Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

Background

Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.

Bilateral breast keloids in an elderly woman associated with bilateral breast cancers and high concentration of serum tumor growth factor‐β

We report a case of bilateral annular breast keloids in a 72‐year‐old woman who had been suffering from bilateral breast cancers. Histopathologically, the keloids showed unique distribution of α‐SMA+, CD34? myofibroblasts and α‐SMA?, CD34+ fibroblasts depending on the region. High serum levels of tumor growth factor‐β were detected at 6 months after the development of the breast keloids, but not at 10 months. CD163‐positive cells were abundantly detected in the skin of the elevated portion of the keloids. In contrast, these cells were considerably less numerous in the skin of the central healing portion compared with the skin of the elevated expanding portion. One interesting idea based on these results is that high levels of tumor growth factor‐β released from CD163‐positive cells played a crucial role in the formation of breast keloids through active induction of fibroblast differentiation into myofibroblasts. The present case strongly supports the previously proposed idea that keloids can form as a paraneoplastic phenomenon in breast cancer patients with keloid constitution.     

Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.     

Role of the HLA System in the Pathogenesis of Dupuytren’s Disease

Dupuytren's disease (DD) is a familial, fibroproliferative, irreversible, and progressive disease of the palmar fascia, yet with unknown etiology. However, there is compelling evidence which has consistently suggested a genetic ethiopathogenesis given the high occurrence among the Northern European extraction, familial nature, and demonstration of concordance in twins. DD is an incurable, recurrent, and potentially debilitating disease with limited and ineffective treatments. Although a number of possible candidate genes have been investigated including matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-β) genes, as yet, no consistent genetic biomarker has been identified for DD. The highly polymorphic human leukocyte antigen (HLA) region is an ideal biomarker target. There have been some coherent data within the literature to suggest a genotype to phenotype association between certain HLA loci and a number of fibrotic disorders such as keloid and scleroderma, markedly with class II molecules and disease pervasiveness and clinical progression. The aim of this review, therefore, was to investigate the evidence indicative of both positive and negative associations between particular HLA alleles and DD. There is a clear association with specific HLA alleles and predilection or protection to DD, though there is a pressing need for further supportive data. The most promising of links to the HLA region in terms of a definitive genetic biomarker is with the class II HLA-DR loci. This paper presents a detailed account of the immunogenetic component of DD and explores the possible mechanisms of association between specific HLA molecules and susceptibility to DD.     

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

Background

An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO).

Objective

To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA).

Design, setting, and participants

Patients with NDO (n = 10) or IDO (n = 11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064.

Interventions

Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit.

Measurements

Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes).

Results and limitations

Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment.

Conclusions

Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.     

肌成纤维细胞与医源性胆管狭窄的相关性研究

目的探讨肌成纤维细胞（MFB）在医源性胆管狭窄形成过程中的作用及医源性胆管狭窄的形成机制。方法通过建立家兔肝外胆管损伤修复模型,分别于术后1周、3周、3个月、6个月取材行光镜、电镜观察,并免疫组织化学染色观察d平滑肌肌动蛋白（α-SMA）。结果MFB功能活跃,持续存在于整个胆道愈合过程;α-SMA表达于肌成纤维细胞胞浆,术后1周-6个月表达均较强,与正常对照比较差异有统计学意义（P〈0．01）,术后各期表达差异无统计学意义（P〉0．05）。结论MFB功能活跃,持续存在,是导致胆道瘢痕性挛缩和管腔狭窄的主要原因。     

CD34<Superscript>+</Superscript> fibrocytes in tubular carcinomas and radial scars of the breast

The present study was undertaken to analyze whether and to what extent CD34⁺ fibrocytes and -smooth muscle actin (-SMA)-positive myofibroblasts occur in the stroma of radial scars and tubular carcinoma of the breast. We investigated a total of 24 radial scars obtained from 23 females and a total of 43 tubular carcinomas. All tubular carcinomas showed a virtually complete loss of CD34⁺ fibrocytes paralleled by a gain of -SMA-positive myofibroblasts. The peripheral parts of radial scars harbored CD34⁺ fibrocytes comparable to normal breast tissue. In 23 of 24 radial scars, the central core was characterized by a loss of CD34⁺ fibrocytes accompanied by the presence of -SMA-positive myofibroblasts in six cases, a pattern that up to now has only been described in malignant breast lesions. This finding underlines the close relationship between tubular carcinomas and radial scars. We conclude CD34- and -SMA immunohistochemistry to be valuable adjunctive tools in distinguishing radial scars from tubular carcinomas. In the present study, the presence of CD34⁺ fibrocytes excluded malignancy. The absence of CD34⁺ fibrocytes paralleled by the presence of -SMA myofibroblasts indicated malignancy in most cases, although it has to be carefully considered that in a minority of cases (6 of 24) the central core of radial scars may disclose this stromal composition.This revised version was published online September 2003 with corrections to size and format of Fig. 1     

日本血吸虫感染兔肝肌成纤维细胞的动态变化及其意义

目的观察血吸虫病兔肝纤维化形成过程中肌成纤维细胞的动态变化,探讨肝纤维化发病机理。方法随机选取60只新西兰兔,每只感染日本血吸虫尾蚴（80±1）条,于感染后不同时间取其肝脏组织做成常规石蜡块,再分别进行HE染色、苦味酸天狼红染色及α－SMA免疫组织化学染色,然后观察肉芽肿大小动态变化情况,半定量分析肝纤维化程度及α－SMA阳性细胞即肌成纤维细胞表达情况;在感染后第28周用吡喹酮彻底杀虫治疗后进行γ-干扰素抗肝纤维化治疗,对照组用注射生理盐水。结果感染后第6周出现肉芽肿,大小为（13±6）×104μm2,第8周到达高峰,为（20±9）×104μm2,其后随时间的推移肉芽肿逐渐缩小,至感染后第24周后不再有明显变化（P＞0．05）,而肝纤维化程度逐渐加重;α－SMA阳性细胞于炎症早期在汇管区已有表达,为（1．1±0．3）分,炎症后期在病灶区及肝窦均有大量表达,为（7．3±1．5）分;感染后第28周生理盐水组肝纤维化程度达（5．3±1．9）分,模型组为（7．0±1．7）分,干扰素组则为（2．8±1．0）分。结论肝肌成纤维细胞是血吸虫病肝纤维化形成及发展的关键细胞。     

Immunohistochemical and electron microscopical characterization of stromal cells in nasopharyngeal angiofibromas

Twenty-eight cases of nasopharyngeal angiofibroma were studied immunohistochemically for cytoskeletal phenotyping of stromal cells. Electron microscopy was also used to study the ultrastructure of five of the tumors. All typical stromal cells showed intensive immunostaining for vimentin, but were negative for smooth muscle actin and desmin. Ultrastructurally, most of these cells appeared to be exclusively fibroblasts. However, in some areas stromal cells were seen that morphologically resembled myofibroblasts by their shapes and arrangement, and were characterized by the coexpression of vimentin and smooth muscle actin. Electron microscopy confirmed their myofibroblastic nature. The present study showed that the typical stromal cells in nasopharyngeal angiofibromas were fibroblasts and not myofibroblasts. In these tumors myofibroblasts occurred only focally, in connection with fibrotic areas and exclusively as a vimentin+/actin+ cytoskeletal phenotype. This indicates that myofibroblasts are not primary stromal tumor cells in nasopharyngeal angiofibromas, but occur due to regressive changes.     

Ultrastructural spectrum of solitary fibrous tumor: a unique perivascular tumor with alternative lines of differentiation

Eight tumors diagnosed as solitary fibrous tumor (SFT) of the oral cavity were studied. Histologic spectrum was entirely comparable with the extrapleural SFT of other sites. One tumor had glomus tumor-like foci. Immunohistochemical results confirmed most of the previous observations, indicating characteristic expression of vimentin, CD34, bcl-2, and CD99. Factor XIIIa and -smooth muscle actin were less commonly reactive and a very few cells were faintly positive for factor VIII-related antigen and Ulex europaeus agglutinin 1. All were essentially negative for S-100 protein, desmin, CD31, and CD68. In stark contrast to the conclusive immunoprofile, ultrastructural investigation of six tumors demonstrated considerable cellular heterogeneity. Other than fibroblasts, perivascular undifferentiated cells and pericytes predominated, but endothelial cells were regularly present. There was a distinctive proliferation of pericytic cells in four tumors, one of which had glomoid foci of myopericytes. The extreme increase in number of Weibel-Palade bodies occurred in voluminous capillary endothelium. Occasional single and clustered cells with consistent features of endothelium showed intracytoplasmic lumen formation. Such composite cells constituted an integral segment of richly vascularized SFT. Myofibroblastic form smooth muscle differentiation was present in only a minority of cells. From phenotypic analysis by electron microscopy, SFT may originate from a unique, perivascular multipotent mesenchyme sharing with its lineage with pericytes, fibroblasts, and infrequently, endothelium. Consequently, morphological features of SFT may become diversely varied by whether predominantly constituent cells are undifferentiated, pericytic or fibroblastic in nature.