Fibrotic and Vascular Remodelling of Colonic Wall in Patients with Active Ulcerative Colitis

open16noIntestinal fibrosis is a complication of inflammatory bowel disease [IBD]. Although fibrostenosis is a rare event in ulcerative colitis [UC], there is evidence that a fibrotic rearrangement of the colon occurs in the later stages. This is a retrospective study aimed at examining the histopathological features of the colonic wall in both short-lasting [SL] and long-lasting [LL] UC. Surgical samples of left colon from non-stenotic SL [a parts per thousand currency sign 3 years, n = 9] and LL [a parts per thousand yen 10 years, n = 10] UC patients with active disease were compared with control colonic tissues from cancer patients without UC [n = 12] to assess: collagen and elastic fibres by histochemistry; vascular networks [CD31/CD105/nestin] by immunofluorescence; parameters of fibrosis [types I and III collagen, fibronectin, RhoA, alpha-smooth muscle actin [alpha-SMA], desmin, vimentin], and proliferation [proliferating nuclear antigen [PCNA]] by western blot and/or immunolabelling. Colonic tissue from both SL-UC and LL-UC showed tunica muscularis thickening and transmural activated neovessels [displaying both proliferating CD105-positive endothelial cells and activated nestin-positive pericytes], as compared with controls. In LL-UC, the increased collagen deposition was associated with an up-regulation of tissue fibrotic markers [collagen I and III, fibronectin, vimentin, RhoA], an enhancement of proliferation [PCNA] and, along with a loss of elastic fibres, a rearrangement of the tunica muscularis towards a fibrotic phenotype. A significant transmural fibrotic thickening occurs in colonic tissue from LL-UC, together with a cellular fibrotic switch in the tunica muscularis. A full-thickness angiogenesis is also evident in both SL- and LL-UC with active disease, as compared with controls.openIppolito, Chiara; Colucci, Rocchina; Segnani, Cristina; Errede, Mariella; Girolamo, Francesco; Virgintino, Daniela; Dolfi, Amelio; Tirotta, Erika; Buccianti, Piero; Di Candio, Giulio; Campani, Daniela; Castagna, Maura; Bassotti, Gabrio; Villanacci, Vincenzo; Blandizzi, Corrado; Bernardini, NunziaIppolito, Chiara; Colucci, ROCCHINA LUCIA; Segnani, Cristina; Errede, Mariella; Girolamo, Francesco; Virgintino, Daniela; Dolfi, Amelio; Tirotta, Erika; Buccianti, Piero; Di Candio, Giulio; Campani, Daniela; Castagna, Maura; Bassotti, Gabrio; Villanacci, Vincenzo; Blandizzi, Corrado; Bernardini, Nunzi

Immunohistochemical Analysis of Myenteric Ganglia and Interstitial Cells of Cajal in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease with alterations of colonic motility, which influence clinical symptoms. Although morpho-functional abnormalities in the enteric nervous system have been suggested, in UC patients scarce attention has been paid to possible changes in the cells that control colonic motility, including myenteric neurons, glial cells, and interstitial cells of Cajal (ICC). This study evaluated the neural-glial components of myenteric ganglia and ICC in the colonic neuromuscular compartment of UC patients by quantitative immunohistochemical analysis. Full-thickness archival samples of the left colon were collected from 10 patients with UC (5 M, 5 F; age range, 45-62 years) who underwent elective bowel resection. The colonic neuromuscular compartment was evaluated immunohistochemically in paraffin cross-sections. The distribution and number of neurons, glial cells and ICC were assessed by anti-HuC/D, -S100β and -c-Kit antibodies, respectively. Data were compared with findings on archival samples of normal left colon from 10 sex- and age-matched control patients, who underwent surgery for uncomplicated colon cancer. Compared to controls, patients with UC showed: (a) reduced density of myenteric HuC/D-positive neurons and S100β-positive glial cells, with a loss over 61% and 38%, respectively, and increased glial cell/neuron ratio; (b) ICC decrease in the whole neuromuscular compartment. The quantitative variations of myenteric neuro-glial cells and ICC indicate considerable alterations of the colonic neuromuscular compartment in the setting of mucosal inflammation associated with UC, and provide a morphological basis for better understanding the motor abnormalities often observed in UC patients

Muscle and vascular remodelling in inflamed, fibrotic colon of patients with ulcerative colitis

Background. Intestinal fibrosis is a common complication of inflammatory bowel diseases, affecting patients with both Crohn’s disease and ulcerative colitis (UC). Of note, the progression of intestinal fibrosis has been recently considered to depend on distinct processes from those involved in inflammation [1]. In this context, angiogen- esis is currently regarded as a good candidate of active gut disease, closely related to fibrogenesis [2]. Therefore, studies on the multifactorial pathways promoting these processes are needed for understanding the pathophysiology of fibrosis, and there- by identifying anti-fibrogenic therapies. Aim. The present study was performed to evaluate the distribution of fibrotic tissue, the behaviour of smooth muscle cells and the presence of neovessels in the colon of UC patients. Patients and Methods. Full- thickness left colonic samples were studied, from patients with established and phar- macologically unresponsive UC for the following parameters: collagen and elastic fib- ers by histochemistry; fibrotic and profibrotic factors [type 1 and 3 collagens, elastin, fibronectin, vimentin, alpha-smooth muscle actin (α-SMA), proliferating nuclear anti- gen (PCNA), RhoA] by immunohistochemistry and western blot; vascular networks [CD31, CD105, nestin] by confocal microscopy immunofluorescence. Results. A sig- nificant increase in collagen fibers and decrease in elastin content were detected in the colon from UC patients as compared with controls. The increment of type 1 and 3 collagens, fibronectin, vimentin, PCNA and RhoA expression was associated with alpha-SMA decrease in the tunica muscularis of UC colon. A relevant rearrangement of vascular networks was observed in the fibrotic tunica muscularis, with neovessels displaying both proliferating CD105+ endothelial cells and activated nestin+ pericytes. Conclusion. The present data show that a significant muscle and vascular remodel- ling occurs in inflamed colonic tissues from UC patients, suggesting that, under these conditions, smooth muscle cells and vascular cells may be involved in fibrogenic pro- cesses by cell transition to mesenchymal phenotype.

Transmural remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration

Background and Aim. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor clinical signs, among which gastrointestinal disturbances represent relevant manifestations [1]. Nevertheless, the morphological alterations associated with intestinal dysfunctions in PD have been barely investigated [2]. The present study was aimed at investigating the remodelling of colonic wall in a rat model of PD with central dopaminergic denervation by intra-nigral injection of the neuro-toxin 6-hydroxydopamine (6-OHDA). Methods. Histopathological analysis of the whole colonic wall was performed 4 and 8 weeks after central 6-OHDA injection. Inflammatory infiltrates, collagen deposition as well as the remodelling of intestinal epithelial barrier and tunica muscularis were examined by microscopic techniques (histochemistry/immunohistochemistry/confocal immunofluorescence). Results. Colonic tissue from 8-week 6-OHDA rats were significantly altered, as compared with controls. The tunica mucosa showed: eosinophil infiltration; altered lining epithelium (reduced claudin-1 and transmembrane 16A protein expression) and goblet cells (increased mucus expression); enhanced glial fibrillar acid protein-positive cells and vimentin-positive fibroblast-like cells. Along with transmural collagen deposition, significant changes were observed also in the tunica muscularis: reduced expression of alpha-smooth muscle actin/desmin and increased proliferation index in smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia. Conclusions. A full-thickness structural remodelling occurs in the colon of PD rats 8 weeks after central dopaminergic denervation; the main changes include an alteration of the colonic epithelial barrier along with the activation of the mucosal defence and fibrotic switch of the colonic wall. Overall, these findings suggest that: a) early histological modifications occur in the colon of rats with experimental PD at both mucosal and muscular level; b) these changes and the fibrotic alterations might contribute to bowel motor dysfunctions associated with PD

Magma-carbonate interaction: an experimental study on ultrapotassic rocks from Alban Hills ( Central Italy)

The Alban Hills ultrapotassic volcanic district is one of the main districts emplaced during Quaternary time along the Tyrrhenian margin of Italy. Alban Hills lava flows and scoria clasts are made up essentially of clinopyroxenes and leucites and their chemical composition is mostly K-foiditic. Differentiated products (MgO < 3 wt.%) are characterised by low SiO2 concentration (< 50 wt.%) and geochemical features indicate that this unique differentiation trend is driven by crystal fractionation plus carbonate crust interaction. Notably, the Alban Hills Volcanic District was emplaced into thick limestone units. With the aim of constraining the magmatic differentiation, we performed experiments on the Alban Hills parental composition (plagioclase-free phono-tephrite) under anhydrous, hydrous, and hydrous-carbonated conditions. Experiments were carried out at 1 atm, 0.5 GPa and 1 GPa, temperatures ranging from 1050 to 1300 °C, and H2 O and CaCO3 in the starting material up to 2 and 7 wt.%, respectively. The experiments performed at 0.5 GPa are the most representative of the Alban Hills plumbing system. Clinopyroxene and leucite are the main phases occurring under all the investigated conditions and the liquidus phases. Nevertheless, our experimental results demonstrate that the occurrence of CaCO3 in the starting material strongly affects phase relations. Experiments performed under hydrous conditions crystallize magnetite and phlogopite at relatively high temperature. This early crystallization drives the glass composition towards a silica enrichment, resulting in a differentiation trend moving from phono-tephritic (Alban Hills parental composition) to phonolitic compositions. This is in contrast with micro-textural evidence showing late crystallization of magnetite and phlogopite in the natural products and with the composition of the juvenile products. On the contrary, in the CaCO3 -bearing experiments (i.e., simulating magma–carbonate interaction) the magnetite and phlogopite stability fields are strongly reduced. As a consequence, the melt differentiation is mainly controlled by the cotectic crystallization of clinopyroxene and leucite, resulting in a differentiation trend moving towards K-foiditic compositions. These experimental results are in agreement with micro-textural features and chemical compositions of Alban Hills natural products and with the magmatic differentiation model inferred by geochemical data. Magma–carbonate interaction is not a rare process and its occurrence has been demonstrated for different plumbing systems. However, the uniqueness of the Alban Hills liquid line of descent suggests that the efficacy of the carbonate contamination process is controlled by different factors, the dynamics of the plumbing system being one of the most important

Magma-carbonate interaction: An experimental study on ultrapotassic rocks from Alban Hills (Central Italy)

The Alban Hills ultrapotassic volcanic district is one of the main districts emplaced during Quaternary time along the Tyrrhenian margin of Italy. Alban Hills lava flows and scoria clasts are made up essentially of clinopyroxenes and leucites and their chemical composition is mostly K-foiditic. Differentiated products (MgO < 3 wt.%) are characterised by low SiO2 concentration (< 50 wt.%) and geochemical features indicate that this unique differentiation trend is driven by crystal fractionation plus carbonate crust interaction. Notably, the Alban Hills Volcanic District was emplaced into thick limestone units. With the aim of constraining the magmatic differentiation, we performed experiments on the Alban Hills parental composition (plagioclase-free phono-tephrite) under anhydrous, hydrous, and hydrous-carbonated conditions. Experiments were carried out at 1 atm, 0.5 GPa and 1 GPa, temperatures ranging from 1050 to 1300 degrees C, and H2O and CaCO3 in the starting material up to 2 and 7 wt.%, respectively The experiments performed at 0.5 GPa are the most representative of the Alban Hills plumbing system. Clinopyroxene and leucite are the main phases occurring under all the investigated conditions and the liquidus phases. Nevertheless, our experimental results demonstrate that the occurrence of CaCO3 in the starting material strongly affects phase relations. Experiments performed under hydrous conditions crystallize magnetite and phlogopite at relatively high temperature. This early crystallization drives the glass composition towards a silica enrichment, resulting in a differentiation trend moving from phono-tephritic (Alban Hills parental composition) to phonolitic compositions. This is in contrast with micro-textural evidence showing late crystallization of magnetite and phlogopite in the natural products and with the composition of the juvenile products. On the contrary, in the CaCO3-bearing experiments (i.e., simulating magma-carbonate interaction) the magnetite and phlogopite stability fields are strongly reduced. As a consequence, the melt differentiation is mainly controlled by the cotectic crystallization of clinopyroxene and leucite, resulting in a differentiation trend moving towards K-foiditic compositions. These experimental results are in agreement with micro-textural features and chemical compositions of Alban Hills natural products and with the magmatic differentiation model inferred by geochemical data. Magma-carbonate interaction is not a rare process and its occurrence has been demonstrated for different plumbing systems. However, the uniqueness of the Alban Hills liquid line of descent suggests that the efficacy of the carbonate contamination process is controlled by different factors, the dynamics of the plumbing system being one of the most important. (c) 2007 Elsevier B.V. All rights reserved