Degradation Of Elastic Fibers Research Articles

Molecular mechanisms of green tea polyphenols with protective effects against skin photoaging

ABSTRACTWhereas green tea has historically been consumed in high quantities in Northeast Asia, its popularity is also increasing in many Western countries. Green tea is an abundant source of plant polyphenols exhibiting numerous effects that are potentially beneficial for human health. Accumulating evidence suggests that green tea polyphenols confer protective effects on the skin against ultraviolet (UV) irradiation-induced acceleration of skin aging, involving antimelanogenic, antiwrinkle, antioxidant, and anti-inflammatory effects as well as prevention of immunosuppression. Melanin pigmentation in the skin is a major defense mechanism against UV irradiation, but pigmentation abnormalities such as melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation can also cause serious health and aesthetic issues. Furthermore, UV irradiation initiates the degradation of fibrillar collagen and elastic fibers, promoting the process of skin aging through deep wrinkle formation and loss of tissue elasticity. UV irradiation-induced formation of free radicals also contributes to accelerated photoaging. Additionally, immunosuppression caused by UV irradiation plays an important role in photoaging and skin carcinogenesis. In this review, we summarize the current literature regarding the antimelanogenic, antiwrinkle, antioxidant, and immunosuppression preventive mechanisms of green tea polyphenols that have been demonstrated to protect against UV irradiation-stimulated skin photoaging, and gauge the quality of evidence supporting the need for clinical studies using green tea polyphenols as anti-photoaging agents in novel cosmeceuticals.

PET Imaging of Abdominal Aortic Aneurysm with 64Cu-Labeled Anti-CD105 Antibody Fab Fragment.

The critical challenge in abdominal aortic aneurysm (AAA) research is the accurate diagnosis and assessment of AAA progression. Angiogenesis is a pathologic hallmark of AAA, and CD105 is highly expressed on newly formed vessels. Our goal was to use (64)Cu-labeled anti-CD105 antibody Fab fragment for noninvasive assessment of angiogenesis in the aortic wall in a murine model of AAA. Fab fragment of TRC105, a mAb that specifically binds to CD105, was generated by enzymatic papain digestion and conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) for (64)Cu labeling. The binding affinity/specificity of NOTA-TRC105-Fab was evaluated by flow cytometry and various ex vivo studies. BALB/c mice were anesthetized and treated with calcium phosphate to induce AAA and underwent weekly PET scans using (64)Cu-NOTA-TRC105-Fab. Biodistribution and autoradiography studies were also performed to confirm the accuracy of PET results. NOTA-TRC105-Fab exhibited high purity and specifically bound to CD105 in vitro. Uptake of (64)Cu-NOTA-TRC105-Fab increased from a control level of 3.4 ± 0.1 to 9.5 ± 0.4 percentage injected dose per gram (%ID/g) at 6 h after injection on day 5 and decreased to 7.2 ± 1.4 %ID/g on day 12, which correlated well with biodistribution and autoradiography studies (i.e., much higher tracer uptake in AAA than normal aorta). Of note, enhanced AAA contrast was achieved, due to the minimal background in the abdominal area of mice. Degradation of elastic fibers and highly expressed CD105 were observed in ex vivo studies. (64)Cu-NOTA-TRC105-Fab cleared rapidly through the kidneys, which enabled noninvasive PET imaging of the aorta with enhanced contrast and showed increased angiogenesis (CD105 expression) during AAA. (64)Cu-NOTA-TRC105-Fab PET may potentially be used for future diagnosis and prognosis of AAA.

Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background.

Thoracic aortic aneurysms (TAA) are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.

Regulation of ABCC6 Trafficking and Stability by a Conserved C-terminal PDZ-Like Sequence

Mutations in the ABCC6 ABC-transporter are causative of pseudoxanthoma elasticum (PXE). The loss of functional ABCC6 protein in the basolateral membrane of the kidney and liver is putatively associated with altered secretion of a circulatory factor. As a result, systemic changes in elastic tissues are caused by progressive mineralization and degradation of elastic fibers. Premature arteriosclerosis, loss of skin and vascular tone, and a progressive loss of vision result from this ectopic mineralization. However, the identity of the circulatory factor and the specific role of ABCC6 in disease pathophysiology are not known. Though recessive loss-of-function alleles are associated with alterations in ABCC6 expression and function, the molecular pathologies associated with the majority of PXE-causing mutations are also not known. Sequence analysis of orthologous ABCC6 proteins indicates the C-terminal sequences are highly conserved and share high similarity to the PDZ sequences found in other ABCC subfamily members. Genetic testing of PXE patients suggests that at least one disease-causing mutation is located in a PDZ-like sequence at the extreme C-terminus of the ABCC6 protein. To evaluate the role of this C-terminal sequence in the biosynthesis and trafficking of ABCC6, a series of mutations were utilized to probe changes in ABCC6 biosynthesis, membrane stability and turnover. Removal of this PDZ-like sequence resulted in decreased steady-state ABCC6 levels, decreased cell surface expression and stability, and mislocalization of the ABCC6 protein in polarized cells. These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein.

The next generation of RAGE modulators: implications for soluble RAGE therapies in vascular inflammation

The next generation of RAGE modulators: implications for soluble RAGE therapies in vascular inflammation

Investigating the Role of (2S,4R)-4-Hydroxyproline in Elastin Model Peptides

Post-translational modifications play a key role in defining the biological functions of proteins. Among them, the hydroxylation of proline producing the (2S,4R)-4-hydroxyproline (Hyp) is one of the most frequent modifications observed in vertebrates, being particularly abundant in the proteins of the extracellular matrix. In collagen, hydroxylation of proline plays a critical role, conferring the correct structure and mechanical strength to collagen fibers. In elastin, the exact role of this modification is not yet understood. Here we show that Hyp-containing elastin polypeptides have flexible molecular structures, analogously to proline-containing polypeptides. In turn, the self-assembly of the elastin peptides is significantly altered by the presence of Hyp, evidencing different supramolecular structures. Also the in vitro susceptibility to protease digestion is changed. These findings give a better insight into the elastic fiber formation and degradation processes in the extracellular matrix. Furthermore, our results could contribute in defining the subtle role of proline structural variants in the folding and self-assembly of elastin-inspired peptides, helping the rational design of elastin biomaterials.

Micellar Electrokinetic Chromatography with Laser Induced Detection and liquid chromatography tandem mass-spectrometry-based desmosine assays in urine of patients with Chronic Obstructive Pulmonary Disease: A comparative analysis

Evidences accumulated over the past years that desmosines could be attractive indicators of elastic fibre degradation in Chronic Obstructive Pulmonary Disease have raised substantial interest with the development of reliable assays to measure their concentration in body fluids. It is a firm belief of researchers working in this field that accurate assessment of desmosine concentration would improve the understanding of elastin metabolism disorders and allow these cross-links to become a useful tool in the diagnosis and clinical management of these diseases. From among the variety of techniques available on the market, HPLC; CE and LC–MS have proved to be successful tools for measuring desmosines in biological fluids. However, differences in the analytical performance of methods may hinder the comparability of data, thus limiting the analytical strength and clinical utility of methods themselves. To address the relative contribution of different factors to the exact quantification of desmosines, the full potential of MEKC-LIF and LC–MS, the two systems that better than others offer more selective and sensitive detection for desmosine analysis, was studied on 56 urine samples. The results of this systematic comparative study underline the significant benefits of LC–MS over MEKC-LIF in terms of precision and sensitivity. Nevertheless, MEKC-LIF could be an attractive alternative in routine laboratories lacking the LC–MS instrumentation and skills to run these methods.

Calcification resistance for photooxidatively crosslinked acellular bovine jugular vein conduits in right-side heart implantation

This study aimed to investigate the effect of decellularization plus photooxidative crosslinking and ethanol pretreatment on bioprosthetic tissue calcification. Photooxidatively crosslinked acellular (PCA) bovine jugular vein conduits (BJVCs) and their photooxidized controls (n = 5 each) were sterilized in a graded concentration of ethanol solutions for 4 h, and used to reconstruct dog right ventricular outflow tracts. At 1-year implantation, echocardiography showed similar hemodynamic performance, but obvious calcification for the photooxidized BJVC walls. Further histological examination showed intense calcium deposition colocalized with slightly degraded elastic fibers in the photooxidized BJVC walls, with sparsely distributed punctate calcification in the valves and other areas of walls. But PCA BJVCs had apparent degradation of elastic fibers in the walls, with only sparsely distributed punctate calcification in the walls and valves. Content assay demonstrated comparable calcium content for the two groups at preimplantation, whereas less calcium for the PCA group in the walls and similar calcium in the valvular leaflets compared with the photooxidized group at 1-year retrieval. Elastin content assay presented the conduit walls of PCA group had less elastin content at preimplantation, but similar content at 1-year retrieval compared with the photooxidized group. Phospholipid analysis showed phospholipid extraction by ethanol for the PCA group was more efficacious than the photooxidized group. These results indicate that PCA BJVCs resist calcification in right-side heart implantation owing to decellularization, further photooxidative crosslinking, and subsequent phospholipid extraction by ethanol at preimplantation.

Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation

BackgroundAortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA.Methods and FindingsImmunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE−/− mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01–0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45–87% reduction, P<0.05). Similarly, EP4+/−/ApoE−/− mice exhibited significantly less AAA formation than EP4+/+/ApoE−/− mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/− mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10–100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release.ConclusionAn EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.

Analysis of the molecular mobility of collagen and elastin in safe, atheromatous and aneurysmal aortas

Aim of the studyIn this study, we propose to use a thermal technique, Differential Scanning Calorimetry (DSC) to follow the evolution of elastin and collagen in safe and pathological cardiovascular tissues. Patients and methodsThe first part of this study deals with the analysis of the elastin network and associated proteins during ageing (from children to old persons) in aortic walls. The second part is devoted to the characterization of the collagenic phase in aneurysms. In both cases, physical data are correlated with biochemical analyses. Results and conclusionFor old persons aortas with atheromatous stades, elastin and associated proteins are found to interpenetrate to form a homogenous phase. Abdominal aortic aneurysms (AAA) are characterized by structural alterations of the aortic wall resulting from the degradation of elastic fibers and an increase of collagen/elastin ratio. Notable modifications are evidenced between collagen from control tissue and collagen from AAA, particularly concerning the thermal denaturation. Biochemical and thermal results are compatible with the increase of new collagen deposition and/or impairment of the collagen phase stability in the extracellular matrix of AAAs.

Milk-flow, ultrasonographic, theloscopic, and histopathological characteristics of the teat in cows with toxic mastitis

The milk-flow, imaging, and histopathological characteristics of the teat in five cows with toxic mastitis were investigated. Teats were grouped into type I (without gross and histopathological abnormality), type II (no abnormal gross findings, but with histopathological abnormality), and type III (with gross and histopathological abnormality). Normal teats from six cows served as controls. Type II and III teats had lower milk-flow, compared with the controls. Ultrasonography revealed no abnormal findings, except for irregular mucosal surface in type II teats and absence of hyperechoic line along the teat canal in type III teats. The theloscopic findings varied from normal to mucosal abnormalities in type II and III teats. Histopathology demonstrated epithelial changes, congestion, hemorrhage, edema, cellular infiltration, and elastic fiber degradation in type II and III teats, with the type III teats showing severe changes. Toxic mastitis was characterized by impaired milk-flow and various degrees of imaging and histopathological abnormality.

Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice

Mechanical ventilation with O₂-rich gas (MV-O₂) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-β activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease. To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O₂-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest. Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O₂ for 8-24 hours; control animals breathed 40% O₂ without MV. At study's end, lungs were harvested to assess key variables noted below. MV-O₂ of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O₂-induced changes. Intratracheal elafin, by blocking lung protease activity, prevented MV-O₂-induced elastin degradation, TGF-β activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O₂. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O₂ and might be targeted therapeutically to prevent MV-O₂-induced lung injury.

Cutis laxa: analysis of metalloproteinases and extracellular matrix expression by immunohistochemistry and histochemistry

Upregulation of matrix metalloproteinases (MMPs) and downregulation of tissue inhibitors of metalloproteinases (TIMP) have been reported in cultured fibroblasts from patients with congenital cutis laxa (CL) or anetoderma. We determined the protein expressions of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, TIMP-1 and collagen I, collagen III in vivo, to confirm their roles in the pathogenesis of cutis laxa. The protein expression of the MMPs and collagens from skin lesions of CL were detected by immunohistochemistry and analyzed by image analysis software. Markedly increased MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, TIMP-1 associated with alteration of elastic and collagen fibers were found in two cases of CL, whereas increased MMP-3, MMP-9, MMP-12 accompanying a degradation of elastic fibers were detected in the third case. These results suggest an elevated expression of MMPs may play a role in the evolution or genesis of CL.

New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review

Calcific aortic stenosis is a progressive disease characterized by massive fibrosis andmineralization of the valve leaflets. The aim of this study was to determine whether the onset of native calcific aortic stenosis is associated primarily with matrix remodelling events, and particularly with elastin degradation. The immunohistochemical expression profile of matrix degradating enzymes and tenascin-C was investigated in both healthy and native calcified aortic valves. Collagen and elastic tissue were studied by light microscopy and electron microscopy. Immunophenotypic analysis of inflammatory cells was carried out by using monoclonal antibodies to macrophages, T and B lymphocytes. Immunoreactivity for tenascin-C and matrix metalloproteinase-12 (MMP-12) was associated with areas of dense mineralization, which were characterized by fibrosis, fragmentation and calcification of elastic fibres a positive reaction was also found around small islands of calcification. MMP-11 was not detected in the diseased valves. Osteopontin and osteonectin were also found at sites of mineralization. All calcified valves examined showed inflammatory cell infiltration. Our results demonstrate the direct involvement of MMP-12 in native aortic valve stenosis. MMP-mediated degradation of elastic fibres might contribute actively to valve mineralization by inducing calcium deposition onto fragmented elastin.

Pathogenesis of Involutional Ectropion and Entropion: The Involvement of Matrix Metalloproteinases in Elastic Fiber Degradation

Purpose: To determine the elastic fiber content and ultrastructure as well as the expression of elastin-degrading enzymes in biopsy specimens from patients with involutional ectropion and entropion.Materials and Methods: Twenty consecutive patients with involutional ectropion (group 1) and twenty consecutive patients with entropion (group 2) were matched with twenty control patients (basal cell carcinoma) regarding age and gender. Full-thickness eyelid resections performed in study and control patients were examined by light and transmission electron microscopy, computer-assisted measurements, and immunohistochemistry using antibodies against matrix metalloproteinase (MMP)-2, MMP- 7, and MMP-9. The Kruskal-Wallis test and the Pearson chi-square test were performed.Results: Histopathologic analysis of the surgical specimens from patients with involutional ectropion and entropion showed a significant loss of elastic fibers in the eyelid skin, the pretarsal orbicularis oculi muscle, the perimeibomian tarsal stroma, and the intermeibomian tarsal stroma (P < 0.001). Residual elastic fibers revealed an abnormal ultrastructure. Immunohistochemistry demonstrated a significant overexpression of MMP- 2, MMP-7, and MMP-9 in the eyelid skin, the pretarsal orbicularis oculi muscle, the perimeibomian tarsal stroma, the intermeibomian tarsal stroma, and the conjunctiva in groups 1 and 2 compared to controls (P < 0.001).Conclusions: The present findings indicate that upregulation of elastolytic enzymes contributes to elastic fibre degradation in patients with involutional ectropion and entropion.

Elastolysis mediodermalis - case report and review of literature

Elastolysis mediodermalis is a rare disorder typically observed in middle-aged women. Sites of predilection are the trunk and upper arms. The clinical picture varies and may appear as cigarette paper-like wrinkling, perifollicular protrusions or reticular erythema. In contrast to the different clinical morphology, there is a consistent histology, i. e. localized, band-shaped, and rarely focal loss of elastic fibers in the middle dermis. The etiology of elastolysis mediodermalis is unclear. UV radiation or immunological mechanisms may increase the release of matrix metalloproteinases, leading to a degradation of elastic fibers. There is no effective treatment for this condition.

Role of Elastic Fibers on Cardiovascular Disease

An important factor in the transition from an open to a closed circulatory system was a change in vessel wall that are dynamic structure composed of cells and extracellular matrix. The component of arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle cells. Elastin and elastin associated protein are synthesized and secreted by vascular smooth muscle cells and are the major extracellular matrix component deposited in the vascular wall. Pathological states related to hypertension or atherosclerosis is associated with vascular wall remodeling, which is deleterious for cardiovascular function. Elastic fiber may be key factors in the pathophysiology of hypertensive or atherosclerotic vascular remodeling. The well-known effects of cardiovascular disease on the deterioration and the promoted degradation of elastic fiber result to loss of arterial wall resilience. Recently, several studies have highlighted new roles for individual components of elastic fiber and their degraded products. This review describes current knowledge regarding components of elastic fibers and discusses relationship between their structural abnormalities and cardiovascular diseases.

Characterization of aneurysmal aortas by biochemical, thermal, and dielectric techniques

Abdominal aortic aneurysms (AAA) are characterized by structural alterations of the aortic wall resulting from the degradation of elastic fibres and an increase of collagen/elastin ratio. In this study we investigated the chain dynamics of AAA tissues by two techniques generally used for the characterization of polymers, Differential scanning calorimetry (DSC) and thermally stimulated currents (TSC), and we correlated the obtained data with biochemical analyses. The thermal denaturation of collagen observed by DSC allowed us to evaluate the thermal stability of the triple helix domain: notable modifications were evidenced between collagen from control tissue and collagen from AAA, particularly concerning the thermal denaturation. The dielectric analysis of pathologic aortic walls by TSC revealed a relevant change of collagen mobility in AAA, with the occurrence of a specific mode of relaxation between -60 and -40°C. Biochemical, thermal, and dielectric results are compatible with increase of new collagen deposition and/or impairment of the collagen phase stability in the extracellular matrix of AAAs.

Mammary-type Tubulolobular Carcinoma of Anogenital Mammary-like Glands With Prominent Stromal Elastosis

To the Editor: Following the original description of mammary type tubulolobular carcinoma of the anogenital area, presumably originating in anogenital mammary-like glands (AGMLG) in 2006,7 we have recently observed a similar case. The neoplasm in this newly encountered case fulfilled the criteria for a tubulolobular carcinoma as defined in mammary pathology,5 and was almost identical to the original cutaneous example.7 Additionally, there was prominent stromal elastosis, a feature identical to that seen in association with invasive breast carcinomas, and not earlier recognized in carcinomas of the anogenital area. The patient was a 45-year-old female who presented with a 2-cm, asymptomatic solitary nodule in the vulva with unknown duration. Clinical investigation revealed no extracutaneous involvement; specifically, there was no mammary tumor. An enlarged lymph node in the right inguinal area was noted, but it proved negative on sentinel node biopsy, as did 2 other lymph nodes from the same region, and 3 left inguinal lymph nodes removed during a lymphadenectomy. After a wide surgical excision (specimen 4×2×1.2 cm), the patient is alive without signs of metastasis or recurrence at 4-year follow-up. Histopathologically, the tumor was composed of uniform round-to-ovoid cells arranged in a single-file pattern intermixed with areas manifesting round tubules often showing decapitation secretion at the luminal border. The neoplastic elements were arranged in a targetoid fashion or grew diffusely. The tubules were mainly composed of a single-cell layer without any evidence of a peripheral myoepithelial cell layer. Rare small solid aggregations were also noted. There were areas with perineural and intraneural invasion, especially in the foci, in which the tumor areas resembled an infiltrative lobular carcinoma (Figs. 1A–D). Immunohistochemically, the tumor cells in both ductal-like and lobular-like components reacted positively for E-cadherin. A remarkable feature was the prominent stromal elastosis emerging as clumps and masses of elastic material around individual neoplastic tubules (periductal elastosis) within the stroma (diffuse elastosis) and in association of vessel walls (vascular elastosis) highlighted by elastic stains (Fig. 1E, F). The residua of intact AGMLG were not recognized.FIGURE 1.: An infiltrative neoplasm in the dermis (A) containing areas with tubular formation and areas resembling infiltrative lobular carcinoma of the breast; areas of periductal, diffuse, and vascular elastosis can be discerned (B–D). Stromal elastosis is highlighted by elastic stains (E, F).In the breast, tubulolobular carcinoma was originally described as a tubular variant of lobular carcinoma,5 but many investigators nowadays regard neoplasm as a variant of invasive ductal carcinoma with a lobular growth pattern.2,12 There was only 1 earlier report of this tumor type in the skin.7 The neoplasm was suggested to originate from AGMLG, a normal constituent of the anogenital area, earlier considered to represent ectopic breast tissue.14 Lesions of AGMLG show a striking microscopic resemblance to their mammary counterparts.15 A majority of these lesions are epithelial or biphasic stromal epithelial neoplasms, including fibroadenoma and phyllodes tumors.8,9,10 Stromal changes in lesions of AGMLG seem to be also identical to those seen in their mammary counterparts. The most prominent stromal lesion is probably pseudoangiomatous stromal hyperplasia recognized in the anogenital area in 2005.6 In this case study, stromal elastosis seemed identical to that seen in mammary carcinomas. This feature is unusual for dermatopathologic cases. The prototype of the changes in the elastic tissue compartment, sometimes associated with cutaneous neoplasms, is a solar elastosis attributed to the degradation of collagen or elastic fibers owing to excessive sun exposure. Stromal elastosis in mammary carcinoma is an entirely different pathologic process characterized by the presence of excess elastic fibers in a diffuse manner within the stroma in the periductal location or around blood vessels. It is usually seen in invasive mammary carcinomas, especially ductal carcinomas but has been rarely found in benign lesions3 or even intact breast, wherein it is less prominent.4 Infiltrating neoplastic cells, when invading the basal lamina of the mammary ducts, are thought to stimulate periductal fibroblasts or myofibroblasts to produce elastic fibers.1,11,13 In normal circumstances, these cells are not engaged in elastic fibers production. Grossly, such stromal elastosis can be recognized as “chalky streaks.”1 This case of tubulolobular carcinoma of the vulva further highlights similarities between lesions of AGMLG and their mammary counterparts, including “secondary” stromal phenomena. Stromal elastosis is not a feature in invasive carcinomas of the skin, regardless of the histopathologic type. The likely explanation is that the stroma of AGMLG is physiologically different from the dermis and reacts to various stimuli in a manner similar to the mammary stroma. Maria Teresa Fernandez-Figueras, MD* Michal Michal, MD† Dmitry V. Kazakov, MD, PhD† *Department of Pathology Hospital Universitari Germans Trias i Pujol, Autonomous University of Barcelona Barcelona, Spain †Sikl's Department of Pathology Charles University Medical Faculty Hospital Pilsen, Czech Republic

Tissu conjonctif de soutien et genèse des prolapsus

The pathophysiology of pelvic floor disorders still remains not well understood. Increasing age as well as vaginal multiparity are the main commonly accepted factors. The hypothesis of a defect of connective tissues of the pelvic floor with aging due to collagen deficiency and/or elastic fiber degradation is often highlighted. The issue of a potential protective role of HRT is also discussed although the recent results from the WHI would suggest a negative impact of HRT on urinary incontinence, especially when HRT is initiated in elderly women, far from the menopause. Nevertheless, environmental factors cannot explain the full pathogenesis of pelvic organ prolapse (POP) and the contribution of genetic factors to the development of pelvic floor disorders is widely recognized. Support for a genetic influence on POP derives from reports suggesting that heritability is a strong contributing factor and a familial history of POP is considered as a classical risk factor. However, the characterization of the underlying molecular mechanisms remains limited, since POP may be considered the end result of a multifactorial process leading to destruction of vaginal wall connective tissue. Experimental studies in mice with null mutations in the genes encoding different putative factors involved in elastic fibers remodeling and homeostasis are crucial in the understanding of the pathogenesis of POP. Mice with null mutation in the gene encoding lysyl oxidase-like 1 ( LOXL1) or fibulin-5, demonstrate signs of elastinopathy including the development of a POP in the postpartum. Likewise, homeobox genes such as HOXA11, which are essential in the embryonic development of the urogenital tract might also be involved in the pathogenesis of POP. The better understanding of the underlying determinants of pelvic floor disorders with a special focus on genetic factors may offer new therapeutic strategies, in addition to or replacement of surgical procedures.