RESUMO
The currently accepted approach to treatment of idiopathic pulmonary fibrosis (IPF) is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in IPF aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor (TGF)-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
Assuntos
Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Ensaios Clínicos como Assunto , Fator de Crescimento do Tecido Conjuntivo , Etanercepte , Matriz Extracelular/efeitos dos fármacos , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Imunoglobulina G/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
RATIONALE: Usual interstitial pneumonia (UIP) is characterized by extracellular matrix deposition and the development of pulmonary fibrosis. Fibroblastic foci found in the lung are believed to represent an early stage in the evolution of this disease. OBJECTIVES: To compare gene expression profiles in different components of lung tissue (fibroblastic foci, adjacent epithelium, and areas of type 2 pneumocyte hyperplasia) from patients with UIP, and contrast these profiles to distal, uninvolved (control) alveolar tissue from patients undergoing lung resection for cancer. METHODS: Lung resection tissue (UIP, n = 11; controls, n = 11) was snap-frozen for subsequent laser capture microdissection, followed by mRNA extraction, linear amplification, and quantitative real-time polymerase chain reaction. RESULTS: In patients with UIP, tissue inhibitor of matrix metalloprotease-1 and matrix metalloprotease (MMP)-2 gene expression was up-regulated within the fibroblastic foci compared with the overlying epithelium (p = 0.03, p = 0.02), and to control alveoli (p = 0.001, p = 0.04), respectively. MMP-9 and MMP-7, as well as osteopontin, were up-regulated in fibroblastic foci (p = 0.01, p = 0.08, p = 0.08), the adjacent epithelium (p = 0.001, p = 0.001, p = 0.03), and the hyperplastic type 2 pneumocytes (p = 0.02, p = 0.001, p = 0.08), respectively, compared with control alveoli. CONCLUSION: Altered gene expression of important profibrotic mediators in the different cellular lung compartments in patients with UIP likely plays an important role in pathogenesis of the deranged extracellular matrix deposition and subsequent fibrosis in this condition.
Assuntos
Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/patologia , Idoso , Estudos de Casos e Controles , Fator de Crescimento do Tecido Conjuntivo , Feminino , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Osteopontina , RNA Mensageiro/metabolismo , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Crescimento Transformadores/genética , Fatores de Crescimento Transformadores/metabolismoRESUMO
Platelets are a major source of transforming growth factor-beta1 (TGF-beta1) in the circulation as they release latent growth factor in response to activation. We report here that human platelets, when stimulated with thrombin, activated a significant proportion of the latent TGF-beta released. Latent TGF-beta activation was independent of cytokine release, since activation was delayed compared to platelet degranulation. Activation occured in releasates and did not require the continuous presence of platelets. Classical mechanisms of latent TGF-beta activation were not involved, since activation was not affected by gene deletion and/or inhibitors of the known TGF-beta activators/co-factors, thrombospondin-1 (TSP-1), mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR), plasminogen/plasmin, or several other candidate proteases. In contrast, latent TGF-beta activation was significantly inhibited by the furin inhibitors, decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone and L-hexaarginine. We show that platelets contain a furin-like enzyme which is released upon platelet activation. We conclude that, following activation, platelets release and activate latent TGF-beta1 via mechanisms involving the release and activity of a furin-like proprotein convertase. This novel mechanism of latent TGF-beta activation might represent an important mediator and therapeutic target of platelet TGF-beta1 functions, for example, in early wound repair, fibrosis, or arteriosclerosis.