapse in UC and suggest that the stem cell niche in the colon may influence pathogenesis of the disease.

Acute liver injury induced by low dose dimethylnitrosamine alters mediators of hepatic vascular flow.

Alterations in liver vascular tone play an important role in chronic liver disease. The hepatic stellate cell (HSC) and mediators such as nitric oxide (NO) and hydrogen sulfide (H2S) have been implicated in regulation of vascular tone and intra-hepatic pressure. Though these have been studied in chronic liver damage, changes in response to acute liver injury induced by hepatotoxins such as dimethyl nitrosamine are not well understood. Liver injury was induced in mice by a single intra-peritoneal injection of dimethylnitrosamine (DMN), following which animals were sacrificed at 24, 48 and 72 h. Changes in vascular mediators such as NO and H2S as well as stellate cell activation was then examined. It was found that a single low dose of DMN in mice is sufficient to induce activation of hepatic stellate cells within 24 h, accompanied by oxidative stress, compromised metabolism of H2S and decreased levels of the von Willebrand factor (vWF) cleaving protease; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which functions in intravascular thrombosis. A suppression of hepatic NO levels is also initiated at this time point, which progresses further and is sustained up to 72 h, at which point the HSC activation is still present. Compromised levels of ADAMTS13 and H2S metabolism however, begin to recover by 48 h and are almost similar to control by 72 h. In conclusion, these data suggest that even moderate acute insults in the liver can have far reaching consequences on a number of mediators of vascular flow in the liver.

Acute fatty liver of pregnancy: an update on mechanisms.

Acute fatty liver of pregnancy (AFLP), characterized by hepatic microvesicular steatosis, is a sudden catastrophic illness occurring almost exclusively in the third trimester of pregnancy. Defective fatty acid oxidation in the fetus has been shown to be associated with this disease. Since the placenta has the same genetic makeup as the fetus and as AFLP patients generally recover following delivery, we hypothesized that the placenta might be involved in pathogenesis of this disease. In an animal model of hepatic microvesicular steatosis (using sodium valproate), we found that microvesicular steatosis results in mitochondrial structural alterations and oxidative stress in subcellular organelles of the liver. In placentas from patients with AFLP, we observed placental mitochondrial dysfunction and oxidative stress in subcellular organelles. In addition, defective placental fatty acid oxidation results in accumulation of toxic mediators such as arachidonic acid. Escape of these mediators into the maternal circulation might affect the maternal liver resulting in microvesicular steatosis.

Liver injury in acute fatty liver of pregnancy: possible link to placental mitochondrial dysfunction and oxidative stress.

UNLABELLED: Acute fatty liver of pregnancy (AFLP) is a rare disorder which is fatal if not recognized and treated early. Delivery of the feto-placental unit results in dramatic improvement in maternal liver function, suggesting a role for the placenta. However, the mechanisms by which defects in the fetus or placenta lead to maternal liver damage are not well understood and form the focus of this study. Placenta and serum were obtained at delivery from patients with AFLP, and placental mitochondria and peroxisomes were isolated. Placental mitochondrial function, oxidative stress, and fatty acid composition as well as serum antioxidants, oxidative and nitrosative stress markers, and fatty acid analysis were carried out. Hepatocytes in culture were used to evaluate cell death, mitochondrial function, and lipid accumulation on exposure to fatty acids. Oxidative stress was evident in placental mitochondria and peroxisomes of patients with AFLP, accompanied by compromised mitochondrial function. Increased levels of arachidonic acid were also seen in AFLP placenta when compared to control. Patients with AFLP also had a significant increase in oxidative and nitrosative stress markers in serum, along with decreased antioxidant levels and elevated levels of arachidonic acid. These levels of arachidonic acid were capable of inducing oxidative stress in hepatocyte mitochondria accompanied by induction of apoptosis. Exposure to arachidonic acid also resulted in increased lipid deposition in hepatocytes. CONCLUSION: Oxidative stress in placental mitochondria and peroxisomes is accompanied by accumulation of toxic mediators such as arachidonic acid, which may play a causative role in maternal liver damage seen in AFLP.