Fibrogenesis & Tissue Repair最新文献

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.

Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.

Background: The dynamic process of epithelial-to-mesenchymal transition (EMT) is a causal event in kidney fibrosis. This cellular phenotypic transition involves activation of transcriptional responses and remodeling of cellular structures to change cellular function. The molecular mechanisms that directly contribute to the re-establishment of the epithelial phenotype are poorly understood.

Results: Here, we discuss recent studies from our group and other laboratories identifying signaling pathways leading to the reversal of EMT in fibrotic models. We also present evidence that transcriptional factors such as the ZEB proteins are important regulators for reversal of EMT.

Conclusion: These studies provide insights into cellular plasticity and possible targets for therapeutic intervention.

This review provides an introduction to mass spectrometry based proteomics and discusses several proteomics approaches that are relevant in understanding the pathophysiology of fibrotic disorders and the approaches that are frequently used in biomarker discovery.

Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.

Fibrotic disorders are commonplace, take many forms and can be life-threatening. No better example of this exists than the progressive fibrosis that accompanies all chronic renal disease. Renal fibrosis is a direct consequence of the kidney's limited capacity to regenerate after injury. Renal scarring results in a progressive loss of renal function, ultimately leading to end-stage renal failure and a requirement for dialysis or kidney transplantation. Although it manifests itself histologically as an increase in extracellular matrix, we know that the histological appearance can be caused by a de novo synthesis of matrix (primarily collagen), or a disproportionate loss of renal parenchyma. In both cases the process depends on a resident mesenchymal cell, the so-called myofibroblast, and is independent of disease etiology. Potentially we can ameliorate fibrosis, either indirectly by modifying the environment the kidney functions in, or more directly by interfering with activation and function of myofibroblasts. However, while renal fibrosis shares many features in common with the wound healing response in other organs, we also recognise that the consequences can be highly kidney specific. This review highlights the similarities and differences between this process in the kidney and other organs, and considers the therapeutic implications.

Sustained inflammation upon chronic liver injury induces the development of liver fibrosis in mice and men. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating inflammation by releasing proinflammatory cytokines and chemokines as well as activating hepatic stellate cells (HSC). Recent studies in mice demonstrate that these actions are only partially conducted by liver-resident macrophages, classically termed Kupffer cells, but largely depend on recruitment of monocytes into the liver. Monocytes are circulating precursors of tissue macrophages and dendritic cells (DC), which comprise two major subsets in blood, characterized by the differential expression of chemokine receptors, adhesion molecules and distinct markers, such as Ly6C/Gr1 in mice or CD14 and CD16 in humans. Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages. The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents. In contrast, chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration in hepatic inflammation by controlling their survival and differentiation into functionally diverse macrophage subsets. In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis. Moreover, experimental animal models indicate that monocytes/macrophages and DCs are not only critical for fibrosis progression, but also for fibrosis regression, because macrophages can also degrade extracellular matrix proteins and exert anti-inflammatory actions. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.

A discrepancy between oxygen availability and demand has been found in most chronic kidney diseases (CKD) irrespective of etiology. This results from a combination of structural and functional changes that are commonly associated with the development of fibrosis, which include a reduction in peritubular blood flow, luminal narrowing of atherosclerotic vessels, capillary rarefaction and vascular constriction due to altered expression of vasoactive factors and signaling molecules (e.g. angiotensin II, endothelin, nitric oxide). Consistent with decreased renal oxygenation in CKD is the increased expression of the oxygen-sensitive α-subunit of hypoxia-inducible factor (HIF)-1. HIF transcription factors are members of the Per-ARNT-Sim (PAS) family of heterodimeric basic helix-loop-helix transcription factors and consist of an oxygen-sensitive α-subunit and a constitutively expressed β-unit, also known as the aryl-hydrocarbon-receptor nuclear translocator (ARNT) or HIF-β. Recent experimental evidence suggests that prolonged activation of HIF signaling in renal epithelial cells enhances maladaptive responses, which lead to fibrosis and further tissue destruction. Cell type-specific functions of individual HIF transcription factors and their relevant transcriptional targets are discussed in the context of renal fibrogenesis.

The wound-healing process induced by chronic hepatitis C virus (HCV) infection triggers liver damage characterized by fibrosis development and finally cirrhosis. Liver Transplantation (LT) is the optimal surgical treatment for HCV-cirrhotic patients at end-stage liver disease. However, acute cellular rejection (ACR) and HCV recurrence disease represent two devastating complications post-LT. The accurate differential diagnosis between both conditions is critical for treatment choice, and similar histological features represent a challenge for pathologists. Moreover, the HCV recurrence disease severity is highly variable post-LT. HCV recurrence disease progression is characterized by an accelerated fibrogenesis process, and almost 30% of those patients develop cirrhosis at 5-years of follow-up. Whole-genome gene expression (WGE) analyses through well-defined oligonucleotide microarray platforms represent a powerful tool for the molecular characterization of biological process. In the present manuscript, the utility of microarray technology is applied for the ACR and HCV-recurrence biological characterization in post-LT liver biopsy samples. Moreover, WGE analysis was performed to identify predictive biomarkers of HCV recurrence severity in formalin-fixed paraffin-embedded liver biopsies prospectively collected.

Lung fibrosis is the final common pathway of a large variety of chronic lung disorders, named interstitial lung diseases. The most aggressive form is the idiopathic pulmonary fibrosis [IPF] characterized by alveolar epithelial cell injury/activation, expansion of the fibroblast/myofibroblast population, and the exaggerated accumulation of extracellular matrix [ECM] components which ultimately result in the destruction of the lung parenchyma. Several matrix metalloproteases [MMPs] are upregulated in the IPF lungs and have been shown to actively participate in the pathogenesis of the disease through extracellular matrix remodeling and basement membrane disruption. However, MMPs can also breakdown molecules that mediate cell-cell and cell-ECM interactions, and can activate growth factors and growth factor receptors indicating that they likely contribute to other local biopathological processes such as apoptosis, migration, proliferation and angiogenesis.