Fibroproliferative Disorders Research Articles

Alleviation of the doxorubicin-induced nephrotoxicity by fasudil in vivo and in vitro

ObjectiveTreatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by side effects. We have previously demonstrated that fasudil, a Rho/ROCK inhibitor, has antioxidant, anti-inflammatory and anti-apoptotic effects in contrast-induced acute kidney injury model. The present study to investigated the possible protective effect of fasudil, on DOX-induced nephrotoxicity. Materials and methodIn vivo: Forty male C57BL/6 male mice were randomly divided into 4 groups: Control group, DOX treatment group (DOX group), DOX + low dose fasudil (DOX + L group), DOX + high dose fasudil (DOX + H group). Mice in 2–4 groups received DOX (2.5 mg/kg, i.p.) once a week for 8 weeks. The 3 and 4 group were given 2 mg/kg/d or 10 mg/kg/d fasudil before DOX injection. respectively. Meanwhile, the control group received saline. At the end of week eight, blood samples were collected for biochemical testing. The kidneys were removed for histological, immunohistochemical, Western blot, quantitative real-time PCR (qRT-PCR), and molecular detection. In vitro: NRK-52E cells were treated with 40 uM fasudil for 12 h, then incubated with 1 uM DOX for 24 h. Cells then collected for qRT-PCR and Western blot. ResultsIn vivo, fasudil treatment ameliorated DOX-induced immunofluorescence reaction of DNA damage-related factors (8-OHdG), decreased the expression of Bax, Caspase-3, p16, p21 and p53, and increased the expression of protein of Bcl-2, Bmi-1 and Sirt-1. In the mouse model, administration of fasudil significantly ameliorated DOX-induced kidney damage, suppressed cell apoptosis and senescence, ameliorated redox imbalance and DNA damage. At the same time, DOX produced obvious kidney damage revealed by kidney functions changes: increased serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations. In addition, kidney tissue staining in the DOX group showed abnormal structure and fibroproliferative disorders. And DOX could promote the oxidation and senescence of kidney cells, leading to increased expression of 8-OHdG and senescence and apoptosis-related factors. On the contrary, fasudil treatment can effectively inhibit redox imbalance and DNA damage caused by DOX, and inhibit cell senescence and apoptosis. Fasudil can inhibit excessive activation of Rho/ROCK signaling pathway, thereby improving kidney tissue fibrosis and recovery kidney function. ConclusionFasudil has a protective effect on DOX-induced nephrotoxicity in mice and NRK-52E cells, which can inhibit oxidative stress and DNA damage, inhibit apoptosis, and delays cell senescence by inhibiting RhoA/Rho kinase (ROCK) signaling pathway.

Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis.

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Lysyl oxidase (LOX) is a copper-dependent amine oxidase whose primary function is the covalent crosslinking of collagens in the extracellular matrix (ECM). We investigated the role of LOX in the pathophysiology of SSc. LOX mRNA and protein levels were increased in lung fibroblasts of SSc patients compared with healthy controls and IPF patients. In vivo, bleomycin induced LOX mRNA expression in lung tissues, and LOX activity increased in the circulation of mice with pulmonary fibrosis, suggesting that circulating LOX parallels levels in lung tissues. Circulating levels of LOX were reduced upon amelioration of fibrosis with an antifibrotic peptide. LOX induced ECM production at the transcriptional level in lung fibroblasts, human lungs, and human skin maintained in organ culture. In vivo, LOX synergistically exacerbated fibrosis in bleomycin-treated mice. Further, LOX increased the production of interleukin (IL)-6, and the increase was mediated by LOX-induced c-Fos expression, the nuclear localization of c-Fos, and its engagement with the IL-6 promoter region. Our findings demonstrate that LOX expression and activity correlate with fibrosis in vitro, ex vivo, and in vivo. LOX induced ECM production via upregulation of IL-6 and nuclear localization of c-Fos. Thus, LOX has a direct pathogenic role in SSc-associated fibrosis that is independent of its crosslinking function. Our findings also suggest that measuring circulating LOX levels and activity can be used for monitoring response to antifibrotic therapy.

Serious complications and risk of re-operation after Dupuytren\u2019s disease surgery: a population-based cohort study of 121,488 patients in England

Dupuytren’s disease (DD) is a common fibro-proliferative disorder of the palm. We estimated the risk of serious local and systemic complications and re-operation after DD surgery. We queried England’s Hospital Episode Statistics database and included all adult DD patients who were surgically treated. A longitudinal cohort study and self-controlled case series were conducted. Between 1 April 2007 and 31 March 2017, 121,488 adults underwent 158,119 operations for DD. The cumulative incidence of 90-day serious local complications was low at 1.2% (95% CI 1.1–1.2). However, the amputation rate for re-operation by limited fasciectomy following dermofasciectomy was 8%. 90-day systemic complications were also uncommon at 0.78% (95% CI 0.74–0.83), however operations routinely performed under general or regional anaesthesia carried an increased risk of serious systemic complications such as myocardial infarction. Re-operation was lower than previous reports (33.7% for percutaneous needle fasciotomy, 19.5% for limited fasciectomy, and 18.2% for dermofasciectomy). Overall, DD surgery performed in England was safe; however, re-operation by after dermofasciectomy carries a high risk of amputation. Furthermore, whilst serious systemic complications were unusual, the data suggest that high-risk patients should undergo treatment under local anaesthesia. These data will inform better shared decision-making regarding this common condition.

The Effect of Roselle (Hibiscus sabdariffa L.) Flowers Extract on the Apoptosis of Fibroblast Proliferation in Keloids

BACKGROUND: Keloid is a benign fibroproliferative dermal disorder as a result of dysregulation wound healing process in susceptible individuals. The pathogenesis is not clearly known yet, but upregulation of transforming growth factor-β1 (TGF-β1) was found to have a significant role in inducing hyperproliferation of fibroblast cells. Roselle (Hibiscus sabdariffa L.) flower extract has been found to have high content of polyphenols. Some studies have shown inhibition effect of H. sabdariffa polyphenols extract on TGF-β1, and as result affects fibroblast proliferation. Therefore, roselle flower extract might have a significant role in the prevention of keloid formation.
 AIM: The objective of the study was to determine the effect of roselle flower extract on fibroblast cells proliferation in human keloid.
 METHODS: An experimental controlled trial of 10 different concentrations (1.96 μg/ml, 3.91 μg/ml, 7.81 μg/ml, 15.63 μg/ml, 31.25 μg/ml, 62.50 μg/ml, 125 μg/ml, 250 μg/ml, 500 μg/ml, and 1000 μg/ml) of roselle (H. sabdariffa L.) flower extract was done on cultured fibroblast cells originated from human keloid biopsied tissue. Tunnel assay was done to evaluate the apoptosis rate of the cultured fibroblast cells on each concentration. Determination of TGF-β1 titer of the cultured human keloid fibroblast cells in and cytotoxicity assay of the extract on cultured normal human fibroblast cells in each concentration were done with enzyme-linked immunosorbent assay method. All the assays were done in triple repetition. Statistical analysis using linear regression test was done to determine the association between the concentration of roselle flower extract with apoptosis rate and TGF-β1 titer. One-way ANOVA was used to analyze the results of cytotoxicity assay.
 RESULTS: Apoptosis rate of the cultured fibroblast cells was found to be increased dose dependently with roselle flower extract concentration (r2 = 0.797; p < 0.05). TGF-β1 titer was inversely related with the extract concentration (r2 = 0.501; p < 0.05). Cytotoxicity assay revealed that no differences in absorbance value and viability cells were found in each concentration.
 CONCLUSION: Roselle (H. sabdariffa L.) flower extract was found to induce apoptosis of the cultured fibroblast cells and reduction of TGF-β1 titer in dose-dependent pattern, without cytotoxicity effect against human fibroblast cells.

Anti-fibrotic Actions of Equine Interleukin-10 on Transforming Growth Factor-Beta1-Stimulated Dermal Fibroblasts Isolated From Limbs of Horses.

Fibroproliferative disorders occur in both humans and horses following skin injury. In horses, wound healing on the limb is often complicated by the formation of fibroproliferative exuberant granulation tissue, characterized by persistent expression of pro-fibrotic transforming growth factor-beta1 (TGF-β1) and deficient expression of anti-inflammatory interleukin-10 (IL-10). IL-10 has been shown to directly modulate fibrotic gene expression in human fibroblasts, so we hypothesized that equine IL-10 (eIL-10) may exert similar anti-fibrotic effects on equine dermal fibroblasts. Cell-lines were created from the limb skin of six individual horses. Recombinant eIL-10 was produced and purified, and its effects on the cells investigated in the presence and absence of equine TGF-β1 (eTGF-β1). Myofibroblast differentiation and collagen production were examined using immunofluorescent cytometry, cell contractility in a collagen gel assay, and fibrotic gene expression using quantitative PCR. In response to eTGF-β1, fibroblasts increased in contractility and expression of alpha-smooth muscle actin, collagen types 1 and 3, and matrix metalloproteinase 1, 2, and 9. Equine IL-10 limited cell contractility and production of alpha-smooth muscle actin and type 3 collagen, and decreased mRNA levels of eCol3a1 and eMMP9, while increasing that of eMMP1. Opposing effects on eTGF-βR3 and eIL-10R1 gene expression were also observed, with mRNA levels decreasing following eTGF-β1 treatment, and increasing with eIL-10 treatment. These findings indicate that eIL-10 limits the pro-fibrotic effects of eTGF-β1, potentially through the modulation of fibrotic and receptor gene expression. Further investigations are warranted to assess the therapeutic utility of eIL-10 in the treatment of exuberant granulation tissue.

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy.

Neuronal Precursor Cell Expressed Developmentally Down Regulated 4 (NEDD4) Gene Polymorphism Contributes to Keloid Development in Egyptian Population.

BackgroundKeloids represent chronic fibroproliferative skin disorders in which there is deposition of extracellular components, especially type 1 collagen, fibronectin and elastin, in excessive amounts. NEDD4 is associated with fibrosis found in abnormal wound healing through increased fibroblast proliferation and regulation of type 1 collagen expression. The exact etiology of keloid formation is undefined, but the role of genetic factors was demonstrated.ObjectiveTo investigate the polymorphism of the NEDD4 gene rs8032158 in a sample of Egyptian patients who have keloids.MethodsThe current case–control study was conducted in 160 unrelated subjects; 100 keloid patients and 60 ages and sex coincided with apparently healthy controls. All subjects underwent a complete history, and weight and length were measured to calculate body mass index (BMI). The Vancouver Scar Scale (VSS) was used to assess keloid severity. An analysis of the polymorphism of the NEDD4 gene rs8032158 T/C was performed using taqman allelic discrimination (real-time PCR).ResultsThe rs8032158 CC genotype was observed significantly in keloid patients and increased the risk of keloid development by approximately 2 times (p = 0.003, OR = 1.80). The C allele significantly increased the risk of keloid development by approximately 2 times (P = 0.002, OR = 2.08). The carriers of the CC genotype were significantly associated with severe keloid form and with the highest VSS values.ConclusionThe polymorphism of the NEDD4 gene rs8032158 could participate in the formation of keloids in the Egyptian population. The NEDD4 rs8032158 CC genotype may have a role in keloid severity.

Dupuytren's Contracture: Incidence of Injury-Induced Cases and Specific Clinical Expression.

Background and objectives: Dupuytren’s contracture is a chronic fibroproliferative hand disorder with a varying pattern of genetic predisposition across different regions and populations. Traumatic events have been found to have influence on the development of this illness and are likely to trigger different clinical forms of this disease. The aim of this study was to evaluate the phenomenon of development of Dupuytren’s contracture (DC) following an acute injury to the hand, and to observe the incidence and clinical diversity of such cases in daily clinical practice. Materials and Methods: We collected data of patients presenting with primary Dupuytren’s contracture in the Lithuanian population and evaluated the occurrence and clinical manifestation of this specific type of DC, arising following acute hand trauma. The diagnosis of DC was based on clinical signs and physical examination. Digit contractures were measured by goniometry, and the staging was done according to Tubiana classification. Injury-induced (injury-related) cases were identified using the “Criteria for recognition of Dupuytren’s contracture after acute injury” (established by Elliot and Ragoowansi). Results: 29 (22%) of a total of 132 cases were injury-induced DCs. Twenty-six of 29 patients in this group presented with stage I–II contractures. Duration of symptoms was 6 (SD 2.2) and 3.8 (SD 2.2) years in the injury-related and injury-unrelated DC groups, respectively. Mean age on the onset of symptoms in the injury-induced and non-injury-induced groups was 52 (SD 10.7) and 56 (SD 10.9), respectively. Patients from both groups expressed strong predisposition towards development of DC. Conclusions: Around one-fifth of patients seeking treatment for primary Dupuytren’s contracture seemed to suffer from injury-induced Dupuytren’s contracture. We noted that injury to the wrist and hand seems to trigger the development of less progressive Dupuytren’s contracture in younger age. Prospective randomized studies are required to confirm our findings.

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

Tissue fibrosis underlies the majority of human mortality to date with close to half of all reported deaths having a fibrotic etiology. The progression of fibrosis is very complex and reputed irreversible once established. Although some preventive options are being reported, therapeutic options are still scarce and in very high demand, given the rise of diseases linked to fibroproliferative disorders. Our work explored four platforms, complementarily, in order to screen preventive and therapeutic potentials of the antiparasitic drug Praziquantel as a possible antifibrotic. We applied the mouse CCl4-driven liver fibrosis model, the mouse chronic schistosomiasis liver fibrosis model, as well as novel 2D and 3D human cell-based co-culture of human hepatocytes, KCs (Kupffer cells), LECs (Liver Endothelial Cells), HSCs (Hepatic Stellate Cells) and/or myofibroblasts to mimic in vivo fibrotic responses and dynamics. Praziquantel showed some effect on fibrosis marker when preventively administered before severe establishment of fibrosis. However, it failed to potently reverse already established fibrosis. Together, we provided a novel sophisticated multi-assay screening platform to test preventive and therapeutic antifibrotic candidates. We further demonstrated a direct preventive potential of Praziquantel against the onset of fibrosis and the confirmation of its lack of therapeutic potential in reversing already established fibrosis.

Benefits of extracorporeal shock waves for keloid treatment: A pilot study

Keloids are fibroproliferative skin disorders characterized by the progressive deposition of collagen. Recently, extracorporeal shock wave therapy (ESWT) has been used to treat pathologic scars. Herein, we conducted a study to compare the efficacy of intralesional injections (ILIs) of triamcinolone acetonide (TA) used alone, or in combination with ESWT for keloids. Forty patients were randomized equally into two groups in this 12-week comparative clinical trial. Group A was treated with TA ILIs and ESWT, and group B was treated with TA ILIs alone. At week 12, both groups showed acceptable improvements in nearly all dimensions evaluated, and these improvements were statistically more significant in group A. Group A showed a higher mean percentage reduction in lesion length, width, and height and in the Vancouver Scar Scale score than group B (all P < .05). More patients in group A than in group B had scores of ≥4, which indicated improvements that were good or excellent, on the patient global assessment and investigator global assessment. No serious adverse events occurred. This study suggests that ESWT could be a new, effective and acceptable adjuvant treatment option for keloids.

Overview on Keloid Disorder: Phenotypic Spectrum, Connective Tissue Pathology, and Treatment Development

Overview on Keloid Disorder: Phenotypic Spectrum, Connective Tissue Pathology, and Treatment Development

Comprehensive Strategy for Keloid Treatment: Experience at Shanghai Ninth People's Hospital

ABSTRACT Keloids are a notorious fibroproliferative disorder that may cause cosmetic concerns and life inconvenience. Various methods such as surgery, injection, and laser have been used; however, single treatments are at risk of recurrence; therefore, comprehensive therapy is the better solution. Here, we focused on the management of different medical interventions according to subjective and objective conditions of keloid patients and summarized several clinical comprehensive strategies based on our clinical experience. One original concept of laser combined with radiotherapy was also introduced as a promising method, especially for wide-based pathological scars.

The Keloid Disorder: Heterogeneity, Histopathology, Mechanisms and Models.

Keloids constitute an abnormal fibroproliferative wound healing response in which raised scar tissue grows excessively and invasively beyond the original wound borders. This review provides a comprehensive overview of several important themes in keloid research: namely keloid histopathology, heterogeneity, pathogenesis, and model systems. Although keloidal collagen versus nodules and α-SMA-immunoreactivity have been considered pathognomonic for keloids versus hypertrophic scars, conflicting results have been reported which will be discussed together with other histopathological keloid characteristics. Importantly, histopathological keloid abnormalities are also present in the keloid epidermis. Heterogeneity between and within keloids exists which is often not considered when interpreting results and may explain discrepancies between studies. At least two distinct keloid phenotypes exist, the superficial-spreading/flat keloids and the bulging/raised keloids. Within keloids, the periphery is often seen as the actively growing margin compared to the more quiescent center, although the opposite has also been reported. Interestingly, the normal skin directly surrounding keloids also shows partial keloid characteristics. Keloids are most likely to occur after an inciting stimulus such as (minor and disproportionate) dermal injury or an inflammatory process (environmental factors) at a keloid-prone anatomical site (topological factors) in a genetically predisposed individual (patient-related factors). The specific cellular abnormalities these various patient, topological and environmental factors generate to ultimately result in keloid scar formation are discussed. Existing keloid models can largely be divided into in vivo and in vitro systems including a number of subdivisions: human/animal, explant/culture, homotypic/heterotypic culture, direct/indirect co-culture, and 3D/monolayer culture. As skin physiology, immunology and wound healing is markedly different in animals and since keloids are exclusive to humans, there is a need for relevant human in vitro models. Of these, the direct co-culture systems that generate full thickness keloid equivalents appear the most promising and will be key to further advance keloid research on its pathogenesis and thereby ultimately advance keloid treatment. Finally, the recent change in keloid nomenclature will be discussed, which has moved away from identifying keloids solely as abnormal scars with a purely cosmetic association toward understanding keloids for the fibroproliferative disorder that they are.

Keloid and Hypertrophic Scar Formation, Prevention, and Management: Standard Review of Abnormal Scarring in Orthopaedic Surgery.

Keloid and hypertrophic scar formation after orthopaedic surgical closure is a complex issue. The nature and location of procedures maximize wound tension, leave foreign bodies, and diminish dermal supply, all potentiating keloid formation. There is little discussion regarding the pathophysiology and management of this recurrent problem in orthopaedic literature. Keloid formation is a fibroproliferative disorder resulting in extensive production of extracellular matrix and collagen, but prevention and treatment is poorly understood. Patient and surgical factors contributing to the development of this condition are discussed. The treatments include both medical and surgical therapies that work at a biologic level and attempt to produce a cosmetic and complication-free management strategy. Medical options that have been investigated include combinations of intralesional steroid therapy, laser therapy, and biologics. Preventive surgical closure and excision remain mainstays of treatment. Radiation therapy has also been used in refractory cases with mixed results. Despite medical therapies and surgical excision aimed at treating the resulting scar, recurrence rate is very high for all modalities that have been studied to this point. Future work is being done to better understand the pathophysiology leading to keloid and hypertrophic scar formation in an effort to find preventive methods as compared to treatment strategies.

Tratamiento no quirúrgico de la enfermedad de Dupuytren con aponeurotomía percutánea con aguja: 10 años de experiencia

IntroductionDupuytren's disease is a fibroproliferative disorder of the palmar aponeurosis that leads to digital flexion contractures. This disabling condition can be treated with a minimally invasive procedure, called percutaneous needle aponeurotomy (PNA). ObjectiveTo report the results of 10 years of experience treating Dupuytren's contracture by PNA in the rheumatology hand unit of our department. MethodsWe conducted a retrospective study with a description of method to perform PNA and analysis of post-procedure results. ResultsThere were 197 patients with Dupuytren's disease. Ninety-eight patients (49.7%) underwent PNA, corresponding to 117 treated fingers. Good immediate results were achieved in 84% of the patients, with results being better in those with less advanced stages. Recurrences occurred in 12% of the patients. The complication rate was 1.7%. ConclusionOur results confirm the value of this technique especially in the early stages of Dupuytren's disease, with immediate satisfactory results and a low rate of complications.

Comparison of Nd: YAG Laser and Combined Intense Pulsed Light and Radiofrequency in the Treatment of Hypertrophic Scars: A Prospective Clinico-Histopathological Study.

Hypertrophic scars are fibroproliferative disorders, seen after burn, trauma, and/or surgery. We aimed to compare the clinical and histopathological results of 1064-nm Nd:YAG laser and combined intense pulsed light and radiofrequency in the treatment of hypertrophic scars. Fifty patients with hypertrophic scars were included in this prospective, randomized study. Twenty-five patients were treated with Nd:YAG laser and 25 patients with combined intense pulsed light and radiofrequency (E-light). The scars were evaluated at baseline, during and at 3 months after the final treatment session using the Vancouver scar scale. Biopsy specimens from scars were obtained before, during, and 3 months after the final treatment session and were stained with hematoxylin and eosin stain, Masson's trichrome stain, and immunostaining procedures for collagen I, collagen III, and TGF-β1. Significant improvements in the total Vancouver scar scale scores before and after the treatment in both groups (P < 0.001); however, a significant difference between both groups (P < 0.001), regarding the E-light, which showed better response than Nd:YAG laser. Hematoxylin and eosin and Masson's trichrome staining showed arrangement and thinning of collagen bundles and reduction in collagen density by in both groups, but the collagen bundles thinning and parallelism were more obvious in the E-light group. Significant decrease in the concentration of collagen I, collagen III, and TGF-β1 in the E-light group as compared with the laser group (P = 0.005, P = 0.003 and P < 0.001, respectively). Both modalities were successful in the treatment of hypertrophic scars; however, a significant improvement in the clinical and histopathological findings was detected with the E-light method.

Shedding LIGHT and TL1A on fibrosis

Abstract Anti-inflammatory drugs have so far failed to reduce fibrosis and tissue remodeling in the clinic. Alternatively, 5 TNF inhibitors have been FDA approved to treat different inflammatory diseases and are safe to administer to patients. In human, LIGHT and its receptors have been linked to numerous autoimmune and inflammatory diseases with fibrotic components. We show that blocking LIGHT signaling in isolation is efficient in reducing fibrosis in the skin and lung of mice induced with bleomycin to mimic human SSc and IPF, as well as in 2 severe allergen-driven models of asthma and atopic dermatitis. Neutralizing LIGHT signaling through its receptors by genetic deletion or antibody blocking, dramatically decreased fibrosis in the lungs and skins. Moreover the specific deletion of LIGHT-receptor HVEM on keratinocytes or the therapeutic blocking of LIGHT-HVEM interaction post-disease onset, abrogated skin fibrosis. LIGHT seems to play a central role since it can control the expression of major pro-fibrotic factors such as TSLP, IL-13, TGF-b and Periostin. Also LIGHT alone can induce a fibro-proliferative disorder that mimics human SSc, when administered alone. Lastly we observed an upregulation of LIGHT and its receptors in lung biopsies of patients suffering from asthma, SSc and IPF. More recently, we discovered another TNF family Member called TL1A can also potentiate fibrosis similarly to LIGHT and which signaling can promote tissue remodeling. Using antagonistic fusion proteins to neutralize LIGHT and TL1A signaling, we treated skin fibrosis and observed greater efficacy when LIGHT and TL1A were targeted concomitantly. The relevance of this work to fibrosis therapies associated with asthma, AD, SSc and IPF are tremendous.

Larp6 Regulates Collagen mRNA by Targeted Unwinding of a Conserved Stem‐Loop

Collagen is the most abundant protein in the human body and a key component of the extracellular matrix. Regulation of collagen production in key to the development of fibroproliferative disorders; everything from scarring to cardiovascular disease. La ribonucleoprotein 6 (Larp6) is an RNA binding protein which has recently been shown to regulate collagen production by binding to a conserved region at the translation start site of collagen mRNA. This interaction appears to be critical to directing RNA to the rough ER for translation initiation. Additionally, LARP6 interaction with a number of molecular chaperones appears to be important for regulating collagen production. We hypothesize that LARP6 utilizes conformational selection in the recognition and discrimination of collagen mRNAs and that tertiary interactions dictate mRNA fate. In vitro RNA chaperone assays, translation assays, RNAi, confocal microscopy, and NMR and SAX structural studies are employed to interrogate these interactions. New information regarding the structures and dynamics that determine the Larp6 interaction with collagen mRNA may inform novel therapeutic targets that can mitigate fibroproliferative disease.Support or Funding InformationP20GM109095

Prevalence of Peyronie and Ledderhose Diseases in a Series of 730 Patients with Dupuytren Disease.

Dupuytren, Peyronie, and Ledderhose diseases are related fibroproliferative disorders characterized by abnormalities in the connective tissue of the palm of the hand, the tunica albuginea of the penis, and the sole of the foot, respectively. Concomitant prevalence rates of these diseases have only been described in a few small populations. This article aims to report on a large population and to raise awareness in surgeons treating Dupuytren disease for concurring related fibroproliferative disorders. Patients diagnosed as having Dupuytren disease were recruited from outpatient clinics in the northern part of the Netherlands from 2007 to 2016. Questionnaires concerning demographics, clinical characteristics, the coexistence of Ledderhose and/or Peyronie diseases, and other factors were filled in by the participants and by plastic surgeons. For 730 men with Dupuytren disease, the surgeons' reported prevalence rate of Peyronie disease was 7.8 percent and of Ledderhose disease was 16.1 percent. The participants themselves reported prevalence rates of 8.8 percent for Peyronie disease and of 22.0 percent for Ledderhose disease. In the Dupuytren patient cohort, the prevalence of Peyronie disease was lower than that described in the literature. The prevalence of Ledderhose disease corresponded with the rates from the literature. However, both were underreported by plastic surgeons, which calls for a rise in awareness, recognition, and referral to a urologist when the conditions are bothersome or symptomatic.

Modulation of NLRP3 Inflammasome through Formyl Peptide Receptor 1 (Fpr-1) Pathway as a New Therapeutic Target in Bronchiolitis Obliterans Syndrome.

Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. We investigated, using transgenic mice, the mechanisms through which the deficiency of IL-1β/IL-18, Casp-1, or Fpr-1 genes could be protective in an experimental model of BOS, induced in mice by allogeneic heterotopic tracheal transplantation. Fpr-1 KO mice showed a marked reduction in histological markers of BOS and of mast cell numbers compared to other groups. Molecular analyses indicated that the absence of the Fpr-1 gene was able to decrease NF-κB nuclear translocation and modulate NLRP3 inflammasome signaling and the mitogen-activated protein kinase (MAPK) pathway in a more significant way compared to other groups. Additionally, Fpr-1 gene deletion caused a reduction in resistance to the apoptosis, assessed by the TUNEL assay. Immunohistochemical analyses indicated changes in nitrotyrosine, PARP, VEGF, and TGF-β expression associated with the pathology, which were reduced in the absence of the Fpr1 gene more so than by the deletion of IL-1β/IL-18 and Casp-1. We underline the importance of the NLRP3 inflammasome and the pathogenic role of Fpr-1 in experimental models of BOS, which is the result of the modulation of immune cell recruitment together with the modulation of local cellular activation, suggesting this gene as a new target in the control of the pathologic features of BOS.