Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

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Phenotypic modulation in lipocytes in experimental liver fibrosis

The presence of a-smooth muscle actin (smA)-positive cells has recently been reported in the fibrotic liver. Lipocytes have been considered to play important roles in hepatic fibrosis. However, the relation of the a-smA-positive cells and lipocytes has not been determined. The biological implication of a-smA expression remains unknown. To study these questions, we carried out double immunofluorescent staining of a-smA and desmin (a marker for lipocytes), or a-smA and collagen, and double immunohistochemical staining of a-smA and 5-bromo-2'-deoxyuridine (BrdUrd) in carbon tetrachloride-induced fibrotic rat livers. In normal and control livers, a-smA-positive cells were not seen in the lobules, whereas scattered desmin-positive cells were present. With the development of hepatic fibrosis, a-smA was expressed only in a portion of desmin-positive cells located predominantly around collagen bundles. A number of a-smA-positive cells in the lobules were labelled with BrdUrd. These results suggest phenotypic modulation in lipocytes and differentiation of lipocytes towards myofibroblast-like cells, since a-smA is expressed with desmin in myofibroblasts in scar tissue. The expression of a-smA may be related to events of the fibrotic process, such as tissue contraction or fibrogenesis per se.     

Matrix metalloproteinase-2 from bronchial epithelial cells induces the proliferation of subepithelial fibroblasts

BACKGROUND: In bronchial asthma, subepithelial fibrosis in the conducting airways is associated with increased numbers of subepithelial fibroblasts. OBJECTIVE: This study examined the hypothesis that MMP-2 from airway epithelial cells induces the proliferation of subepithelial fibroblasts. METHODS: Using primary bronchial epithelial cells MMP-2, MT1-MMP and TIMP-2 mRNA expression were assessed by Northern blotting and RT-PCR. Primary bronchial epithelial cells transfected with constructs encoding pro-MMP-2 and MT1-MMP (MMP-14). RESULTS: Transfected cells showed enhanced expression of the appropriate mRNA species by RT-PCR and enhanced MMP-2 or MT1-MMP activity by zymography. Active MMP-2 levels in epithelial supernatants were increased most by cotransfection with pro-MMP-2 and MT1-MMP encoding constructs. By measuring tritiated thymidine incorporation, supernatants from transfected cells were found to enhance DNA synthesis of primary airway fibroblast cultures compared with controls. There was a strong correlation (r = 0.9, P < 0.01) between MMP-2 levels in epithelial cell conditioned media and fibroblast proliferation as indicated by DNA synthesis. The MMP inhibitor 1,10-phenanthroline attenuated the increased proliferation, while the addition of exogenous purified MMP-2 alone also increased fibroblast proliferation. CONCLUSIONS: Our results support a role for MMP-2 in mediating cross-talk between epithelial cells and myofibroblasts.     

Diffuse inflammatory pseudotumor of the testis,the epididymis and the spermatic cord

Inflammatory pseudotumors have been recognized in many parts of the body. A case of a diffuse variant which involved the testis, the epididymis and the spermatic cord is described. The patient had enlarged left testis for several months. Clinically, the lesion mimicred cancer. Histologically, the lesion contained hyalinized fibrous tissue with spindle cells, plasma cells and lymphocytes. Gradual involvement of vascular channels by the cellular elements of inflammatory pseudotumor was observed. Results of immunohistochemical studies showed a myofibroblast differentiation in the majority of spindle cells: intense antibody staining for smooth muscle actin, muscle specific actin, and vimentin. The ultrastructural findings, intracytoplasmic filaments with dense bodies, were also consistent with the myofibroblastic nature of these cells. The histiocyte differentiation of spindle cells is questionable in our case, because only scattered histiocyte-like cells showed positivity with the KP-1 (CD-3) antibody.     

Human decidual stromal cells express alpha-smooth muscle actin and show ultrastructural similarities with myofibroblasts.

Previous reports in human and mouse material demonstrated that decidual stromal cells expressed antigens associated with haematopoietic cells, exerted immune functions, and originated from bone marrow. These findings suggested that these cells belonged to the haematopoietic lineage. We purified and expanded in culture precursors of human decidual stromal cells, and found in electron microscopic images that the ultrastructure of these cells was similar to that of myofibroblasts, which are of mesenchymal origin. The relationship between these two types of cell was confirmed by the detection (by flow cytometry) in the decidual precursors of alpha-smooth muscle actin, a contractile microfilament expressed solely by smooth muscle cells, myofibroblasts and related cells. This filament was also detected in decidual stromal cells decidualized in vitro by the effect of progesterone. We also found vimentin in decidual precursors and decidualized cells. This intermediate filament has been previously reported to be expressed by all decidual stromal cells and also by myofibroblasts. Desmin, another intermediate filament expressed by myofibroblasts, was not detected in the decidual precursors; however, this filament was observed in decidualized cells. The expression of alpha-smooth muscle actin by decidual stromal cells was also found by immunostaining in cryostat sections of early decidua. Our results suggest that decidual stromal cells are related to myofibroblasts.     

Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts

Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary‐like structures. The release of microvesicles from Hmyos was dose‐dependently induced by the serum protein α‐2‐macroglobulin. Using flow cytometry, we revealed the presence of the α‐2‐macroglobulin receptor—low‐density lipoprotein receptor‐related protein 1—on the surface of Hmyos. The inhibition of the binding of α‐2‐macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α‐2‐Macroglobulin modulates the release of these microvesicles through interaction with low‐density lipoprotein receptor‐related protein 1.     

Emerging targets for the treatment of scleroderma

Introduction: Scleroderma is an often-fatal autoimmune connective tissue disease. Recommendations for treating digital ulcers and pulmonary hypertension in scleroderma have recently been established by the European League Against Rheumatism. Conversely, although many valuable insights have been generated into the molecular mechanism underlying the persistent fibrotic phenotype in scleroderma, no safe, clinically proven effective treatment has been found for this aspect of the disease.

Areas covered: Recent evidence suggests that, based on genome-wide molecular profiling, scleroderma can be loosely divided into ‘fibroproliferative' and ‘inflammatory' cohorts. The latter cohort contains patients with localized and ‘limited' disease, as well as a small subset of those with ‘diffuse' disease. Drugs targeting either B cells or ILs might be useful to treat patients who possess an ‘inflammatory' gene expression signature.

Expert opinion: In the future, a ‘personalized medicine' approach might be used to treat patients with scleroderma: individuals with an ‘inflammatory' gene expression signature may be successfully treated with drugs specifically targeting the immune system. Indeed, drugs currently approved for other rheumatic disease might also be used to treat scleroderma patients bearing an ‘inflammatory' gene expression profile.     

Low-grade Sarcomas with CD34-Positive Fibroblasts and Low-Grade Myofibroblastic Sarcomas

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.