Accumulation Of Scar Tissue Research Articles

Inflammatory Network of Liver Fibrosis and How It Can Be Targeted Therapeutically

Liver fibrosis is a complex, dynamic process associated with a broad spectrum of chronic liver diseases and acute liver failure, characterised by the dysregulated intrahepatic production of extracellular matrix proteins replacing functional liver cells with scar tissue. Fibrosis progresses due to an interrelated cycle of hepatocellular injury, triggering a persistent wound-healing response. The accumulation of scar tissue and chronic inflammation can eventually lead to cirrhosis and hepatocellular carcinoma. Currently, no therapies exist to directly treat or reverse liver fibrosis; hence, it remains a substantial global disease burden. A better understanding of the intricate inflammatory network that drives the initiation and maintenance of liver fibrosis to enable the rationale design of new intervention strategies is required. This review clarifies the most current understanding of the hepatic fibrosis cellular network with a focus on the role of regulatory T cells, and a possible trajectory for T cell immunotherapy in fibrosis treatment. Despite good progress in elucidating the role of the immune system in liver fibrosis, future work to better define the function of different immune cells and their mediators at different fibrotic stages is needed, which will enhance the development of new therapies.

Inhibition of chloride intracellular channel protein 1 (CLIC1) ameliorates liver fibrosis phenotype by activating the Ca2+-dependent Nrf2 pathway

Persistent damage to liver cells leads to liver fibrosis, which is characterized by the accumulation of scar tissue in the liver, ultimately leading to cirrhosis and serious complications. Because it is difficult to reverse cirrhosis once it has progressed, the primary focus has been on preventing the progression of liver fibrosis. However, studies on therapeutic agents for liver fibrosis are still lacking. Here, we investigated that the natural dipeptide cyclic histidine-proline (CHP, also known as diketopiperazine) shows promising potential as a therapeutic agent in models of liver injury by inhibiting the progression of fibrosis through activation of the Nrf2 pathway. To elucidate the underlying biological mechanism of CHP, we used the Cellular Thermal Shift Assay (CETSA)-LC–MS/MS, a label-free compound-based target identification platform. Chloride intracellular channel protein 1 (CLIC1) was identified as a target whose thermal stability is increased by CHP treatment. We analyzed the direct interaction of CHP with CLIC1 which revealed a potential interaction between CHP and the E228 residue of CLIC1. Biological validation experiments showed that knockdown of CLIC1 mimicked the antioxidant effect of CHP. Further investigation using a mouse model of CCl4-induced liver fibrosis in wild-type and CLIC1 KO mice revealed the critical involvement of CLIC1 in mediating the effects of CHP. Taken together, our results provide evidence that CHP exerts its anti-fibrotic effects through specific binding to CLIC1. These insights into the mechanism of action of CHP may pave the way for the development of novel therapeutic strategies for fibrosis-related diseases.

PRIMARY MYELOPHYBROSIS: RECOGNIZING ONCET TO COMPLICATIONS

Myelofibrosis is the accumulation of scar tissue in the bone marrow so that blood cells cannot develop properly. Myeloproliferative disorders, myelofibrosis is classified into two, namely primary myelofibrosis and secondary myelofibrosis. In contrast to secondary myelofibrosis, primary myelofibrosis can occur without being preceded by myeloproliferative disorders or other diseases. In a 2013 meta-analysis study in Europe, the incidence of primary myelofibrosis (PMF) was around 0.3 per 100,000 per year. PMF may result from increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling. The most common clinical features found in patients with PMF are splenomegaly, hepatomegaly, fatigue, anemia, leukocytosis, and thrombocytosis. Currently the only treatment modality capable of prolonging survival or healing potential in MF is allogeneic hematopoietic stem cell transplantation (AHSCT) especially for high or very high risk patients.

Cardiac fibrosis and atrial fibrillation

Abstract Cardiac fibrosis is characterized by the imbalance of production and degradation of the extracellular matrix. The result of this process is an accumulation of scar tissue, which is associated with many pathological processes such as excessive mechanical stress on the heart, inflammation, ischemia, oxidative stress, or excessive neurohormonal activation. Fibrotic response results in damaged heart architecture and dysfunction of the heart. Cardiac fibrosis leads to increased stiffness of the left ventricle and arteries, promotes disorders of contraction and relaxation of the heart, disrupts electrophysiology of heart cells, and induces arrhythmias. Atrial fibrillation is one of the most common arrhythmias. It is associated with a deterioration in the quality of life and more frequent use of medical assistance. It is also an instantaneous risk factor for many diseases, including stroke. The underlying cause of this arrhythmia is electrical and structural remodeling induced by cardiac fibrosis. Therefore, much attention is paid to the search for biochemical markers that would allow non-invasive determination of the degree of this fibrosis. The promising markers include galectin-3, human epididymis protein 4 (HE4), serum soluble ST2, and adipose triglyceride lipase (ATGL). Studies have shown that plasma concentrations of these substances reflect the degree of myocardial fibrosis and are indirectly associated with AF. There are high hopes for the use of these markers in patients undergoing arrhythmia ablation. More research is needed to confirm that these markers can be used to estimate the chance of maintaining sinus rhythm in patients after ablation.

Lung-targeted SERCA2a Gene Therapy: From Discovery to Therapeutic Application in Bleomycin-Induced Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by an accumulation of scar tissue within the lungs and the common presence of usual interstitial pneumonia. Unfortunately, only a few FDA-approved therapeutic options are currently available for the treatment of IPF and IPF remains associated with poor prognosis. Therefore, the identification of new pharmacological targets and strategies are critical for the treatment of IPF. This commentary aims to further discuss the role of sarcoplasmic reticulum Ca2+-ATPase 2a and its downstream signaling in IPF. Finally, this commentary offers new insights and perspectives regarding the therapeutic potential of AAV-mediated SERCA2A gene therapy as an emerging therapy for respiratory diseases.

Multimodal virtual histology of rabbit vocal folds by nonlinear microscopy and nano computed tomography.

Human vocal folds (VFs) possess a unique anatomical structure and mechanical properties for human communication. However, VFs are prone to scarring as a consequence of overuse, injury, disease or surgery. Accumulation of scar tissue on VFs inhibits proper phonation and leads to partial or complete loss of voice, with significant consequences for the patient's quality of life. VF regeneration after scarring provides a significant challenge for tissue engineering therapies given the complexity of tissue microarchitecture. To establish an effective animal model for VF injury and scarring, new histological methods are required to visualize the wound repair process of the tissue in its three-dimensional native environment. In this work, we propose the use of a combination of nonlinear microscopy and nanotomography as contrast methods for virtual histology of rabbit VFs. We apply these methods to rabbit VF tissue to demonstrate their use as alternatives to conventional VF histology that may enable future clinical studies of this injury model.

Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe.

Fibrogenesis is the active production of extracellular matrix in response to tissue injury. In many chronic diseases persistent fibrogenesis results in the accumulation of scar tissue, which can lead to organ failure and death. However, no non-invasive technique exists to assess this key biological process. All tissue fibrogenesis results in the formation of allysine, which enables collagen cross-linking and leads to tissue stiffening and scar formation. We report herein a novel allysine-binding gadolinium chelate (GdOA), that can non-invasively detect and quantify the extent of fibrogenesis using magnetic resonance imaging (MRI). We demonstrate that GdOA signal enhancement correlates with the extent of the disease and is sensitive to a therapeutic response.

Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine‐Based Probe

AbstractFibrogenesis is the active production of extracellular matrix in response to tissue injury. In many chronic diseases persistent fibrogenesis results in the accumulation of scar tissue, which can lead to organ failure and death. However, no non‐invasive technique exists to assess this key biological process. All tissue fibrogenesis results in the formation of allysine, which enables collagen cross‐linking and leads to tissue stiffening and scar formation. We report herein a novel allysine‐binding gadolinium chelate (GdOA), that can non‐invasively detect and quantify the extent of fibrogenesis using magnetic resonance imaging (MRI). We demonstrate that GdOA signal enhancement correlates with the extent of the disease and is sensitive to a therapeutic response.

490. Electroporation-Mediated Gene Transfer of Caveolin-1 Protects from Bleomycin-Induced Pulmonary Fibrosis Through Regulating Activation of Inflammasome

Pulmonary fibrosis (PF) is a progressive chronic interstitial lung disease associated with high morbidity and mortality. It is characterized by increased deposition of extracellular matrix proteins and the accumulation of scar tissue in the lung interstitium, resulting from alveolar epithelial injury and the accumulation of inflammatory cells. Currently, there is no effective therapy. Gene therapy is a promising approach to treat a variety of lung diseases, including pulmonary fibrosis. Caveolin-1 (Cav-1) is a major component of caveolae, and has been found greatly reduced expression in the lungs of PF patients. Moreover, Cav-1-deficient mice develop spontaneous pulmonary fibrosis. To investigate if Cav-1 can protect from bleomycin-induced pulmonary fibrosis, we delivered plasmids expressing Cav-1 driven by the ubiquitin promoter using electroporation. PF was induced 2 days after gene transfer by intratracheal administration of bleomycin (2 unit/kg). We found that electroporation-mediated gene transfer of Cav-1 to the lung significantly protected from subsequent bleomycin-mediated fibrogenesis by histological analysis and the expression of alpha-smooth muscle actin (alpha-SMA) and collagen measurement. We also found attenuated recruitment of neutrophils and monocytes and/or macrophages in bronchoalveolar lavage (BAL) fluid after gene transfer of Cav-1 compared with vector control. The underlying mechanism was associated with reduced activation of the inflammasome by determining the expression of cleaved caspase-1 and IL-1 beta in both mouse models and cultured cells after overexpression of Cav-1. These results demonstrate that Cav-1 might be a potential target for treatment of pulmonary fibrosis.

Mechanistic links between aging and lung fibrosis

Our understanding of the biology of aging has advanced significantly in recent years. This has resulted in the recent formulation of the "hallmarks of aging" that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that results from the accumulation of scar tissue in the lungs of affected individuals. IPF is a disease of aging that most commonly affects human subjects older than 60years of age. While progress has been made in elucidating key pathological processes in IPF, the relationship of these processes to those that occur during aging are not well defined. In this review, we explore existing and emerging paradigms in the pathogenesis of IPF in light of the recently defined hallmarks of aging.

Psychological Impact of Peyronie's Disease: A Review

Peyronie's disease (PD) is characterized by an accumulation of scar tissue in the tunica albuginea of the penis that causes curvature and deformity. PD can result in psychological distress, depression, or anxiety, which often goes untreated. To review the current literature on the psychological impact of PD, educate healthcare providers about the psychological components of the disease, and propose interventions that address the psychological and sexual challenges patients and their partners may encounter. We performed a MEDLINE search, limited to English, using the terms "Peyronie's disease" AND "psychological" OR "psychosocial," and select references were included for review. Critical review of the currently available English language literature. PD and its associated deformity often impairs sexual relations and frequently leads to psychological and psychosocial sequelae for affected individuals. Many men experience depression, low self-esteem, and emotional distress; these problems markedly diminish the quality of life for affected individuals. The literature suggests that as many as 81% of men report "emotional difficulties," 48% report clinically meaningful depression (26% moderate; 21% severe), and 54% report relationship problems due to PD. The challenges imposed by PD include alterations in sexual relationships, restrictions on intimacy, social isolation, and stigmatization, all of which are linked and reinforce each other. Physicians may be unaware of the psychological sequelae suffered by patients and their partners. Improved awareness and education about the psychological consequences and treatment options for PD are necessary among healthcare providers. To best help patients and optimize outcomes, a team-based approach is needed that includes psychosocial assessment and appropriate resource referrals for the patient and his sexual partner.

Mass transfer by advection and diffusion from a drug-eluting stent

Stents are often used to maintain the diameter of the coronary artery lumen. The insertion of a stent into an artery often results in the accumulation of scar tissue in response to the stent’s presence. Drug-eluting stents dispense a drug designed to limit the growth of such scar tissue, thus reducing the likelihood of restenosis. The trajectory of the eluted drug is of critical clinical importance. The bifurcation of the drug between the artery tissue and the blood-carrying lumen is a highly relevant issue to the success of stenting. Prior simulations of this issue have dealt with highly specific situations. Here, the problem is nondimensionalized in order to obtain universal solutions. The results, in terms of the Sherwood number, are reported in terms of the Reynolds and Schmidt numbers, and a mass-transfer version of the Biot number. It was found that the highest rates of mass transfer occurred at the forwardmost portion of the stent. The rate of drug delivery to the lumen was greater than that to the artery tissue.

Small-duct sclerosing cholangitis associated with Schistosoma mansoni

A 17-year-old girl presented with a history of elevated alkaline phosphatase and gamma-glutamyl transpeptidase (γGT) levels for several years. She was asymptomatic and did not have jaundice, pruritus, abdominal pain, nausea, vomiting, weight loss, rashes, or diarrhea. Viral hepatitis serologies, autoimmune serologies, and thyroid studies were all normal. γGT, gamma-glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography. She had a past medical history of anxiety, which was treated with Celexa. Otherwise, she was healthy and had no major childhood illnesses or history of substance abuse. She had traveled extensively with her family during her childhood, notably to Northern and Eastern Africa and Southeast Asia. Her physical examination was unremarkable. An abdominal ultrasound examination was performed, and the findings were normal. Magnetic resonance cholangiopancreatography (MRCP) showed mild beading of the intrahepatic ducts consistent with the diagnosis of primary sclerosing cholangitis involving the small ducts. The patient was started on ursodiol (300 mg three times per day), and her alkaline phosphatase and γGT levels promptly normalized. Subsequently, colonoscopy was performed to rule out concomitant inflammatory bowel disease. The mucosa appeared normal on endoscopic examination, but random biopsy samples were taken to rule out quiescent colitis. The pathology specimens revealed schistosoma eggs, and stool studies were positive for Schistosoma mansoni. Percutaneous liver biopsy was then performed to evaluate hepatic involvement. There were portal intravenular granulomas in two triads with a schistosoma egg with otherwise minimal lobular fibrosis There was no evidence of mucopolysaccharide production or hyperplasia of the ductular epithelium (Fig. 1). An endoscopic examination was negative for esophageal varices. She was treated with praziquantel, and ursodiol was continued. One year later, repeat MRCP showed minimal changes with resolution of duct dilation in segment 6. Portal triad demonstrating an intravenular granuloma surrounding a schistosoma egg. Onion-skinning fibrosis impinging on small interlobular ducts can also be noted. The over all histological examination showed minimal portal fibrosis with focal areas of periportal extensions. Schistosomiasis, which is also known as bilharzia, affects more than 207 million people worldwide, with 1 of every 30 people infected with the trematode. Free cercariae penetrate the skin, travel to the pulmonary vessels, and then eventually lodge in the liver; there, they mature, mate, and migrate distally against the venous flow in the portal system. Eggs pass through the intestinal wall into the bowel lumen. Chronic disease results from the ongoing host response to accumulating tissue-trapped eggs. There is a CD4+ T cell response to the egg antigen, and this drives the formation of granulomas around the eggs. When the eggs die in the liver, granulomas involute and leave fibrous plaques. Over a period of years, the accumulation of scar tissue can cause the hepatic vessels to become fibrotic and thereby lead to presinusoidal venous obstruction and portal hypertension. Hepatic function is typically preserved. The characteristic periportal lesion, Symmers' pipestem fibrosis, can be seen on imaging and resected specimens. Bile duct abnormalities associated with schistosomiasis have been described infrequently. Biliary changes in S. mansoni–infected mice were initially reported by Bedi and Isseroff in 1979.1 Bile duct hyperplasia occurs in response to neighboring S. mansoni injury to portal areas, and these changes do not seem to regress despite antiparasitic treatment.2 However, elevations in alkaline phosphatase and γGT levels are common in patients with schistosomiasis, and there is evidence that these perturbations normalize with ursodeoxycholic acid.3 Histological abnormalities of the intrahepatic ducts were originally described in patients by Vianna et al.4; almost all cases demonstrated periductal fibrosis with onion skinning. A schistosomiasis cholangiopathy with abnormal MRCP findings has also been described, and this infection should be included as a cause of ductopenia.5

SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Idiopathic pulmonary fibrosis (IPF) is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in IPF patients, we isolated fibroblasts from patients with IPF and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in IPF. We found that IPF fibroblasts constitutively expressed increased basal levels of SPARC, plasminogen activator inhibitor-1 (PAI-1), and active beta-catenin compared with control cells. Control of basal PAI-1 expression in IPF fibroblasts was regulated by SPARC-mediated activation of Akt, leading to inhibition of glycogen synthase kinase-3beta and activation of beta-catenin. Additionally, IPF fibroblasts (but not control fibroblasts) were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of SPARC or beta-catenin. These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated SPARC, giving rise to activated beta-catenin, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosis-resistant phenotype. Disruption of this pathway may represent a novel therapeutic target in IPF.

The Role of PPARs in Lung Fibrosis

Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARα agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARα agonist significantly inhibited the fibrotic response, while PPARα knockout mice developed more serious fibrosis. PPARβ/δ appears to play a critical role in regulating the transition from inflammation to wound healing. PPARβ/δ agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγ agonists. PPARγ ligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARγ ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARα and PPARγ agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

Relaxin in cardiovascular and renal disease

Fibrosis (organ scarring) is a hallmark of many forms of cardiovascular and renal disease, and causes organ dysfunction and structural changes when normal tissue is replaced with scar tissue; the accumulation of scar tissue being a leading cause of death around the world. Despite deep organ scarring potentially existing in many forms (including myocardial and vascular sclerosis, renal interstitial fibrosis, and glomerulosclerosis), current therapies have only had limited success in delaying end-stage disease. The peptide hormone relaxin is emerging as a potent antifibrotic therapy with rapid-occurring efficacy. Recent studies have demonstrated the antifibrotic actions of relaxin in experimental models of cardiac and renal disease in vivo, and the various levels at which relaxin acts to inhibit fibroblast-induced collagen overproduction leading to fibrosis, in vitro. Separate studies using relaxin gene-knockout mice have demonstrated the significance of endogenous relaxin as a naturally occurring and protective moderator of collagen turnover, while the therapeutic potential of relaxin has been enhanced by its ability to promote vasodilation and renal hyperfiltration. This review will summarize these coherent findings as a means of highlighting the clinical potential of relaxin in cardiovascular and renal disease.

A New Esophageal Plug

An esophageal fistula plug was constructed from polyvinyl chloride pipe at a material cost of approximately S3.50. The plug has a plastisol and metal washer and is held together with a hose clamp. The hose clamp is adjusted to exert light pressure on the neck by the washers to reduce scar tissue around the tistula. The size of the plug can be varied by changing the diameter of the pipe allowing it to be used as a fistula dialator. Successful diet sampling with esophageally fistulated animals requires maintenance of an adequate tistula opening. Closure of the fistula because of swelling or accumulation of scar tissue will restrict passage of extrusa from the fistula. Loss of fistula plugs or extended sampling from animals with removable plugs usually results in swelling and closure of the fistula opening (Anderson and Mertz 1982). This makes replacement of the plug difficult and stressful to the animal. The accumulation of scar tissue around the fistula is normal and may limit the usefulness of a fistulated animal. This paper describes an inexpensive removable fistula plug that reduces formation of scar tissue and assists in expanding fistula openings that have closed because of trauma or were not of the desired size following initial surgery.

The Treatment of Trigeminal Neuralgia

Three therapeutic measures are considered effective in the treatment for tic douloureux; trichlorethglene inhalat,ions, alcohol injections, and section of the nerve. Trichlorethylene, a volatile dru, u which produces rather marked cerebral circulatory change, used at regular intervals as an inhalant has given some patients relief. Alcohol when injected gives temporary relief; it usually requires no hospitaliza,tion and is free from any mortality. Five per cent of the patients injected were not, relieved while the average period of relief in 156 injections was eleven months. When injections are repeated the period of relief becomes shorter, due to the accumulation of scar tissue about the nerve. Surgery is usually the final treatment, for patients who have had almost everything else therapeutically. The simplest operat,ion is the avulsion of the peripheral branches such as the supraorbital or infraorbital. The subntmtnl approach of Frazier was used in the majority of cases.