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1.
Nat Chem Biol ; 17(3): 307-316, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33510451

RESUMO

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.


Assuntos
Anti-Inflamatórios/farmacologia , Transportador de Glucose Tipo 4/genética , Atrofia Muscular/tratamento farmacológico , Receptores de Glucocorticoides/química , Transdução de Sinais/efeitos dos fármacos , Células A549 , Regulação Alostérica , Animais , Anti-Inflamatórios/síntese química , Linhagem Celular Transformada , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Lipopolissacarídeos/administração & dosagem , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
2.
FASEB J ; 35(12): e21999, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34748223

RESUMO

The Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators drive Creb1-mediated transcription effects on metabolism in many tissues, but the in vivo effects of Crtc2/Creb1 transcription on skeletal muscle metabolism are not known. Skeletal muscle-specific overexpression of Crtc2 (Crtc2 mice) induced greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity, supported by upregulation of key metabolic genes. Crtc2 overexpression led to greater weight loss during alternate day fasting (ADF), selective loss of fat rather than lean mass, maintenance of higher energy expenditure during the fast and reduced binge-eating during the feeding period. ADF downregulated most of the mitochondrial electron transport genes, and other regulators of mitochondrial function, that were substantially reversed by Crtc2-driven transcription. Glucocorticoids acted with AMPK to drive atrophy and mitophagy, which was reversed by Crtc2/Creb1 signaling. Crtc2/Creb1-mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb1 regulates metabolism and weight loss.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Metabolismo Energético , Jejum , Resistência à Insulina , Músculo Esquelético/fisiologia , Fatores de Transcrição/fisiologia , Redução de Peso/fisiologia , Animais , Masculino , Camundongos , Camundongos Transgênicos
3.
Nat Chem Biol ; 13(1): 111-118, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27870835

RESUMO

Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor, and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade
4.
EMBO J ; 33(9): 1027-43, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24674967

RESUMO

During the stress response to intense exercise, the sympathetic nervous system (SNS) induces rapid catabolism of energy reserves through the release of catecholamines and subsequent activation of protein kinase A (PKA). Paradoxically, chronic administration of sympathomimetic drugs (ß-agonists) leads to anabolic adaptations in skeletal muscle, suggesting that sympathetic outflow also regulates myofiber remodeling. Here, we show that ß-agonists or catecholamines released during intense exercise induce Creb-mediated transcriptional programs through activation of its obligate coactivators Crtc2 and Crtc3. In contrast to the catabolic activity normally associated with SNS function, activation of the Crtc/Creb transcriptional complex by conditional overexpression of Crtc2 in the skeletal muscle of transgenic mice fostered an anabolic state of energy and protein balance. Crtc2-overexpressing mice have increased myofiber cross-sectional area, greater intramuscular triglycerides and glycogen content. Moreover, maximal exercise capacity was enhanced after induction of Crtc2 expression in transgenic mice. Collectively these findings demonstrate that the SNS-adrenergic signaling cascade coordinates a transient catabolic stress response during high-intensity exercise, which is followed by transcriptional reprogramming that directs anabolic changes for recovery and that augments subsequent exercise performance.


Assuntos
Tolerância ao Exercício/genética , Músculo Esquelético/metabolismo , Sistema Nervoso Simpático/metabolismo , Fatores de Transcrição/fisiologia , Animais , Animais Recém-Nascidos , Catecolaminas/metabolismo , Catecolaminas/farmacologia , Células Cultivadas , Tolerância ao Exercício/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Condicionamento Físico Animal/fisiologia
7.
J Exp Med ; 218(10)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34427588

RESUMO

T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule-like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti-PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Imunoterapia/métodos , Melanoma Experimental/patologia , Animais , Linfócitos T CD8-Positivos/patologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Melanoma Experimental/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Neoplasias/mortalidade , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
8.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32302378

RESUMO

Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiological functions remain enigmatic. Using a recently developed MDR1-knockin reporter allele (Abcb1aAME), we found that constitutive MDR1 expression among hematopoietic cells was observed in cytolytic lymphocytes-including CD8+ cytotoxic T lymphocytes (CTLs) and natural killer cells-and regulated by Runt-related (Runx) transcription factors. Whereas MDR1 was dispensable for naive CD8+ T cell development, it was required for both the normal accumulation of effector CTLs following acute viral infection and the protective function of memory CTLs following challenge with an intracellular bacterium. MDR1 acted early after naive CD8+ T cell activation to suppress oxidative stress, enforce survival, and safeguard mitochondrial function in nascent CTLs. These data highlight an important endogenous function of MDR1 in cell-mediated immune responses and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counterproductive.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linfócitos T Citotóxicos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Sobrevivência Celular , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Feminino , Regulação da Expressão Gênica , Loci Gênicos , Hematopoese , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitose , Estresse Oxidativo
9.
Thromb Haemost ; 100(1): 90-100, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18612543

RESUMO

The activity of plasmin plays a critical role in the development of chronic glomerulonephritis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of plasmin generation. We hypothesized that TAFI is involved in the pathogenesis of glomerulonephritis because it inhibits plasmin generation. To demonstrate this hypothesis, we compared the development of immune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulonephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addition, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were significantly decreased in TAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI-knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may constitute a novel molecular target for the therapy of this disease.


Assuntos
Carboxipeptidase B2/metabolismo , Fibrinolisina/metabolismo , Glomerulonefrite/prevenção & controle , Rim/enzimologia , Animais , Complexo Antígeno-Anticorpo , Batroxobina/farmacologia , Carboxipeptidase B2/deficiência , Carboxipeptidase B2/genética , Complemento C3/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fibrina/metabolismo , Fibrinogênio/metabolismo , Fibrinólise , Fibrinolíticos/farmacologia , Fibrose , Glomerulonefrite/sangue , Glomerulonefrite/enzimologia , Glomerulonefrite/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Testes de Função Renal , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Knockout , Fatores de Tempo
10.
Am J Respir Crit Care Med ; 176(12): 1251-60, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17901412

RESUMO

RATIONALE: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury. OBJECTIVES: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis. METHODS: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells. CONCLUSIONS: These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.


Assuntos
Imunossupressores/farmacologia , NF-kappa B/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Células Jurkat , Camundongos , Compostos Orgânicos/farmacologia , Fibrose Pulmonar/induzido quimicamente
11.
Diabetes Res Clin Pract ; 78(2): 208-10, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17490777

RESUMO

We investigated that the association of MCP-1 polymorphism at position -2518 with insulin sensitivity and insulin secretion by measuring the fasting and post-challenge glucose and insulin levels during 75g OGTT in 409 non-diabetic Japanese subjects. The blood sampling was performed before glucose loading and after 30 and 120 min. Polymorphism was evaluated by PCR-RFLP method by genomic DNA isolated from peripheral blood leukocytes. The genotype distribution was 44.8% for G/G, 46.0% for G/A and 9.2% for A/A. The plasma glucose levels were significantly increased in A/A as compared to G/G (p<0.05), but it was not compared with G/A at 120 min. The serum insulin levels were significantly increased in A/A as compared to G/A (p<0.05) or G/G (p<0.05) at 30 min. Moreover, the serum insulin levels in A/A were significantly increased compared with G/A (p<0.02) or G/G (p<0.005) at 120 min. Elevation in post-challenge glucose (120 min) and insulin levels (30 and 120 min) suggests that reduced insulin sensitivity during glucose loading occurs in subjects with A/A polymorphism. The present study demonstrates that the A/A polymorphism of the MCP-1 gene at position -2518 is associated with insulin resistance during glucose loading in non-diabetic Japanese subjects.


Assuntos
Glicemia/metabolismo , Quimiocina CCL2/genética , Insulina/sangue , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Povo Asiático/genética , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/genética , Japão , Pessoa de Meia-Idade
12.
Cell Chem Biol ; 24(1): 35-45, 2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-28042045

RESUMO

Environmental estrogens and anti-hormone therapies for breast cancer have diverse tissue- and signaling-pathway-selective outcomes, but how estrogen receptor alpha (ERα) mediates this phenotypic diversity is poorly understood. We implemented a statistical approach to allow unbiased, parallel analyses of multiple crystal structures, and identified subtle perturbations of ERα structure by different synthetic and environmental estrogens. Many of these perturbations were in the sub-Å range, within the noise of the individual structures, but contributed significantly to the activities of synthetic and environmental estrogens. Combining structural perturbation data from many structures with quantitative cellular activity profiles of the ligands enabled identification of structural rules for ligand-specific allosteric signaling-predicting activity from structure. This approach provides a framework for understanding the diverse effects of environmental estrogens and for guiding iterative medicinal chemistry efforts to generate improved breast cancer therapies, an approach that can be applied to understanding other ligand-regulated allosteric signaling pathways.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Estrogênios/metabolismo , Antineoplásicos Hormonais/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Diabetes Res Clin Pract ; 73(2): 150-7, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16458385

RESUMO

We investigated the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and their relation with clinical and metabolic parameters in non-obese type 2 diabetic patients. The plasma levels of TAFI and PAI-1 were evaluated in 47 non-obese type 2 diabetic patients and 31 normal subjects. The intra-abdominal visceral and subcutaneous fat areas were measured by computed tomography (CT). The degree of insulin resistance was evaluated by the euglycemic-hyperinsulinemic clamp technique using artificial pancreas. The plasma levels of TAFI (169.0+/-108.8% versus 103.7+/-52.3%; p<0.001, mean+/-S.D.) and PAI-1 (82.7+/-54.5ng/ml versus 52.9+/-51.7ng/ml; p<0.05) were significantly higher in non-obese type 2 diabetic patients than in normal subjects. Univariate analysis showed that the plasma TAFI levels are significantly and inversely correlated with the glucose infusion rate (GIR) (r=-0.42, p<0.005) in all diabetic patients. Moreover, the plasma levels of TAFI were significantly correlated with fasting plasma glucose levels (r=0.47, p<0.001) and HbA(1c) (r=0.38, p<0.005) in all subjects. The plasma levels of PAI-1 were significantly and proportionally correlated with the visceral fat area (r=0.42, p<0.005) and body mass index (r=0.33, p<0.05). There was no significant correlation between plasma levels of TAFI and PAI-1 (r=0.04). These results show that the plasma levels of TAFI and PAI-1 differently correlate with insulin resistance and visceral fat accumulation, suggesting that different factors are implicated in the plasma elevation of TAFI and PAI-1 in non-obese type 2 diabetes mellitus.


Assuntos
Carboxipeptidase B2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/anatomia & histologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Índice de Massa Corporal , Carboxipeptidase B2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo
14.
Elife ; 3: e02057, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24771768

RESUMO

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.DOI: http://dx.doi.org/10.7554/eLife.02057.001.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Adenilato Quinase/metabolismo , AMP Cíclico/metabolismo , Receptor alfa de Estrogênio/química , Feminino , Humanos , Interleucina-6/genética , Ligantes , Células MCF-7 , Regiões Promotoras Genéticas , Conformação Proteica , Resveratrol , Fator de Necrose Tumoral alfa/metabolismo
16.
Eur J Immunol ; 36(12): 3334-45, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17125141

RESUMO

Tenascin C (TN-C) is an extracellular matrix glycoprotein whose expression is increased in several inflammatory diseases of the lung, including bronchial asthma. However, the exact function of TN-C in the pathogenesis of lung inflammation remains unclear. In the present study, we compared the degree of bronchial asthma in wild-type and TN-C-deficient (-/-) BALB/c mice. Bronchial asthma was induced by sensitization and challenge with ovalbumin. Littermates treated with saline were used as controls. Cytokines in bronchoalveolar lavage fluid and plasma were measured by enzyme immunoassays. The number of eosinophils in the lung was significantly increased in wild-type mice compared with TN-C-knockout mice. Airway hyperreactivity, NF-kappaB activation and concentrations of monocyte chemoattractant protein-1, IL-5, IL-13, metalloproteinase-9 and immunoglobulin-E in the bronchoalveolar lavage fluid were significantly decreased in ovalbumin-sensitized/challenged TN-C-knockout mice compared with their wild-type counterparts. In vitro experiments disclosed that TN-C significantly stimulates the secretion of IL-5, IL-13, IFN-gamma and immunoglobulin-E from spleen lymphocytes. These observations suggest that TN-C is involved in the pathogenesis of bronchial asthma.


Assuntos
Alérgenos/administração & dosagem , Alérgenos/imunologia , Asma/genética , Tenascina/deficiência , Tenascina/genética , Animais , Asma/imunologia , Asma/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Tenascina/fisiologia , Células Th2/metabolismo
17.
Am J Pathol ; 168(4): 1086-96, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16565485

RESUMO

Decreased fibrinolytic function favors the development of pulmonary fibrosis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a strong suppressor of fibrinolysis, but its role in lung fibrosis is unknown. Therefore, we compared bleomycin-induced lung fibrosis in TAFI-deficient, heterozygous, and wild-type mice. The animals were sacrificed 21 days after bleomycin administration, and markers of lung fibrosis and inflammation were measured. The bronchoalveolar lavage fluid levels of total protein, neutrophil proteases (elastase, myeloperoxidase), cytokines (tumor necrosis factor-alpha, interleukin-13), chemokine (monocyte chemoattractant protein-1), coagulation activation marker (thrombin-antithrombin complex), total soluble collagen, and growth factors (platelet-derived growth factor, transforming growth factor-beta1, granulocytic-macrophage growth factor) were significantly decreased in knockout mice compared to wild-type mice. Further, histological findings of fibrosis, fibrin deposition, and hydroxyproline and collagen content in the lung were significantly decreased in knockout mice compared to wild-type mice. Depletion of fibrinogen by ancrod treatment led to equalization in the amount of fibrosis and collagen deposition in the lungs of knockout and wild-type mice. No difference was detected in body temperature or arterial pressure between the different mouse phenotypes. These results suggest that the anti-fibrinolytic activity of TAFI promotes lung fibrosis by hindering the rate at which fibrin is degraded.


Assuntos
Bleomicina , Carboxipeptidase B2/metabolismo , Fibrinogênio/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Antitrombina III/metabolismo , Pressão Sanguínea , Temperatura Corporal , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Carboxipeptidase B2/deficiência , Carboxipeptidase B2/genética , Colágeno/metabolismo , Citocinas/metabolismo , Fibrina/metabolismo , Substâncias de Crescimento/metabolismo , Hidroxiprolina/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Knockout , Elastase Pancreática/metabolismo , Peptídeo Hidrolases/metabolismo , Peroxidase/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
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