bromochloroacetic-acid and Fibrosis

Mechanical forces are known to regulate homeostasis of the skin and play a role in the pathogenesis of skin diseases. The epidermis consists of keratinocytes that are tightly adhered to each other by cell junctions. Defects in keratins or desmosomal/hemidesmosomal proteins lead to the attenuation of mechanical strength and formation of intraepidermal blisters in the case of epidermolysis bullosa simplex. The dermis is rich in extracellular matrix, especially collagen, and provides the majority of tensile force in the skin. Keloid and hypertrophic scar, which is the result of over-production of collagen by fibroblasts during the wound healing, are associated with extrinsic tensile forces and changes of intrinsic mechanical properties of the cell. Increasing evidences shows that stiffness of the skin environment determines the regenerative ability during wound healing process. Mechanotransduction pathways are also involved in the morphogenesis and cyclic growth of hair follicles. The development of androgenetic alopecia is correlated to tensile forces generated by the fibrous tissue underlying the scalp. Acral melanoma predominantly occurs in the weight-bearing area of the foot suggesting the role of mechanical stress. Increased dermal stiffness from fibrosis might be the cause of recessive dystrophic epidermolysis bullosa associated squamous cell carcinoma. Strategies to change the mechanical forces or modify the mechanotransduction signals may lead to a new way to treat skin diseases and promote skin regeneration.

Topics: Collagen; Desmosomes; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Keratinocytes; Keratins; Mechanotransduction, Cellular; Skin; Skin Diseases; Wound Healing

Keratocystoma is a rare benign tumour of the salivary glands. We report a patient who presented with a mass in the left parotid gland that was treated by subtotal parotidectomy and he was free of recurrence seven years later. After histological and immunohistochemical examinations we identified a keratocystoma.

Topics: Adult; Epithelial Cells; Fibrosis; Humans; Keratins; Ki-67 Antigen; Male; Metaplasia; Parotid Neoplasms; Transcription Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

We report a case of unilateral polycystic disease of the parotid gland. Only eight cases of this disease have previously been published in the English language literature, and seven of them were bilateral. Thus, we are reporting the second case of unilateral involvement. The disease is apparently limited to the parotid gland and to women. Clinically, a fluctuating, long-standing, nontender parotid gland swelling is usually noticed in adulthood. Histologically, there are numerous epithelial-lined cysts, which appear to be derived from intercalated ducts. This disease probably represents a developmental condition.

Topics: Actins; Aged; Cysts; Edema; Epithelium; Female; Fibrosis; Humans; Keratins; Parotid Diseases; S100 Proteins

It is widely accepted that radicular cysts (apical periodontal cysts) are commonly lined with stratified squamous epithelium without keratin formation. However, we identified a case of maxillary radicular cyst with remarkable keratinization and atypical proliferation of the lining epithelium among the 207 radicular cyst cases seen at our department. Histopathological and clinical findings of these cysts were reviewed.

Topics: Cell Division; Cytoplasmic Granules; Epithelium; Fibrosis; Granulation Tissue; Humans; Hyalin; Keratins; Keratosis; Male; Maxillary Diseases; Middle Aged; Radicular Cyst

We sought to characterize the angiofibrotic and apoptotic effects of vascular endothelial growth factor (VEGF)-inhibition on fibrovascular epiretinal membranes in eyes with traction retinal detachment because of proliferative diabetic retinopathy.. Membranes were excised from 20 eyes of 19 patients (10 randomized to intravitreal bevacizumab, 10 controls) at vitrectomy. Membranes were stained with antibodies targeting connective tissue growth factor (CTGF) or VEGF and colabeled with antibodies directed against endothelial cells (CD31), myofibroblasts, or retinal pigment epithelium markers. Quantitative and colocalization analyses of antibody labeling were obtained through immunofluorescence confocal microscopy. Masson trichrome staining, cell counting of hematoxylin and eosin sections, and terminal dUTP nick-end labeling staining were performed.. High levels of fibrosis were observed in both groups. Cell apoptosis was higher (P = 0.05) in bevacizumab-treated membranes compared with controls. The bevacizumab group had a nonsignificant reduction in colocalization in CD31-CTGF and cytokeratin-VEGF studies compared with controls. Vascular endothelial growth factor in extracted membranes was positively correlated with vitreous levels of VEGF; CTGF in extracted membranes was negatively correlated with vitreous levels of CTGF.. Bevacizumab suppresses vitreous VEGF levels, but does not significantly alter VEGF or CTGF in diabetic membranes that may be explained by high baseline levels of fibrosis. Bevacizumab may cause apoptosis within fibrovascular membranes.

Topics: Actins; Angiogenesis Inhibitors; Apoptosis; Bevacizumab; Cell Proliferation; Connective Tissue Growth Factor; Diabetic Retinopathy; Epiretinal Membrane; Fibrosis; Humans; Intravitreal Injections; Keratins; Platelet Endothelial Cell Adhesion Molecule-1; Prospective Studies; Receptors, Vascular Endothelial Growth Factor; Retina; Vascular Endothelial Growth Factor A; Vitrectomy

Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumours, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases.. Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumours displayed nonclassic histology with prominent stromal fibrosis, and keratin AE1/AE3 was expressed either diffusely (N = 2) or focally (N = 2). In one tumour, keratin expression was limited to the sclerotic area. All tumours coexpressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumours harboured NR4A3 fusions, including TAF15::NR4A3 (N = 1) and EWSR1::NR4A3 (N = 3). Two cases were initially considered as most consistent with myoepithelial tumours based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumours tested as EMCs.. We identified a small subset of EMCs characterised by keratin expression and prominent stromal fibrosis. This histological pattern must be recognised in the differential diagnosis of myoepithelial tumours because misclassification may lead to the erroneous prediction of tumour behaviour and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.

Topics: Adult; Calmodulin-Binding Proteins; Chondrosarcoma; Female; Fibrosis; Humans; Keratins; Male; Myoepithelioma; RNA-Binding Proteins; S100 Proteins; Soft Tissue Neoplasms

2-(4-morpholinoethyl)- 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) is a selective sigma 1 receptor agonist. It has been shown that PRE-084 protected various tissues from experimental injury. However, no reports are available on its effect on renal fibrosis. Rat model of adenine-induced chronic kidney disease was chosen to study this. Adenine feeding in rats caused renal dysfunction as shown by increased serum creatinine and reduced creatinine clearance along with increased high molecular weight (HMW) urine protein excretion. Further, adenine feeding induced profibrotic changes in the kidney as reflected by increased expression of alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1) and matrix metalloproteinase-2 (MMP-2) activity; reduced cytokeratin expression. Further, there was excess deposition of extracellular matrix in the kidney, a striking character of fibrosis. However, administration of PRE-084 to adenine fed rats led to reduction in creatinine and proteinuria parameters partly. This was accompanied by reduced expression of α-SMA, FSP-1 and MMP-2 activity and slight restoration of cytokeratin levels leading to reduced extracellular matrix deposition in the kidney. These data demonstrate that PRE-084 partly ameliorated renal dysfunction and exhibited anti-fibrotic potential in the kidney of adenine fed rats.

Topics: Adenine; Animals; Creatinine; Fibrosis; Keratins; Kidney Diseases; Matrix Metalloproteinase 2; Morpholines; Rats

Corneal haze post refractive surgery is prevented by mitomycin c (MMC) treatment though it can lead to corneal endothelial damage, persistent epithelial defects and necrosis of cells. Suberanilohydroxamic acid (SAHA) however has been proposed to prevent corneal haze without any adverse effects. For clinical application we have investigated the short and long term outcome of cells exposed to SAHA. Human donor cornea, cultured limbal epithelial cells, corneal rims and lenticules were incubated with SAHA and MMC. The cells/tissue was then analyzed by RT-qPCR, immunofluorescence and western blot for markers of apoptosis and fibrosis. The results reveal that short term exposure of SAHA and SAHA + MMC reduced apoptosis levels and increased αSMA expression compared to those treated with MMC. Epithelial cells derived from cultured corneal rim that were incubated with the MMC, SAHA or MMC + SAHA revealed enhanced apoptosis, reduced levels of CK3/CK12, ∆NP63 and COL4A compared to other treatments. In SAHA treated lenticules TGFβ induced fibrosis was reduced. The results imply that MMC treatment for corneal haze has both short term and long term adverse effects on cells and the cellular properties. However, a combinatorial treatment of SAHA + MMC prevents expression of corneal fibrotic markers without causing any adverse effect on cellular properties.

Topics: Adult; Apoptosis; Cells, Cultured; Collagen Type IV; Epithelium, Corneal; Female; Fibrosis; Humans; Keratins; Male; Middle Aged; Mitomycin; Vorinostat

Endometriosis is a common disorder of unknown etiology, and non-surgical therapies are still a challenge. To understand the pathogenesis and preclinical testing of drugs for endometriosis, animal models are highly desirous. Herein, we carried out longitudinal characterization of a mouse model for endometriosis where uterine tissue was transplanted onto the intestinal mesentery. During the course of lesion development from day 15 to 60 post-induction, the ectopic endometrium became pale, fluid-filled and the animals developed peritoneal adhesions. Most lesions resembled a well-differentiated type of endometriosis and ~13% of animals had mixed type of lesions. There was extensive stromal compaction in the ectopic tissue. During the progression of endometriosis, there was increased proliferation of epithelial and stromal cells as evident by PCNA staining.

Topics: Animals; Aromatase; Cadherins; Cell Proliferation; Choristoma; Disease Models, Animal; Endometriosis; Endometrium; Epithelial Cells; Epithelial-Mesenchymal Transition; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Interferon-gamma; Interleukin-1beta; Keratins; Mesentery; Mice; Myofibroblasts; Proliferating Cell Nuclear Antigen; Stromal Cells; Transplantation, Autologous; Transplantation, Heterotopic; Tumor Necrosis Factor-alpha

Peritoneal dialysis (PD) is often used to treat patients with end stage renal disease, and its long-term complications include excessive inflammation and oxidative stress. Allograft inflammatory factor 1 (AIF-1), as a cytoplasmic protein, is originally identified from infiltrating macrophages, and it was associated with inflammation in the cells other than macrophages, such as endothelial cells and vascular smooth muscle cells. To clarify the molecular mechanisms of AIF-1-modulated pathological changes in the peritoneum during PD, we first detected the AIF-1 expression in peritoneal tissues from PD mice. Results revealed that the pro-fibrotic stimulation caused AIF-1 upregulation and triggered inflammation in peritoneal tissues, and that AIF-1 co-expressed with pan-cytokeratin (a marker of peritoneal mesothelial cells). We next treated primary mouse peritoneal mesothelial cells (pan-cytokeratin and intercellular adhesion molecule 1 positive cells) with 50 or 100 ng/mL recombinant AIF-1, and evaluated the direct effects of AIF-1 on these cells in vitro. We found that exogenous AIF-1 treatment induced inflammation and oxidative stress in mesothelial cells. Apart from the augmented IL-6 and TNF-α secretion, the level of ROS was upregulated and the activity of anti-oxidative SOD was reduced in cells exposed to AIF-1. Moreover, AIF-1 simulation triggered the activation of NF-κB pathway-enhanced the conversion of IκB to phosphorylated IκB and promoted the translocation of NF-κB p65 from cytoplasm into nucleus. Additionally, AIF-1-evoked inflammation in peritoneal mesothelial cells was attenuated by the addition of NF-κB inhibitor (BAY 11-7082). In brief, this study provides us novel information to understand the molecular regulation mechanisms of AIF-1 in peritoneal fibrosis.

Topics: Allografts; Animals; Calcium-Binding Proteins; Epithelial Cells; Fibrosis; I-kappa B Proteins; Inflammation; Keratins; Macrophages; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; NF-kappa B; Oxidative Stress; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum; Reactive Oxygen Species; Signal Transduction; Transcription Factor RelA

Plasmin has recently been reported to be associated with renal fibrosis in experimental models, but its role in human renal diseases is unclear.. Fifty-seven patients with IgA nephropathy (IgAN) were evaluated retrospectively. Plasmin in their renal biopsy tissues was assessed by in situ zymography using a plasmin-sensitive synthetic peptide, and the relationships between patients' histologic or clinical parameters and their renal plasmin activity [assessed semiquantitatively by calculating the positively stained percentage of the total tubulointerstitial (TI) area] were evaluated.. Plasmin activity was observed almost exclusively in the TI space (mainly in the interstitium and partly in the tubular epithelial cells) and was significantly stronger in patients with TI lesion (tubular atrophy/interstitial fibrosis and tubulointerstitial inflammation) than in those without TI lesion. It was significantly and positively correlated with the global glomerulosclerosis rate and significantly and negatively correlated with estimated glomerular filtration rate not only at the time of renal biopsy but also at the end of the follow-up period. Double stainings for plasmin activity and inflammatory cells, cytokeratin, or α-smooth muscle actin (α-SMA) in selected patients revealed TI infiltration of inflammatory cells, attenuated tubular epithelial expression of cytokeratin, and augmented interstitial expression of α-SMA close to upregulated plasmin activity in the TI space.. These data suggest that TI plasmin is associated with TI inflammation leading to renal fibrosis, and can cause the decline in renal function seen in patients with IgAN. Reducing plasmin in situ may therefore be a promising therapeutic approach slowing renal fibrogenesis and improving renal function.

Topics: Actins; Adolescent; Adult; Aged; Biomarkers; Biopsy; Disease Progression; Epithelial Cells; Female; Fibrinolysin; Fibrosis; Fluorescent Antibody Technique; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Keratins; Kidney Tubules; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Young Adult

Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)-NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS-NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis.. We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection.. In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice.. Disruption of the eNOS-NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.

Topics: Animals; Fibrosis; Guanylate Cyclase; Isoenzymes; Keratins; Male; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Vimentin

Chronic rhinosinusitis (CRS) defines a group of disorders characterized by persistent inflammation of the sinonasal tract. Epithelial changes and structural remodelling are present, but whether epithelial differentiation is altered remains uncertain.. To evaluate the differentiation state of the sinonasal epithelium in CRS, sinonasal biopsies from patients with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP), or with allergic rhinitis (AR), as compared to controls, were processed by immunohistochemistry and RT-qPCR for terminal differentiation (E-cadherin, high molecular weight cytokeratins (Hmw CK) and CK5, vimentin) and lineage differentiation (ß-tubulin IV+ ciliated cells, MUC5AC+ goblet cells, p63 + basal cells). Findings were correlated with subepithelial fibrosis and clinical CT score.. Expression of E-cadherin was decreased at protein and mRNA levels in CRSwNP and CRSsNP, as compared to controls. Staining for Hmw CKs was also reduced in CRSwNP and CRSsNP, and CK5 mRNA was decreased in CRSwNP. These features were not due to changes in lineage specification, but associated with increases in vimentin-expressing epithelial cells. In addition, vimentin expression correlated with the basement membrane thickening and with CT score, as well as with tissue eosinophils.. Features of epithelial dedifferentiation towards a mesenchymal phenotype are observed in CRSwNP and CRSsNP and correlate with airway fibrosis and inflammation.

Topics: Adolescent; Adult; Aged; Airway Remodeling; Cadherins; Case-Control Studies; Cell Count; Cell Dedifferentiation; Chronic Disease; Epithelial-Mesenchymal Transition; Female; Fibrosis; Gene Expression; Goblet Cells; Humans; Keratins; Male; Middle Aged; Nasal Polyps; Phenotype; Respiratory Mucosa; Rhinitis; Risk Factors; Sinusitis; Tomography, X-Ray Computed; Vimentin; Young Adult

The aim of this study was to evaluate the possible protective effects of Urtica dioica (UD) against liver damage in the common bile duct-ligated rats. A total of 24 male Sprague Dawley rats were divided into three groups, namely, control, bile duct ligation (BDL) and BDL + received UD groups, containing eight animals in each group. The rats in UD-treated groups were given UD oils (2 ml/kg) once a day intraperitoneally for 2 weeks starting 3 days prior to BDL operation. The change demonstrating the bile duct proliferation and fibrosis in expanded portal tracts includes the extension of proliferated bile ducts into the lobules; inflammatory cell infiltration into the widened portal areas were observed in BDL group. Treatment of BDL with UD attenuated alterations in liver histology. The α-smooth muscle actin, cytokeratin-positive ductular proliferation and the activity of terminal deoxynucleotidyl transferase dUTP nick end labeling in the BDL were observed to be reduced with the UD treatment. The data indicate that UD attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis.

Topics: Actins; Animals; Antioxidants; Cell Proliferation; Cholestasis; Common Bile Duct; DNA Nucleotidylexotransferase; Fibrosis; Immunohistochemistry; In Situ Nick-End Labeling; Keratins; Liver; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Urtica dioica

To develop a large animal model of proliferative vitreoretinopathy (PVR) in the swine to eventually study disease pathophysiology, as well as novel therapies.. PVR was induced in domestic swine by creation of a posterior vitreous detachment, creation of a retinal detachment by the injection of subretinal fluid, and intravitreal injection of green fluorescent protein-positive retinal pigment epithelial (GFP+ RPE) cells. Control eyes had the same surgical procedures without RPE cell injection. PVR was clinically graded on days 3, 7, and 14. Animals were euthanized on day 14, and enucleated eyes were analyzed by light microscopy and immunohistochemistry.. Injection of GFP+ RPE cells into the vitreous cavity produced localized, traction retinal detachments by day 14 in all eyes (14 of 14); in contrast, the retina spontaneously reattached by day 3 and remained attached in all control eyes (10 of 10). Contractile epiretinal membranes on the inner retinal surface that caused the traction retinal detachments consisted predominantly of GFP+ RPE cells. These cells stained positive for cytokeratin, confirming their epithelial origin, and also expressed α-SMA and fibronectin, markers for myofibroblasts and fibrosis, respectively.. We established a swine PVR model that recapitulates key clinical features found in humans and, thus, can be used to study the pathophysiology of PVR, as well as new novel therapies. GFP+ RPE cells injected into the vitreous cavity formed contractile membranes on the inner retinal surface and caused localized traction retinal detachments.

Topics: Actins; Animals; Disease Models, Animal; Epiretinal Membrane; Female; Fibronectins; Fibrosis; Green Fluorescent Proteins; Keratins; Luminescent Agents; Myofibroblasts; Retina; Retinal Detachment; Retinal Pigment Epithelium; Swine; Vitreoretinopathy, Proliferative

• To quantify fibrotic lesions in renal tissues obtained from patients with large calculi and to evaluate association with renal function. • Presence of epithelial-mesenchymal transition (EMT) in stone-containing renal tissues was investigated.. • In all, 50 patients with nephrolithiasis with large calculi and matched healthy controls (37) were recruited. • Plasma creatinine (Cr) and corrected Cr clearance (CCr) were determined in all subjects. • Of the 50 patients, 38 had renal tissue available for histological analysis. Fibrosis was assessed by Masson's trichrome staining. Co-expression of epithelial cytokeratins and mesenchymal markers [α-smooth muscle actin (αSMA) and vimentin] in renal tubular cells was detected by dual immunofluorescence staining. • Expression of fibronectin, transforming growth factor β₁ (TGF-β₁) and CD68 were investigated.. • Overall, the kidney function of the patients was significantly reduced, indicated by increased plasma Cr and decreased corrected CCr compared with healthy controls. • Inflammation grading in renal tissues of the patients was correlated with the percentage of the fibrotic area. Renal fibrosis was inversely correlated with renal function. • Cytokeratins co-expressed with αSMA and vimentin were found in nephrolithiatic renal tubular cells, and these cells strongly expressed fibronectin and TGF-β₁. • Infiltration of CD68-positive cells was a common finding in the inflamed renal sections.. • Kidneys of large stone-forming patients had robust signs of inflammation and fibrosis, and there was a close correlation of renal fibrosis with renal dysfunction. • This is the first study to show evidence for renal tubular cells showing signs of EMT in large stone-containing kidneys. Plausibly, TGF-β₁ triggers EMT, which at least in part contributes to large stone-induced renal fibrosis.

Topics: Actins; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Case-Control Studies; Creatinine; Cross-Sectional Studies; Epithelial-Mesenchymal Transition; Fibronectins; Fibrosis; Humans; Keratins; Kidney; Kidney Tubules; Male; Middle Aged; Nephrolithiasis; Transforming Growth Factor beta1; Vimentin

The mechanisms that control fibroproliferation and matrix deposition in lung fibrosis remain unclear. We speculate that vitamin D deficiency may contribute to pulmonary fibrosis since vitamin D deficiency has been implicated in several diseases. First, we confirmed the presence of vitamin D receptors (VDRs) in cultured NIH/3T3 and lung fibroblasts. Fibroblasts transfected with a vitamin D response element-reporter construct and exposed to the active vitamin D metabolite, 1,25(OH)(2)D(3), showed increased promoter activity indicating VDR functionality in these cells. Testing the effects of 1,25(OH)(2)D(3) on fibroblasts treated with transforming growth factor beta1 (TGFbeta1), considered a driver of many fibrotic disorders, we found that 1,25(OH)(2)D(3) inhibited TGFbeta1-induced fibroblast proliferation in a dose-dependent fashion. 1,25(OH)(2)D(3) also inhibited TGFbeta1 stimulation of alpha-smooth muscle actin expression and polymerization and prevented the upregulation of fibronectin and collagen in TGFbeta1-treated fibroblasts. Finally, we examined how 1,25(OH)(2)D(3) affects epithelial-mesenchymal transformation of lung epithelial cells upon exposure to TGFbeta1. We showed that the TGFbeta1-induced upregulation of mesenchymal cell markers and abnormal expression of epithelial cell markers were blunted by 1,25(OH)(2)D(3). These observations suggest that under TGFbeta1 stimulation, 1,25(OH)(2)D(3) inhibits the pro-fibrotic phenotype of lung fibroblasts and epithelial cells.

Topics: Actins; Animals; Cadherins; Calcitriol; Cell Line; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Collagen Type I; Collagen Type III; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Keratins; Lung; Membrane Proteins; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Phosphoproteins; Plasminogen Activator Inhibitor 1; Proliferating Cell Nuclear Antigen; Rats; Receptors, Calcitriol; Transforming Growth Factor beta1; Vitamin D; Vitamin D Response Element; Zonula Occludens-1 Protein

The immature disc nucleus pulposus (NP) consists of notochordal cells (NCs). With maturation NCs disappear in humans, to be replaced by chondrocyte-like mature NP cells (MNPCs); this change in cell phenotype coincidences with early signs of disc degeneration. The reasons for NC disappearance are important to understand disc degeneration, but remain unknown, yet. This study investigated, whether loading induced a change from a notochordal nucleus phenotype to a chondrocyte-like one. An in vivo disc compression model with fixateur externe was used in 36 mature rabbits. Discs were compressed for different time periods (1, 28, 56 days), and compared with uncompressed control discs (56 days without treatment), and discs with sham compression (28 days). Nucleus cell phenotype was determined by histology and immunohistochemistry. NCs, but not MNPCs highly expressed bone-morphogenetic-protein 2 and cytokeratin 8, thus NC and MNPC numbers could be determined. A histologic score was used to detect structural endplate changes after compression (28 days). Control and sham compressed discs contained around 70% NCs and 30% MNPCs, to be decreased to <10% NCs after 28-56 days of loading. NC density fell sharply by >50% after 28-56 days of compression (P < 0.05 vs. controls). Signs of decreased endplate cellularity and increased endplate sclerosis and fibrosis were found after loading. These experiments show that NCs were less resistant to mechanical stress than MNPCs suggesting that increased intradiscal pressures after loading, and limited nutrition through structurally altered endplates could instigate the disappearance of NCs.

Topics: Animals; Bone Morphogenetic Proteins; Cell Differentiation; Cell Lineage; Chondrocytes; Disease Models, Animal; Female; Fibrocartilage; Fibrosis; Immunohistochemistry; Intervertebral Disc; Intervertebral Disc Displacement; Keratins; Notochord; Phenotype; Rabbits; Sclerosis; Stem Cells; Stress, Mechanical; Weight-Bearing

Dietary salt intake has been linked to hypertension and cardiovascular disease through volume-mediated effects. Accumulating evidence points to direct negative influence of salt intake independent of volume overload, such as cardiac and renal fibrosis, mediated through transforming growth factor beta (TGF-beta). Epithelial-to-mesenchymal transition (EMT) has been implicated as a key process in chronic fibrotic diseases, such as chronic kidney disease or heart failure. The potential role of dietary salt intake on cell transdifferentiation has never been investigated. This study analysed the effect of dietary salt intake on EMT and fibrosis in the peritoneal membrane (PM) in a rat model.. Twenty-eight Wistar rats were randomized to a normal salt (NS) or a high salt (HS) intake. NS and HS rats had free access to tap water or NaCl 2% as drinking water, respectively. After 2 weeks, samples of peritoneum were taken, and TGF-beta(1), Interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) mRNA expression were quantified with qRT-PCR. Fibrosis and submesothelial PM thickness were scored. EMT was evaluated using fluorescence staining with cytokeratin and alpha smooth muscle actin (alpha-SMA).. Dietary salt intake caused peritoneal fibrosis and thickening of the submesothelial layer and induced EMT as identified by colocalization of cytokeratin and alpha-SMA in cells present in the submesothelial layer. Peritoneal TGF-beta(1) and IL-6 mRNA expression were upregulated in the HS group.. High dietary salt intake induces EMT and peritoneal fibrosis, a process coinciding with upregulation of TGF-beta1.

Topics: Actins; Animals; Epithelial Cells; Female; Fibrosis; Interleukin-6; Keratins; Mesoderm; Peritoneum; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Patients on long-term peritoneal dialysis develop progressive peritoneal fibrosis and loss of mesothelial layer. Regeneration of the mesothelium has been reported in the normal peritoneum but not the fibrotic peritoneum. Moreover, the origin of the regenerated mesothelial cells remains obscure. The aim of this study was to investigate mesothelial regeneration in fibrotic peritoneum induced by chlorhexidine gluconate.. Peritoneal fibrosis was induced by injection of CG into the peritoneal cavity of Wistar rats. After injection, the abdomen was opened, and the parietal fibrotic peritoneum with mesothelial cells was stripped from the abdominal wall, and then the abdominal incision was closed. Rats were sacrificed, and peritoneal tissues were dissected out at 0, 1, 3, 5, or 7 days after the stripping procedure.. Spindle-shaped cells with microvilli appeared on the surface of stripped peritoneum at day 3 after denudation. Immunohistochemistry identified staining for vimentin, a marker of mesoderm cells, in the spindle-shaped cells at days 3, 5, and 7. Expression of alpha-SMA was observed in the same cells at days 3 and 5, but not 7. Expression of cytokeratin and HBME-1, markers for mesothelial cells, in these cells was delayed until day 7.. Mesothelium can regenerate on the fibrotic peritoneum. The regenerated mesothelial cells seem to originate from vimentin-positive mesenchymal cells.

Topics: Actins; Animals; Biomarkers, Tumor; Chlorhexidine; Epithelium; Fibrosis; Keratins; Male; Peritoneal Diseases; Peritoneum; Rats; Rats, Wistar; Regeneration; Vimentin

The purpose of our study was to describe clinical and histopathological features of sixty one patients with histological diagnosis of syringoma over four year period in our dermatology clinic in Korea. Female:male ratio was 6.6:1 with onset of age during 2nd and 3rd decades in more than half of the patients in our study. The most frequently involved site was eyelids (43 cases, 70.5%) and the most common color of lesion was skin-color (30 cases, 49.2%). In 34 cases, characteristic tad-pole appearances (55.7%) were observed. Basal hyperpigmentation was observed more frequently in brown-colored lesion (p=0.005). Fibrosis was observed more frequently in erythematous lesion (p=0.033). Keratin cyst was observed less frequently in genital involved group (p=0.006). We also performed immunohistochemical stain for the presence of progesterone receptor (PR) and estrogen receptor (ER) in fifty six cases with negative results.

Topics: Adolescent; Adult; Aged; Child; Eyelids; Female; Fibrosis; Humans; Hyperpigmentation; Immunohistochemistry; Keratins; Korea; Male; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Sweat Gland Neoplasms; Syringoma; Treatment Outcome

Tubulo-interstitial fibrosis in dogs may result from primary injury to the interstitium or develop secondary to other renal diseases. As in human renal pathology, tubular epithelial cells (TEC) are believed to actively participate in the mechanisms of renal fibrosis. In this study, we examined the changes in the tubular epithelial component in two specific canine diseases. Immunohistochemistry showed the expression of the epithelial marker cytokeratin, the smooth muscle marker alpha-SMA, the mesenchymal marker vimentin and PCNA in 20 dogs with membranous glomerulonephritis and membrano-proliferative glomerulonephritis. Results showed that the loss of the epithelial marker in TEC was directly correlated to the grade of tubulo-interstitial disease present and independent of the type of glomerulonephritis. Varying degrees of vimentin positivity were detected in tubular epithelium in areas of inflammation, and low numbers of scattered alpha-SMA-positive cells were also observed. Immunohistochemistry showed that epithelial tubular cells lose their cytokeratin staining characteristics and transdifferentiate into cells exhibiting key mesenchymal immunophenotypic feature of vimentin-positive staining in both diseases investigated. The integrity of the tubular basement membrane is likely to be fundamental in maintaining the epithelial phenotype of TEC. Animal models provide opportunities for investigating the pathogenesis of renal fibrosis in humans.

Topics: Actins; Animals; Cell Differentiation; Dogs; Epithelial Cells; Female; Fibrosis; Glomerulonephritis; Keratins; Kidney Tubules; Male; Vimentin

Type 1A diabetes is characterized by a long prodromal phase during which autoantibodies to islet antigens are present. Nevertheless, we lack data on the pancreatic pathology of subjects who are positive for islet autoantibodies (to islet autoantigens GAD65, insulin, and ICA512).. In this manuscript, we describe a novel strategy in obtaining pancreata and pancreatic lymph nodes from islet autoantibody-positive organ donors that involves careful coordination among the laboratory and the organ donor provider organization.. We developed a rapid screening protocol for islet autoantibodies measurement of organ donors to allow identification of positive subjects before organ harvesting. In this way we were able to obtain pancreata and pancreatic lymph nodes from subjects with and without islet autoimmunity.. The organ donors used in this study were obtained from the general community.. The population studied consisted of 112 organ donors (age range 1 month to 86 yr, mean age 39 yr).. The main outcome measure of this study consisted of evaluating the pancreatic histology and identify T cells autoreactive for islet antigens in the pancreatic lymph nodes.. To date we have identified three positive subjects and obtained the pancreas for histological evaluation from one of the autoantibody-positive donors who expressed ICA512 autoantibodies. Although this subject did not exhibit insulitis, lymphocytes derived from pancreatic lymph nodes reacted to the islet antigen phogrin.. In summary, these results indicate that it is possible to screen organ donors in real time for antiislet antibodies, characterize pancreatic histology, and obtain viable T cells for immunological studies.

Topics: Adolescent; Adult; Aged; Autoantibodies; Chromogranins; Enzyme-Linked Immunosorbent Assay; Female; Fibrosis; Glucagon; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Keratins; Leukocyte Common Antigens; Lymph Nodes; Male; Middle Aged; Pancreas; T-Lymphocytes; Tissue Donors

Pancreatic endocrine tumours (PET) containing ductules are an uncommon histological variant. Considerable conjecture surrounds the origin and histogenesis of the ductules. Opinions range from the ductules being an inherent part of the tumour, to others who feel they are merely entrapped. A study of 21 cases of this variant was undertaken with particular attention paid to the distribution and morphology of the ductules, the presence of entrapped acinar tissue and the surrounding uninvolved pancreatic tissue.. Twenty-one cases were detailed occurring in either gender equally and with a wide age range (19-85 years). All cases, except one, were sporadic, the vast majority were located in the tail and were of small size (less than 2.0 cm). All cases were typified by stromal fibrosis, either diffuse (15) or in the form of septae (6). Embedded within the fibrous tissue were ductular structures, some of which were dilated and ectatic. The ductules were centrally located (5), at the periphery of the tumour (9) or diffusely scattered throughout the lesion (7). All cases showed ductulo-insular complexes. Insulin was demonstrated in 15 immunohistochemically.. It is likely that in some cases the ductules are entrapped as the tumour grows into surrounding normal pancreatic tissue and the ductular proliferation is a secondary phenomenon. In a proportion of cases, the ductules are likely to be a part of the tumour arising as part of focal chronic inflammation or as a result of the growth factor effects of insulin, in cases associated with insulin production. There is nothing to suggest that the ductules confer any special biological characteristics to the PET and are merely a histological nuance. However, some cases may have a dominant tubular component, which could present problems at frozen section where the association with fibrosis may invoke a mistaken diagnosis of pancreatic ductal adenocarcinoma or chronic pancreatitis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Islet Cell; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Fibrosis; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Keratins; Male; Middle Aged; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis, Chronic

Macropathologic types of gallbladder cancer are mostly polyp type, intumescent type, and cauliflower form lump. Its histological types include well or poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and undifferentiated cancer. This research was to explore the clinicopathologic features of gallbladder adenocarcinoma with marked stromal fibrosis.. Pathology of 19 cases of gallbladder adenocarcinoma with marked stromal fibrosis was observed using a light microscopy and SP immunohistochemistry. Clinicopathologic features of 19 patients were analyzed.. Most of the patients had long-term history of cholecystitis gallbladder calculus. B ultrasound showed that the gallbladder wall was irregularly thickened or presented nodosity. Observed with naked eyes, gallbladder adenocarcinoma with marked stromal fibrosis did not form cancer nodule and extrude into the gallbladder lumen, the gallbladder wall showed regional thickening, a few cases showed diffuse irregular thickening. Observed under a light microscope, the adenocarcinoma cells were mostly arranged as single layers, seldom arranged as multiple layers, and formed adenoid structures with different sizes, various shapes, and irregular arrangement; the nuclei were heterogenic with haryomitosis presented in a few cases; inflammatory cells were infiltrated in hyperplastic fibrous connective tissue of some cases. According to immune phenotyping, CK (AE1/AE3), CK (AE1), CK7 (OV-TL12/30), CK8 (C51), CK18 (Dc-10), CK19 (RCK108), and EMA (Mc-5) showed strong expression, CEA (COL-1), CK20 (Ks20. 4), and MUC-5AC (CLH2) showed moderate expression, and MUC-2 (B306. 1) showed weak expression; CK17 (E3) showed focal expression.. The clinical manifestation, macropathologic type, histological characteristics of gallbladder adenocarcinoma with stromal fibrosis are different from other types of adenocarcinoma. Its genesis may be related to chronic cholecystitis: long-term inflammation causes regional hyperplasia and heterogeneity of the gland body, lead to focal or regional thickening of the gallbladder wall, and result in gallbladder adenocarcinoma with stromal fibrosis finally.

Topics: Adenocarcinoma; Adult; Aged; Cholecystectomy; Diagnosis, Differential; Female; Fibrosis; Follow-Up Studies; Gallbladder; Gallbladder Neoplasms; Humans; Immunohistochemistry; Immunophenotyping; Keratins; Male; Middle Aged

Expression and pharmacological studies support a contribution of cyclooxygenase (COX)-2 to mammary gland tumorigenesis. In a recent transgenic study, mouse mammary tumor virus promoter-driven COX-2 expression in mouse mammary glands was shown to result in alveolar hyperplasia, dysplasia, and carcinomas after multiple rounds of pregnancy and lactation. In the study presented here, the effects of constitutive COX-2 overexpression in keratin 5-positive myoepithelial and luminal cells, driven by the keratin 5 promoter in a hormone-independent manner, was investigated. In nulliparous female mice, aberrant COX-2 overexpression correlated with increased prostaglandin (PG) E(2) levels and caused cystic duct dilatations, adenosis, and fibrosis whereas carcinomas developed rarely. This phenotype depended on COX-2-mediated PGE(2) synthesis and correlated with increased expression of proliferation-associated Ki67 in epithelial cells. No changes in the expression of apoptosis-related Bcl-2, caspase 3, or p53 were observed. Hyperproliferation of the mammary gland epithelial cells was associated with increased aromatase mRNA levels in this tissue. The spontaneous pathologies bear analogies to the human breast with fibrocystic changes. Intriguingly, strong COX-2 expression was observed in fibrocystic changes, as compared to low expression in normal breast epithelium. These results show for the first time that aberrant COX-2 expression contributes to the development of fibrocystic changes (FC), indicating that COX-2 and COX-2-mediated PG synthesis represent potential targets for the therapy of this most frequent benign disorder of the human breast.

Topics: Animals; Biopsy; Breast; Caspase 3; Caspases; Cell Proliferation; Cyclooxygenase 2; Cystic Duct; Enzyme-Linked Immunosorbent Assay; Epithelium; Female; Fibrosis; Flow Cytometry; Humans; Immunoblotting; Immunohistochemistry; Keratin-15; Keratin-5; Keratins; Ki-67 Antigen; Mammary Glands, Animal; Membrane Proteins; Mice; Mice, Transgenic; Phenotype; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transgenes; Tumor Suppressor Protein p53

To evaluate the utility of peritoneal pathologic samples, unrelated to peritoneal dialysis (PD) treatment, for the study of peritoneal fibrosis and inflammation.. Comparative morphologic and immunohistochemical study of peritoneal pathologic samples unrelated to PD with peritoneal biopsies from PD patients with special emphasis on the expression of myofibroblastic and epithelial-to-mesenchymal transition markers.. Regarding morphology, PD-related simple fibrosis was less cellular, with greater stromal hyalinization, determining a homogeneous, hypocellular aspect of the submesothelium. In contrast, non-PD fibrosis was more cellular with an extracellular matrix showing a dense and fibrillar quality with wide bundles of collagen. Hylinazing vasculopathy was only present in PD samples. Myofibroblastic differentiation and epithelial-to-mesenchymal transition were common findings in all situations of peritoneal fibrosis. Calponin and calretinin are useful cellular markers to study such fibrogenic mechanisms and correlate with other well-known markers such as a -SMA and cytokeratins. Their expression was much more intense in those samples showing acute inflammation (peritonitis).. Non-PD models of peritoneal fibrosis seem very useful to evaluate important features of human peritoneal pathology such us fibrogenesis, and inflammation. Fibrogenic events such as myofibroblastic differentiation and epithelial-to-mesenchymal transition are evident in these tissue samples allowing us to use them as an accessible source for in vivo and ex vivo studies. Both events show their maximal expression in situations of acute inflammation supporting the important role that peritonitis episodes play in the progression of fibrosis.

Topics: Actins; Biomarkers; Biopsy; Calbindin 2; Calcium-Binding Proteins; Calponins; Case-Control Studies; Cell Differentiation; Edema; Epithelium; Fibrin; Fibroblasts; Fibrosis; Hernia, Inguinal; Humans; Hyalin; Keratins; Microfilament Proteins; Neutrophils; Peritoneum; S100 Calcium Binding Protein G; Sclerosis; Tissue Adhesions

The hallmark of failing renal transplants is tubular atrophy and interstitial fibrosis (TA/IF). Injury to tubular epithelial cells (TEC) could contribute to fibrogenesis via epithelial-mesenchymal transition (EMT). We examined the features of EMT in renal transplants that developed TA/IF. Biopsies from 10 allograft kidneys with impaired function and TA/IF and 10 biopsies from transplants with stable function were compared to their implantation biopsies. Relative to implantation biopsies, TEC in TA/IF kidneys showed loss of epithelial markers (E-cadherin, cytokeratin) with altered distribution. Some TEC also showed new cytoplasmic expression of mesenchymal markers vimentin, S100A4, and alpha smooth muscle actin (alpha-SMA) and collagen synthesis marker heat shock protein (HSP-47), both in deteriorating and atrophic tubules. Double immunostaining showed coexpression of cytokeratin and vimentin, S100A4 and HSP-47, indicating intermediate stages of EMT in TA/IF. These changes were absent or much less in transplants with stable function. EMT features in the TA/IF group correlated with serum creatinine (vimentin, S100A4, HSP-47), history of T-cell-mediated rejection (cytokeratin, S100A4) and proteinuria (cytokeratin). These findings support a model in which the TEC damage induces loss of epithelial features and expression of fibroblast features, as a common pathway of deterioration by either immunologic or nonimmunologic processes.

Topics: Actins; Adult; Atrophy; Biomarkers; Cadherins; Cell Differentiation; Epithelial Cells; Female; Fibroblasts; Fibrosis; Graft Rejection; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Humans; Keratins; Kidney Transplantation; Kidney Tubules; Male; Serpins; Transplantation, Homologous; Vimentin

During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids that cause epithelial-to-mesenchymal transition of mesothelial cells, fibrosis, and angiogenesis. Ultrafiltration failure is associated with high transport rates and increased vascular surface, indicating the implication of vascular endothelial growth factor (VEGF). Sources of VEGF in vivo in PD patients remain unclear. We analyzed the correlation between epithelial-to-mesenchymal transition of mesothelial cells and both VEGF level and peritoneal functional decline.. Effluent mesothelial cells were isolated from 37 PD patients and analyzed for mesenchymal conversion. Mass transfer coefficient for creatinine (Cr-MTC) was used to evaluate peritoneal function. VEGF concentration was measured by using standard procedures. Peritoneal biopsy specimens from 12 PD patients and 6 controls were analyzed immunohistochemically for VEGF and cytokeratin expression.. Nonepithelioid mesothelial cells from effluent produced a greater amount of VEGF ex vivo than epithelial-like mesothelial cells (P < 0.001). Patients whose drainage contained nonepithelioid mesothelial cells had greater serum VEGF levels than those with epithelial-like mesothelial cells in their effluent (P < 0.01). VEGF production ex vivo by effluent mesothelial cells correlated with serum VEGF level (r = 0.6; P < 0.01). In addition, Cr-MTC correlated with VEGF levels in culture (r = 0.8; P < 0.001) and serum (r = 0.35; P < 0.05). Cr-MTC also was associated with mesothelial cell phenotype. VEGF expression in stromal cells, retaining mesothelial markers, was observed in peritoneal biopsy specimens from high-transporter patients.. These results suggest that mesothelial cells that have undergone epithelial-to-mesenchymal transition are the main source of VEGF in PD patients and therefore may be responsible for a high peritoneal transport rate.

Topics: Adult; Aged; Biopsy; Cell Differentiation; Cell Membrane Permeability; Cells, Cultured; Epithelial Cells; Epithelium; Female; Fibrosis; Glucose; Hemodialysis Solutions; Hemoperitoneum; Humans; Keratins; Kidney Failure, Chronic; Male; Mesoderm; Middle Aged; Neovascularization, Pathologic; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Peritonitis; Stromal Cells; Vascular Endothelial Growth Factor A

Peritoneal fibrosis is one of the most common morphological changes observed in continuous ambulatory peritoneal dialysis (CAPD) patients. Both resident fibroblasts and new fibroblast-like cells derived from the mesothelium by epithelial-to-mesenchymal transition are the main cells involved fibrogenesis. In order to establish markers of peritoneal impairment and pathogenic clues to explain the fibrogenic process, we conducted an immunohistochemical study focused on peritoneal fibroblasts. Parietal peritoneal biopsies were collected from four patient groups: normal controls ( n = 15), non-CAPD uremic patients ( n = 17), uremic patients on CAPD ( n = 27) and non-renal patients with inguinal hernia ( n = 12). To study myofibroblastic conversion of mesothelial cells, alpha-smooth muscle actin (SMA), desmin, cytokeratins and E-cadherin were analyzed. The expression of CD34 by fibroblasts was also analyzed. Fibroblasts from controls and non-CAPD uremic patients showed expression of CD34, but no myofibroblastic or mesothelial markers. The opposite pattern was present during CAPD-related fibrosis. Expression of cytokeratins and E-cadherin by fibroblast-like cells and alpha-SMA by mesothelial and stromal cells supports that mesothelial-to-myofibroblast transition occurs during CAPD. Loss of CD34 expression correlated with the degree of peritoneal fibrosis. The immunophenotype of fibroblasts varies during the progression of fibrosis. Myofibroblasts seem to derive from both activation of resident fibroblasts and local conversion of mesothelial cells.

Topics: Adult; Aged; Antigens, CD34; Cadherins; Epithelium; Female; Fibroblasts; Fibrosis; Humans; Immunohistochemistry; Interleukin-1; Keratins; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Transforming Growth Factor beta; Uremia

Oval cell proliferation is known to occur in experimental models of hepatic regeneration and carcinogenesis. Recent studies have suggested that activation of progenitor cells, representing the human counterpart of oval cells, may play a role in hepatic diseases. Therefore, we evaluated putative progenitor cells in chronic viral hepatitis.. Forty-one needle liver biopsy specimens from patients with chronic hepatitis B and 43 specimens from patients with chronic hepatitis C were examined histologically. The grade (histological activity index (HAI)) and stage (degree of fibrosis) were determined on routinely stained sections. The number of progenitor cells was assessed semiquantitatively on cytokeratin 7- (CK 7-) stained sections.. In both aetiological categories of chronic viral hepatitis, progenitor cell numbers were found to increase in parallel to the HAI, as well as to the stage of disease. Features suggestive of hepatocytic differentiation of progenitor cells were also noted on immunohistochemical stains for CK 7 and 'hepatocyte-specific' antigen.. In chronic hepatitis B and chronic hepatitis C, progenitor cell activation is correlated with the grade and stage of disease. Proliferating progenitor cells may play a role in hepatic regeneration occurring in this setting.

Topics: Cell Differentiation; Fibrosis; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatocytes; Humans; Immunohistochemistry; In Vitro Techniques; Keratin-7; Keratins; Liver; Stem Cells

To observe the transdifferentiation of renal tubular epithelial cells in tubulointerstitial fibrosis.. The renal tubulointerstitial fibrosis model in Wistar rats was established by unilateral renal vein ligature. The rats were kept 25 days after renal vein ligature. The kidneys were dissected every 5 days by killing 5 rats. The morphological changes of the kidney were observed by light microscopy, electron microscopy, polarizing microscopy and immunohistochemistry method.. The histological changes showed tubular atrophy and disappearance, widening of intertubular spaces with increased lymphocytes and mononuclear cells infiltration and fibrosis. The CK marker in injured and atrophic epithelial cells gradually weakened, but the alpha-SMA, vimentin, TGF-beta(1), collagen I and III showed gradually stronger positivity for immunohistochemistry. Some interstitial cells became positive for CK. Electron microscopy revealed decreased mitochondria, increased endoplasmic reticulum and microfilament of the tubular epithelial cells which merged into the interstitium. During the early stage of tubulointerstitial fibrosis, there was proliferation of type III collagen and then followed by type I collagen at later stage when observing the Sirius Red stained sections under the polarizing microscope.. Tubular epithelial cells can transdifferentiate to fibroblasts during the process of tubulointerstitial fibrosis.

Topics: Actins; Animals; Cell Differentiation; Collagen; Epithelial Cells; Fibrosis; Immunohistochemistry; Keratins; Kidney Tubules; Male; Rats; Rats, Wistar

The epithelial alteration in interstitial pneumonias is one of the repair processes at the sites of disease activity. Regenerative epithelial cells may participate in remodeling of the lung. To determine the phenotype of regenerative epithelial cells in usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the expression of Clara cell 10KD protein (CC10), cytokeratin (CK) 14 and 17, surfactant apoprotein (SP)-A, KL-6/MUC1, transforming growth factor (TGF) beta2 were examined in 25 patients with UIP, 9 patients with NSIP and normal lung tissues from 10 patients with lung cancer. In honeycomb lesions of UIP, non-ciliated columnar cells mainly expressed CC10, cuboidal cells expressed CC10, CK17, CK14 and SP-A in descending order. Fibroblastic foci are covered by CK17, CK14, CC10, and a few SP-A positive flattened or cuboidal cells. Regenerative epithelium in NSIP mainly comprised cuboidal cells expressing SP-A, CC10 and CK17. KL-6 was more remarkably expressed in cuboidal and non-ciliated columnar cells both in UIP and NSIP. Expression of TGFbeta2 was observed in cuboidal and flattened epithelium. In severe fibrotic areas, CC10 expressing cells were more prominent, while SP-A positive cells were more prominent in less fibrotic areas. Regenerative epithelial cells in remodeling area in UIP may be derived from bronchiolar basal cells and Clara cells, while most of those in NSIP may be derived from type II pneumocytes. The different origin of regenerative epithelium may reflect the severity and extent of the injury and the degree of consequent fibrosis in UIP and NSIP.

Topics: Antigens; Antigens, Neoplasm; Apoproteins; Bronchi; Enzyme Inhibitors; Epithelial Cells; Female; Fibroblasts; Fibrosis; Glycoproteins; Humans; Keratins; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Mucin-1; Mucins; Phenotype; Phospholipases; Proteins; Pulmonary Surfactant-Associated Proteins; Regeneration; Transforming Growth Factor beta; Transforming Growth Factor beta2; Uteroglobin

The canals of Hering (CoH), converging from the hepatic lobule onto the portal tract, connect bile canaliculi to the interlobular bile ducts, and represent the most proximal portion of the bile drainage pathway with a cholangiocyte lining. In this study we sought to ascertain whether this proximal pathway is involved by the disease process in primary biliary cirrhosis (PBC), which uniformly affects small bile ducts while sparing medium- and large-sized ducts. Ten biopsy specimens with early-stage PBC were compared with 6 normal control livers. Adjacent 4-micron-thick sections of routinely processed, formalin-fixed tissue were immunostained for CK19 and HLA-DR. Each terminal portal tract was assigned a stage: 0, normal; 1, bile duct damage or loss; 2, bile ductular proliferation; or 3, periportal fibrosis. The ratio of the number of CoH to number of portal tracts (i.e., the c/p ratio) was calculated for the control biopsies and individual portal tracts at each stage of PBC. The numbers of CoH were decreased in all stages of PBC (P <0.0001), with the fewest found around portal tracts at stages 0 and 1 and the most around portal tracts at stages 2 and 3, but never at normal levels. HLA-DR was expressed focally on bile ducts and CoH in PBC, but was absent in normal controls. We conclude that CoH are destroyed in PBC in concert with the destruction of small bile ducts. This destruction appears to be an early event, because CoH numbers are lowest around stage 0 portal tracts, which still contain normal bile ducts.

Topics: Bile Ducts, Intrahepatic; Biopsy; Fibrosis; Formaldehyde; HLA-DR Antigens; Humans; Immunohistochemistry; Keratins; Liver; Liver Cirrhosis, Biliary; Tissue Fixation

To elucidate histological changes in the pituitary gland and adenomas following radiotherapy, two irradiated pituitary glands and seven irradiated non-functioning adenomas were studied. The latter included four cases with conventional radiation (CR) and three cases with radiosurgery: two with gamma knife radiosurgery (GKR) and one with stereotactic fractionated radiotherapy (SRT). The specimens were obtained 10 months to 10 years (mean 58 months) after the radiotherapy. Irradiated pituitary glands showed diffuse fibrosis in the adenohypophysis, whereas irradiated adenomas showed either mild or no fibrosis in five CR/SRT cases and diffuse thick hyaline deposits in two GKR cases. No necrosis was observed. Stellate-shaped S-100 protein-positive cells were greater in number in the irradiated pituitary glands than in the normal glands. Pituitary cells with dense granular reactivity for mitochondrial protein, cytochrome oxidase, and Mn-SOD, mimicking oncocytes, were greater in number in the irradiated adenohypophysis but did not show any change in cell size. Many irradiated pituitary cells and some irradiated adenoma cells were densely positive with anticytokeratin 1,5,10,14 antibody whereas non-irradiated counterparts were negative. In adenomas, MIB-1 labeling index remained unchanged after the radiation. The results may indicate that radiation-induced fibrosis was associated with an increased number of folliculo-stellate cells, mitochondrial dysfunction, and squamous metaplasia. These findings were prominent in irradiated pituitary cells and may participate in delayed pituitary hypofunction following radiotherapy. In irradiated adenoma cells, similar findings were observed but diffuse fibrosis was absent. The histological changes were more intensive in adenomas following GKR than those following CR.

Topics: Adenoma; Aged; Antibodies, Antinuclear; Antibodies, Monoclonal; Female; Fibrosis; Humans; Hypopituitarism; Keratins; Male; Pituitary Gland, Anterior; Pituitary Irradiation; Pituitary Neoplasms; Radiosurgery; S100 Proteins; Superoxide Dismutase

In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) in epithelial growth and differentiation, transgenic mice were generated carrying the CDK4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypertrophy were observed. The hyperproliferative phenotype of these transgenic mice was independent of D-type cyclin expression because no overexpression of these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinous layer compared with normal epidermis, and a mild hyperkeratosis in the cornified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by connective tissue. Also, abnormal expression of keratin 6 associated with the hyperproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the role of CDK4 as a mediator of proliferation in epithelial cells independent of D-type cyclin expression.

Topics: Animals; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; Epidermis; Fibrosis; Humans; Hyperplasia; Hypertrophy; Keratins; Mice; Mice, Transgenic; Proto-Oncogene Proteins; Retinoblastoma Protein; Skin; Skin Physiological Phenomena

The paucicellular variant of anaplastic carcinoma is an infrequent type of thyroid tumor. It was described as a tumor characterized by very low cellularity and prominent fibrosis, probably secondary to extensive infarction. These features could lead to an erroneous diagnosis of Riedel's thyroiditis. In this paper, we report the clinical and pathological features of two new cases of this unusual entity. Tumor cells were negative for thyroglobulin immunostaining and positive for keratins and p53. Although the number of reported cases is small, the cumulative data on these two cases and the previously reported ones lead us to suggest that the paucicellular variant may occur in younger patients than the conventional anaplastic thyroid carcinoma and that the tumor may be associated with a less aggressive tendency to local progression and metastasis.

Topics: Aged; Biopsy, Needle; Carcinoma; Diagnosis, Differential; Female; Fibrosis; Humans; Keratins; Male; Middle Aged; Thyroglobulin; Thyroid Neoplasms; Tumor Suppressor Protein p53

Response of the renal tubules to proteinuria is implicated in progression of renal disease. Experimentally, proteinuria causes increased tubular synthesis of macrophagic and other chemokines, with increased tubular cellular proliferation and apoptosis, leading to interstitial inflammation and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans.. Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 patients with lupus nephritis were studied, with a subset of 34 biopsies also stained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profile counts performed.. Positive correlations were found between increasing levels of proteinuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macrophages, interstitial inflammation and fibrosis, but not with tubulointerstitial immunofluorescence. Significant positive correlations also were found with the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0.36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong correlations with serum creatinine (S(Cr)) as well. All were reduced at Bx2, generally in parallel to the reduction in proteinuria. Tubulointerstitial immune deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They show only limited correlation with SCr and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesions, interstitial inflammation or interstitial fibrosis at either biopsy, whereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin correlated strongly with S(Cr) (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy.. In this study both proteinuria and SCr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes> tubular macrophages> interstitial inflammation> interstitial fibrosis, corresponding to current experimental models, but not previously demonstrated in humans.

Topics: Creatinine; Fibrosis; Humans; Immunohistochemistry; Keratins; Kidney Tubules; Lupus Nephritis; Macrophages; Proliferating Cell Nuclear Antigen; Proteinuria

The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen-producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis.. The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, alpha-smooth muscle actin (alpha-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype.. Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilated or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchymal transformation (EMT) in this process. Most FSP1+ fibroblasts were alpha-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix. alpha-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in alpha-SMA+ cells.. Many nonoverlapping as well as fewer overlapping populations of FSP1+ and alpha-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while alphaSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are alpha-SMA+.

Topics: Actins; Animals; Biomarkers; Cadherins; Calcium-Binding Proteins; Fibroblasts; Fibrosis; Fluorescent Antibody Technique; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Keratins; Kidney; Male; Mice; Mice, Inbred DBA; Polycystic Kidney Diseases; S100 Calcium-Binding Protein A4; S100 Proteins

Clomiphene citrate is chemically related to non-steroidal estrogens, and has antiestrogenic properties. It is used in the treatment of anovulatory female infertility and its therapeutic effect mainly depends on inhibiting the negative feedback effects of endogenous estrogen by stimulating the gonadotropin releasing hormone. Today, it is also used in the treatment of male infertility.. In this study the effects of clomiphene citrate on skin maturation in neonatal rats were investigated.. Forty Spraque-Dawley female newborn rats were separated into two control and two experimental groups (n = 10). One day after birth. experimental newborn rats were given clomphene citrate subcutaneously in a dosage of 100 mg/kg/day for five days. The first experimental group of rats were anesthetised at 21 days whereas the second experimental group of rats were then anestetised on day 28. Biopsies were taken immediately from the perineal skin. Histopathological assessments were made and compared with their control groups.. In both the experimental groups of newborn rats, increased keratinization and irregular hypertrophy were observed in the epidermal cells. Disorganization of the basal layer cells and hyperplasia were found to be more prominent in the first experimental group and dermal fibrosis and lymphohistiocytic inflammatory cell infiltration were especially prominent around the sebaceous glands in the second experimental group.. The administration of clomiphene citrate in newborn rats showed impaired skin maturation.

Topics: Animals; Animals, Newborn; Clomiphene; Epidermis; Female; Fibrosis; Histiocytes; Hyperplasia; Keratins; Lymphocytes; Rats; Rats, Sprague-Dawley; Sebaceous Glands; Skin

Skin malignancies can originate in burn scars (Marjolin's ulcer). The most common is squamous cell carcinoma, usually appearing years after injury. Split-thickness skin graft donor sites as a source of malignant transformation are far less frequent and demonstrate a shorter interval between surgery and tumor onset. Keratoacanthomas have rarely been reported to arise in such scars. We describe the simultaneous occurrence of keratoacanthomas on a spontaneously healed second-degree burn on the flank and in the scar of a skin graft donor site on the thigh, 4 months after a 40% total body surface area burn.

Topics: Burns; Cicatrix; Dermis; Eosinophils; Epidermis; Fibrosis; Humans; Keratins; Keratoacanthoma; Lymphocytes; Male; Middle Aged; Skin Transplantation

Matrix metalloproteinases (MMPs) are invariably upregulated in the stromal compartment of epithelial cancers and appear to promote invasion and metastasis. Here we report that phenotypically normal mammary epithelial cells with tetracycline-regulated expression of MMP3/stromelysin-1 (Str1) form epithelial glandular structures in vivo without Str1 but form invasive mesenchymal-like tumors with Str1. Once initiated, the tumors become independent of continued Str1 expression. Str1 also promotes spontaneous premalignant changes and malignant conversion in mammary glands of transgenic mice. These changes are blocked by coexpression of a TIMP1 transgene. The premalignant and malignant lesions have stereotyped genomic changes unlike those seen in other murine mammary cancer models. These data indicate that Str1 influences tumor initiation and alters neoplastic risk.

Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Cell Differentiation; Cells, Cultured; Epithelial Cells; Female; Fibrosis; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genome; Humans; Hyperplasia; Keratins; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 3; Mesoderm; Mice; Mice, SCID; Mice, Transgenic; Pregnancy; Stromal Cells; Tissue Inhibitor of Metalloproteinase-1; Vimentin

By introducing certain irritants into the middle ear it is possible to produce cholesteatoma. Propylene glycol, the main agent used for this purpose, produces a long-standing inflammation that causes hyperplasia and migration of the epithelium through an intact tympanic membrane. In the present investigation topical prednisolone was used in order to inhibit the production of cholesteatoma. The results indicate that there is a marked decrease in inflammation and hence experimental cholesteatoma production when prednisolone is administered into the middle ear.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Cholesteatoma, Middle Ear; Ear, Middle; Epithelium; Fibrosis; Glucocorticoids; Granulation Tissue; Hyperplasia; Inflammation; Injections; Irritants; Keratins; Otitis Media; Prednisolone; Propylene Glycol; Rats; Rats, Wistar; Temporal Bone; Tympanic Membrane

Subarachnoid haemorrhage (SAH) often leads to subarachnoid fibrosis and resultant normal pressure hydrocephalus; however, how subarachnoid fibrosis occurs is unknown. We examined the changes within arachnoid granulations (AGs) and the subarachnoid space (SAS) chronologically at the parasagittal region obtained from patients with SAH at autopsy and made comparison with controls by immunostaining for cytokeratin, specific marker for leptomeningeal cells and by the elastica Masson-Goldner methods. Within a week some AGs were torn, and many inflammatory cells filled the AGs and SAS. Cytokeratin positive cells were scarce. During the next two weeks cytokeratin positive cells increased. After three weeks, AGs and SAS were filled by dense deposits of extracellular matrices surrounded by multiple layers of leptomeningeal cells.

Topics: Arachnoid; Cell Division; Extracellular Matrix; Fibrosis; Granulation Tissue; Humans; Hydrocephalus, Normal Pressure; Immunoenzyme Techniques; Keratins; Meninges; Subarachnoid Hemorrhage; Subarachnoid Space; Time Factors

A 22-year-old man had had a dome-shaped tumor on his penis for one year. Neither his particular past history nor family history was available. The excised specimen contained numerous von Kossa-positive deposits. Four types of histologic pattern were identified: 1) a cystic structure filled with amorphous material lined by a few layers of epithelial cells, 2) a cyst containing calcified deposits in the keratinous material, 3) a large calcified nodule lined by attenuated epithelial cyst walls, 4) numerous calcium collections without an epithelial wall. The cystic structure showed the histologic features of syringoma or sweat duct milia. The luminal cells of the cyst showed positive immunoreactivity for both keratin and carcinoembryonic antigen. These findings suggested that the keratinous contents of syringoma had gradually calcified, the cyst wall had been attenuated, and, finally, numerous calcium collections without an epithelial wall were formed. Our case further supported the hypothesis that penile calcinosis as well as scrotal calcinosis might derive from syringoma.

Topics: Adult; Calcinosis; Carcinoembryonic Antigen; Connective Tissue; Cysts; Epithelium; Fibrosis; Humans; Keratins; Male; Penile Diseases; Sweat Glands

Severe ethanol-induced liver damage is characterized by fibrous dissociation of liver cell plates leading to many apparently isolated hepatocytes. Three-dimensional reconstruction, however, revealed hepatocytes that were surrounded by connective tissue as endpoints of "parenchymal pillars" or in association with liver cell plates and bile ductules. Double immunofluorescence studies displayed the expression of cytokeratin (CK) 7 in bile ducts, including bile ductules, but also in some hepatocytes still organized in liver cell plates. The other bile duct, typical CK, namely CK 19, was only detectable in few hepatocytes. However, the expression of CK 7 and/or CK 19 was less frequent in hepatocytes that were closely associated with bile ductules. CK 7 and CK 19 were also found in some, but not all, Mallory bodies. These observations indicate that the expression of these two CKs is neither related to a transformation of hepatocytes to bile duct-like structures ("ductal metaplasia") nor to the formation of Mallory bodies. Furthermore, double immunofluorescence studies revealed small groups of hepatocytes and bile ductules that were encircled by basement membrane material, thus suggesting the formation of "secretory units."

Topics: Aged; Bile Ducts; Cell Communication; Cell Membrane; Endoplasmic Reticulum; Extracellular Matrix; Female; Fibrosis; Fluorescent Antibody Technique; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Keratins; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Mesoderm; Middle Aged

Obstructive sialoadenitis was examined by immunohistochemical techniques for keratin (MoAb KL1, PKK1 and K8.12) and actin. Electronmicroscopy (EMS) was used to identify ultrastructural changes in myoepithelial cells and ductal basal cells. With immunohistochemistry, actin staining was used as a marker of myoepithelium, MoAbs KL1 and PKK1 for ductal luminal cells, and MoAb K8.12 for ductal basal cells. Histologic features of the lesion usually showed degenerative changes of acinar and duct cells with cell infiltration and fibrous replacement. Immunohistochemical findings indicated that actin staining in the changed myoepithelial cells was irregularly positive or negative, and also keratin staining in luminal and ductal basal cells was reduced or disappeared. Ultra-structural features of the changed myoepithelial cells indicated that these cells appeared less altered than adjacent acinar and ductal cells and showed increased amounts of lipid droplets and lipofuscin granules, and also wrinkled processes filled the prominent myofilament material.

Topics: Actins; Acute Disease; Cell Membrane; Chronic Disease; Cytoplasm; Epithelium; Fibrosis; Humans; Immunohistochemistry; Keratins; Microscopy, Electron; Organelles; Sialadenitis; Submandibular Gland; Submandibular Gland Diseases

The calcifying odontogenic cyst (COC) is a rare lesion without specific clinical characteristics. Its diagnosis is essentially histopathological showing the presence of ghost cells associated with narrow squamous epithelium, the basal strata of which consist of clearly delineated cells differentiating in areas of the stellate reticulum in a similar way to ameloblastoma. The results of ultrastructural observations of the ghost cells as well as histochemical and immunohistochemical studies suggest that they are the sites of abnormal keratinisation. The aim of this study of one COC mas to locate the stages in epithelial maturation associated with the formation of ghost cells. Six monoclonal antibodies were used; three with a wide spectrum (KL1, AE3, AE1), two with a narrow spectrum against high molecular weight cytokeratins (AE2, AE8) and one against vimentin (M725). Histopathological examination of the COC revealed three different types of cells in the epithelial lining and the epithelial islands; small basal cubic cells surrounding larger ones placed centrally or suprabasally; balloon shaped cells or flattened ghost cells rolled up on themselves to resemble keratinising pearls, or cornifying cells. The ghost cells and cornifying cells had an altered distribution of their cytokeratins demonstrated by the absence of staining of antibodies against cytokeratins. The differentiated cells adjacent to them showed cytokeratins typical of squamous epithelium rather than those associated with the process of keratinization. The coexistence of cornifying and ghost cells testifies to the great potential of odontogenic epithelium to form numerous epithelial islands.

Topics: Adult; Calcinosis; Cell Membrane; Connective Tissue; Epithelium; Fibrosis; Humans; Hyperplasia; Keratins; Male; Odontogenic Tumors; Vimentin