Scarring Response Research Articles

A comparison of two types of preperitoneal mesh prostheses in stoma surgery: application to an animal model

The aim of this study is to compare the integration of two types of prostheses (high and low density, written as HD and LD, respectively) implanted around the stoma to reinforce the abdominal wall to prevent parastomal eventration. The surgical technique used for preperitoneal placement of the prostheses is also described. We performed terminal sigmoid colostomies on 16 porcine animals. In 8 of the animals, HD prostheses were placed around the stoma in preperitoneal position, while in the other 8, we implanted wide-pore LD prostheses using the same surgical technique. The following macroscopic variables were then measured: adhesion, extrusion, stenosis, and retraction. A morphological study was also carried out to evaluate the foreign body reaction and the formation of neovascularization and collagen. All animals were killed 3months after surgery. Differences were observed with regard to retraction (47±17.8% for HD vs. 55±19.4% for LD) and extrusion (50% for HD vs. 0% for LD). These differences did not reach statistical significance. There was a great amount of scarring for both types of prostheses, with stomal stenosis being observed in all cases. The number and consistency of intra-abdominal adhesions was low and similar for both types of prostheses. Neither eventration nor necrosis was observed for either type. With regard to the tissue response, we observed both fibrosis and calcification phenomena in the peristomal areas of the LD prostheses. In the HD group, there was both a lower scarring response and a higher foreign body response, with the areas of the prostheses remaining intact. Both types of prostheses are appropriate for preperitoneal placement in the experimental model used, leading to few intra-abdominal adhesions. Still, due to their integration characteristics, LD prostheses are more appropriate for implanting around the colon since they do not seem to lead to extrusions. When using prostheses, however, it is also essential to consider the important phenomenon of retraction, which is more common with LD mesh.

A mechanochemical model of striae distensae

Striae distensae, otherwise known as stretch marks, are common skin lesions found in a variety of clinical settings. They occur frequently during adolescence or pregnancy where there is rapid tissue expansion and in clinical situations associated with corticosteroid excess. Heralding their onset is the appearance of parallel inflammatory streaks aligned perpendicular to the direction of skin tension. Despite a considerable amount of investigative research, the pathogenesis of striae remains obscure. The interpretation of histologic samples – the major investigative tool – demonstrates an association between dermal lymphocytic inflammation, elastolysis, and a scarring response. Yet the primary causal factor in their aetiology is mechanical; either skin stretching due to underlying tissue expansion or, less frequently, a compromised dermis affected by normal loads. In this paper, we investigate the pathogenesis of striae by addressing the coupling between mechanical forces and dermal pathology. We develop a mathematical model that incorporates the mechanical properties of cutaneous fibroblasts and dermal extracellular matrix. By using linear stability analysis and numerical simulations of our governing nonlinear equations, we show that this quantitative approach may provide a realistic framework that may account for the initiating events.

Transforming growth factor β1-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1

BackgroundTransforming growth factor-β1 (TGF-β1) is an important regulator of cell migration and plays a role in the scarring response in injured brain. It is also reported that 5-lipoxygenase (5-LOX) and its products, cysteinyl leukotrienes (CysLTs, namely LTC4, LTD4 and LTE4), as well as cysteinyl leukotriene receptor 1 (CysLT1R) are closely associated with astrocyte proliferation and glial scar formation after brain injury. However, how these molecules act on astrocyte migration, an initial step of the scarring response, is unknown. To clarify this, we determined the roles of 5-LOX and CysLT1R in TGF-β1-induced astrocyte migration.MethodsIn primary cultures of rat astrocytes, the effects of TGF-β1 and CysLT receptor agonists on migration and proliferation were assayed, and the expression of 5-LOX, CysLT receptors and TGF-β1 was detected. 5-LOX activation was analyzed by measuring its products (CysLTs) and applying its inhibitor. The role of CysLT1R was investigated by applying CysLT receptor antagonists and CysLT1R knockdown by small interfering RNA (siRNA). TGF-β1 release was assayed as well.ResultsTGF-β1-induced astrocyte migration was potentiated by LTD4, but attenuated by the 5-LOX inhibitor zileuton and the CysLT1R antagonist montelukast. The non-selective agonist LTD4 at 0.1 to 10 nM also induced a mild migration; however, the selective agonist N-methyl-LTC4 and the selective antagonist Bay cysLT2 for CysLT2R had no effects. Moreover, CysLT1R siRNA inhibited TGF-β1- and LTD4-induced astrocyte migration by down-regulating the expression of this receptor. However, TGF-β1 and LTD4 at various concentrations did not affect astrocyte proliferation 24 h after exposure. On the other hand, TGF-β1 increased 5-LOX expression and the production of CysLTs, and up-regulated CysLT1R (not CysLT2R), while LTD4 and N-methyl-LTC4 did not affect TGF-β1 expression and release.ConclusionsTGF-β1-induced astrocyte migration is, at least in part, mediated by enhanced endogenous CysLTs through activating CysLT1R. These findings indicate that the interaction between the cytokine TGF-β1 and the pro-inflammatory mediators CysLTs in the regulation of astrocyte function is relevant to glial scar formation.

Hepatic Stimulator Substance Alleviates Toxin-Induced and Immune-Mediated Liver Injury and Fibrosis in Rats

Liver fibrosis is a common scarring response to chronic liver injury. It is a precursor to cirrhosis and liver carcinoma. Hepatic stimulator substance (HSS), a known liver-specific but species-nonspecific growth factor, has been shown to protect hepatocytes from various toxins. We have investigated the effects of HSS therapy on carbon tetrachloride (CCl(4))-induced and porcine-serum-mediated hepatic injury and fibrosis. We hypothesize that HSS might attenuate liver injury and fibrosis by suppressing oxidative stress, down-regulating profibrogenic factors, and blocking HSCs activation. This report demonstrated that HSS therapy diminished α-smooth muscle actin expression, decreased intrahepatic reactive oxygen species (ROS) level, and down-regulated transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF)-BB, and tissue inhibitor of metalloproteinase (TIMP)-1 expression. In addition, HSS treatment significantly protected the liver from injury by improving liver function tests and histological architecture of the liver. These results provided novel insights into the mechanisms of HSS in the protection of the liver. Our results suggested that HSS might be a therapeutic antifibrotic agent for the treatment of liver fibrosis.

Modulation of Postoperative Scarring with Tacrolimus and Octreotide in Experimental Glaucoma Filtration Surgery

Purpose: The purposes of this study were to investigate the effects of topically administrated Tacrolimus and Octreotide on modulation of postoperative scarring in experimental glaucoma filtration surgery and to compare the antifibrotic properties of these agents with mitomycin-C (MMC).Material and methods: A total of 28 New Zealand rabbits weighing 2.5–3 kg were randomly divided into a surgical control (SC) group and three experimental groups. Standard filtration surgeries were performed on the right eyes of all the rabbits. The rabbits in the SC group received only vehicle after the surgeries, whereas the rabbits in the three experimental groups were treated either with 0.4 mg/mL MMC during the surgery (MMC group) or with 0.3 mg/mL Tacrolimus drop four times a day (TT group) or with 10 µg/mL Octreotide drop three times a day (OT group) for 14 days. The animals were killed on day 14, eyes were enucleated and histologically and immunohistochemically analyzed.Results: In SC group mean fibroblast, mononuclear cell number and fibroblast growth factor-β (FGF-β), transforming growth factor-β (TGF-β) immunostaining intensity was higher than all treatment groups. In OT group mean fibroblast number was lesser than MMC (p < 0.01) and TT (p < 0.05) group. In TT group mean fibroblast number was lesser than MMC group (p < 0.05). Mean mononuclear cell number was similar between MMC, OT and TT groups (p > 0.05). In MMC, OT and TT groups mean TGF-β and FGF-β immunostaining intensity was similar (p > 0.05).Conclusions: Topically administration of Tacrolimus and Octreotide effectively reduced the subconjuntival scarring response 2 weeks after experimental glaucoma filtration surgery.

Clinical strategies for the alleviation of contractures from a predictive mathematical model of dermal repair

Hypertrophic scars arise when there is an overproduction of collagen during wound healing. These are often associated with poor regulation of the rate of programmed cell death (apoptosis) of the cells synthesizing the collagen or by an exuberant inflammatory response that prolongs collagen production and increases wound contraction. Severe contractures that occur, e.g., after a deep burn, can cause loss of function especially if the wound is over a joint such as the elbow or knee. Recently, we have developed a morphoelastic mathematical model for dermal repair that incorporates the chemical, cellular, and mechanical aspects of dermal wound healing. Using this model, we examine pathological scarring in dermal repair by first assuming a smaller than usual apoptotic rate for myofibroblasts, and then considering a prolonged inflammatory response, in an attempt to determine a possible optimal intervention strategy to promote normal repair, or terminate the fibrotic scarring response. Our model predicts that in both cases it is best to apply the intervention strategy early in the wound healing response. Further, the earlier an intervention is made, the less aggressive the intervention required. Finally, if intervention is conducted at a late time during healing, a significant intervention is required; however, there is a threshold concentration of the drug or therapy applied, above which minimal further improvement to wound repair is obtained.

The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda.

Globally, BCG vaccination varies in efficacy and has some non-specific protective effects. Previous studies comparing BCG strains have been small-scale, with few or no immunological outcomes and have compared TB-specific responses only. We aimed to evaluate both specific and non-specific immune responses to different strains of BCG within a large infant cohort and to evaluate further the relationship between BCG strain, scarring and cytokine responses. Infants from the Entebbe Mother and Baby Study (ISRCTN32849447) who received BCG-Russia, BCG-Bulgaria or BCG-Denmark at birth, were analysed by BCG strain group. At one year, interferon-gamma (IFN-γ), interleukin (IL)-5, IL-13 and IL-10 responses to mycobacteria-specific antigens (crude culture filtrate proteins and antigen 85) and non-mycobacterial stimuli (tetanus toxoid and phytohaemagglutinin) were measured using ELISA. Cytokine responses, scar frequency, BCG associated adverse event frequency and mortality rates were compared across groups, with adjustments for potential confounders. Both specific and non-specific IFN-γ, IL-13 and IL-10 responses in 1341 infants differed between BCG strain groups including in response to stimulation with tetanus toxoid. BCG-Denmark immunised infants showed the highest cytokine responses. The proportion of infants who scarred differed significantly, with BCG scars occurring in 52.2%, 64.1% and 92.6% of infants immunised with BCG Russia, BCG-Bulgaria and BCG-Denmark, respectively (p<0.001). Scarred infants had higher IFN-γ and IL-13 responses to mycobacterial antigens only than infants without a scar. The BCG-Denmark group had the highest frequency of adverse events (p=0.025). Mortality differences were not significant. Both specific and non-specific immune responses to the BCG vaccine differ by strain. Scarring after BCG vaccination is also strain-dependent and is associated with higher IFN-γ and IL-13 responses to mycobacterial antigens. The choice of BCG strain may be an important factor and should be evaluated when testing novel vaccine strategies that employ BCG in prime-boost sequences, or as a vector for other vaccine antigens.

Gingival Fibroblasts Display Reduced Adhesion and Spreading on Extracellular Matrix: A Possible Basis for Scarless Tissue Repair?

Unlike skin, oral gingiva do not scar in response to injury. The basis of this difference is likely to be revealed by comparing the responses of dermal and gingival fibroblasts to fibrogenic stimuli. Previously, we showed that, compared to dermal fibroblasts, gingival fibroblasts are less responsive to the potent pro-fibrotic cytokine TGFβ, due to a reduced production of endothelin-1 (ET-1). In this report, we show that, compared to dermal fibroblasts, human gingival fibroblasts show reduced expression of pro-adhesive mRNAs and proteins including integrins α2 and α4 and focal adhesion kinase (FAK). Consistent with these observations, gingival fibroblasts are less able to adhere to and spread on both fibronectin and type I collagen. Moreover, the enhanced production of ET-1 mRNA and protein in dermal fibroblasts is reduced by the FAK/src inhibitor PP2. Given our previous observations suggesting that fibrotic fibroblasts display elevated adhesive properties, our data suggest that scarring potential may be based, at least in part, on differences in adhesive properties among fibroblasts resident in connective tissue. Controlling adhesive properties may be of benefit in controlling scarring in response to tissue injury.

Melittin attenuates liver injury in thioacetamide-treated mice through modulating inflammation and fibrogenesis

Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Following injury, an acute inflammation response takes place resulting in moderate cell necrosis and extracellular matrix damage. Melittin, the major bioactive component in the venom of honey bee Apis mellifera, is a 26-residue amphipathic peptide with well-known cytolytic, antimicrobial and proinflammatory properties. However, the molecular mechanisms responsible for the anti-inflammatory activity of melittin have not been elucidated in liver fibrosis. We investigated whether melittin ameliorates liver inflammation and fibrosis in thioacetamide (TAA)-induced liver fibrosis. Two groups of mice were treated with TAA (200 mg/L, in drinking water), one of the groups of mice was co-treated with melittin (0.1 mg/kg) for 12 weeks while the other was not. Hepatic stellate cells (HSCs) were cultured with tumor necrosis factor α in the absence or presence of melittin. Melittin suppresses the expression of proinflammatory cytokines through the nuclear factor (NF)-κB signaling pathway. Moreover, melittin reduces the activity of HSCs in vitro, and decreases the expression of fibrotic gene responses in TAA-induced liver fibrosis. Taken together, melittin prevents TAA-induced liver fibrosis by inhibiting liver inflammation and fibrosis, the mechanism of which is the interruption of the NF-κB signaling pathway. These results suggest that melittin could be an effective agent for preventing liver fibrosis.

Augmenter of liver regeneration (ALR) gene therapy attenuates CCl4-induced liver injury and fibrosis in rats

Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Augmenter of liver regeneration (ALR) has been shown to protect hepatocytes from various toxins. The aim of this study was to investigate the effects of ALR gene therapy on liver injury and fibrosis induced by CCl4 in rats and further explore the underlying mechanisms. Human ALR expression plasmid was delivered via the tail vein. ALR gene therapy might protect the liver from CCl4-induced injury and fibrogenesis by attenuating the mitochondrial dysfunction, suppressing oxidative stress, and inhibiting activation of HSCs. This report demonstrated that ALR gene therapy protected against the ATP loss, increased the activity of ATPase, decreased intrahepatic reactive oxygen species level, and down-regulated transforming growth factor-β1, platelet-derived growth factor-BB, and α-smooth muscle actin expression. Following gene transfer liver function tests were significantly improved. In brief, ALR gene therapy might be an effective therapeutic reagent for liver fibrosis with potential clinical applications.

Mechanical Tension Increases CCN2/CTGF Expression and Proliferation in Gingival Fibroblasts via a TGFβ-Dependent Mechanism

Unlike skin, oral gingival do not scar in response to tissue injury. Fibroblasts, the cell type responsible for connective tissue repair and scarring, are exposed to mechanical tension during normal and pathological conditions including wound healing and fibrogenesis. Understanding how human gingival fibroblasts respond to mechanical tension is likely to yield valuable insights not only into gingival function but also into the molecular basis of scarless repair. CCN2/connective tissue growth factor is potently induced in fibroblasts during tissue repair and fibrogenesis. We subjected gingival fibroblasts to cyclical strain (up to 72 hours) using the Flexercell system and showed that CCN2 mRNA and protein was induced by strain. Strain caused the rapid activation of latent TGFβ, in a fashion that was reduced by blebbistatin and FAK/src inhibition, and the induction of endothelin (ET-1) mRNA and protein expression. Strain did not cause induction of α-smooth muscle actin or collagen type I mRNAs (proteins promoting scarring); but induced a cohort of pro-proliferative mRNAs and cell proliferation. Compared to dermal fibroblasts, gingival fibroblasts showed reduced ability to respond to TGFβ by inducing fibrogenic mRNAs; addition of ET-1 rescued this phenotype. Pharmacological inhibition of the TGFβ type I (ALK5) receptor, the endothelin A/B receptors and FAK/src significantly reduced the induction of CCN2 and pro-proliferative mRNAs and cell proliferation. Controlling TGFβ, ET-1 and FAK/src activity may be useful in controlling responses to mechanical strain in the gingiva and may be of value in controlling fibroproliferative conditions such as gingival hyperplasia; controlling ET-1 may be of benefit in controlling scarring in response to injury in the skin.

Validation of the Glaucoma Filtration Surgical Mouse Model for Antifibrotic Drug Evaluation

Glaucoma is a progressive optic neuropathy, which, if left untreated, leads to blindness. The most common and most modifiable risk factor in glaucoma is elevated intraocular pressure (IOP), which can be managed surgically by filtration surgery. The postoperative subconjunctival scarring response, however, remains the major obstacle to achieving long-term surgical success. Antiproliferatives such as mitomycin C are commonly used to prevent postoperative scarring. Efficacy of these agents has been tested extensively on monkey and rabbit models of glaucoma filtration surgery. As these models have inherent limitations, we have developed a model of glaucoma filtration surgery in the mouse. We show, for the first time, that the mouse model typically scarred within 14 d, but when augmented with mitomycin C, more animals maintained lower intraocular pressures for a longer period of time concomitant with prolonged bleb survival to beyond 28 d. The morphology of the blebs following mitomycin C treatment also resembled well-documented clinical observations, thus confirming the validity and clinical relevance of this model. We demonstrate that the antiscarring response to mitomycin C is likely to be due to its effects on conjunctival fibroblast proliferation, apoptosis and collagen deposition and the suppression of inflammation. Indeed, we verified some of these properties on mouse conjunctival fibroblasts cultured in vitro. These data support the suitability of this mouse model for studying the wound healing response in glaucoma filtration surgery, and as a potentially useful tool for the in vivo evaluation of antifibrotic therapeutics in the eye.

The inhibitory effect of chimeric decoy oligodeoxynucleotide in the regulation of transcription factors NF‐¥êB and Sp1 in an animal model of liver cirrhosis

Liver fibrosis is a process of healing and scarring in response to chronic liver injury. Following injury an acute inflammation response takes place resulting in moderate cell necrosis and extracellular matrix damage. To develop a novel therapeutic approach in hepatic fibrogenesis, we examined the simultaneous suppression of the transcription factor NF‐κB and Sp1, which regulate acute inflammation and continuous deposition of extracellular matrix in liver fibrosis. In this study, we employed chimeric decoy oligodeoxynucleotide containing the consensus sequences of both NF‐κB and Sp1 binding sites, to suppress these transcription factors simultaneously. Treatment of chimeric decoy oligodeoxynucleotide reduced the activity of hepatic stellate cells in vitro, and decreased the expression of fibrotic and proinflammatory gene responses in a mouse model of liver fibrosis. These results suggest that chimeric decoy oligodeoxynucleotide strategy might be the potential therapeutic application to prevent liver fibrosis.

SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery.

간경화 동물모델에서 Chimeric decoy oligodeoxynucleotide로 억제되는 NF-κB와 Sp1 전사인자 발현 억제 효과에 대한 연구

간섬유화는 지속적인 간세포 손상에 대한 수복현상으로 일어나며, 급성 염증반응과 같은 손상이 주어진 후에는 간세포의 괴사 및 세포외기질의 축적이 일어나게 된다. 간섬유화에 대한 새로운 치료방법을 모색하기 위하여 본 연구에서는 간섬유화 과정에서 염증 반응과 관련된 NF-<TEX>$\kappa$</TEX>B와 세포외기질의 축적과 관련된 Sp1전사인자를 동시에 조절하여 간섬유화 억제효과를 관찰하고자 하였다. 전사인자인 Sp1과 NF-<TEX>$\kappa$</TEX>B를 동시에 억제하기 위하여 한 분자 내에 Sp1과 NF-<TEX>$\kappa$</TEX>B의 전사인자와 결합하는 부위를 가지는 Chimeric (Chi) decoy oligodeoxynucleotide (ODN)을 제작하였다. Chi decoy ODN은 활성화된 간성상세포에서 간섬유화 와 관련된 유전자 발현을 억제시켰으며, 섬유화 동물모델에서도 간 조직의 염증 반응 및 섬유화 관련 인자의 발현을 현저히 억제시켰다. 따라서 Chi decoy ODN은 간섬유화 및 활성화된 간성상세포의 활성을 억제할 수 있는 유전자 치료제로 고려될 수 있을 것으로 사료된다. Liver fibrosis is a process of healing and scarring in response to chronic liver injury. Following injury, an acute inflammation response takes place resulting in moderate cell necrosis and extracellular matrix damage. To develop a novel therapeutic approach in hepatic fibrogenesis, we examined the simultaneous suppression of the transcription factors NF-<TEX>$\kappa$</TEX>B and Sp1, which regulate acute inflammation and continuous deposition of extracellular matrix in liver fibrosis. We employed chimeric decoy oligodeoxynucleotide containing the consensus sequences of both NF-<TEX>$\kappa$</TEX>B and Sp1 binding sites, to suppress these transcription factors simultaneously. Treatment of chimeric decoy oligodeoxynucleotide reduced the activity of hepatic stellate cells in vitro, and decreased the expression of fibrotic and proinflammatory gene responses in a mouse model of liver fibrosis. These results suggest that chimeric decoy oligodeoxynucleotide strategy can be a potential therapeutic application to prevent liver fibrosis.

Assessment of the Integrin α5β1 Antagonist JSM6427 in Proliferative Vitreoretinopathy Using In Vitro Assays and a Rabbit Model of Retinal Detachment

To explore the role of integrin alpha5beta1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression alpha5beta1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule alpha5beta1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model. Expression of alpha5beta1 was evaluated on activated ARPE-19 cells by flow cytometry and on PVR membranes by immunohistochemistry. ARPE-19 cells were used in fibronectin-dependent adhesion and migration assays with various concentrations of JSM6427; IC(50) was calculated. In the rabbit model, eyes were intravitreally injected with vehicle or JSM6427 on day 0 or 1 after retinal detachment; BrdU was administered intravitreally on day 3, and retinal tissues were harvested on day 3 (4 hours later) or 7. Retinal scarring, cellular proliferation, and inflammatory responses were quantified, and retinal morphology was analyzed in retinal sections. Activated ARPE-19 cells and PVR membranes expressed high levels of alpha5beta1; expression was low in control eyes. JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC(50), 7.1 +/- 2.5 microM) and inhibition of migration (IC(50), 6.0 +/- 4.5 microM). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (Müller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachment. JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of alpha5beta1-fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.

Combined Treatment with Bevacizumab and 5-Fluorouracil Attenuates the Postoperative Scarring Response after Experimental Glaucoma Filtration Surgery

This study evaluated the use of combined bevacizumab with 5-fluorouracil (5-FU) on postoperative scarring and bleb survival after experimental glaucoma filtration surgery in comparison to the agents alone. Filtration surgery was performed on 26 female New Zealand White rabbits. The rabbits were allocated to one of four treatments: 5-FU combined with bevacizumab, 5-FU alone, bevacizumab alone, or phosphate buffered saline (PBS). The subconjunctival injections were administered immediate postoperatively and weekly for 3 weeks. Clinical assessment and bleb photography were performed. Histologic staining determined the presence of subconjunctvial fibrosis and mRNA expression of collagen I and fibronectin in the tissue was quantified. Bevacizumab in combination with 5-FU resulted in a greater antifibrotic effect compared with monotherapy with 5-FU or bevacizumab alone, as evidenced by the attenuation in fibronectin and mature collagen I expression and deposition (P < 0.05). In addition, this was associated with a 100% bleb survival at day 28 in the combined treatment group compared with monotherapy (50% bevacizumab [P < 0.05] and 25% 5-FU [P < 0.001]). Conjunctival vascularity significantly reduced with bevacizumab treatment both alone and in combination with 5-FU. The results provide compelling evidence that combined bevacizumab and 5-FU offers superior antifibrotic effect over monotherapy in a model of glaucoma filtration surgery, while prolonging bleb survival at the same time. A synergistic effect is suggested to be present.

Control of the skin scarring response

There comes a time when the understanding of the cutaneous healing process becomes essential due to the need for a precocious tissue repair to reduce the physical, social, and psychological morbidity. Advances in the knowledge on the control of interaction among cells, matrix and growth factors will provide more information on the Regenerative Medicine, an emerging area of research in medical bioengineering. However, considering the dynamism and complexity of the cutaneous healing response, it is fundamental to understand the control mechanism exerted by the interaction and synergism of both systems, cutaneous nervous and central nervous, via hypothalamus hypophysis-adrenal axis, a relevant subject, but hardly ever explored. The present study reviews the neuro-immune-endocrine physiology of the skin responsible for its multiple functions and the extreme disturbances of the healing process, like the excess and deficiency of the extracellular matrix deposition.

Renal α‐smooth muscle actin: A new prognostic factor for lupus nephritis

Systemic lupus erythematosus (SLE) is the prototype of autoimmune disease where renal involvement is frequent and always severe. Histological prognostic factors proposed for lupus nephritis (LN) including the World Health Organization and International Society of Nephrology/Renal Pathology Society--Working Group on the Classification classifications, active (AI) and chronicity (CI) indices may not predict response to treatment. The aim of this study was to correlate alpha-smooth muscle actin (alpha-SMA) expression, an early marker of glomerular and interstitial response to injury, to AI and CI, renal scarring progression and response to treatment. Fifty-seven kidney biopsy specimens obtained from 32 patients suffering from LN were studied. Twenty patients with class IV LN at first biopsy were identified to study renal progression to chronic renal failure until the use of immunosuppressive treatment. Interstitial alpha-SMA (I-alpha-SMA) was correlated only with CI (P < 0.001) whereas mesangial alpha-SMA (M-alpha-SMA) was correlated with neither LN activity (P = 0.126) nor sclerosis (P = 0.297). Only I-alpha-SMA was correlated with renal failure (P = 0.01). We divided patients with class IV LN into progressors and non-progressors based on the slope of serum creatinine. At first biopsy, M-alpha-SMA and I-alpha-SMA, but not AI and CI, were correlated with renal failure progression (M-alpha-SMA, 9.7b1.1 vs 7.8b1.4, P = 0.004; and I-alpha-SMA, 9.3b1.1 vs 6.5b3.2, P = 0.011). The study data highlight that I-alpha-SMA immunostain in class IV LN patients was correlated with chronicity indices. Moreover, M-alpha-SMA and I-alpha-SMA expression in first biopsy predicted renal progression modality. alpha-SMA expression may therefore be a useful marker to predict renal prognosis in LN.

Keeping your senescent cells under control

Keeping your senescent cells under control