RESUMO
Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting.
Assuntos
Metástase Neoplásica/patologia , Neoplasias/patologia , Células Estromais/patologia , Animais , Membrana Basal/patologia , Humanos , Invasividade Neoplásica/patologia , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Prognóstico , Transdução de SinaisRESUMO
The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin ß1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Membrana Basal , Melanócitos , Vitiligo , Vitiligo/patologia , Vitiligo/metabolismo , Melanócitos/patologia , Melanócitos/metabolismo , Membrana Basal/patologia , Membrana Basal/metabolismo , Humanos , Animais , Camundongos , Metaloproteinase 2 da Matriz/metabolismo , Fibroblastos/patologia , Fibroblastos/metabolismo , Masculino , Feminino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
The extracellular matrix surrounding the tumor undergoes changes in its organization during the metastasis process. The present study aims to quantify total collagen, collagen I (Col I) and collagen III (Col III), analyze the alignment of collagen fibers and assess the basement membrane integrity in samples from patients with metastatic and non-metastatic prostate cancer. Tissue samples from 60 patients were classified into groups based on prognostic parameters: better prognosis (n = 20), worse prognosis without metastasis (n = 23) and metastatic (n = 17). Picrosirius red with further analysis under polarizing microscope was used to quantify (with validation using immunohistochemistry) and analyze collagen alignment, and Periodic Acid Schiff staining was used to analyze the basement membrane integrity. The Col I/Col III ratio was found to be higher in the metastatic group than in the groups with better prognosis (p = 0.012) and worse prognosis without metastasis (p = 0.018). Basement membrane integrity constitution in malignant tumor tissue differed from that of adjacent non-tumor tissue (p < 0.001). Moreover, the worsening in the tumor tissue integrity was positively correlated with worse prognostic parameters. All in all, absence of Col III and basement membrane integrity might be indicators of poor prognosis in prostate cancer.
Assuntos
Membrana Basal , Biomarcadores Tumorais , Colágeno Tipo III , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Membrana Basal/metabolismo , Membrana Basal/patologia , Prognóstico , Biomarcadores Tumorais/metabolismo , Idoso , Colágeno Tipo III/metabolismo , Pessoa de Meia-Idade , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologiaRESUMO
The increasing prevalence of diabetes has resulted in a global epidemic1. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells2-4. Diabetes also impairs the functions of endothelial cells5 and disturbs the communication between endothelial cells and pericytes6. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.
Assuntos
Membrana Basal/patologia , Vasos Sanguíneos/patologia , Angiopatias Diabéticas/patologia , Modelos Biológicos , Organoides/patologia , Organoides/transplante , Proteínas Adaptadoras de Transdução de Sinal , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Artérias/citologia , Artérias/efeitos dos fármacos , Arteríolas/citologia , Arteríolas/efeitos dos fármacos , Membrana Basal/citologia , Membrana Basal/efeitos dos fármacos , Vasos Sanguíneos/citologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/crescimento & desenvolvimento , Proteínas de Ligação ao Cálcio , Angiopatias Diabéticas/enzimologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Hiperglicemia/complicações , Técnicas In Vitro , Mediadores da Inflamação/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Organoides/citologia , Organoides/efeitos dos fármacos , Pericitos/citologia , Pericitos/efeitos dos fármacos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Receptor Notch3/metabolismo , Transdução de Sinais , Vênulas/citologia , Vênulas/efeitos dos fármacosRESUMO
Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.
Assuntos
Glomerulosclerose Segmentar e Focal , Nefrite Hereditária , Humanos , Membrana Basal Glomerular/patologia , Colágeno Tipo IV/genética , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Parafina , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Membrana Basal/patologiaRESUMO
Atypical antiglomerular basement membrane (anti-GBM) nephritis can be defined as linear GBM staining for monotypic or polytypic immunoglobulin (Ig) by immunofluorescence (IF) without a diffuse crescentic pattern. We describe the clinicopathologic features of 6 patients (18 biopsies) in this first series of recurrent atypical anti-GBM nephritis after kidney transplantation. Recurrent glomerulonephritis occurred at a mean of 3.8 months posttransplant (range 1-7 months). Three index biopsies were for clinical indication, and 3 were protocol biopsies. Glomerular histologic changes were mild, with 2 showing segmental endocapillary hypercellularity, 1 focal glomerular microangiopathy, and the others no significant glomerular histologic changes. All 6 allografts showed monotypic linear glomerular Ig staining by IF: IgG kappa (n = 2), IgG lambda, IgA kappa, IgA lambda, and IgM lambda. Follow-up biopsies were available for 5 patients and showed similar histologic and IF findings without evidence of significant progression. No patients had detectable serum anti-GBM antibody or monoclonal proteins. The mean serum creatinine level on follow-up (24-62 months posttransplant) was 1.8 (range 0.93-2.77) mg/dL; no grafts were lost to recurrent disease. This series demonstrates that monotypic atypical anti-GBM recurs in the allograft and supports the idea that this disease is due to a circulating monoclonal protein.
Assuntos
Glomerulonefrite , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Membrana Basal/patologia , Autoanticorpos , Anticorpos Monoclonais , Imunoglobulina G , Imunoglobulina ARESUMO
BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.
Assuntos
Doença Antimembrana Basal Glomerular , Ratos , Humanos , Animais , Doença Antimembrana Basal Glomerular/tratamento farmacológico , Doença Antimembrana Basal Glomerular/etiologia , Ácido Butírico , Acetato de Sódio , Propionatos/farmacologia , Ratos Endogâmicos WKY , Membrana Basal/metabolismo , Membrana Basal/patologiaRESUMO
BACKGROUND: This study sought to investigate the prognostic value of basement membrane (BM)-associated gene expressions in oral cancer. METHODS: We harvested and integrated data on BM-associated genes (BMGs), the oral cancer transcriptome, and clinical information from public repositories. After identifying differentially expressed BMGs, we used Cox and Lasso regression analyses to create a BMG-based risk score for overall survival at various intervals. We then validated this score using the GSE42743 cohort as a validation set. The prognostic potential of the risk scores and their relations to clinical features were assessed. Further, we conducted functional pathway enrichment, immune cell infiltration, and immune checkpoint analyses to elucidate the immunological implications and therapeutic potential of the BMG-based risk score and constituent genes. To confirm the expression levels of the BMG LAMA3 in clinical samples of oral cancer tissue, we performed quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. RESULTS: The BMGs LAMA3, MMP14, and GPC2 demonstrated notable prognostic significance, facilitating the construction of a BMG-based risk score. A higher risk score derived from BMGs correlated with a poorer survival prognosis for oral cancer patients. Moreover, the risk-associated BMGs exhibited a significant relationship with immune function variability (P < 0.05), discrepancies in infiltrating immune cell fractions, and immune checkpoint expressions (P < 0.05). The upregulated expression levels of LAMA3 in oral cancer tissues were substantiated through qRT-PCR and immunohistochemical staining. CONCLUSION: The BMG-based risk score emerged as a reliable prognostic tool for oral cancer, meriting further research for validation and potential clinical application.
Assuntos
Membrana Basal , Biomarcadores Tumorais , Neoplasias Bucais , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Prognóstico , Membrana Basal/metabolismo , Membrana Basal/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Feminino , Perfilação da Expressão Gênica , Masculino , Laminina/genéticaRESUMO
BACKGROUND: To examine the effect of internal limiting membrane peeling on the inner retinal layers in patients without macular pathological condition. METHODS: A prospective nonrandomized trial of patients undergoing pars plana vitrectomy with internal limiting membrane peeling for pathologic condition outside the macula was performed. Optical coherence tomography including macular ganglion cell layer, inner plexiform layer, and peripapillary retinal nerve fiber layer imaging was performed before surgery, 1, 3, and 6 months postoperatively, and at the end of follow-up (ranges between 4 and 17 months). Patients with any macular pathological condition on optical coherence tomography before surgery were excluded. The main outcome measure was change in thickness of the ganglion cell layer and inner plexiform layer. RESULTS: Ten patients who underwent pars plana vitrectomy with internal limiting membrane peeling for macula-on retinal detachment were included in the analysis. The mean age was 55 years, and the mean follow up was 10.8 months. All patients completed at least two postoperative follow-up visits that included an optical coherence tomography as per the protocol (range 2-6 months). There was an immediate reduction in the global (G), inferotemporal, superotemporal, and superior (S) ganglion cell layer thickness at the first follow up as compared with the preoperative state ( P = 0.028, P = 0.027, P = 0.026, and P = 0.027 respectively). From the first follow-up visit onward until the final follow-up, the thinning persisted, although there was no further statistically significant thinning. CONCLUSION: Peeling of the internal limiting membrane causes significant ganglion cell layer thinning in maculae without pathologic condition before surgery. At up to 17 months of follow-up, this effect seems to be immediate and nonprogressive.
Assuntos
Membrana Basal , Fibras Nervosas , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Acuidade Visual , Vitrectomia , Humanos , Tomografia de Coerência Óptica/métodos , Vitrectomia/métodos , Feminino , Estudos Prospectivos , Masculino , Pessoa de Meia-Idade , Células Ganglionares da Retina/patologia , Membrana Basal/cirurgia , Membrana Basal/patologia , Idoso , Fibras Nervosas/patologia , Seguimentos , Adulto , Descolamento Retiniano/cirurgia , Descolamento Retiniano/diagnóstico , Membrana Epirretiniana/cirurgia , Membrana Epirretiniana/diagnóstico , Macula Lutea/patologia , Macula Lutea/diagnóstico por imagemRESUMO
Reticular basement membrane (RBM) thickening may occur in children with allergic bronchial asthma (BA), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). Its functional consequences remain unknown. We investigated the relationship between baseline RBM thickness and subsequent spirometry. In our cohort follow-up study, patients aged 3-18 yr with BA, CF, and PCD and controls underwent baseline lung clearance index (LCI) measurement, spirometry, and endobronchial biopsy sampling. Total RBM and collagen IV-positive layer thickness were measured. Trends in forced vital capacity (FVC), forced expired volume in 1 s (FEV1), and FEV1/FVC were analyzed during follow-up, and their relationship to baseline characteristics was studied using univariate analysis and multiple regression models. Complete baseline data were available in 19 patients with BA, 30 patients with CF, 25 patients with PCD, and 19 controls. The RBM was thicker in patients with BA (6.33 ± 1.22 µm), CF (5.60 ± 1.39 µm), and PCD (6.50 ± 1.87 µm) than in controls (3.29 ± 0.55 µm) (all P < 0.001). The LCI was higher in patients with CF (15.32 ± 4.58, P < 0.001) and PCD (10.97 ± 2.46, P = 0.002) than in controls (7.44 ± 0.43). The median follow-up times were 3.6, 4.8, 5.7, and 1.9 years in patients with BA, CF, PCD, and controls, respectively. The z-scores of FEV1 and FEV1/FVC deteriorated significantly in all groups except in controls. In patients with CF and PCD, trends in FEV1 z-scores correlated with baseline LCI and RBM; in BA, it correlated with collagen IV. In multiple regression models, RBM morphology and ventilation inhomogeneity could predict up to 84.4% of variability in spirometry trends. In conclusion, baseline LCI value and RBM morphology may predict trends in subsequent spirometry.NEW & NOTEWORTHY This paper deals with the relationship between reticular basement membrane (RBM) morphology at baseline and follow-up spirometry in children with asthma, cystic fibrosis, and primary ciliary dyskinesia. For the first time, to our knowledge, the possibility to predict subsequent lung function development using selected baseline characteristics (reticular basement membrane morphology from endobronchial biopsy and ventilation inhomogeneity from nitrogen multiple breath washout test) is proposed. Corresponding predictive models are presented.
Assuntos
Asma , Transtornos da Motilidade Ciliar , Fibrose Cística , Criança , Humanos , Seguimentos , Fibrose Cística/patologia , Volume Expiratório Forçado , Pulmão/patologia , Espirometria , Asma/patologia , Inflamação/patologia , Membrana Basal/patologia , ColágenoRESUMO
Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.
Assuntos
Doença Antimembrana Basal Glomerular , Glomerulonefrite , Ratos , Animais , Autoanticorpos , Laminina , Rim/patologia , Colágeno Tipo IV , Membrana Basal/patologia , AutoantígenosRESUMO
Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against the glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and severe alveolar hemorrhage. The noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, contains the main target autoantigen in this disease. Epitope mapping studies of α3(IV)NC1 have identified several nephritogenic epitopes and critical residues that bind to autoantibodies and trigger anti-GBM disease. The discovery of novel target antigens has revealed the heterogeneous nature of this disease. In addition, both epitope spreading and mimicry have been implicated in the pathogenesis of anti-GBM disease. Epitope spreading refers to the development of autoimmunity to new autoepitopes, thus worsening disease progression, whereas epitope mimicry, which occurs via sharing of critical residues with microbial peptides, can initiate autoimmunity. An understanding of these autoimmune responses may open opportunities to explore potential new therapeutic approaches for this disease. We review how current advances in epitope mapping, identification of novel autoantigens, and the phenomena of epitope spreading and mimicry have heightened the understanding of autoimmunity in the pathogenesis of anti-GBM disease, and we discuss prospects for immunotherapy.
Assuntos
Doença Antimembrana Basal Glomerular , Humanos , Doença Antimembrana Basal Glomerular/terapia , Autoanticorpos , Autoantígenos , Autoimunidade , Membrana Basal/patologia , Colágeno Tipo IV , Epitopos , ImunoterapiaRESUMO
In Alport mice, activation of the endothelin A receptor (ETA R) in mesangial cells results in sub-endothelial invasion of glomerular capillaries by mesangial filopodia. Filopodia deposit mesangial matrix in the glomerular basement membrane (GBM), including laminin 211 which activates NF-κB, resulting in induction of inflammatory cytokines. Herein we show that collagen α1(III) is also deposited in the GBM. Collagen α1(III) localized to the mesangium in wild-type mice and was found in both the mesangium and the GBM in Alport mice. We show that collagen α1(III) activates discoidin domain receptor family, member 1 (DDR1) receptors both in vitro and in vivo. To elucidate whether collagen α1(III) might cause podocyte injury, cultured murine Alport podocytes were overlaid with recombinant collagen α1(III), or not, for 24 h and RNA was analyzed by RNA sequencing (RNA-seq). These same cells were subjected to siRNA knockdown for integrin α2 or DDR1 and the RNA was analyzed by RNA-seq. Results were validated in vivo using RNA-seq from RNA isolated from wild-type and Alport mouse glomeruli. Numerous genes associated with podocyte injury were up- or down-regulated in both Alport glomeruli and cultured podocytes treated with collagen α1(III), 18 of which have been associated previously with podocyte injury or glomerulonephritis. The data indicate α2ß1 integrin/DDR1 co-receptor signaling as the dominant regulatory mechanism. This may explain earlier studies where deletion of either DDR1 or α2ß1 integrin in Alport mice ameliorates renal pathology. © 2022 Boys Town National Research Hospital. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Nefrite Hereditária , Podócitos , Animais , Membrana Basal/patologia , Colágeno Tipo III , Colágeno Tipo IV/genética , Receptor com Domínio Discoidina 1/genética , Membrana Basal Glomerular/patologia , Humanos , Integrina alfa2beta1 , Camundongos , Camundongos Knockout , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Podócitos/patologia , Pseudópodes/patologia , RNARESUMO
A seminal event in cancer progression is the ability of the neoplastic cell to mobilize the necessary machinery to breach surrounding extracellular matrix barriers while orchestrating a host stromal response that ultimately supports tissue-invasive and metastatic processes. With over 500 proteolytic enzymes identified in the human genome, interconnecting webs of protease-dependent and protease-independent processes have been postulated to drive the cancer cell invasion program via schemes of daunting complexity. Increasingly, however, a body of evidence has begun to emerge that supports a unifying model wherein a small group of membrane-tethered enzymes, termed the membrane-type matrix metalloproteinases (MT-MMPs), plays a dominant role in regulating cancer cell, as well as stromal cell, traffic through the extracellular matrix barriers assembled by host tissues in vivo. Understanding the mechanisms that underlie the regulation and function of these metalloenzymes as host cell populations traverse the dynamic extracellular matrix assembled during neoplastic states should provide new and testable theories regarding cancer invasion and metastasis.
Assuntos
Matriz Extracelular/patologia , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Neoplasias/patologia , Animais , Membrana Basal/patologia , Humanos , Células Estromais/patologiaRESUMO
In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet's basement membrane (DBM) critically regulate the localization, availability and, therefore, the functions of transforming growth factor (TGF)ß1, TGFß2, and platelet-derived growth factors (PDGF) that modulate myofibroblast development. Defective regeneration of the EBM, and notably diminished perlecan incorporation, occurs via several mechanisms and results in excessive and prolonged penetration of pro-fibrotic growth factors into the stroma. These growth factors drive mature myofibroblast development from both corneal fibroblasts and bone marrow-derived fibrocytes, and then the persistence of these myofibroblasts and the disordered collagens and other matrix materials they produce to generate stromal scarring fibrosis. Corneal stromal fibrosis often resolves completely if the inciting factor is removed and the BM regenerates. Similar defects in BM regeneration are likely associated with the development of fibrosis in other organs where perlecan has a critical role in the modulation of signaling by TGFß1 and TGFß2. Other BM components, such as collagen type IV and collagen type XIII, are also critical regulators of TGF beta (and other growth factors) in the cornea and other organs. After injury, BM components are dynamically secreted and assembled through the cooperation of neighboring cells-for example, the epithelial cells and keratocytes for the corneal EBM and corneal endothelial cells and keratocytes for the corneal DBM. One of the most critical functions of these reassembled BMs in all organs is to modulate the pro-fibrotic effects of TGFßs, PDGFs and other growth factors between tissues that comprise the organ.
Assuntos
Membrana Basal/patologia , Doenças da Córnea/patologia , Fibrose/patologia , Proteoglicanas de Heparan Sulfato/deficiência , Fator de Crescimento Transformador beta/metabolismo , Animais , Membrana Basal/metabolismo , Doenças da Córnea/genética , Doenças da Córnea/metabolismo , Fibrose/genética , Fibrose/metabolismo , Humanos , Fator de Crescimento Transformador beta/genéticaRESUMO
PURPOSE: To assess study design and a range of anatomical and functional changes after internal limiting membrane (ILM) peeling using forceps developed for atraumatic ILM pick-up compared to standard forceps. METHODS: We conducted a masked proof-of concept randomised controlled trial (RCT) on 65 patients who underwent ILM peeling for idiopathic full-thickness macular hole (FTMH) using etched-tip forceps (etched-tip group, 33 eyes) compared to standard ILM forceps (smooth-tip group, 32 eyes). Patients were assessed preoperatively, 3 weeks, 3 and 6 months postoperatively. RESULTS: The primary closure rate was 95.4%. There was no statistically significant difference between the groups in terms of final visual acuity (66.9 vs 70.9 ETDRS letters, p = 0.13), difference of visual field mean deviation (1.32 vs 1.14 decibels), and number of eyes with pick-up-related retinal haemorrhages (16% vs 16%, p = 0.96), swelling of arcuate nerve fibre layer lesions (63% vs 55%, p = 0.54), number of dissociated optic nerve fibre layer lesions (31.4 vs 41.0, p = 0.16), nor inner retina defects (37% vs 22%, p = 0.17). Similar changes in inner retinal volumes were detected in all 9 sectors of an ETDRS grid except for a trend (p = 0.06) towards a lower reduction in the inferior inner sector in the etched-tip group. CONCLUSIONS: The study was successfully completed with masking maintained and a low risk of bias. Multiple endpoints relating to ILM peeling were assessed, and estimates were provided that can be used for future studies. Although the study was not powered to assess any specific endpoint, the anatomical and functional outcomes assessed did not significantly differ.
Assuntos
Membrana Epirretiniana , Perfurações Retinianas , Humanos , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Membrana Epirretiniana/cirurgia , Vitrectomia , Membrana Basal/cirurgia , Membrana Basal/patologia , Tomografia de Coerência Óptica , Retina/patologia , Estudos RetrospectivosRESUMO
In light chain amyloidosis (LA), the massive glomerular and vascular amyloid deposition leading to interstitial fibrosis/tubular atrophy (IFTA) is thought to be responsible for renal failure. The amyloid deposition in the interstitium and the tubular basement membrane (TBM) has received less attention in the study of LA. We, therefore, collected clinical and laboratory data on patients diagnosed with LA in our Nephrology Department and studied amyloid deposition in the TBM. Twelve LA patients were diagnosed by renal biopsy during a seven-year period. In 4 of the 12, amyloid deposition could also be detected in the TBM. In our first case of a patient with diabetes mellitus, non-amyloid fibrils resembling 'diabetic fibrillosis' were also seen by electron microscopy. Despite the double damage, IFTA was negligible, blood vessels were unaffected, and the glomerular deposition was segmental. In the other three cases, significant (>50%) IFTA and a severely reduced estimated glomerular filtration rate were already detected at the time of diagnosis and amyloid deposition was also observed in the blood vessels. These findings indicate the importance of TBM amyloid deposition in the progression of renal disease. This may represent a late-stage presentation of the disease with a heavy LC burden.
Assuntos
Amiloidose , Nefropatias , Humanos , Rim/patologia , Amiloidose/diagnóstico , Amiloidose/patologia , Nefropatias/diagnóstico , Nefropatias/patologia , Glomérulos Renais/patologia , Membrana Basal/patologiaRESUMO
Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.
Assuntos
Doença Antimembrana Basal Glomerular , Animais , Humanos , Doença Antimembrana Basal Glomerular/tratamento farmacológico , Rituximab/uso terapêutico , Autoanticorpos , Ciclofosfamida/uso terapêutico , Fatores Biológicos , Membrana Basal/patologiaRESUMO
Both asthma and COPD are heterogeneous diseases identified by characteristic symptoms and functional abnormalities, with airway obstruction common in both diseases. Asthma COPD overlap (ACO) does not define a single disease but is a descriptive term for clinical use that includes several overlapping clinical phenotypes of chronic airways disease with different underlying mechanisms. This literature review was initiated to describe published studies, identify gaps in knowledge, and propose future research goals regarding the disease pathology of ACO, especially the airway remodeling changes and inflammation aspects. Airway remodeling occurs in asthma and COPD, but there are differences in the structures affected and the prime anatomic site at which they occur. Reticular basement membrane thickening and cellular infiltration with eosinophils and T-helper (CD4+) lymphocytes are prominent features of asthma. Epithelial squamous metaplasia, airway wall fibrosis, emphysema, bronchoalveolar lavage (BAL) neutrophilia, and (CD8+) T-cytotoxic lymphocyte infiltrations in the airway wall are features of COPD. There is no universally accepted definition of ACO, nor are there clearly defined pathological characteristics to differentiate from asthma and COPD. Understanding etiological concepts within the purview of inflammation and airway remodeling changes in ACO would allow better management of these patients.
Assuntos
Asma/etiologia , Asma/terapia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/terapia , Remodelação das Vias Aéreas , Asma/fisiopatologia , Membrana Basal/patologia , Transição Epitelial-Mesenquimal , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
Tubular basement membrane (TBM) deposits are very uncommon in non-lupus membranous nephropathy. We report 5 patients with membranous nephropathy and extensive TBM deposits following allogeneic hematopoietic cell transplant. Patients presented with nephrotic syndrome (3 also had acute kidney injury) late post-transplant in association with chronic graft-versus-host disease (cGVHD). Kidney biopsies revealed global subepithelial and extensive TBM immune complex deposits, accompanied by acute tubular injury (n = 4) and tubulointerstitial inflammation (n = 4). Proteomic analysis of glomeruli in 4 cases identified PLA2R in 1, with no significant protein spectra for PLA2R, THSD7A, EX1/2, NELL-1, PCDH7, NCAM1, or SEMA3B detected in the remaining 3. On follow-up (for a mean 42 months), 4 patients had complete and 1 partial remission following prednisone and/or rituximab therapy. We propose that membranous nephropathy with extensive TBM deposits is a distinctive clinicopathologic lesion associated with allogeneic hematopoietic cell transplant. Pathogenesis likely involves cGVHD-driven antibodies against glomerular and TBM components, the identity of which remains to be elucidated.