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With regards to cardiovascular health, frequent consumption of fried foods is discouraged, despite a lack of clear evidence of a direct link between eating oxidative frying oil (OFO) and cardiovascular diseases. In this study, male Sprague Dawley rats were exposed to diets containing fresh or fried soybean oil (groups C and O, respectively) from in utero to 28 weeks of age. A subset of rats in group O was supplemented with vitamin E (500 mg/kg of DL-α-tocopherol acetate; group OE) from 8 week of age onward to mitigate oxidative stress associated with OFO ingestion. Echocardiography, cardiac histology and indices associated with ATP production and calcium cycling in cardiac tissues were measured. Compared to group C, there was cardiac hypertrophy, fibrosis and diastolic dysfunction, in groups O and OE, with no differences between the latter two groups. Although cardiac mRNA levels of genes associated with mitochondrial biogenesis and function were increased, there were lower ATP concentrations and higher transcripts of uncoupling proteins in groups O and OE than in group C. In addition, decreases in phosphorylation of phospholamban and Ca 2+ /calmodulin-dependent protein kinase II activity, plus increased protein phosphatase 2A activity in groups O and OE, implied calcium cycling required for cardiac function was disrupted by OFO consumption. We concluded that long-term OFO exposure resulted in cardiac hypertrophy, fibrosis and diastolic dysfunction that was not mitigated by vitamin E supplementation. Underlying mechanisms were partly attributed to inefficient energy production via uncoupled phosphorylation and disrupted calcium cycling., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-β1/MMP-9 signaling pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) to chronic kidney disease (CKD) progression has become a life-threatening disease. However, an effective therapeuticstrategyis still needed. The pathophysiology of AKI-to-CKD progression involves chronic inflammation and renal fibrosis driven by macrophage activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In this study, we modulated macrophage infiltration through oral administration of the CSF-1R inhibitor GW2580 in an ischemia-reperfusion (I/R)-induced AKI model to evaluate its therapeutic effects on preventing the progression of AKI to CKD. We found that GW2580 induced a significant reduction in the number of macrophages in I/R-injured kidneys and attenuated I/R-induced renal injury and subsequent interstitial fibrosis. By flow cytometry, we observed that the reduced macrophages were primarily Ly6C + inflammatory macrophages in the GW2580-treated kidneys, while there was no significant difference in the number and percentage of Ly6C - CX3CR1 + macrophages. We further found that these reduced macrophages also demonstrated some characteristics of M2-like macrophages, which have been generally regarded as profibrotic subtypes in chronic inflammation. These results indicate the existence of phenotypic and functional crossover between Ly6C + and M2-like macrophages in I/R kidneys, which induces AKI worsening to CKD. In conclusion, therapeutic GW2580 treatment alleviates acute renal injury and subsequent fibrosis by reducing Ly6C + M2-like macrophage infiltration in ischemia-induced AKI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Renal fibrosis is a contributor to chronic kidney disease and an important predictor of long-term prognosis. We developed a dual soluble epoxide hydrolase inhibitor-PPAR-γ agonist (sEHi/PPAR-γ), RB394, and investigated its ability to attenuate renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. RB394 efficacy was compared to an sEH inhibitor (sEHi), a PPAR-γ agonist rosiglitazone (Rosi), or their combination (sEHi + Rosi). All interventional treatments were administrated in drinking water 3 days after UUO induction surgery and continued for 7 days. UUO mice developed renal fibrosis with higher collagen formation and RB394 significantly attenuated fibrosis (P < 0.05). Renal expression of α-smooth muscle actin (α-SMA) was elevated in UUO mice and all treatments except sEHi significantly attenuated renal α-SMA expression. Renal mRNA expression fibrotic and fibrosis regulators were higher in UUO mice and RB394 and sEHi + Rosi treatments attenuated their expression. Renal inflammation was evident in UUO mice with increased infiltration of CD45 and F4/80 positive cells. RB394 and sEHi + Rosi treatments attenuated renal inflammation in UUO mice. UUO mice had renal tubular and vascular injury. Renal tubular and vascular injuries were attenuated to a greater extent by RB394 and sEHi + Rosi than sEHi or Rosi treatment alone. Renal mRNA expression of oxidative stress markers were significantly higher in UUO mice (P < 0.05). RB394 and sEHi + Rosi attenuated expression of oxidative stress markers to a greater extent than other interventional treatments (P < 0.05). These findings demonstrate that RB394 can attenuate renal fibrosis by reducing renal inflammation, oxidative stress, tubular injury, and vascular injury. In conclusion, RB394 demonstrates exciting potential as a therapeutic for renal fibrosis and chronic kidney disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fibrosis denotes excessive scarring, which exceeds the normal wound healing response to injury in many tissues. Although the extracellular matrix deposition appears unstructured disrupting the normal tissue architecture and subsequently impairing proper organ function, fibrogenesis is a highly orchestrated process determined by defined sequences of molecular signals and cellular response mechanisms. Persistent injury and parenchymal cell death provokes tissue inflammation, macrophage activation and immune cell infiltration. The release of biologically highly active soluble mediators (alarmins, cytokines, chemokines) lead to the local activation of collagen producing mesenchymal cells such as pericytes, myofibroblasts or Gli1 positive mesenchymal stem cell-like cells, to a transition of various cell types into myofibroblasts as well as to the recruitment of fibroblast precursors. Clinical observations and experimental models highlighted that fibrosis is not a one-way road. Specific mechanistic principles of fibrosis regression involve the resolution of chronic tissue injury, the shift of inflammatory processes towards recovery, deactivation of myofibroblasts and finally fibrolysis of excess matrix scaffold. The thorough understanding of common principles of fibrogenic molecular signals and cellular mechanisms in various organs - such as liver, kidney, lung, heart or skin - is the basis for developing improved diagnostics including biomarkers or imaging techniques and novel antifibrotic therapeutics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fibroblast proliferation is considered to be a major cause in the process of epidural fibrosis formation. Autophagy is a tightly-regulated catabolic process in charge of degrading intracellular components. Although autophagy has been associated with fibrosis of different tissues, the effect of autophagy on epidural fibrosis is still unknown. The aim of this study was to investigate the function and mechanism of autophagy induced by Artesunate (ART), a classical antimalarial agent extracted from the Chinese medicinal herb. In vitro, the effect of ART on inducing fibroblast autophagy was evaluated via LC3 immunofluorescent staining, Transmission Electron Microscopy (TEM) and western blotting analysis. Moreover, the effect of ART on inhibiting fibroblast proliferation was investigated by CCK-8 assay, EdU incorporation assay, flow cytometry and western blotting analysis. Results indicated that ART could induce autophagy and inhibit proliferation in fibroblasts. The inhibitory effect of ART on fibroblast proliferation was associated with the upregulation of p53 and p21 waf1/cip1 proteins. Intriguingly, 3-MA, a classical autophagy inhibitor, attenuated ART-induced p53/p21 waf1/cip1 pathway activation and fibroblast proliferation inhibition. In vivo, the effect of ART on reducing epidural fibrosis was detected by histological macroscopic assessment, hydroxyproline content analysis, histological and immunohistochemical staining. The results revealed that ART had significant suppressive effects on epidural fibrosis following laminectomy in rats. In conclusion, this research demonstrated that ART could inhibit fibroblast proliferation and reduce epidural fibrosis formation after laminectomy, and the potential mechanism might through autophagy cascade-mediated p53/p21 waf1/cip1 pathway. It might provide a novel reagent for reducing epidural fibrosis after spinal laminectomy surgery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cell behavior is influenced by the biophysical properties of their microenvironments, and the linear elastic properties of substrates strongly influences adhesion, migration, and differentiation responses. Because most biological tissues exhibit non-linear elastic properties, there is a growing interest in understanding how the viscous component of materials and tissues influences cell fate. Here we describe the use of microgel thin films with controllable non-linear elastic properties for investigating the role of material loss tangent on cell adhesion, migration, and myofibroblastic differentiation, which have implications in fibrotic responses. Fibroblast modes of migration are dictated by film loss tangent; high loss tangent induced ROCK-mediated amoeboid migration while low loss tangent induced Rac-mediated mesenchymal cell migration. Low loss tangent films were also associated with higher levels of myofibroblastic differentiation. These findings have implications in fibrosis and indicate that slight changes in tissue viscoelasticity following injury could contribute to early initiation of fibrotic related responses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fibrosis is characterized by excess deposition of extracellular matrix (ECM). However, the ECM changes during fibrosis not only quantitatively but also qualitatively. Thus, the composition is altered as the expression of various ECM proteins changes. Moreover, also posttranslational modifications, secretion, deposition and crosslinkage as well as the proteolytic degradation of ECM components run differently during fibrosis. As several of these processes involve redox reactions and some of them are even redox-regulated, reactive oxygen species (ROS) influence fibrotic diseases. Redox regulation of the ECM has not been studied intensively, although evidences exist that the alteration of the ECM, including the redox-relevant processes of its formation and degradation, may be of key importance not only as a cause but also as a consequence of fibrotic diseases. Myofibroblasts, which have differentiated from fibroblasts during fibrosis, produce most of the ECM components and in return obtain important environmental cues of the ECM, including their redox-dependent fibrotic alterations. Thus, myofibroblast differentiation and fibrotic changes of the ECM are interdependent processes and linked with each other via cell-matrix contacts, which are mediated by integrins and other cell adhesion molecules. These cell-matrix contacts are also regulated by redox processes and by ROS. However, most of the redox-catalyzing enzymes are localized within cells. Little is known about redox-regulating enzymes, especially the ones that control the formation and cleavage of redox-sensitive disulfide bridges within the extracellular space. They are also important players in the redox-regulative crosstalk between ECM and cells during fibrosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fibrosis is a common process characterized by excessive extracellular matrix (ECM) accumulation after inflammatory injury, which is also a crucial cause of aging. The process of fibrosis is involved in the pathogenesis of most diseases of the heart, liver, kidney, lung, and other organs/tissues. However, there are no effective therapies for this pathological alteration. Annually, fibrosis represents a huge financial burden for the USA and the world. 5'-AMP-activated protein kinase (AMPK) is a pivotal energy sensor that alleviates or delays the process of fibrogenesis. In this review, we first present basic background information on AMPK and fibrogenesis and describe the protective roles of AMPK in three fibrogenic phases. Second, we analyze the protective action of AMPK during fibrosis in myocardial, hepatic, renal, pulmonary, and other organs/tissues. Third, we present a comprehensive discussion of AMPK during fibrosis and draw a conclusion. This review highlights recent advances, vital for basic research and clinical drug design, in the regulation of AMPK during fibrosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1β and TGF-β1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1β and TGF-β1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Methionine sulfoxide reductase A (MsrA), which stereospecifically catalyzes the reduction of methionine-S-sulfoxide, is an important reactive oxygen species (ROS) scavenger. Tissue fibrosis is a maladaptive repair process following injury, associated with oxidative stress. In this study, we investigated the role of MsrA in unilateral ureteral obstruction (UUO)-induced kidney fibrosis and its underlying mechanisms by using MsrA gene-deleted mice (MsrA(-/-)). MsrA deletion increased collagen deposition in the interstitium and the expression of collagen III and α-smooth muscle actin in the UUO kidneys, indicating that MsrA deficiency exacerbated the progression of UUO-induced kidney fibrosis. UUO reduced the kidney expression of MsrA, MsrB1, and MsrB2, thereby decreasing MsrA and MsrB activity. UUO increased hydrogen peroxide and lipid peroxidation levels and the ratio of oxidized glutathione (GSSG) to total glutathione (GSH) in the kidneys. The UUO-induced elevations in the levels of these oxidative stress markers and leukocyte markers were much higher in the MsrA(-/-) than in the MsrA(+/+) kidneys, the latter suggesting that the exacerbated kidney fibrosis in MsrA(-/-) mice was associated with enhanced inflammatory responses. Collectively, our data suggest that MsrA plays a protective role in the progression of UUO-induced kidney fibrosis via suppression of fibrotic responses caused by oxidative stress and inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study aimed to assess the impact of pulmonary inflammation on early fibrotic response in rats challenged with increasing doses of lipopolysaccharide (LPS). Twenty-four rats were randomized and infused with three different increasing doses of continuous LPS infusion (n=8/group) while being ventilated with low tidal volumes and open-lung positive end-expiratory pressure. Another eight animals served as uninjured control group. Hemodynamics, gas exchange, respiratory system mechanics, lung histology, α-smooth muscle actin, plasma cytokines, and mRNA expression of cytokines and type I and III procollagen in lung tissue were assessed. We found impaired hemodynamics and gas exchange as well as higher histological lung injury scores and α-smooth muscle actin expressions in the medium LPS dose compared to control and the lower LPS dose. The highest LPS dose did not cause further aggravation of these findings. In all LPS groups type I and III procollagen decreased compared to controls and there was a negative correlation between type III procollagen-RNA expression and proinflammatory mediators., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Over the past decade, various implantable devices have been developed to treat diseases that were previously difficult to manage such diabetes, chronic pain, and neurodegenerative disorders. However, translation of these novel technologies into clinical practice is often difficult because fibrotic encapsulation and/or rejection impairs device function after body implantation. Ideally, cells of the host tissue should perceive the surface of the implant being similar to the normal extracellular matrix. Here, we developed an innovative approach to provide implant surfaces with adhesive protein micropatterns. The patterns were designed to promote adhesion of fibroblasts and macrophages by simultaneously suppressing fibrogenic activation of both cell types. In a rat model, subcutaneously implanted silicone pads provided with the novel micropatterns caused 6-fold lower formation of inflammatory giant cells compared with clinical grade, uncoated, or collagen-coated silicone implants. We further show that micropatterning of implants resulted in 2-3-fold reduced numbers of pro-fibrotic myofibroblast by inhibiting their mechanical activation. Our novel approach allows controlled cell attachment to implant surfaces, representing a critical advance for enhanced biointegration of implantable medical devices., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The composite physiologic index (CPI), which is derived from FEV1, FVC, and diffusing capacity, has been developed to predict the extent of fibrosis on high-resolution computed tomography (HRCT). However, the relevance to the forced oscillation technique (FOT) is not fully understood. We hypothesized that FOT would independently predict the CPI in interstitial lung disease (ILD). In this cross-sectional study we assessed the relationship between pulmonary function tests, forced oscillatory parameters, and the degree of fibrosis in ILD. Spirometry, evaluation of diffusing capacity for carbon monoxide, and the broadband frequency FOT were performed in 93 patients with a clinical/HRCT diagnosis of ILD. The CPI was calculated and fibrosis extent was measured by HRCT and scored. Univariate analyses revealed that, of the forced oscillatory parameters, inspiratory resonant frequency best correlated with FVC, FEV1, diffusing capacity, CPI, and fibrosis score. In multiple regression analyses, CPI was independently predicted by inspiratory resonant frequency and fibrosis score (model R(2)=0.405, p<0.0001)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Protease-activated receptor (PAR) 2 is a G-protein-coupled receptor that is activated by mast cell tryptase. PAR-2 activation augments profibrotic pathways through the induction of extracellular matrix proteins. PAR-2 is widely expressed in hepatic stellate cells (HSCs), but the role of tryptase/PAR-2 interaction in liver fibrosis is unclear. We studied the development of bile duct ligation (BDL)-induced hepatic fibrosis in rats treated with mast cell tryptase inhibitor APC 366, and showed that APC 366 reduced hepatic fibrosis scores, collagen content and serum biochemical parameters. Reduced fibrosis was associated with decreased expression of PAR-2 and α-smooth muscle actin (α-SMA). Our findings demonstrate that mast cell tryptase induces PAR-2 activation to augment HSC proliferation and promote hepatic fibrosis in rats. Treatment with tryptase antagonists may be a novel therapeutic approach to prevent fibrosis in patients with chronic liver disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The press-fit hip acetabular prosthesis implantation can cause crack formation in the thin regions surrounding the acetabular. As a consequence the presence of cracks in this region can lead to poor fixation and fibrous tissue formation., Methods: Numerical and experimental models of commercial press-fit hip replacements were developed to compare the behavior between the intact and implanted joints. Numerical models with an artificial crack and without crack were considered. The iliac and the femur were created through 3D geometry acquisition based on composite human replicas and 3D-Finite Element models were generated., Findings: The mechanical behavior was assessed numerically and experimentally considering the principal strains. The comparison between Finite Element model predictions and experimental measurements revealed a maximum difference of 9%. Similar distribution of the principal strains around the acetabular cavity was obtained for the intact and implanted models. When comparing the Von Mises stresses, it is possible to observe that the intact model is the one that presents the highest stress values in the entire acetabular cavity surface., Interpretation: The crack in the posterior side changes significantly the principal strain distribution, suggesting bone loss after hip replacement. Relatively to micromotions, these were higher on the superior side of the acetabular cavity and can change the implant stability and bone ingrowth., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether ischemic postconditioning effects on the development of tubulointerstitial fibrosis follow acute renal ischemia-reperfusion., Methods: Rat models of warm renal I/R were established by clamping left pedicles for 45 minutes after right nephrectomy, both with and without treatment with ischemic postconditioning, and then reperfused for up to 12 weeks. Hematoxylin-eosin (H&E) and Masson's trichrome staining were used to assess renal fibrosis. The expression spot and protein levels of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and phospho-Smad2 were also analyzed., Results: Our data showed that patchy inflammation and tubulointerstitial fibrosis were found 12 weeks later in rats subjected to I/R alone or with postconditioning. Tubulointerstitial fibrosis worsened further in rats subjected to 45-minute ischemia-reperfusion, accompanied by the increased expressions of α-SMA, TGF-β1, and phospho-Smad2 at the end of 12 weeks. In contrast, the above histologic changes and molecular expressions were significantly attenuated in rats of ischemic postconditioning group., Conclusion: The results indicated that 45-minute I/R injury may cause tubulointerstitial fibrosis in the long term, and ischemic postconditioning has beneficial effects on renal fibrosis. Its mechanisms may involve inhibition of the TGF-β1/phospho-Smad2 pathway to exert protective effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cold exposure is associated with an increased prevalence of cardiovascular disease although the mechanism is unknown. Metallothionein, a heavy-metal-scavenging antioxidant, protects against cardiac anomalies. This study was designed to examine the impact of metallothionein on cold exposure-induced myocardial dysfunction, intracellular Ca(2+) derangement, fibrosis, endoplasmic reticulum (ER) stress, and apoptosis. Echocardiography, cardiomyocyte function, and Masson trichrome staining were evaluated in Friend virus B (FVB) and cardiac-specific metallothionein transgenic mice after cold exposure (3 months, 4 °C). Cold exposure increased plasma levels of norepinephrine, endothelin-1, and TGF-β; reduced plasma NO levels and cardiac antioxidant capacity; enlarged ventricular end-systolic diameter; compromised fractional shortening; promoted reactive oxygen species (ROS) production and apoptosis; and suppressed the ER stress markers Bip, calregulin, and phospho-eIF2α, accompanied by cardiac fibrosis and elevated levels of matrix metalloproteinases and Smad-2/3 in FVB mice. Cold exposure-induced echocardiographic, histological, ER stress, ROS, apoptotic, and fibrotic signaling changes (but not plasma markers) were greatly improved by metallothionein. In vitro metallothionein induction by zinc chloride ablated H(2)O(2)- but not TGF-β-induced cell proliferation in fibroblasts. In summary, our data suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of myocardial fibrosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To examine the effect of L- and T/L-type calcium channel blockers on interstitial fibrosis in chronic unilateral ureteral obstruction (UUO). Tubulointerstitial fibrosis is a common outcome of several progressive renal diseases. Calcium channel blockers are widely used for the treatment of hypertension with renal diseases; however, the direct effect of calcium channel blockers on renal diseases independent of lowering blood pressure has not been fully elucidated., Methods: Sprague-Dawley rats were divided into 3 treatment groups: (1) vehicle control; (2) nifedipine, an L-type calcium channel blockers; and (3) efonidipine, a T/L-type calcium channel blockers. Treatment was initiated 1 day before and continued until 6 days after creation of the UUO., Results: Tubulointerstitial fibrosis in the obstructed kidney was significantly increased compared with that in the contralateral unobstructed kidney. Furthermore, the increased fibrosis was accompanied by increased fibrogenic signaling expressed by transforming growth factor β1 and connective tissue growth factor mRNA levels, increased oxidative stress expressed by p22phox, p47phox and gp91phox mRNA level. Moreover, treatment with a nonhypotensive dose of efonidipine but not nifedipine in the obstructed kidney significantly suppressed the fibrogenic signaling and the oxidative stress, resulting in reduced tubulointerstitial fibrosis. The plasma aldosterone level in efonidipine-treated animals was increased compared with vehicle-treated animals, although not significantly. The increased plasma aldosterone level did not increase sgk-1 mRNA level in efonidipine but not in nifedipine treated animals., Conclusions: Treatment with efonidipine improved tubulointerstitial fibrosis more effectively than treatment with nifedipine in UUO. The antifibrogenic effect by efonidipine was obtained through suppression of fibrogenic signaling., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To analyze risk factors for postoperative recurrence of fibrovascular tissue in eyes with aggressive posterior retinopathy of prematurity (AP ROP) treated with early vitreous surgery., Design: Retrospective, consecutive, observational case series., Methods: Thirty-one patients (50 eyes) with AP ROP who underwent early vitreous surgery between March 2005 and April 2008 participated. Eyes with stage 4A or 4B disease in which fibrovascular tissue was not attached to the vitreous base were included; those in which fibrovascular tissue was attached extensively to vitreous base or those without dense photocoagulation to the nonvascularized retina were excluded. Eligible eyes were divided into 2 groups based on postoperative recurrence or no recurrence of fibrovascular tissue. Data on gender, gestational age, birth weight, Apgar score, intubation duration, severe systemic complications, preoperative ROP stage, zone, fibrovascular tissue and vitreous base adhesion, clock hours of fibrovascular tissue, postmenstrual age at the initial application of dense photocoagulation, dense photocoagulation to both vascularized and nonvascularized retina, postmenstrual age at vitrectomy, and intraoperative hemorrhage were collected and analyzed., Results: Fifty eyes of 31 patients underwent early vitrectomy. Seven (14%) eyes were excluded and 43 eyes (86%) were included. Eight (18%) of 43 eyes had a recurrence of fibrovascular tissue. Both univariate and multivariate analysis indicated application of dense photocoagulation to both the vascularized and nonvascularized retina was a significant factor in the decreased recurrence of fibrovascular tissue (P = .002 and P = .008, respectively)., Conclusions: Application of preoperative dense photocoagulation to vascularized and nonvascularized retina may be important for lowering the recurrence of fibrovascular tissue in eyes with AP ROP., (2010 Elsevier Inc. All rights reserved.)

We investigated the effects of normobaric hypoxia on rat lungs and hypothesized that the hypoxic exposure would induce lung injury with pulmonary edema and inflammation ensued by development of fibrosis. Rats were exposed to 10% O(2) in nitrogen over 6-168h. We analyzed cardiovascular function and pulmonary changes, lung histology and mRNA expression of extracellular matrix (ECM) molecules in the lung. Significant hemodynamic changes occurred after 168h of hypoxic exposure. Moderate pulmonary edema appeared after 8h and peaked after 16h of hypoxia. It was accompanied by inflammation, fibrosis and vascular hypertrophy. mRNA expression of transforming growth factor-beta2 and -beta3 was up-regulated in lung tissue after 8h of hypoxia. After 8-16h, mRNA expression of collagen types I and III and of other ECM molecules was significantly elevated and increased further with longer exposure to hypoxia. The time course of hypoxia-induced pulmonary injury resembled that previously observed after continuous norepinephrine infusion in rats.

Occult hepatitis B virus (HBV) infection in individuals without hepatitis B surface antigen (HBsAg) can be identified in hepatitis C virus (HCV) infected patients. However, its role in fibrosis progression remains uncertain. This retrospective study compared the fibrosis progression (defined as fibrosis progression by at least one stage) and progression to severe fibrosis (fibrosis stage 3 or 4) in HCV patients with occult HBV infection. Occult HBV infection was diagnosed by the detection of HBV DNA in the serum of 74 consecutive anti-HCV positive patients by PCR. Thirty-one patients (41.9%) had occult HBV infection. All 74 patients had a median of 2 (range 2-3) liver biopsies. The median time between the first and last liver biopsy was 57.7 (range 15.0-132.8) months. Eleven of the 31 patients with occult HBV infection compared with 12 of the 43 patients without occult HBV infection had fibrosis progression (35.5% versus 27.9%, respectively, p=0.608). Six of the 31 patients with occult HBV infection compared with 8 of the 43 patients without occult HBV infection developed severe fibrosis (19.4% versus 18.6%, respectively, p=0.946). In conclusion, chronic HCV patients with occult HBV co-infection does not seem to progress more than patients without occult HBV infection. However, more large-scale studies are needed before a definite conclusion can be obtained.

The aim of this study was to determine whether an intrapleural injection of barium sulphate would produce pleurodesis in rats. Additionally, respiratory mechanics and pleural remodelling were analysed. Single intrapleural injection of barium sulphate (100%) or saline was given to Wistar rats. Respiratory system, lung, and chest wall elastic, resistive and viscoelastic/inhomogeneous pressures were measured by the end-inflation occlusion method at 2 and 30 days after injection. The pleura were examined for gross and histopathological evidence of pleural inflammation and fibrosis, and the underlying lungs were also studied by morphometry. All pulmonary mechanical parameters increased at day 2, but were not different from control at 30 days after injection. Chest wall mechanical parameters did not change. Macroscopic evaluation demonstrated pleural adherence without haemothorax. Histopathologic analysis showed pleural inflammation and fibrosis. There was no alveolar inflammation or fibrosis in both groups. In conclusion, barium sulphate induced pleurodesis with either no changes in respiratory mechanics or lung lesion at day 30.

This study was designed to investigate possible effects of the Rho-kinase inhibitor, fasudil, on the progression of renal failure in rats with unilateral ureteral obstruction. The renal failure markers monitored were the extent of renal interstitial fibrosis and that of macrophage infiltration. In kidneys with unilateral ureteral obstruction, interstitial fibrosis was observed, using Sirius-Red staining, on day 16 after unilateral ureteral obstruction. Macrophage infiltration was observed by immunohistochemistry, using the antibody, ED1. Interstitial fibrosis and macrophage infiltration were significantly attenuated in fasudil-treated animals. The migration of monocytes in vitro elicited by N-formyl-methionyl-leucyl-phenylalanine was potently inhibited by fasudil and its active metabolite, hydroxyfasudil. These results suggest that inhibition of Rho-kinase produces a reduction of macrophage infiltration and represents a new therapeutic strategy for renal fibrosis, a major factor in the progression to end-stage renal failure., (Copyright 2002 Elsevier Science B.V.)

This review updates the treatment of chronic hepatitis B infection. Complete eradication of hepatitis B virus (HBV) is not possible, so the efficacy of treatment has to be assessed by whether it can limit long-term cirrhosis-related complications. We discuss two major groups of treatments--immunomodulators (interferon alfa, thymosin alpha1, therapeutic vaccines) and nucleoside analogues (lamivudine, adefovir, entecavir, emtricitabine, beta-L-2'-deoxythymidine). To date, interferon alfa and lamivudine are the only two agents approved for chronic hepatitis B. Interferon alfa achieves a short-term outcome of around 20-30% loss of HBeAg. The efficacy is lower in Chinese patients, who are immunotolerant to HBV because of acquisition of the disease during early childhood, than in white patients. This difference is further confirmed on long-term follow-up. Interferon alfa does not affect the development of cirrhosis-related complications in Chinese patients, whereas in white patients, the frequency of long-term complications is reduced if interferon alfa is successful in inducing loss of HBeAg. Lamivudine profoundly suppresses viral replication and achieves an HBeAg seroconversion rate similar to that of interferon alfa. It is equally effective in Chinese and white patients because the main antiviral mechanism is through inhibition of reverse transcription of HBV during viral replication. However, long-term lamivudine therapy is associated with emergence of HBV variants, YMDD variants. Newer nucleoside analogues are being extensively investigated by studies in vivo and in vitro. Combination therapy with two or three nucleoside analogues or immunomodulators plus nucleoside analogues will be the future direction of treatment of chronic hepatitis B.

Purpose: To report a patient with a sight-threatening complication of laser-induced chorioretinal venous anastomosis for treatment of central retinal vein occlusion., Method: A 69-year-old woman with a nonischemic central retinal vein occlusion underwent focal argon laser photocoagulation treatment to create a chorioretinal venous anastomosis., Results: Massive preretinal fibrosis and traction retinal detachment developed over the area of argon laser photocoagulation, which required vitreous surgery., Conclusion: Laser-induced chorioretinal venous anastomosis to treat central retinal vein occlusion can be associated with severe complications, underscoring the need for additional study of this new treatment modality.

Purpose: To determine the applicability of laser segmentation for severing fibrovascular tissue and hyaloid interfaces in the treatment of tractional complications of proliferative diabetic retinopathy., Methods: A prototype neodymium:yttrium-lithium-fluoride (Nd:YLF) picosecond pulse photodisruptive laser was used in eight eyes (seven patients) with proliferative diabetic retinopathy as part of a Food and Drug Administration-approved phase 1 protocol. There were three indications for treatment: type I: distortion and shallow elevation of the macular caused by taut, adherent, posterior hyaloid interface (two eyes); type II: traction retinal detachment involving the fovea (two eyes); and type III: fovea-threatened, traction retinal detachment (four eyes). Traction release was accomplished by laser segmentation of the detached hyaloid interfaces and fibrotic, contracted proliferative tissue. The Nd:YLF uses low pulse energy (0.10 mJ, 1,000 pulses per second for 10 consecutive seconds) that allows tissue cutting near the retinal surface., Results: Both type I eyes had relief of traction forces; visual acuity improved from 20/400 to 20/50 in one eye; the other remained stable. Of the two type II eyes, one had anatomic reattachment of the fovea with improvement in visual acuity (hand movements to 20/50); the second required vitrectomy. Of the four type III eyes, all had anatomic improvement; three maintained pretreatment acuity; the fourth eye developed vitreous hemorrhage at 6 months and underwent vitrectomy. Three treatments (two eyes) caused vitreous hemorrhage that resulted in a transient drop in acuity (1 to 2 lines). No patient developed a retinal break or choroidal hemorrhage., Conclusion: In a small pilot study, the Nd:YLF laser segmented proliferative tissue near the retinal surface and elevated hyaloid interfaces. In selected cases, this may enable flattening of traction retinal detachment or release of retinal distortion.

Various chronic disease processes are characterized by progressive accumulation of connective tissue under-going fibrotic degeneration. Evidence of oxidative reactions is often associated with fibrogenesis occurring in liver, lung, arteries, and nervous system. Moreover, an increasing bulk of experimental and clinical data supports a contributory role of oxidative stress in the pathogenesis of this kind of disease. Indeed, many etiological agents of fibrogenesis stimulate free radical reactions either directly or through inflammatory stimuli. Free radicals, as well as products of their reaction with biomolecules, appear to modulate the activity of the two cellular types mainly involved in the process, namely phagocytes and extracellular matrix-producing cells. Lipid peroxidation and certain lipid peroxidation products induce genetic overexpression of fibrogenic cytokines, the key molecules in the pathomechanisms of fibrosis, as well as increased transcription and synthesis of collagen. Both these events can be downregulated, at least in experimental models, by the use of antioxidants. The effect of oxidative stress on cytokine gene expression appears to be an important mechanism by which it promotes connective tissue deposition.

Purpose: We investigated the therapeutic possibilities of gamma brachytherapy to improve the final functional results of eyes with choroidal hemangiomas, which are benign vascular tumors that can induce progressive impairment of visual acuity., Methods: We treated 41 patients with choroidal hemangioma with cobalt-60 applicators. The lesions consisted of 39 circumscribed hemangiomas and two diffuse hemangiomas in patients with Sturge-Weber syndrome. Before treatment, visual acuity in the affected eye was 20/200 in ten patients, 20/200 to 20/50 in 17 patients, 20/40 to 20/25 in 11 patients, and 20/20 in three patients. All patients were symptomatic. The macula was infiltrated by the tumor in 12 eyes (29.3%). There was retinal detachment in 40 eyes (97.6%), cystoid edema in ten eyes (24.4%), subretinal fibrosis in eight eyes (19.5%), and areolar atrophy in two eyes (4.9%)., Results: After treatment, the retina was reattached in all eyes, and the tumor progressively transformed into a flat scar. The postirradiation macular lesions that we identified were pigment migrations in the macular region, subretinal fibrosis, and an areolar atrophic scar. We correlated the functional results at two, five, and ten years after treatment with the initial visual acuity, and with pre-existing and posttreatment macular lesions., Conclusions: Our results suggest that radiotherapy is a valuable therapeutic modality for choroidal hemangiomas, particularly in hemangiomas that involve the macula, and for tumors associated with bullous retinal detachment.

Corporeal fibrosis and erectile impotence are known sequelae of priapism. Fibrosis following priapism may make subsequent placement of a penile prosthesis, especially inflatable devices, difficult or impossible. A case is described in which a self-contained inflatable prosthesis (Dynaflex) was successfully placed to treat impotence resulting from idiopathic priapism. However, fibrosis of the distal tunica albuginea of the corpora cavernosa rendered them noncompressible, and thus precluded inflation of the device with its distally placed pump mechanism. This anatomic problem is added to the list of potential contraindications to placement of self-contained inflatable penile prostheses, and the advisability of having patients who desire such a prosthesis also choose a secondary prosthesis type is emphasized.

Ten eyes of nine patients developed submacular fibrotic scars without fluorescein angiographic evidence of choroidal neovascularization between two and 11 months (mean, 6.1 months) after argon laser treatment for diabetic macular edema. In four eyes, development of the subretinal scar was associated with visual acuity loss of two, two, four, and eight lines of Snellen visual acuity, respectively, within five to 11 months of laser treatment. At the final follow-up visit, the visual acuity of the eyes with two lines of visual acuity loss had returned to within one line of the initial value, but the visual acuity of the eyes with more severe initial visual acuity loss did not recover notably. In four eyes, fibrous submacular strands extended from macular laser scars, suggesting an iatrogenic role of the laser in inducing this complication.

In recent years aqueous drainage implants have become a useful adjuvant in the treatment of refractory glaucomas. The Molteno implant is one of the most widely used devices for providing a permanent channel of aqueous flow from the anterior chamber to a collecting reservoir in the posterior subconjunctival space. Recently, modifications in design and surgical technique of the Molteno implant have enhanced its success rate, with a reduction in complications such as prolonged hypotony, anterior chamber flattening, and tube-corneal touch. These modifications include intracamerally injecting hyaluronic acid, using a needle track to provide an opening into the anterior chamber for the tube, performing the operation in two stages, using a double plate, temporarily ligating the tube, using a donor scleral patch, and giving adjunctive antifibrotic therapy. The rationale for application of the Molteno implant, the indications, techniques, results, and complications are described.