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ABSTRACT: Intravenous plasminogen replacement therapy for patients with plasminogen deficiency type 1 (hypoplasminogenemia) was recently approved for marketing in the US. In this case report, the authors describe a 33-year-old man with hypoplasminogenemia who developed nonhealing postsurgical wounds following trauma to his right hand despite receiving standard treatment for 4 months. The patient was enrolled in a compassionate-use protocol with intravenous plasminogen replacement therapy and experienced prompt resolution of surgical wounds. He was the first human patient to receive replacement therapy with plasminogen, human-tvmh in the US and first to demonstrate cutaneous wound healing in addition to resolution of ligneous lesions attributable to plasminogen deficiency type 1.
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Plasminogênio , Cicatrização , Humanos , Masculino , Adulto , Cicatrização/efeitos dos fármacos , Plasminogênio/deficiência , Plasminogênio/uso terapêutico , Administração Intravenosa , Resultado do Tratamento , Traumatismos da Mão/complicações , Traumatismos da Mão/cirurgia , Ferida Cirúrgica/tratamento farmacológico , Ferida Cirúrgica/complicações , Conjuntivite , Dermatopatias GenéticasRESUMO
INTRODUCTION: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring. AIM: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients. METHODS: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim. RESULTS: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment. CONCLUSION: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care.
Assuntos
Plasminogênio , Humanos , Plasminogênio/deficiência , Plasminogênio/uso terapêuticoRESUMO
BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE. METHODS: An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires. RESULTS: Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy-efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime. CONCLUSION: This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.
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Angioedemas Hereditários , Humanos , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/genética , Angioedemas Hereditários/prevenção & controle , Fator XII/genética , Fator XII/uso terapêutico , Plasminogênio/genética , Plasminogênio/uso terapêutico , MutaçãoRESUMO
Plasminogen activating inhibitor-1 (PAI-1) is associated with poor clinical outcomes, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancer. Cutaneous angiosarcoma (CAS) is a vascular tumor histologically characterized by detachment of endothelial cell-derived tumor cells. Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, angiogenesis-promoting factors are potential drug targets in CAS. In this study, the expression of PAI-1 was examined in 31 cases of CAS, and the immunomodulatory effects of PAI-1 on a human CAS cell line, ISO-HAS-B, were evaluated. We found that, of the angiogenesis-promoting factors, PAI-1 was expressed in almost all cases of CAS, and PAI-1 increased the mRNA expressions of IL-23p19, VEGF-C, CXCL5 and CCL20 on ISO-HAS-B. Moreover, PAI-1 stimulated ISO-HAS-B culture supernatant promoted favourable tube networks, suggesting that these tumor-derived factors promote the pro-angiogenic effect on tumor development. In addition, IL-23p19 was expressed in 61.3% of cases, whereas VEGF-C was expressed in 41% of cases. The results of the present study suggest that PAI-1 promotes angiogenesis that results in tumor progression in CAS.
Assuntos
Hemangiossarcoma , Neoplasias Cutâneas , Humanos , Hemangiossarcoma/tratamento farmacológico , Hemangiossarcoma/patologia , Subunidade p19 da Interleucina-23 , Plasminogênio/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Serina Proteases , Fator C de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3 application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser speckle imaging) 10 minutes after therapy administration (35.8 ± 17.1%; P = .001 39.3 ± 13.1%; P < .0001; 15.6 ± 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 ± 11.2 mm3; P = .033; 16.1 ± 13.9 mm3; P = .018; 26.6 ± 5.6 mm3, respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 ± 8.8%; P = .216; 16.3 ± 13.9%; P = .151; 10.1 ± 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 ± 11.4 mm3; P < .001; 23.6 ± 11.1 mm3; P = .188; 30.3 ± 10.9 mm3, respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.
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AVC Isquêmico , Acidente Vascular Cerebral , Tromboembolia , Trombose , Camundongos , Humanos , Animais , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Fator de von Willebrand/uso terapêutico , Fibrina/metabolismo , Terapia Trombolítica , Plasminogênio/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismoRESUMO
Mechanical thrombectomy is a highly effective treatment for acute ischemic stroke caused by large-vessel occlusion in the anterior cerebral circulation, significantly increasing the likelihood of recovery to functional independence. Until recently, whether intravenous thrombolysis before mechanical thrombectomy provided additional benefits to patients with acute ischemic stroke-large-vessel occlusion remained unclear. Given that reperfusion is a key factor for clinical outcome in patients with acute ischemic stroke-large-vessel occlusion and the efficacy of both intravenous thrombolysis and mechanical thrombectomy is time-dependent, achieving complete reperfusion with a single pass should be the primary angiographic goal. However, it remains undetermined whether extending the procedure with additional endovascular attempts or local lytics administration safely leads to higher reperfusion grades and whether there are significant public health and cost implications. Here, we outline the current state of knowledge and research avenues that remain to be explored regarding the consistent therapeutic benefit of intravenous thrombolysis in anterior circulation strokes and the potential place of adjunctive intra-arterial lytics administration, including alternative thrombolytic agent place.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos , Humanos , Plasminogênio/uso terapêutico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombectomia/métodos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual , Resultado do TratamentoRESUMO
Ligneous conjunctivitis (LC) is a rare form of pseudomembranous chronic conjunctivitis caused by a deficiency in plasminogen activity. Due to its rarity, little is known about this disorder. We hereby report a case of ligneous conjunctivitis, describing the clinical findings, the biological diagnosis and the treatment of this rare disease.
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Transtornos de Proteínas de Coagulação , Conjuntivite , Transtornos de Proteínas de Coagulação/complicações , Conjuntivite/diagnóstico , Conjuntivite/tratamento farmacológico , Conjuntivite/etiologia , Humanos , Marrocos , Plasminogênio/deficiência , Plasminogênio/uso terapêutico , Dermatopatias GenéticasRESUMO
Ligneous conjunctivitis is an uncommon form of chronic and recurrent conjunctivitis characterized by a thick, "woody," yellowish pseudomembranous lesion on the tarsal conjunctiva. Plasminogen deficiency plays an important role in this disease, which affects the mucous membranes, including the conjunctiva as well as other systemic organs. In rare cases, congenital hydrocephalus is associated with this disease. We present the case of a 21-year-old woman with delayed-onset bilateral ligneous conjunctivitis and a history of congenital hydrocephalous in infancy. She was treated with topical ophthalmic medication and surgical excision.
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Conjuntivite , Dermatopatias Genéticas , Feminino , Humanos , Adulto Jovem , Túnica Conjuntiva/patologia , Conjuntivite/diagnóstico , Conjuntivite/etiologia , Conjuntivite/tratamento farmacológico , Plasminogênio/uso terapêutico , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/tratamento farmacológico , Dermatopatias Genéticas/patologiaRESUMO
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.
Assuntos
Plasminogênio/fisiologia , Animais , Antifibrinolíticos/uso terapêutico , Encéfalo/enzimologia , Conjuntivite/fisiopatologia , Ativação Enzimática , Fibrina/metabolismo , Fibrinolisina/fisiologia , Fibrinólise/fisiologia , Fibrinolíticos/uso terapêutico , Humanos , Imunidade/fisiologia , Infecções/fisiopatologia , Inflamação , Camundongos , Plasminogênio/química , Plasminogênio/deficiência , Plasminogênio/farmacologia , Plasminogênio/uso terapêutico , Radiodermite/tratamento farmacológico , Receptores de Superfície Celular/fisiologia , Dermatopatias Genéticas/fisiopatologia , Trombose/diagnóstico , Trombose/tratamento farmacológico , Ácido Tranexâmico/farmacologia , Ácido Tranexâmico/uso terapêutico , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia , Ferimentos e Lesões/tratamento farmacológicoRESUMO
BACKGROUND: Lungs from patients with coronavirus disease 2019 (COVID-19) have shown typical signs of acute respiratory distress syndrome (ARDS), formation of hyaline membrane mainly composed of fibrin and 'ground-glass' opacity. Previously, we showed plasminogen itself is a key regulator in fibrin degradation, wound healing and infection. AIM: We aimed to investigate whether plasminogen can improve lung lesions and hypoxemia of COVID-19. DESIGN: Thirteen clinically moderate, severe or critical COVID-19 patients were treated with atomization inhalation of freeze-dried plasminogen. METHODS: Levels of their lung lesions, oxygen saturation and heart rates were compared before and after treatment by computed tomography scanning images and patient monitor. RESULTS: After plasminogen inhalation, conditions of lung lesions in five clinically moderate patients have quickly improved, shown as the decreased range and density of 'ground glass' opacity. Improvements of oxygen saturation were observed in six clinically severe patients. In the two patients with critical conditions, the oxygen levels have significantly increased from 79-82% to 91% just about 1 h after the first inhalation. In 8 of 13 patients, the heart rates had slowed down. For the five clinically moderate patients, the difference is even statistically significant. Furthermore, a general relief of chest tightness was observed. CONCLUSION: Whereas it is reported that plasminogen is dramatically increased in adults with ARDS, this study suggests that additional plasminogen may be effective and efficient in treating lung lesions and hypoxemia during COVID-19 infections. Although further studies are needed, this study highlights a possible hope of efficiently combating this rapid epidemic emergency.
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Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hipóxia/tratamento farmacológico , Plasminogênio/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/fisiopatologia , Feminino , Fibrinolíticos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipóxia/virologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Oxigenoterapia/métodos , Pandemias , Plasminogênio/administração & dosagem , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/fisiopatologia , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-ß signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.
Assuntos
Fibrinolíticos/uso terapêutico , Plasminogênio/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Fibrinolíticos/farmacologia , Humanos , Camundongos , Plasminogênio/farmacologiaAssuntos
Transtornos de Proteínas de Coagulação/complicações , Gengivite/patologia , Gengivite/terapia , Conjuntivite/complicações , Conjuntivite/diagnóstico , Assistência Odontológica/métodos , Fibrinolíticos/uso terapêutico , Gengivite/prevenção & controle , Humanos , Plasminogênio/uso terapêutico , Turquia/epidemiologiaRESUMO
Ligneous conjunctivitis is a rare form of chronic and recurrent bilateral conjunctivitis, in which thick membranes develop on the tarsal conjunctiva and on other mucosae. We report the case of a 55-year old female patient with bilateral ligneous conjunctivitis who was successfully treated with 50% heterologous serum. There was no recurrence or side effects after one-year follow-up. We suggest the use of 50% heterologous serum should be further studied to better determine its efficacy as a treatment option for ligneous conjunctivitis.
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Plasminogênio/deficiência , Soro , Conjuntivite/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Plasminogênio/uso terapêutico , Dermatopatias Genéticas/patologia , Resultado do TratamentoAssuntos
Transtornos de Proteínas de Coagulação/tratamento farmacológico , Terapia de Reposição de Enzimas , Transtornos da Audição/tratamento farmacológico , Plasminogênio/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Adolescente , Transtornos de Proteínas de Coagulação/genética , Códon de Terminação , Transtornos da Audição/etiologia , Transtornos da Audição/genética , Humanos , Masculino , Pneumonia Bacteriana/etiologia , Pneumonia Bacteriana/genética , Infecções por Pseudomonas/etiologia , Infecções por Pseudomonas/genéticaRESUMO
ABSTRACT Ligneous conjunctivitis is a rare form of chronic and recurrent bilateral conjunctivitis, in which thick membranes develop on the tarsal conjunctiva and on other mucosae. We report the case of a 55-year old female patient with bilateral ligneous conjunctivitis who was successfully treated with 50% heterologous serum. There was no recurrence or side effects after one-year follow-up. We suggest the use of 50% heterologous serum should be further studied to better determine its efficacy as a treatment option for ligneous conjunctivitis.
RESUMO A conjuntivite lenhosa é uma forma rara de conjuntivite bilateral crônica e recorrente, na qual há formação de membranas espessas na conjuntiva tarsal e em outras mucosas. Relatamos o caso de uma paciente de 55 anos com conjuntivite lenhosa bilateral, que obteve sucesso no tratamento com soro heterólogo em concentração de 50%. Não houve recorrência após um ano de seguimento e nem efeitos colaterais ao tratamento. Dessa forma, o uso de soro heterólogo a 50% poderia ser mais estudado para melhor avaliação de sua eficácia como opção de tratamento para a conjuntivite lenhosa.
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Humanos , Feminino , Plasminogênio/deficiência , Soro , Plasminogênio/uso terapêutico , Dermatopatias Genéticas/patologia , Resultado do Tratamento , Conjuntivite/patologia , Pessoa de Meia-IdadeRESUMO
Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a rare autosomal recessive disorder that leads to the development of thick, wood-like pseudomembranes on mucosal surfaces, mostly seen in conjunctivas named as ''ligneous conjunctivitis''. Local conjunctival use of fresh frozen plazma (FFP) in combination with other eye medications such as cyclosporin and artificial tear drops may relieve the symptoms. Topical treatment with plasminogen eye drops is the most promising treatment that is not yet available in Turkey.
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Conjuntivite/terapia , Plasminogênio/deficiência , Dermatopatias Genéticas/terapia , Humanos , Soluções Oftálmicas/uso terapêutico , Plasma , Plasminogênio/administração & dosagem , Plasminogênio/uso terapêutico , TurquiaRESUMO
Microplasminogen (µPlg), a truncated form of human plasminogen, has considerable potential as a direct-acting thrombolytic agent. To further develop µPlg into a thrombolytic agent with anti-thrombus properties, we constructed two µPlg variants containing tripeptide Arg-Gly-Asp (RGD) and tetrapeptide Gly-Pro-Arg-Pro (GPRP) by site-directed mutagenesis. The recombinant cDNAs were expressed in yeast (Pichia pastoris) and purified to high homogeneity by Ni-NTA affinity chromatography. The specific activities of RGD-µPlg and GPRP-µPlg were 7.7 and 13.3 U/mg, respectively, as determined using the fibrin-plate method. RGD-µPlg significantly inhibited ADP-induced platelet aggregation, which was 33.6- and 14.1-fold higher than the native µPlg and GPRP-µPlg, respectively. On the other hand, GPRP-µPlg prolonged thrombin-initialized fibrinogen polymerization in a concentration-dependent manner, which was 9.2- and 5.7-fold stronger than µPlg and RGD-µPlg, respectively. Under activation by urokinase, µPlg, RGD-µPlg, and GPRP-µPlg all showed over 80 % conversions to their active enzyme in 24 h. The structure models that docked RGD-µPlg and µPlg activation loops into the enzymatic active site of urokinase showed that Pro559 to Asp559 mutation of RGD-µPlg led to an alteration in the interaction, which possibly explains the slowed activation of RGD-µPlg by urokinase over an 80-min period. In conclusion, this study has presented two recombinant µPlg variants with anti-platelet aggregation and anti-fibrinogen clotting activity, thus suggesting the anti-thrombosis properties of these two µPlg derivatives.
Assuntos
Fibrinólise/efeitos dos fármacos , Fibrinolíticos/química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Plasminogênio/uso terapêutico , Fibrinogênio/efeitos dos fármacos , Fibrinogênio/metabolismo , Fibrinolíticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Oligopeptídeos/genética , Fragmentos de Peptídeos/genética , Plasminogênio/genética , Agregação Plaquetária/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/normasRESUMO
There is evidence that plasminogen K1-5 (PlgK1-5) directly affects tumour cells and inflammation. Therefore, we analysed if PlgK1-5 has immediate effects on hepatoma cells and inflammatory factors in vitro and in vivo. In vitro, effects of plasmid encoding PlgK1-5 (pK1-5) on Hepa129, Hepa1-6, and HuH7 cell viability, apoptosis, and proliferation as well as VEGF and TNF-alpha expression and STAT3-phosphorylation were investigated. In vivo, tumour growth, proliferation, vessel density, and effects on vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF-alpha) expression were examined following treatment with pK1-5. In vivo, pK1-5 halved cell viability; cell death was increased by up to 15% compared to the corresponding controls. Proliferation was not affected. VEGF, TNF-alpha, and STAT3-phosphorylation were affected following treatment with pK1-5. In vivo, ten days after treatment initiation, pK1-5 reduced subcutaneous tumour growth by 32% and mitosis by up to 77% compared to the controls. Vessel density was reduced by 50%. TNF-alpha levels in tumour and liver tissue were increased, whereas VEGF levels in tumours and livers were reduced after pK1-5 treatment. Taken together, plasmid gene transfer of PlgK1-5 inhibits hepatoma (cell) growth not only by reducing vessel density but also by inducing apoptosis, inhibiting proliferation, and triggering inflammation.
Assuntos
Carcinoma Hepatocelular/patologia , Técnicas de Transferência de Genes , Mediadores da Inflamação/metabolismo , Neoplasias Hepáticas/patologia , Plasmídeos/metabolismo , Plasminogênio/genética , Plasminogênio/uso terapêutico , Tela Subcutânea/patologia , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Terapia Genética , Humanos , Masculino , Camundongos , Microvasos/patologia , Fosforilação , Plasmídeos/genética , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: The purpose of this study was to investigate the role of plasminogen (Plg) in stem cell-mediated cardiac repair and regeneration after myocardial infarction (MI). BACKGROUND: An MI induces irreversible tissue damage, eventually leading to heart failure. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with Plg activators significantly improves the clinical outcome in MI by restoring cardiac perfusion. However, the role of Plg in stem cell-mediated cardiac repair remains unclear. METHODS: An MI was induced in Plg-deficient (Plg(-/-)) and wild-type (Plg(+/+)) mice by ligation of the left anterior descending coronary artery. Stem cells were visualized by in vivo tracking of green fluorescent protein (GFP)-expressing BM cells after BM transplantation. Cardiac function, stem cell homing, and signaling pathways downstream of Plg were examined. RESULTS: Granulocyte colony-stimulating factor, a stem cell mobilizer, significantly promoted BM-derived stem cell (GFP(+)c-kit(+) cell) recruitment into the infarcted heart and stem cell-mediated cardiac repair in Plg(+/+) mice. However, Plg deficiency markedly inhibited stem cell homing and cardiac repair, suggesting that Plg is critical for stem cell-mediated cardiac repair. Moreover, Plg regulated C-X-C chemokine receptor type 4 (CXCR4) expression in stem cells in vivo and in vitro through matrix metalloproteinase-9. Lentiviral reconstitution of CXCR4 expression in BM cells successfully rescued stem cell homing to the infarcted heart in Plg-deficient mice, indicating that CXCR4 has a critical role in Plg-mediated stem cell homing after MI. CONCLUSIONS: These findings have identified a novel role for Plg in stem cell-mediated cardiac repair after MI. Thus, targeting Plg may offer a new therapeutic strategy for stem cell-mediated cardiac repair after MI.