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Biomedical subjects

C Surrenti

Publications and source records attributed to C Surrenti.

At least 19 recordsLinked to original sources
PubMed2000

Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis.

Chronic alcoholic pancreatitis (CAP) is characterized by progressive pancreatic fibrosis and loss of the acinar cell mass, but the pathogenesis of pancreatic fibrosis in the human is poorly understood. It has been recently suggested that lipid peroxidation-derived aldehydes such as 4-hydroxynonenal (HNE) are involved in tissue damage and fibrosis in other organs. The aim of this study was to evaluate the role of oxidative stress in the development of alcohol-induced pancreatic fibrosis in humans, and to assess the contribution of pancreatic periacinar stellate cells (PSC) in the in vivo synthesis of extracellular matrix components during CAP. Lipid peroxidation was evaluated in tissue specimens obtained from patients with CAP who underwent surgical procedures, by immunohistochemistry using a monoclonal antibody directed against HNE-protein adducts. Immunohistochemical determination of collagen type I, alpha-smooth muscle actin (alpha-SMA), and the beta subunit of human platelet-derived growth factor (PDGF-Rbeta) was also performed. In addition, the tissue mRNA expression of procollagen I, PDGF-Rbeta, and transforming growth factor-beta1 (TGF-beta1) was evaluated by in situ hybridization. In CAP, increased formation of HNE-protein adducts was evident in acinar cells adjacent to the interlobular connective tissue that stained positively for collagen type I. HNE staining was absent in normal pancreas. Several non-parenchymal periacinar cells (PSC) underlay the HNE-stained acinar cells. Those PSC stained positively for alpha-SMA and PDGF-Rbeta and showed active synthesis of procollagen type I by in situ expression of the specific mRNAs. The pattern of expression of PDGF-Rbeta mRNA reflected that observed in immunostaining, showing increased amounts of transcripts in PSC. TGF-beta1 mRNA expression was increased in CAP, but transcripts were found in several cell types including PSC, acinar, and ductal cells. These results indicate that significant lipid peroxidation phenomena occur in CAP and that they are associated with active synthesis of collagen by PSC.

Actins↗
PubMed2000

Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells.

During liver injury, hepatic stellate cells (HSC) acquire a myofibroblast-like phenotype associated with reduction of lipid droplets, increased collagen synthesis, and proliferation. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipocyte differentiation and controls gene transcription in response to various activators including prostanoids and antidiabetic thiazolidinediones. We explored whether the presence of PPARgamma and its transcriptional activity were involved in control of HSC proliferation in vitro. PPARgamma ligands, 15-deoxy-triangle up(1214) prostaglandin J(2) (15d-PGJ(2)) and ciglitizone, significantly decrease platelet-derived growth factor (PDGF)-induced proliferation in activated human HSC and inhibit alpha smooth muscle actin (alpha-SMA) expression during HSC transdifferentiation. Treatment with 9-cis retinoic acid (9-cisRA) and LG268, ligands of the heterodimerization partner retinoic X receptor (RXR), had a negligible effect in PDGF-treated cells but caused a further reduction of proliferation when used in combination with ciglitizone. Transfection experiments with a reporter gene consisting of 3 copies of a PPAR response element (peroxisome proliferator response element [PPRE](3)-tk-luciferase) showed a progressive reduction of PPAR transcriptional activity during plastic-induced HSC transdifferentiation. Cotransfection with human PPARgamma expression vector restored the PPRE(3)-tk-luciferase reporter expression and the increased level of the receptor in activated HSC-inhibited cell proliferation in a dose-dependent manner. Incubation of human PPARgamma-cotransfected HSC with PDGF strongly inhibited luciferase activity and this effect was blocked by the inhibition of the mitogen-activated protein (MAP) kinase signal cascade. Our results indicate that depression of PPARgamma expression and activity is involved in HSC proliferation and that the PPARgamma ligand-mediated activation exerts a previously unrecognized inhibition of PDGF-induced mitogenesis in activated human HSC.

Cell Differentiation↗
PubMed2000

Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine.

Increasing evidence suggests that tachykinins are involved in the control of pathophysiological states, such as inflammation. The precise localization of tachykinin receptors is of paramount importance in the search for their possible physiological and pathological role; in this study, therefore, we attempted to define cellular sites of substance P (NK-1R) and neurokinin A (NK-2R) receptor expression in the healthy and the inflamed human intestine by in situ hybridization and immunohistochemistry. In the normal ileum and colon, NK-1R and NK-2R were localized to smooth muscle cells of the muscularis mucosae and propria and a few inflammatory cells of the lamina propria; NK-1R expression was also found in the muscular wall of submucosal blood vessels, enteric neurons and, to a lesser degree, in surface epithelial cells. Patients with Crohn's disease and ulcerative colitis showed a dramatic increase in NK-1R density relative to controls, in both the inflamed and the uninvolved mucosa. Up-regulation of NK-1R was particularly evident on epithelial cells lining the mucosal surface and crypts, as well as on endothelial cells of capillaries and venules. Also, a marked increase in NK-2R expression was found in both groups of patients on inflammatory cells of the lamina propria, especially eosinophils. Our findings demonstrate that in the normal human intestine NK-1R and NK-2R are expressed in multiple cell types, which are endowed with different physiological functions; in addition, they demonstrate that both NK-1R and NK-2R are up-regulated in patients with Crohn's disease and ulcerative colitis. Taken together, these observations may have important physiological and pathophysiological implications, and provide the rationale for the use of NK-1R and NK-2R antagonists in the treatment of inflammatory bowel disease.

Adolescent↗
PubMed1999

Ethanol-induced alterations of matrix network in the duodenal mucosa of chronic alcohol abusers.

Excessive consumption of alcoholic beverages may be associated with gastrointestinal symptoms, including dyspepsia and diarrhoea. It is not clear whether or not chronic alcohol ingestion damages the mucosa of the small intestine. We investigated the effect of chronic alcohol abuse on the duodenal mucosa, and particularly on its extracellular matrix (ECM) network. Duodenal biopsy specimens were obtained during upper gastrointestinal endoscopy from 50 chronic alcoholics without cirrhosis and 10 healthy subjects. Morphological studies were performed by routine histology, immunohistochemistry and electron microscopy. Morphometry of duodenal tissues was performed with a computerized image analyser. No significant duodenal epithelial changes were found in alcoholics, despite an evident reduction in the enterocyte turnover. Myofibroblast-like cells were significantly increased in the villus stroma of alcoholics in comparison to controls. These cells stained positively for desmin, alpha-smooth muscle actin and for several ECM components. In alcohol abusers the thickness of the mucosal basement membrane was greater and the staining for collagen I and III was enhanced both in the basement membrane and in the villus stroma. A higher expression of tenascin was also seen at the base of villi of alcoholics. Chronic alcohol abuse may induce fibrosis of duodenal villi which is associated with a transformation of villus juxta-parenchymal cells into active subepithelial myofibroblast-like cells able to produce different ECM components.

Adult↗
PubMed1999

Measuring quality of life in dyspeptic patients: development and validation of a new specific health status questionnaire: final report from the Italian QPD project involving 4000 patients.

OBJECTIVE: Despite the fact that gastrointestinal disorders represent one of the most common reasons for medical consultations, formal assessment of patients' health-related quality of life (HRQOL) has been carried out only in a few studies, and in most cases generic questionnaires have been adopted. Because the specific issue of living with dyspeptic problems has been addressed in very few cases and no questionnaire has been shown to be appropriate for the Italian setting, a prospective project was launched to develop a specific HRQOL questionnaire for dyspepsia sufferers tailored to Italian patients but also appropriate in other cultural settings. METHODS: The project consisted in a 3-yr, three-phase survey, in which different versions of the quality of life in peptic disease questionnaire (QPD) were developed through expert and patient focus groups and empiric field studies and then administered to patients recruited in five multicenter studies. Standard psychometric techniques were used to evaluate the validity, reliability, responsiveness, and patient acceptability of the QPD. RESULTS: Three different versions of the QPD questionnaire were self-administered to more than 4000 patients. The final 30-item version, measuring three health concepts related to dyspeptic disease (anxiety induced by pain, social restriction, symptom perception), fulfilled the recommended psychometric criteria in terms of reliability and validity, correlated with health concepts measured with a well-known independent generic HRQOL instrument (the SF-36 Health Survey questionnaire) and was relatively invariant to diagnosis and sociodemographic variables; it also correlated with a measure of gastric pain frequency and was able to detect meaningful differences over time. CONCLUSIONS: Although further validation studies in different cultural and linguistic settings are mandatory before any firm conclusions can be drawn regarding the cross-cultural validity of the QPD, the data obtained provide evidence of the psychometric validity and robustness of the questionnaire when used in a fairly large, well-characterized population of Italian dyspeptic patients.

Adult↗
PubMed1999

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Adolescent↗
PubMed1998

Human hepatic stellate cells express class I alcohol dehydrogenase and aldehyde dehydrogenase but not cytochrome P4502E1.

BACKGROUND/AIMS: Alcohol dehydrogenase, cytochrome P4502E1 (CYP2E1), and aldehyde dehydrogenase are known to play an important role in alcohol metabolism in the liver. Although the ethanol oxidation pathways are mainly localized in hepatocytes, we examine whether human hepatic stellate cells might also metabolize ethanol and acetaldehyde. METHODS: Hepatic stellate cells were isolated from normal human livers and exposed in vitro to 50 mmol/l ethanol or 85 micromol/l acetaldehyde for different periods of time. Alcohol dehydrogenase/aldehyde dehydrogenase activity and CYP2E1 protein expression were measured in hepatic stellate cells. Moreover, alcohol dehydrogenase and aldehyde dehydrogenase mRNA expression were evaluated in hepatic stellate cells. RESULTS: Exposure of hepatic stellate cells to ethanol for 24 h resulted in a 5-fold increase in cell alcohol dehydrogenase activity. The effect of ethanol on alcohol dehydrogenase activity was paralleled by a significant increase in the alcohol dehydrogenase mRNA expression in hepatic stellate cells. Acetaldehyde significantly increased the activity of high affinity aldehyde dehydrogenase in hepatic stellate cells, whereas ethanol was devoid of any effect. Acetaldehyde also induced high affinity aldehyde dehydrogenase mRNA expression in hepatic stellate cells. CYP2E1 was not expressed in hepatic stellate cells either in basal condition or after ethanol/acetaldehyde exposure. CONCLUSIONS: This study shows that human hepatic stellate cells have the capacity to metabolize both ethanol and acetaldehyde through a class I alcohol dehydrogenase- and an aldehyde dehydrogenase-oxidizing pathway. Conversely, no detectable levels of CYP2E1-associated proteins are expressed in these cells.

Acetaldehyde↗
PubMed1998

Serologic detection of CagA positive Helicobacter pylori infection in a northern Italian population: its association with peptic ulcer disease.

BACKGROUND: About 60-70% of Helicobacter pylori strains possess cagA (cytotoxin associated gene A) gene and express its product CagA, a highly immunogenic 128-140 kD protein. Patients infected with CagA positive strains develop serum IgG anti-CagA. A serologic response to CagA has been detected in Helicobacter pylori infected patients with peptic ulcer more frequently than in those with gastritis alone. It is nuclear whether this finding is consistent in different geographical populations. We investigated the relationship between anti-CagA seropositivity and peptic ulcer disease in a Northern Italian population. MATERIALS AND METHODS: We studied 135 H. pylori infected patients: 65 with duodenal ulcer (DU), 28 with gastric ulcer (GU) and 42 with non ulcer dyspepsia (NUD). Sera from these patients were assayed by EIA (enzyme immunoassay) for anti-CagA IgG. RESULTS: A high prevalence of anti-CagA was found associated with DU (86.1%) and GU (96.4%), while NUD patients showed anti-CagA seropositivity of 52.4% (Odd ratio, 5.66; 95% confidence interval, 2.23 to 14.32; p < .001, DU vs. NUD; Odd ratio, 24.5; 95% confidence interval, 3.05 to 197.6; p = .003, GU vs. NUD). DU patients showed anti-CagA seropositivity titer (1.15 (0.61 OD, mean (SD) higher than that of NUD patients (0.78 (0.60 OD, mean (SD) (p < .05). CONCLUSIONS: These data demonstrate in a Northern Italian population that anti-CagA seropositivity is strongly associated with peptic ulcer disease and suggest that CagA might play an important role in ulcer pathogenesis.

Adult↗
PubMed1998

Eradication of Helicobacter pylori reduces the rate of duodenal ulcer rebleeding: a long-term follow-up study.

OBJECTIVES: The long-term efficacy of Helicobacter pylori eradication to reduce the rate of recurrence of peptic ulcer bleeding is still uncertain. We evaluated the rate of duodenal ulcer rebleeding for 48 months after H. pylori eradication. METHODS: Thirty-two male patients with H. pylori infection and duodenal ulcer bleeding were treated with omeprazole (40 mg/day for 4 wk), colloidal bismuth (480 mg/day for 2 wk), amoxicillin (2 g/day for 1 wk), and metronidazole (750 mg/day for 1 wk), and followed up for 48 months. Endoscopy and tests for H. pylori infection were repeated every year. RESULTS: Ulcer healed in all patients, but H. pylori infection persisted or recurred in 11 patients. Within 48 months, rebleeding occurred in nine (81.8%) of these patients, whereas the 21 patients who were persistently negative for H. pylori infection remained asymptomatic without rebleeding (0/ 21 = 0%, p < 0.002) during the whole follow-up. CONCLUSIONS: Eradication of H. pylori can reduce the rate of duodenal ulcer rebleeding for at least 4 yr, thus potentially modifying the natural history of the disease.

Adult↗
PubMed1998

Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis is a chronic inflammatory condition characterized by an altered intestinal immunoinflammatory response. Since increasing evidence indicates that neuropeptides play a key role in the regulation of gastrointestinal immune function, the aims of this study were: a) to determine tissue and plasma levels of Vasoactive Intestinal Polypeptide, Substance P, and Calcitonin Gene-Related Peptide in patients with ulcerative colitis, and b) to ascertain whether a relationship exists between tissue concentrations of neuropeptides and the histological grading of mucosal inflammation. METHODS: A total of 29 patients with active and 39 with inactive ulcerative colitis, and 16 control subjects took part in the study. Biopsy specimens of colonic mucosa and blood samples were obtained from each subject, and neuropeptide concentrations were measured by sensitive and specific radioimmunoassays. RESULTS: Both Vasoactive Intestinal Polypeptide and Substance P concentrations were found to be significantly reduced in endoscopic biopsy specimens of patients with ulcerative colitis compared to controls (p < 0.01 and p = 0.05, respectively), and the reduction appeared to be related to the degree of mucosal inflammation; in contrast, Calcitonin Gene-Related Peptide tissue levels were unchanged. In addition, there was no significant difference in the neuropeptide plasma levels between ulcerative colitis patients and control subjects. CONCLUSIONS: Taken together, our results suggest that the reduction of Vasoactive Intestinal Polypeptide and Substance P is probably a secondary phenomenon, correlated with the degree of mucosal inflammation; whatever the mechanism, the decreased availability of these neuropeptides in the local microenvironment may play an important role in the pathogenesis of ulcerative colitis, by affecting many components of the normal immune response. Moreover, based on our data, the measurement of neuropeptide plasma concentrations does not appear to be a useful tool to monitor disease activity.

Adult↗
PubMed1997

Expression of epidermal growth factor, transforming growth factor-alpha and their receptor in the human oesophagus.

Increasing evidence indicates that epidermal growth factor and transforming growth factor-alpha are involved in the maintenance of oesophageal mucosal integrity. However, their cellular origin and the exact localization of their receptor in the oesophagus are still unclear. Therefore, we examined the expression of the two growth factors and their shared receptor in the normal human oesophagus at both mRNA and protein level, by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction. In addition to being expressed in the proliferative compartment of the oesophageal epithelium, the receptor was found in a variety of cells, including smooth muscle cells, submucosal gland cells and the epithelium lining their ducts. Immunohistochemically, the pattern of distribution of epidermal growth factor paralleled that of its receptor. In situ hybridization demonstrated epidermal growth factor mRNA expression in the oesophageal epithelium and submucosal glands. Additionally, amplified transcripts of predicted size were detected by reverse transcription-polymerase chain reaction, thus confirming that authentic transcripts of the growth factor exist in the normal human oesophagus. Transforming growth factor-alpha mRNA and protein expression, while similar to that of epidermal growth factor, predominated in the more differentiated cell layers of the stratified squamous epithelium. These results demonstrate that the normal oesophagus can synthesize both growth factors. Moreover, the peculiar distribution of these peptides and the concomitant expression of their receptor in multiple cell types suggest that the two growth factors may exert diverse physiological functions in the oesophagus and participate in defence and reparative events following mucosal injury.

Adult↗
PubMed1997

Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide.

Experimental evidence indicates that the lipid peroxidation of biological membranes is often associated with the development of liver fibrosis. We have studied the effect of neutrophil-derived reactive oxygen species (ROS) on collagen synthesis by human hepatic stellate cells (HSC), the major source of collagen in the liver, in a coculture system. Lipid peroxidation in the cocultures was evaluated in terms of either malondialdehyde (MDA) production or the formation of MDA/4-hydroxynonenal protein adducts. The expression of cellular messenger RNAs (mRNAs) was evaluated by either Northern blotting or RNAse protection assay. Nitric oxide (NO) synthase activity in cells was measured by [3H]citrulline formation from [3H]arginine. In vitro exposure of HSC to ROS resulted in the early induction of lipid peroxidation and was associated with a marked increase (threefold) of procollagen I mRNA expression and synthesis. The addition of antioxidants, such as vitamin E or superoxide dismutase (SOD), impaired this stimulation. The inhibition of neutrophil NO formation by N(G)-monomethyl-L-arginine made the ROS-induced stimulation of procollagen I more evident. The addition of xanthine/xanthine oxidase X/XO, a superoxide anion donor, to HSC cultures strongly increased procollagen I synthesis. This stimulation was hampered by the addition of both SOD and sodium nitroprusside (an NO donor). The contribution of HSC to the production of NO in our coculture system was negligible, because inducible NO synthase (iNOS) mRNA was almost undetectable in these cells, and also because the amount of NO produced by HSC stimulated with tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS) was 500 times less than that synthesized by neutrophils. In conclusion, these results indicate that neutrophil-derived ROS may contribute to the development of hepatic fibrosis associated with alcoholic hepatitis. NO produced by neutrophils may exert a "protective" antioxidant effect by operating as a scavenger of superoxide anion.

Humans↗
PubMed1997

Chronic atrophic gastritis and Helicobacter pylori infection in primary biliary cirrhosis: a cross-sectional study with matching.

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by exocrine gland impairment. Up to now there have been no reports dealing with gastric mucosa involvement in this autoimmune condition, which is frequently associated with Sjögren's syndrome. The aim of this study was to investigate the morphologic, biochemical and immunological features of the gastric mucosa in PBC. METHODS: A cross-sectional study with matching was performed. Thirty-three PBC patients (30 F, 3 M, mean age 58 years; 17 with stage II-III, and 16 with stage IV disease) and 33 sex- and age-matched dyspeptic controls were included. Six biopsy specimens from the fundus (2), body (2) and antrum (2) were taken from all patients and controls. A serological assessment was performed for each subject, i.e. pepsinogen A (PGA), pepsinogen C (PGC), gastrin (G), and antibodies against Helicobacter pylori (anti-Hp IgG). RESULTS: Endoscopic gastritis was found in 22 PBC patients (66.6%). There was no difference between PBC patients and controls regarding the percentage of subjects with mild, moderate, severe or atrophic gastritis (AG). There was no difference in gastric mucosal involvement between PBC subjects with or without secondary Sjögren's syndrome. A discrepancy was observed in the data obtained with respect to Helicobacter pylori (H. pylori) infection. H. pylori colonization was significantly more frequent in controls than in PBC patients (79% vs 49%, p < 0.002), but anti-Hp IgG were detected in the same percentage in the two groups (90% vs 83% respectively). There was no difference between the two groups in the PGA, PGC, PGA/PGC ratio, or gastrin. Eight PBC patients had esophageal varices. CONCLUSIONS: PBC patients are not characterized by chronic atrophic gastritis. Even though they present chronic gastritis with the same prevalence as dyspeptic controls, and show signs of previous H. pylori infection as frequently as dyspeptic patients, they are actually much less frequently infected. The reasons for this observation are unclear.

Adult↗
PubMed1995

Role of epidermal growth factor in peptic ulcer healing.

In recent years, increasing interest has been focused on peptide growth factors, and impressive progress has been made in the understanding of their role in tumor development and progression. However, evidence is mounting that peptides such as epidermal growth factor and transforming growth factor-alpha may be of much more physiological than pathological importance. This brief article is intended to give a rapid overview of the available data supporting a role for epidermal growth factor and its human homologue urogastrone in peptic ulcer healing.

Animals↗
PubMed1994

Regulation of undulin synthesis and gene expression in human fat-storing cells by acetaldehyde and transforming growth factor-beta 1: comparison with fibronectin.

Undulin and fibronectin (FN) are large extracellular matrix (ECM) glycoproteins possibly involved in cell-matrix interactions. In this study we analyzed the effect of acetaldehyde and transforming growth factor-beta 1 (TGF-beta 1) on undulin and FN synthesis in cultured fat-storing cells (FSC) isolated from wedge sections of normal human livers. Cultured human FSC expressed two mRNA transcripts (6.5 and 8.5 kb) specific for undulin. Acetaldehyde inhibited both undulin mRNA and protein expression, whereas it had an opposite (stimulatory) effect on FN synthesis. TGF-beta 1 induced a dose-dependent increase of both undulin and FN synthesis in FSC cultures. Furthermore, TGF-beta 1 antagonized the inhibitory effect of acetaldehyde on undulin production and potentiated the stimulatory effect of acetaldehyde on FN synthesis. Since undulin is involved in the supramolecular organization of fibrillar collagens and in their enzymatic degradation, its acetaldehyde-induced inhibition may contribute to ECM rearrangement in the early stages of alcoholic liver fibrosis.

Acetaldehyde↗
PubMed1994

Undulin RNA and protein expression in normal and fibrotic human liver.

We have analyzed the distribution, gene expression and cellular origin of undulin, a large extracellular matrix glycoprotein associated with mature collagen fibrils, in human liver by immunohistochemistry, Northern-blot analysis and in situ hybridization. In normal liver, undulin was distributed as densely packed fibers in portal tract stroma, and as fine fibers along sinusoids, and around central veins. Undulin ribonucleic acid expression was low in normal liver, and confined to mesenchymal cells of portal tract stroma, vessel walls and perisinusoidal space. In fibrotic liver, undulin deposition and gene expression were enhanced in fibrotic stroma and areas of fibrogenesis identified by the presence of active septa and inflammatory infiltrate. Undulin gene expression in fibrotic liver was exclusively localized in mesenchymal cells that could be identified by staining for vimentin, and partially for alpha-smooth muscle actin as (myo)fibroblasts, and possibly fat-storing cells. These data suggest that undulin is a constituent of the hepatic extracellular matrix of normal human liver, and that it participates in the rearrangement of connective tissue occurring in hepatic fibrosis.

Adolescent↗
PubMed1994

Acetaldehyde regulates the gene expression of matrix-metalloproteinase-1 and -2 in human fat-storing cells.

Altered degradation of extracellular matrix has been implicated in the pathogenesis of hepatic fibrosis. We studied the effect of acetaldehyde (AcCHO) on gene expression of matrix-metalloproteinase (MMP)-1 (fibroblast type- interstitial collagenase) and MMP-2 (72 kDa gelatinase-type IV collagenase) in comparison with the AcCHO effect on collagen type I and IV synthesis in cultures of fat-storing cells (FSC) isolated from normal human livers. Cultured human FSC expressed single mRNA transcripts (2.7 and 3.2 kb) specific for MMP-1 and MMP-2, respectively. AcCHO inhibited MMP-1 mRNA levels, whereas it stimulated collagen type I mRNA and protein expression. Opposite AcCHO effects were evident on MMP-2 mRNA and collagen IV synthesis, being MMP-2 up-regulated and collagen IV down-regulated. These data suggest that regulation of MMP-1 and MMP-2 genes by AcCHO may contribute to disruption of the normal basement membrane and its replacement with fibrillar collagens in the early stages of alcoholic liver fibrosis.

Acetaldehyde↗