Papers by Giulio Gabbiani
PubMed, Jul 1, 1996
The alpha-smooth muscle (alpha-SM) actin isoform is expressed normally by vascular SM cells and b... more The alpha-smooth muscle (alpha-SM) actin isoform is expressed normally by vascular SM cells and by stromal fibroblastic cells in pathological conditions leading to fibrosis. In order to investigate the relation between kidney fibrosis and alpha-SM actin expression, we studied 51 renal biopsies from 45 patients: 30 with various forms of glomerulonephritis; 1 with acute tubular necrosis; 1 with acute interstitial nephritis, and 13 renal transplant recipients. The presence of alpha-SM actin was examined by using anti-alpha SM-1, a mouse monoclonal antibody (IgG2 alpha) specific for alpha-SM actin. alpha-SM actin scores were estimated semiquantitatively, as were glomerulosclerosis and interstitial fibrosis. In acute tubular necrosis and in well-functioning grafts, alpha-SM actin expression was limited to vascular SM cells. In glomerular diseases, alpha-SM actin expression was upregulated in mesangial area in 25 of 36 biopsies, and even more frequently in the periglomerular and peritubular interstitium (34 of 36 cases, chi 2 = 7.6, P < 0.01). Whereas glomerular alpha-SM actin expression seemed to decrease as glomerulosclerosis progressed, there was a positive correlation between interstitial alpha-SM actin scores and the degree of interstitial fibrosis. Similarly, interstitial alpha-SM actin expression was found in acutely or chronically rejected kidneys, but not in well-functioning grafts. We conclude that upregulation of alpha-SM actin in the glomerulus indicates mesangial cell activation and is not always correlated with the degree of glomerulosclerosis. In contrast, interstitial upregulation of alpha-SM actin which indicates myofibroblast activation is correlated with the degree of interstitial fibrosis.
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PubMed, 1996
The animal model of hepatic fibrosis induced by bile duct ligation represents an experimental mod... more The animal model of hepatic fibrosis induced by bile duct ligation represents an experimental model of human chronic biliary fibrosis. Much attention has been given to the hepatic stellate cell (HSC), or perisinusoidal cell, as the source of the extracellular matrix proteins. However, in the bile duct ligation model, mesenchymal cells other than HSC may be involved in the early stages of fibrosis development. The current study examined, in Sprague-Dawley rats, proliferation in different liver cell subpopulations as well as expression of alpha-smooth muscle (SM) actin and desmin in portal fibroblasts and HSC at 6 hours and 1, 2, 3, and 7 days after bile duct ligation. Kinetics of liver cell proliferation and of phenotypic modulation of portal fibroblasts and HSC (expression of alpha-SM actin and desmin) was evaluated by immunocytochemistry, immunofluorescence, and immunoelectron microscopy using immunogold technique. In sham-operated animals, the evaluation of proliferation in various liver cell subpopulations revealed nonsignificant changes compared with nonoperated rats. alpha-SM actin was detected in vessel walls but was absent in cells of portal tract and parenchyma. Desmin was expressed in vessel walls and in some fibroblastic cells of portal stroma (8.2 cells/unit area) as well as in HSC in acinar Zones 1 and 3 (15.6 cells/unit area and 7.1 cells/unit area, respectively). In bile duct-ligated rats, 24 and 48 hours after ligation, marked proliferations of bile duct epithelial cells (labeling indices 36.8% and 29.5%, respectively) and of periductular fibroblasts (labeling indices 16.7% and 31.0%, respectively) were observed; thereafter, proliferation decreased for both populations (labeling indices at 7 days 12.0% and 11.6%, respectively). HSC proliferation increased gradually until the third day (labeling index 18.6%) and then leveled off. Immunocytochemistry and immunoelectron microscopy revealed a significant number of cells expressing alpha-SM actin 72 hours after bile duct ligation in the stroma adjacent to proliferating ductules. The number of alpha-SM actin-positive cells increased until the seventh day (251.6 cells/unit area). At all times examined, the distribution of alpha-SM actin was restricted to the connective tissue stroma adjacent to proliferating ductules; alpha-SM actin was not expressed in HSC of the lobule. An expansion of desmin expression was noted in fibroblastic cells in stroma surrounding proliferating ductules until 72 hours after bile duct ligation (74.7 cells/unit area) followed by a plateau. At this time, desmin expression increased also in HSC; as in controls, the number of positive cells was greater in Zone 1 (31.8 cells/unit area) than in Zone 3 (18.5 cells/unit area). Double immunofluorescence staining detected by confocal microscopy showed that the majority of portal fibroblastic cells expressing alpha-SM actin was desmin negative 48 hours after bile duct ligation. From 72 hours, portal fibroblastic cells coexpressing alpha-SM actin and desmin appeared, and their proportion increased until 7 days. The present findings indicate that in the early phase of bile duct ligation, there is a marked and transient proliferation of bile duct epithelial cells associated with proliferation of portal periductular fibroblasts, which rapidly express alpha-SM actin. This fibroblastic population may play a dominant role in the early portal fibrosis after bile duct ligation.
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Cell Adhesion & Migration, May 1, 2012
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PubMed, 1995
Granulation tissue formation and contraction is an important step of second intention wound heali... more Granulation tissue formation and contraction is an important step of second intention wound healing. Granulation tissue develops from the connective tissue surrounding the damaged or missing area and its cellular components are mainly small vessel and inflammatory cells as well as fibroblasts and myofibroblasts. As the wound closes and evolves into a scar, there is an important decrease in cellularity; in particular myofibroblasts disappear. The question arises as to which process is responsible for this cellular loss. During a previous investigation on the expression of alpha-smooth muscle actin in myofibroblasts (Darby I, Skalli O, Gabbiani G, Lab Invest, 1990, 63:21-29), we have observed that in late phases of wound healing, many myofibroblasts show changes compatible with apoptosis and suggested that this type of cell death could be responsible for the disappearance of myofibroblasts. We have now tested this hypothesis by means of morphometry at the electron microscopic level and by in situ end labeling of fragmented DNA. Our results indicate that the number of myofibroblastic and vascular cells undergoing apoptosis increases as the wound closes and support the assumption that this is the mechanism of granulation tissue evolution into a scar. The regulation of apoptotic phenomena during wound healing may be important in scar establishment and development of pathological scarring.
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Springer eBooks, 2006
After the first description of the myofibroblast in granulation tissue of an open wound by means ... more After the first description of the myofibroblast in granulation tissue of an open wound by means of electron microscopy, as an intermediate cell between the fibroblast and the smooth muscle cell, the myofibroblast has been identified both in normal tissues, particularly in locations where there is a necessity of mechanical force development, and in pathological tissues, in relation with hypertrophic scarring, fibromatoses and fibrocontractive diseases as well as in the stroma reaction to epithelial tumors. It is now accepted that fibroblast/myofibroblast transition begins with the appearance of the protomyofibroblast, whose stress fibers contain only beta- and gamma-cytoplasmic actins and evolves, but not necessarily always, into the appearance of the differentiated myofibroblast, the most common variant of this cell, with stress fibers containing alpha-smooth muscle actin. Myofibroblast differentiation is a complex process, regulated by at least a cytokine (the transforming growth factor-beta1), an extracellular matrix component (the ED-A splice variant of cellular fibronectin), as well as the presence of mechanical tension. The myofibroblast is a key cell for the connective tissue remodeling that takes place during wound healing and fibrosis development. On this basis, the myofibroblast may represent a new important target for improving the evolution of such diseases as hypertrophic scars, and liver, kidney or pulmonary fibrosis.
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Birkhäuser Basel eBooks, 2008
... List of contributors Ewa Paleolog, Kennedy Institute of Rheumatology, Faculty of Medicine, Im... more ... List of contributors Ewa Paleolog, Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College, Arthritis Research Campaign Building, 65 Aspenlea Road ... Hypertens Res 26 (Suppl): S93-98 56 Zhao Y, Hague S, Manek S, Zhang L, Bicknell R, Rees MC (1998) PCR ...
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Arteriosclerosis and thrombosis, Mar 1, 1991
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Experimental Cell Research, Jul 1, 1992
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PubMed, 1995
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The International Journal of Developmental Biology, 2004
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Journal of Hepatology, Apr 1, 1999
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Circulation, Nov 11, 2016
Introduction: Atherosclerotic coronary artery disease precipitating sudden cardiac death (SCD) in... more Introduction: Atherosclerotic coronary artery disease precipitating sudden cardiac death (SCD) in the young is peculiar in terms of extent (single vessel), site (left anterior descending branch) and morphology (mostly fibrocellular due to smooth muscle cells [SMC] proliferation, in the absence of thrombosis) of the culprit atherosclerotic plaque (AP). Hypothesis: To characterize the SMCs phenotype in coronary AP from young SCD victims. Methods: Among 652 young ( 75% luminal area) and no thrombosis were selected for the study (all males, age range 17-40 years old, mean 33). AP from older (>40 years old) atherosclerotic SCD victims (n=8, 7 males) and normal coronary segments from young people (n=5, 4 males) were used for comparison. Besides traditional staining, the expression of α-smooth muscle actin (α-SMA), S100A4, smooth...
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Springer eBooks, 1999
Many studies have described changes in the hepatic extracellular matrix (ECM) and the cells invol... more Many studies have described changes in the hepatic extracellular matrix (ECM) and the cells involved in its production during liver injury [1, 2]. In acute liver damage, there may be complete parenchymal regeneration, scar formation, or a combination of both, and fibrogenesis seems to be transient [3]. Several cells of the liver can produce various ECM components. However, the hepatic stellate cell (HSC, also known as Ito or fat-storing cell) is the main source of ECM [24, 25] and has been shown to play a role in fibrogenesis for wound repair in acute injury of the liver [2, 18]. The HSCs can proliferate and rapidly express α smooth muscle (SM) actin, which is indicative of the cell’s involvement in matrix deposition [2, 25–27].
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Cytoskeleton, 1994
... and Cytokines Alexis Desmouliere and Giulio Gabbiani ... Table I11 shows the effect of some c... more ... and Cytokines Alexis Desmouliere and Giulio Gabbiani ... Table I11 shows the effect of some cytokines and extracellular matrix components on granulation tissue formation and myofi-broblast differentiation (see below). Cytokines In 1969, Dumonde et al. ...
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Laboratory Investigation, May 1, 2002
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Wound Healing, Fibrosis, and the Myofibroblast, 2022
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Wound Healing, Fibrosis, and the Myofibroblast, 2022
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American Journal of Respiratory and Critical Care Medicine, 1995
Pulmonary biopsy specimens from ten cases of idiopathic pulmonary fibrosis (IPF) were examined us... more Pulmonary biopsy specimens from ten cases of idiopathic pulmonary fibrosis (IPF) were examined using routine histological stains, including toluidine blue, and immunohistochemistry by means of specific antibodies against alpha-smooth muscle (alpha-SM) actin, desmin, keratin, TGF beta 1, and TNF alpha. The sections were compared with two cases of normal lung. As shown previously, normal alveolar interstitium did not contain alpha-SM actin positive myofibroblasts nor did the alveolar lining contain any significant number of TGF beta 1 or TNF alpha laden epithelial cells. In IPF, during the inflammatory stage, the alveolar myofibroblasts expressed alpha-SM actin and the regenerating type II alveolar epithelium staining strongly with TGF beta 1 and TNF alpha antibodies. The former cytokine was also detected in the interstitial matrix and fibroblastic cells as well as in the wall of vessels. At this stage, a manifest mast cell infiltration was noted. In very fibrotic and cystic alveolar tissue, i.e., at end stage fibrosis, the number of alpha-SM actin positive myofibroblasts as well as that of TNF alpha laden type II epithelial cells diminished, while TGF beta 1 positive cells persisted. Our findings demonstrate that during IPF alveolar type II epithelium constitutes, if not the site of synthesis, at least the main reservoir for TGF beta 1 and TNF alpha. These cytokines, besides their involvement in fibrogenesis, play probably an important role in the expression of alpha-SM actin by alveolar myofibroblasts. Our study suggests the possibility of an interaction between interstitial cells and alveolar epithelium, during IPF.
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Cerebrovascular Diseases, 1992
During the development of atherosclerotic lesions in humans or after hypercholesterolemia or deen... more During the development of atherosclerotic lesions in humans or after hypercholesterolemia or deendothelialization in experimental animals, vascular smooth muscle cells (SMCs) proliferate and migrate f
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PubMed, May 1, 1995
Intimal thickening induced after endothelial denudation of rat aorta is though to be due to migra... more Intimal thickening induced after endothelial denudation of rat aorta is though to be due to migration and proliferation of smooth muscle cells (SMC). When the reendothelialization is achieved, intimal thickening shows an important decrease in cellularity. Using in situ end labeling of fragmented DNA and electron microscopy, we show that this remodeling is accompanied by apoptosis of SMC. The number of apoptotic SMC becomes important 15 days after endothelial injury and reaches a maximum at 20 days; at 45 days the intimal thickening is reendothelialized and no more apoptotic SMC are detected. Apoptotic SMC show nuclear and cytoplasmic condensation as well as cytoplasmic vacuolization. Our results indicate that apoptosis is an important mechanism in the regulation of intimal thickening evolution.
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Papers by Giulio Gabbiani