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3.
FASEB J ; 30(6): 2135-50, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26884454

RESUMO

Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, α-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-ß1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-ß1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-ß1/SMAD3 signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein CCN1 enhances TGF-ß1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica/fisiologia , Lesão Pulmonar/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Células Cultivadas , Proteína Rica em Cisteína 61/genética , Técnicas de Silenciamento de Genes , Humanos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fibrose Pulmonar/metabolismo , Interferência de RNA , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética , Regulação para Cima
4.
Am J Respir Cell Mol Biol ; 54(1): 51-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26072676

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a disease with relentless course and limited therapeutic options. Nintedanib (BIBF-1120) is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanism(s) of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor (TGF)-ß1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-ß signaling, specifically tyrosine phosphorylation of the type II TGF-ß receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-ß signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.


Assuntos
Fibrose Pulmonar Idiopática/prevenção & controle , Indóis/farmacologia , Pulmão/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 7 Relacionada à Autofagia , Proteína Beclina-1 , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Relação Dose-Resposta a Droga , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Biol Chem ; 290(42): 25427-38, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26318453

RESUMO

Contraction is crucial in maintaining the differentiated phenotype of myofibroblasts. Contraction is an energy-dependent mechanism that relies on the production of ATP by mitochondria and/or glycolysis. Although the role of mitochondrial biogenesis in the adaptive responses of skeletal muscle to exercise is well appreciated, mechanisms governing energetic adaptation of myofibroblasts are not well understood. Our study demonstrates induction of mitochondrial biogenesis and aerobic glycolysis in response to the differentiation-inducing factor transforming growth factor ß1 (TGF-ß1). This metabolic reprogramming is linked to the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Inhibition of p38 MAPK decreased accumulation of active peroxisome proliferator-activated receptor γ coactivator 1α in the nucleus and altered the translocation of mitochondrial transcription factor A to the mitochondria. Genetic or pharmacologic approaches that block mitochondrial biogenesis or glycolysis resulted in decreased contraction and reduced expression of TGF-ß1-induced α-smooth muscle actin and collagen α-2(I) but not of fibronectin or collagen α-1(I). These data indicate a critical role for TGF-ß1-induced metabolic reprogramming in regulating myofibroblast-specific contractile signaling and support the concept of integrating bioenergetics with cellular differentiation.


Assuntos
Diferenciação Celular , Metabolismo Energético , Miofibroblastos/metabolismo , Linhagem Celular , Transporte de Elétrons , Glicólise , Humanos , Pulmão/citologia , Pulmão/metabolismo , Mitocôndrias/metabolismo , Miofibroblastos/citologia , Consumo de Oxigênio , Fator de Crescimento Transformador beta1/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Aging Cell ; 21(9): e13674, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35934931

RESUMO

Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential. UCP2 is highly expressed in human IPF lung myofibroblasts and in aged fibroblasts. In an aging murine model of lung fibrosis, the in vivo silencing of UCP2 induces fibrosis regression. These studies indicate a pro-fibrotic function of UCP2 in chronic lung disease and support its therapeutic targeting in age-related diseases associated with impaired tissue regeneration and organ fibrosis.


Assuntos
Fibrose Pulmonar Idiopática , Miofibroblastos , Proteína Desacopladora 2 , Idoso , Animais , Fibroblastos/metabolismo , Fibrose , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Camundongos , Miofibroblastos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
9.
Nat Aging ; 1(2): 205-217, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-34386777

RESUMO

Aging is a risk factor for progressive fibrotic disorders involving diverse organ systems, including the lung. Idiopathic pulmonary fibrosis, an age-associated degenerative lung disorder, is characterized by persistence of apoptosis-resistant myofibroblasts. In this report, we demonstrate that sirtuin-3 (SIRT3), a mitochondrial deacetylase, is downregulated in lungs of IPF human subjects and in mice subjected to lung injury. Over-expression of the SIRT3 cDNA via airway delivery restored capacity for fibrosis resolution in aged mice, in association with activation of the forkhead box transcription factor, FoxO3a, in fibroblasts, upregulation of pro-apoptotic members of the Bcl-2 family, and recovery of apoptosis susceptibility. While transforming growth factor-ß1 reduced levels of SIRT3 and FoxO3a in lung fibroblasts, cell non-autonomous effects involving macrophage secreted products were necessary for SIRT3-mediated activation of FoxO3a. Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that restore susceptibility to apoptosis in fibroblasts via a FoxO3a-dependent mechanism.


Assuntos
Fibrose Pulmonar Idiopática , Sirtuína 3 , Humanos , Animais , Camundongos , Sirtuína 3/genética , Pulmão/metabolismo , Fibrose , Fibrose Pulmonar Idiopática/metabolismo , Expressão Gênica
10.
Sci Signal ; 13(644)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32788339

RESUMO

The oxidation of tyrosine residues to generate o,o'-dityrosine cross-links in extracellular proteins is necessary for the proper function of the extracellular matrix (ECM) in various contexts in invertebrates. Tyrosine oxidation is also required for the biosynthesis of thyroid hormone in vertebrates, and there is evidence for oxidative cross-linking reactions occurring in extracellular proteins secreted by myofibroblasts. The ECM protein fibronectin circulates in the blood as a globular protein that dimerizes through disulfide bridges generated by cysteine oxidation. We found that cellular (fibrillar) fibronectin on the surface of transforming growth factor-ß1 (TGF-ß1)-activated human myofibroblasts underwent multimerization by o,o'-dityrosine cross-linking under reducing conditions that disrupt disulfide bridges, but soluble fibronectin did not. This reaction on tyrosine residues required both the TGF-ß1-dependent production of hydrogen peroxide and the presence of myeloperoxidase (MPO) derived from inflammatory cells, which are active participants in wound healing and fibrogenic processes. Oxidative cross-linking of matrix fibronectin attenuated both epithelial and fibroblast migration and conferred resistance to proteolysis by multiple proteases. The abundance of circulating o,o'-dityrosine-modified fibronectin was increased in a murine model of lung fibrosis and in human subjects with interstitial lung disease compared to that in control healthy subjects. These studies indicate that tyrosine can undergo stable, covalent linkages in fibrillar fibronectin under inflammatory conditions and that this modification affects the migratory behavior of cells on such modified matrices, suggesting that this modification may play a role in both physiologic and pathophysiologic tissue repair.


Assuntos
Movimento Celular/fisiologia , Fibronectinas/metabolismo , Miofibroblastos/metabolismo , Estresse Oxidativo/fisiologia , Peptídeo Hidrolases/metabolismo , Células A549 , Animais , Linhagem Celular , Células Cultivadas , Reagentes de Ligações Cruzadas/química , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/química , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miofibroblastos/citologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Oxirredução , Peroxidase/genética , Peroxidase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Tirosina/análogos & derivados , Tirosina/química , Tirosina/metabolismo
11.
Nat Med ; 24(10): 1627, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30104770

RESUMO

In the version of this article originally published, a grant was omitted from the Acknowledgements section. The following sentence should have been included: "R.B.M. was supported by a Department of Veterans Affairs Merit Award (5I01BX003272)." The error has been corrected in the HTML and PDF versions of this article.

12.
Nat Med ; 24(8): 1121-1127, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29967351

RESUMO

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologia , Metformina/uso terapêutico , Adenilato Quinase/metabolismo , Animais , Bleomicina , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Humanos , Masculino , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia
13.
Sleep Med ; 8(3): 247-51, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17368978

RESUMO

BACKGROUND AND PURPOSE: Prevalence of restless legs syndrome (RLS) in India is unknown. Up to 25% of Caucasian RLS patients also have iron deficiency. The main objective of the study was to find occurrence of RLS in patients with iron deficiency anemia and compare it to non-anemic healthy people. PATIENTS AND METHODS: This was a cross-sectional study from April 2003 to October 2004 done in in-patient and out-patient services of Medicine department, St. John's Medical College Hospital, Bangalore, India. Sixty-four consecutive adult patients with iron deficiency and 256 age- and sex-matched non-anemic participants were interviewed face-to-face. Hemogram was done in all participants, and free erythrocyte protoporphyrin (FEP) and total iron binding capacity (TIBC) in anemic patients. RESULTS: RLS symptoms were present in 6.25% of healthy participants and 34.37% of anemic patients (p<0.001). Chronic menorrhagia (p=0.001) and repeated blood donation (5 times) (p=0.009) were associated with increased RLS occurrence. RLS was associated with delayed onset of sleep (p<0.001). CONCLUSION: RLS, a common occurrence among healthy participants, occurred at a significantly higher rate among iron-deficient anemic patients. Further studies are warranted to better characterize RLS in India.


Assuntos
Anemia Ferropriva/epidemiologia , Países em Desenvolvimento , Síndrome das Pernas Inquietas/epidemiologia , Adulto , Doadores de Sangue , Estudos Transversais , Eritrócitos/metabolismo , Feminino , Humanos , Índia , Proteínas de Ligação ao Ferro/sangue , Masculino , Menorragia/sangue , Menorragia/epidemiologia , Pessoa de Meia-Idade , Protoporfirinas/sangue , Valores de Referência , Síndrome das Pernas Inquietas/sangue , Estatística como Assunto
14.
Sleep Med ; 9(1): 88-93, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17825618

RESUMO

BACKGROUND: The prevalence of restless legs syndrome (RLS) in India is unknown. OBJECTIVES: The primary objective was to assess the occurrence of RLS in residents of Bangalore. The secondary objective was to correlate demographic and socioeconomic factors with RLS occurrence and severity. METHODS: This was a cross-sectional, questionnaire-based survey conducted during August 2005 among adult residents of Bangalore, who participated in a face-to-face interview. Diagnosis of RLS was based on fulfillment of all National Institutes of Health/International Restless Legs Syndrome Study Group (NIH/IRLSSG) essential criteria. Severity of RLS was assessed using the IRLSSG scale. RESULTS: RLS occurred in 27 (2.1%) of 1266 respondents. Predominant symptoms included "pulling," "tingling" and "pain". RLS was associated with delayed sleep onset and RLS severity correlated with the duration of delay in sleep onset. RLS was associated with per-capita income less than the equivalent of US$1/day, education less than high school level, chronic daily alcohol consumption and chronic blood loss. CONCLUSION: This is the first Indian population study on RLS which reveals prevalence of the disorder in a South Indian urban population at 2.1%. Larger studies are warranted to better characterize RLS in India.


Assuntos
Síndrome das Pernas Inquietas/epidemiologia , Índice de Gravidade de Doença , População Urbana/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Projetos de Pesquisa , Inquéritos e Questionários
15.
Ann Am Thorac Soc ; 14(Supplement_5): S383-S388, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29161077

RESUMO

The aging of the human population has resulted in an unprecedented increase in the incidence and prevalence of age-related diseases, including those of the lung. Idiopathic pulmonary fibrosis is a disease of aging, and is characterized by a progressive decline in lung function and high mortality. Recent studies suggest that mitochondrial dysfunction, which can accompany aging phenotypes, may contribute to the pathogenesis of idiopathic pulmonary fibrosis. In this review, we explore current evidence for mitochondrial dysfunction in alveolar epithelial cells, fibroblasts, and immune cells that participate in the fibrotic process. Further, the fates of these cell populations and the potential to target mitochondrial dysfunction as a therapeutic strategy are discussed.


Assuntos
Envelhecimento/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Mitocôndrias/patologia , Envelhecimento/imunologia , Células Epiteliais Alveolares/metabolismo , Fibroblastos/metabolismo , Humanos , Pulmão/fisiopatologia
16.
JCI Insight ; 2(2): e91377, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28138565

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic lung disease characterized by the presence of invasive myofibroblasts in the lung. Currently, there are only two FDA-approved drugs (pirfenidone and nintedanib) for the treatment of IPF. There are no defined criteria to guide specific drug therapy. New methodologies are needed not only to predict personalized drug therapy, but also to screen novel molecules that are on the horizon for treatment of IPF. We have developed a model system that exploits the invasive phenotype of IPF lung tissue. This ex vivo 3D model uses lung tissue from patients to develop pulmospheres. Pulmospheres are 3D spheroids composed of cells derived exclusively from primary lung biopsies and inclusive of lung cell types reflective of those in situ, in the patient. We tested the pulmospheres of 20 subjects with IPF and 9 control subjects to evaluate the responsiveness of individual patients to antifibrotic drugs. Clinical parameters and outcomes were also followed in the same patients. Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/farmacologia , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Piridonas/farmacologia , Esferoides Celulares/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/uso terapêutico , Biópsia , Estudos de Casos e Controles , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Humanos , Indóis/uso terapêutico , Pulmão/patologia , Modelos Biológicos , Medicina de Precisão , Piridonas/uso terapêutico , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fator de Crescimento Transformador beta1/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-28756121

RESUMO

BACKGROUND: Long-term survival of lung transplant recipients (LTRs) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). Recent evidence suggests a role for microbiome alterations in the occurrence of BOS, although the precise mechanisms are unclear. In this study we evaluated the relationship between the airway microbiome and distinct subsets of immunoregulatory myeloid-derived suppressor cells (MDSCs) in LTRs. METHODS: Bronchoalveolar lavage (BAL) and simultaneous oral wash and nasal swab samples were collected from adult LTRs. Microbial genomic DNA was isolated, 16S rRNA genes amplified using V4 primers, and polymerase chain reaction (PCR) products sequenced and analyzed. BAL MDSC subsets were enumerated using flow cytometry. RESULTS: The oral microbiome signature differs from that of the nasal, proximal and distal airway microbiomes, whereas the nasal microbiome is closer to the airway microbiome. Proximal and distal airway microbiome signatures of individual subjects are distinct. We identified phenotypic subsets of MDSCs in BAL, with a higher proportion of immunosuppressive MDSCs in the proximal airways, in contrast to a preponderance of pro-inflammatory MDSCs in distal airways. Relative abundance of distinct bacterial phyla in proximal and distal airways correlated with particular airway MDSCs. Expression of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP), an endoplasmic (ER) stress sensor, was increased in immunosuppressive MDSCs when compared with pro-inflammatory MDSCs. CONCLUSIONS: The nasal microbiome closely resembles the microbiome of the proximal and distal airways in LTRs. The association of distinct microbial communities with airway MDSCs suggests a functional relationship between the local microbiome and MDSC phenotype, which may contribute to the pathogenesis of BOS.

18.
Drugs ; 76(3): 291-300, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26729185

RESUMO

Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the US Food and Drug Administration in 2014 has heralded a new era in its management. Both drugs have demonstrated efficacy in phase III clinical trials by retarding the rate of progression of IPF; neither drug appears to be able to completely arrest disease progression. Advances in the understanding of IPF pathobiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these are under investigation in various stages of clinical development. Here, we provide a brief overview of the drugs that are currently approved and others in phase II clinical trials. Future therapeutic opportunities that target novel pathways, including some that are associated with the biology of aging, are examined. A multi-targeted approach, potentially with combination therapies, and identification of individual patients (or subsets of patients) who may respond more favourably to specific agents are likely to be more effective.


Assuntos
Envelhecimento/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Terapia de Alvo Molecular , Piridonas/uso terapêutico , Envelhecimento/metabolismo , Envelhecimento/patologia , Ensaios Clínicos Fase II como Assunto , Aprovação de Drogas , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/farmacocinética
19.
Sci Rep ; 6: 37445, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869174

RESUMO

Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related chronic diseases, such as cancer and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells (MSCs) in the terminal airways-alveoli by bronchoalveolar lavage (BAL) of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis (IPF), defined as <5% and ≥10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-ß and SHH signaling. Importantly, fibroblast growth factor-10 (FGF-10) was markedly suppressed in IPF subjects with progressive disease, and both TGF-ß1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.


Assuntos
Reprogramação Celular , Fibrose Pulmonar Idiopática/patologia , Células-Tronco Mesenquimais/patologia , Líquido da Lavagem Broncoalveolar/citologia , Progressão da Doença , Regulação para Baixo/genética , Fator 10 de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Genes Controladores do Desenvolvimento , Proteínas Hedgehog/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Imuno-Histoquímica , Pulmão/patologia , Células-Tronco Mesenquimais/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/genética
20.
PLoS One ; 10(2): e0116995, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25658089

RESUMO

Transforming growth factor-ß (TGF-ß) mediates growth-inhibitory effects on most target cells via activation of the canonical SMAD signaling pathway. This growth-inhibitory activity may be coupled with cellular differentiation. Our studies demonstrate that TGF-ß1 inhibits proliferation of primary, non-transformed human lung fibroblasts in association with the induction of myofibroblast differentiation. Differentiated myofibroblasts maintain the capacity to proliferate in response to exogenous mitogenic stimuli and are resistant to serum deprivation-induced apoptosis. These proliferative and anti-apoptotic properties of myofibroblasts are related, in part, to the down-regulation of caveolin-1 (Cav-1) by TGF-ß1. Cav-1 down-regulation is mediated by early activation of p38 MAPK and does not require SMAD signaling. In contrast, myofibroblast differentiation is dependent on activation of the SMAD pathway, but not on p38 MAPK. Thus, combinatorial signaling by TGF-ß1 of myofibroblast differentiation and down-regulation of Cav-1 by SMAD and p38 MAPK pathways, respectively, confer proliferative and apoptosis-resistant properties to myofibroblasts. Selective targeting of this SMAD-independent, p38-MAPK/Cav-1-dependent pathway is likely to be effective in the treatment of pathological conditions characterized by TGF-ß signaling and myofibroblast activation.


Assuntos
Caveolina 1/metabolismo , Proliferação de Células , Sistema de Sinalização das MAP Quinases , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sobrevivência Celular , Humanos , Miofibroblastos/patologia , Proteínas Smad/metabolismo
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