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1.
Proc Natl Acad Sci U S A ; 110(10): E928-37, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23431165

RESUMO

Dupuytren's disease is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function. The cell responsible for development of the disease is the myofibroblast. There is currently no treatment for early disease or for preventing recurrence following surgical excision of affected tissue in advanced disease. Therefore, we sought to unravel the signaling pathways leading to the development of myofibroblasts in Dupuytren's disease. We characterized the cells present in Dupuytren's tissue and found significant numbers of immune cells, including classically activated macrophages. High levels of proinflammatory cytokines were also detected in tissue from Dupuytren's patients. We compared the effects of these cytokines on contraction and profibrotic signaling pathways in fibroblasts from the palmar and nonpalmar dermis of Dupuytren's patients and palmar fibroblasts from non-Dupuytren's patients. Exogenous addition of TNF, but not other cytokines, including IL-6 and IL-1ß, promoted differentiation into specifically of palmar dermal fibroblasts from Dupuytren's patients in to myofibroblasts. We also demonstrated that TNF acts via the Wnt signaling pathway to drive contraction and profibrotic signaling in these cells. Finally, we examined the effects of targeted cytokine inhibition. Neutralizing antibodies to TNF inhibited the contractile activity of myofibroblasts derived from Dupuytren's patients, reduced their expression of α-smooth muscle actin, and mediated disassembly of the contractile apparatus. Therefore, we showed that localized inflammation in Dupuytren's disease contributes to the development and progression of this fibroproliferative disorder and identified TNF as a therapeutic target to down-regulate myofibroblast differentiation and activity.


Assuntos
Contratura de Dupuytren/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/farmacologia , Citocinas/fisiologia , Progressão da Doença , Contratura de Dupuytren/patologia , Contratura de Dupuytren/fisiopatologia , Contratura de Dupuytren/terapia , Fibrose , Quinase 3 da Glicogênio Sintase/fisiologia , Glicogênio Sintase Quinase 3 beta , Humanos , Ativação de Macrófagos , Modelos Biológicos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Miofibroblastos/fisiologia , Fenótipo , Proteínas Recombinantes/farmacologia , Fator de Crescimento Transformador beta1/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Via de Sinalização Wnt
2.
J Plast Reconstr Aesthet Surg ; 68(8): 1132-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25986418

RESUMO

Late presenting and recurrent sternal wound infections post-sternotomy are difficult to treat, with the clinical picture not necessarily reflecting the underlying problem. As a result of our experience, we suggest that these chronic cases should be managed using a different algorithm to acute sternal wound infection. Positron emission tomography combined with computerized tomography (PET-CT) imaging may be potentially useful in enabling accurate localization of disease sites, which guides adequate debridement prior to definitive reconstruction. It may also allow for disease surveillance and monitoring of the response to antimicrobial treatment. We present three cases which support the need for pre-operative imaging using PET-CT.


Assuntos
Osteomielite/diagnóstico , Osteomielite/terapia , Tomografia por Emissão de Pósitrons , Infecção da Ferida Cirúrgica/diagnóstico , Infecção da Ferida Cirúrgica/terapia , Tomografia Computadorizada por Raios X , Idoso , Antibacterianos/uso terapêutico , Ponte de Artéria Coronária/efeitos adversos , Desbridamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Osteomielite/etiologia , Cuidados Pré-Operatórios , Esternotomia/efeitos adversos , Infecção da Ferida Cirúrgica/etiologia
4.
J Invest Dermatol ; 133(12): 2664-2671, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23652794

RESUMO

Myofibroblasts (MFs) are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human MFs derived from patients with Dupuytren's disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three-dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive, or gap junctions effectively inhibited contraction of the collagen matrices and downregulated the MF phenotype. Our data indicate that MFs in part function as a coordinated cellular syncytium, and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells.


Assuntos
Contratura de Dupuytren/fisiopatologia , Junções Intercelulares/fisiologia , Contração Isométrica , Miofibroblastos/patologia , Caderinas/metabolismo , Comunicação Celular , Células Cultivadas , Colágeno/química , Fibroblastos/citologia , Junções Comunicantes/metabolismo , Células Gigantes/metabolismo , Humanos , Microscopia de Fluorescência , Fenótipo , RNA Interferente Pequeno/metabolismo , Pele/citologia
5.
Fibrogenesis Tissue Repair ; 4(1): 9, 2011 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-21453480

RESUMO

BACKGROUND: The mechanism underlying the ability of fibroblasts to contract a collagen gel matrix is largely unknown. Fibroblasts from scarred (lesional) areas of patients with the fibrotic disease scleroderma show enhanced ability to contract collagen relative to healthy fibroblasts. Thrombospondin 1 (TSP1), an activator of latent transforming growth factor (TGF)ß, is overexpressed by scleroderma fibroblasts. In this report we investigate whether activation of latent TGFß by TSP1 plays a key role in matrix contraction by normal and scleroderma fibroblasts. METHODS: We use the fibroblast populated collagen lattices (FPCL) model of matrix contraction to show that interfering with TSP1/TGFß binding and knockdown of TSP1 expression suppressed the contractile ability of normal and scleroderma fibroblasts basally and in response to TGFß. Previously, we have shown that ras/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mediates matrix contraction basally and in response to TGFß. RESULTS: During mechanical stimulation in the FPCL system, using a multistation tensioning-culture force monitor (mst-CFM), TSP1 expression and p-ERK activation in fibroblasts are enhanced. Inhibiting TSP1 activity reduced the elevated activation of MEK/ERK and expression of key fibrogenic proteins. TSP1 also blocked platelet-derived growth factor (PDGF)-induced contractile activity and MEK/ERK activation. CONCLUSIONS: TSP1 is a key mediator of matrix contraction of normal and systemic sclerosis fibroblasts, via MEK/ERK.

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