http://www.fibrogenesis.com The latest research articles published by Fibrogenesis & Tissue Repair 2012-05-07T00:00:00Z Heat shock protein 27 (HSP27) is a multidimensional protein which acts as a protein chaperone and an antioxidant and plays a role in the inhibition of apoptosis and actin cytoskeletal remodeling. In each of these capacities, HSP27 has been implicated in different disease states playing both protective and counter-protective roles. The current review presents HSP27 in multiple disease contexts: renal injury and fibrosis, cancer, neuro-degenerative and cardiovascular disease, highlighting its role as a potential biomarker and therapeutic target. http://www.fibrogenesis.com/content/5/1/7 Aparna Vidyasagar Nancy Wilson Arjang Djamali Fibrogenesis & Tissue Repair 2012, null:7 2012-05-07T00:00:00Z doi:10.1186/1755-1536-5-7 /content/figures/1755-1536-5-7-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 7 2012-05-07T00:00:00Z PDF Background: Transforming growth factor-beta1 (TGF-beta1) is a potent regulator of cell growth and differentiation. TGF-beta1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-beta1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins.Methodology/Principal findingsThe expression of proteins involved in mRNA splicing from TGF-beta1-stimulated lung fibroblasts was compared to non-stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/ 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-beta1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-beta1 significantly induced expression of SRp20, and reducedthe expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by westernblot and immunofluorescence. Conclusions: The results show that TGF-beta1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression. http://www.fibrogenesis.com/content/5/1/6 Oskar Hallgren Johan Malmström Lars Malmström Annika Andersson-Sjöland Marie Wildt Ellen Tufvesson Peer Juhasz Gyorgy Marko-Varga Gunilla Westergren-Thorsson Fibrogenesis & Tissue Repair 2012, null:6 2012-04-28T00:00:00Z doi:10.1186/1755-1536-5-6 /content/figures/1755-1536-5-6-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 6 2012-04-28T00:00:00Z PDF Background: Peroxisome proliferator-activated receptor (PPAR)γ may be a key regulator of connective tissue deposition and remodeling in vivo. PPARγ expression is reduced in dermal fibroblasts isolated from fibrotic areas of scleroderma patients; PPARγ agonists suppress the persistent fibrotic phenotype of this cell type. Previously, we showed that loss of PPARγ expression in fibroblasts resulted in enhanced bleomycin-induced skin fibrosis. However, whether loss of PPARγ expression in skin fibroblasts affects cutaneous tissue repair or homeostasis is unknown. Results: Mice deleted for PPARγ in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, α-smooth muscle actin (α-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARγ expression. Conclusion: PPARγ expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARγ antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively. http://www.fibrogenesis.com/content/5/1/5 Wei Sha Katherine Thompson Jennifer South Murray Baron Andrew Leask Fibrogenesis & Tissue Repair 2012, null:5 2012-04-13T00:00:00Z doi:10.1186/1755-1536-5-5 /content/figures/1755-1536-5-5-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 5 2012-04-13T00:00:00Z XML In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent. http://www.fibrogenesis.com/content/5/1/4 Francisco Caiado Sergio Dias Fibrogenesis & Tissue Repair 2012, null:4 2012-03-12T00:00:00Z doi:10.1186/1755-1536-5-4 /content/figures/1755-1536-5-4-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 4 2012-03-12T00:00:00Z XML Background: The two discoidin domain receptors (DDRs), DDR1 and DDR2 are receptor tyrosine kinases (RTKs) with the unique ability among RTKs to respond to collagen. We have previously shown that collagen I induces DDR1 and matrix metalloproteinase (MMP)-10 expression through DDR2 activation and a Janus kinase (JAK)2 and extracellular signal-regulated kinase (ERK)1/2-mediated mechanism in primary human lung fibroblasts suggesting that these signaling pathways play a role in fibroblast function. Fibroblasts can traverse basement membrane barriers during development, wound healing and pathological conditions such as cancer and fibrosis by activating tissue-invasive programs, the identity of which remain largely undefined. In the present work, we investigated the role of DDRs and DDR-associated signal transduction in these processes. Results: Transwell migration experiments showed that normal human lung fibroblast (NHLF) transmigration through collagen I-coated inserts is mediated by DDR2 and the DDR2-associated signaling kinases JAK2 and ERK1/2, but not DDR1. Additionally, experiments with specific small interfering (si)RNAs revealed that collagen I-induced expression of MMP-10 and MMP-2 is DDR2 but not DDR1 dependent in NHLFs. Our data showed that collagen I increases NHLF migration through collagen IV, the main component of basement membranes. Furthermore, basal and collagen I-induced NHLF migration through collagen IV-coated inserts was both DDR2 and DDR1 dependent. Finally, DDR2, but not DDR1 was shown to be involved in fibroblast proliferation. Conclusions: Our results suggest a mechanism by which the presence of collagen I in situations of excessive matrix deposition could induce fibroblast migration through basement membranes through DDR2 activation and subsequent DDR1 and MMP-2 gene expression. This work provides new insights into the role of DDRs in fibroblast function. http://www.fibrogenesis.com/content/5/1/3 Pedro Ruiz Gabor Jarai Fibrogenesis & Tissue Repair 2012, null:3 2012-02-15T00:00:00Z doi:10.1186/1755-1536-5-3 /content/figures/1755-1536-5-3-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 3 2012-02-15T00:00:00Z XML CCL18, a chemokine with no known receptor, has been implicated in several fibrotic pulmonary diseases associated with T-lymphocyte infiltration. It has been hypothesized that CCL18 may act through CCR6. Gene delivery of human CCL18 to the lungs of wild-type mice induced pulmonary infiltration of T-lymphocytes, less than 5% of which expressed CCR6. In the lungs of CCR6-deficient mice, CCL18-driven infiltration of T-lymphocytes was attenuated but not fully abrogated. It was concluded that CCR6 is not necessary for CCL18-induced changes in mice in vivo and that CCR6 is not the main functional receptor for CCL18 in this model. http://www.fibrogenesis.com/content/5/1/2 Irina Luzina Sergei Atamas Fibrogenesis & Tissue Repair 2012, null:2 2012-01-18T00:00:00Z doi:10.1186/1755-1536-5-2 /content/figures/1755-1536-5-2-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 2 2012-01-18T00:00:00Z XML Genomics and proteomics have become increasingly important in biomedical science in the past decade, as they provide an opportunity for hypothesis-free experiments that can yield major insights not previously foreseen when scientific and clinical questions are based only on hypothesis-driven approaches. Use of these tools, therefore, opens new avenues for uncovering physiological and pathological pathways. Liver fibrosis is a complex disease provoked by a range of chronic injuries to the liver, among which are viral hepatitis, (non-) alcoholic steatohepatitis and autoimmune disorders. Some chronic liver patients will never develop fibrosis or cirrhosis, whereas others rapidly progress towards cirrhosis in a few years. This variety can be caused by disease-related factors (for example, viral genotype) or host-factors (genetic/epigenetic). It is vital to establish accurate tools to identify those patients at highest risk for disease severity or progression in order to determine who are in need of immediate therapies. Moreover, there is an urgent imperative to identify non-invasive markers that can accurately distinguish mild and intermediate stages of fibrosis. Ideally, biomarkers can be used to predict disease progression and treatment response, but these studies will take many years due to the requirement for lengthy follow-up periods to assess outcomes. Current genomic and proteomic research provides many candidate biomarkers, but independent validation of these biomarkers is lacking, and reproducibility is still a key concern. Thus, great opportunities and challenges lie ahead in the field of genomics and proteomics, which, if successful, could transform the diagnosis and treatment of chronic fibrosing liver diseases. http://www.fibrogenesis.com/content/5/1/1 Rebekka Hannivoort Virginia Hernandez-Gea Scott Friedman Fibrogenesis & Tissue Repair 2012, null:1 2012-01-03T00:00:00Z doi:10.1186/1755-1536-5-1 /content/figures/1755-1536-5-1-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 1 2012-01-03T00:00:00Z XML The 16th International Symposium on Cells of the Hepatic Sinusoid (ISCHS) took place in Florence, Italy on 22-24 September 2011. This symposium is a multidisciplinary meeting where new and important findings on the biology of liver cells are presented and discussed. http://www.fibrogenesis.com/content/4/1/27 Krista Rombouts Massimo Pinzani Fibrogenesis & Tissue Repair 2011, null:27 2011-12-13T00:00:00Z doi:10.1186/1755-1536-4-27 /content/figures/1755-1536-4-27-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 27 2011-12-13T00:00:00Z XML Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. http://www.fibrogenesis.com/content/4/1/26 Alexander Aghdassi Julia Mayerle Sandra Christochowitz Frank Weiss Matthias Sendler Markus Lerch Fibrogenesis & Tissue Repair 2011, null:26 2011-12-01T00:00:00Z doi:10.1186/1755-1536-4-26 /content/figures/1755-1536-4-26-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 26 2011-12-01T00:00:00Z XML Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their antifibrotic roles. In this review, we discuss the antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). http://www.fibrogenesis.com/content/4/1/25 Megumi Kanasaki Takako Nagai Munehiro Kitada Daisuke Koya Keizo Kanasaki Fibrogenesis & Tissue Repair 2011, null:25 2011-11-30T00:00:00Z doi:10.1186/1755-1536-4-25 /content/figures/1755-1536-4-25-toc.gif Fibrogenesis & Tissue Repair 1755-1536 ${item.volume} 25 2011-11-30T00:00:00Z XML