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1.
Clin Pulm Med ; 24(4): 163-169, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29081644

RESUMEN

Complicated pleural effusions and empyema with loculation and failed drainage are common clinical problems. In adults, intrapleural fibrinolytic therapy is commonly used with variable results and therapy remains empiric. Despite the intrapleural use of various plasminogen activators; fibrinolysins, for about sixty years, there is no clear consensus about which agent is most effective. Emerging evidence demonstrates that intrapleural administration of plasminogen activators is subject to rapid inhibition by plasminogen activator inhibitor-1 and that processing of fibrinolysins is importantly influenced by other factors including the levels and quality of pleural fluid DNA. Current therapy for loculation that accompanies pleural infections also includes surgery, which is invasive and for which patient selection can be problematic. Most of the clinical literature published to date has used flat dosing of intrapleural fibrinolytic therapy in all subjects but little is known about how that strategy influences the processing of the administered fibrinolysin or how this influences outcomes. We developed a new test of pleural fluids ex vivo, which is called the Fibrinolytic Potential or FP, in which a dose of a fibrinolysin is added to pleural fluids ex vivo after which the fibrinolytic activity is measured and normalized to baseline levels. Testing in preclinical and clinical empyema fluids reveals a wide range of responses, indicating that individual patients will likely respond differently to flat dosing of fibrinolysins. The test remains under development but is envisioned as a guide for dosing of these agents, representing a novel candidate approach to personalization of intrapleural fibrinolytic therapy.

2.
Am J Respir Cell Mol Biol ; 48(1): 44-52, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23002099

RESUMEN

Elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) are associated with pleural injury, but its effects on pleural organization remain unclear. A method of adenovirus-mediated delivery of genes of interest (expressed under a cytomegalovirus promoter) to rabbit pleura was developed and used with lacZ and human (h) PAI-1. Histology, ß-galactosidase staining, Western blotting, enzymatic and immunohistochemical analyses of pleural fluids (PFs), lavages, and pleural mesothelial cells were used to evaluate the efficiency and effects of transduction. Transduction was selective and limited to the pleural mesothelial monolayer. The intrapleural expression of both genes was transient, with their peak expression at 4 to 5 days. On Day 5, hPAI-1 (40-80 and 200-400 nM of active and total hPAI-1 in lavages, respectively) caused no overt pleural injury, effusions, or fibrosis. The adenovirus-mediated delivery of hPAI-1 with subsequent tetracycline-induced pleural injury resulted in a significant exacerbation of the pleural fibrosis observed on Day 5 (P = 0.029 and P = 0.021 versus vehicle and adenoviral control samples, respectively). Intrapleural fibrinolytic therapy (IPFT) with plasminogen activators was effective in both animals overexpressing hPAI-1 and control animals with tetracycline injury alone. An increase in intrapleural active PAI-1 (from 10-15 nM in control animals to 20-40 nM in hPAI-1-overexpressing animals) resulted in the increased formation of PAI-1/plasminogen activator complexes in vivo. The decrease in intrapleural plasminogen-activating activity observed at 10 to 40 minutes after IPFT correlates linearly with the initial concentration of active PAI-1. Therefore, active PAI-1 in PFs affects the outcome of IPFT, and may be both a biomarker of pleural injury and a molecular target for its treatment.


Asunto(s)
Inhibidor 1 de Activador Plasminogénico/genética , Pleura/lesiones , Adenoviridae/genética , Animales , Modelos Animales de Enfermedad , Epitelio/virología , Expresión Génica , Humanos , Operón Lac , Pleura/efectos de los fármacos , Pleura/metabolismo , Pleura/patología , Conejos , Proteínas Recombinantes/genética , Tetraciclina/toxicidad , Terapia Trombolítica/métodos , Transducción Genética
3.
Am J Respir Cell Mol Biol ; 46(2): 173-9, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21852688

RESUMEN

Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by a robust deposition of transitional fibrin that is in part promoted by tumor cells. MPM cells express tissue factor (TF) and the tissue factor pathway inhibitor (TFPI), but their contribution to the pathogenesis of MPM has been unclear. We found that REN MPM cells fail to express TFPI. Based on the tumor growth-promoting properties of TF, we hypothesized that the stable transfection of TFPI into REN MPM cells would decrease their aggressiveness. We tested our hypothesis using in vitro, in vivo, and ex vivo analyses. TFPI knock-in decreased the proliferation, invasion, and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector, and naive control cells were next injected intrapleurally into nude mice. The expression of TFPI significantly decreased tissue invasion, inflammation, and the deposition of fibrin and collagen associated with tumor tissue, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from harvested tumors. The overexpression of TFPI was maintained in cells propagated from TFPI knock-in tumors, and attenuated the activation of Factor X and the invasiveness of tumor cells. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro and in vivo, and that its effect involves the inhibition of TF procoagulant activity. These observations suggest that the interactions of TF and TFPI represent a novel therapeutic target in the treatment of MPM.


Asunto(s)
Lipoproteínas/fisiología , Mesotelioma/prevención & control , Neoplasias Pleurales/prevención & control , Animales , Biomarcadores de Tumor/metabolismo , Progresión de la Enfermedad , Mesotelioma/patología , Ratones , Ratones Desnudos , Neoplasias Pleurales/patología
4.
Am J Respir Cell Mol Biol ; 42(6): 685-96, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19635932

RESUMEN

Malignant pleural mesothelioma (MPM) is a lethal neoplasm for which current therapy is unsatisfactory. The urokinase plasminogen activator receptor (uPAR) is associated with increased virulence of many solid neoplasms, but its role in the pathogenesis of MPM is currently unclear. We found that REN human pleural MPM cells expressed 4- to 10-fold more uPAR than MS-1 or M9K MPM cells or MeT5A human pleural mesothelial cells. In a new orthotopic murine model of MPM, we found that the kinetics of REN cell tumorigenesis is accelerated versus MS-1 or M9K cells, and that REN instillates generated larger tumors expressing increased uPAR, were more invasive, and caused earlier mortality. While REN, MS-1, and M9K tumors were all associated with prominent extravascular fibrin deposition, excised REN tumor homogenates were characterized by markedly increased uPAR at both the mRNA and protein levels. REN cells exhibited increased thymidine incorporation, which was attenuated in uPAR-silenced cells (P < 0.01). REN cells traversed three-dimensional fibrin gels while MS-1, M9K, and MeT5A cells did not. uPAR siRNA or uPAR blocking antibodies decreased REN cell migration and invasion, while uPA and fetal bovine serum augmented the effects. Transfection of relatively low uPAR expressing MS-1 cells with uPAR cDNA increased proliferation and migration in vitro and tumor formation in vivo. These observations link overexpression of uPAR to the pathogenesis of MPM, demonstrate that this receptor contributes to accelerated tumor growth in part through interactions with uPA, and suggest that uPAR may be a promising target for therapeutic intervention.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurales/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Fibrina/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Mesotelioma/genética , Mesotelioma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Interferencia de ARN , ARN Mensajero/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Factores de Tiempo , Transfección , Carga Tumoral , Regulación hacia Arriba , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
5.
Am J Respir Cell Mol Biol ; 43(3): 358-67, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19855086

RESUMEN

The plasminogen activator inhibitor type-1 (PAI-1) effectively blocks the activities of free and receptor-bound urokinase-type plasminogen activator. Incubation of cultured human pleural mesothelial (Met5A) cells with TGF-beta increased PAI-1 protein. TGF-beta, phorbol myristate acetate, and the translation inhibitor cycloheximide induced PAI-1 mRNA and slowed its degradation, suggesting that PAI-1 mRNA could be regulated by interaction of a PAI-1 binding protein (PAI-1 mRNABp) with PAI-1 mRNA. We found that an approximately 60 kD cytoplasmic PAI-1 mRNABp is detectable in cytoplasmic extracts of MeT5A human pleural mesothelial and malignant mesothelioma cells. The PAI-1 mRNABp specifically binds to a 33-nt sequence in the 3' untranslated region of PAI-1 mRNA. Insertion of this 33-nt sequence destabilizes otherwise stable beta-globin mRNA, indicating that the binding sequence accelerates decay of endogenous PAI-1 mRNA. Competitive inhibition by overexpression of the 33-nt binding sequence in MeT5A cells reduced PAI-1 mRNA decay and increased PAI-1 protein and mRNA expression, indicating that the PAI-1 mRNABp destabilizes PAI-1 mRNA by its interaction with the endogenous 33-nt binding sequence. Incubation of Met5A cells with TGF-beta attenuated the interaction of the PAI-1 mRNABp with the 33-nt sequence. By conventional and affinity purification, we isolated the PAI-1 mRNABp and confirmed its identity as 6-phospho-d-gluconate-NADP oxidoreductase, which specifically interacts with the full-length and the 33-nt sequence of the PAI-1 mRNA 3' untranslated region. This newly recognized pathway could influence expression of PAI-1 by mesothelial or mesothelioma cells at the level of mRNA stability in the context of pleural inflammation or malignancy.


Asunto(s)
Regulación de la Expresión Génica , Inhibidor 1 de Activador Plasminogénico/genética , Pleura/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , Transcripción Genética/genética , Northern Blotting , Western Blotting , Carcinógenos/farmacología , Células Cultivadas , Cicloheximida/farmacología , Epitelio/metabolismo , Humanos , Mesotelioma/genética , Mesotelioma/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Pleura/citología , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Estabilidad del ARN , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Acetato de Tetradecanoilforbol/farmacología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
6.
Am J Physiol Lung Cell Mol Physiol ; 297(4): L568-77, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19666776

RESUMEN

The proenzyme single-chain urokinase plasminogen activator (scuPA) more effectively resolved intrapleural loculations in rabbits with tetracycline (TCN)-induced loculation than a range of clinical doses of two-chain uPA (Abbokinase) and demonstrated a trend toward greater efficacy than single-chain tPA (Activase) (Idell S et al., Exp Lung Res 33: 419, 2007.). scuPA more slowly generates durable intrapleural fibrinolytic activity than Abbokinase or Activase, but the interactions of these agents with inhibitors in pleural fluids (PFs) have been poorly understood. PFs from rabbits with TCN-induced pleural injury treated with intrapleural scuPA, its inactive Ser195Ala mutant, Abbokinase, Activase, or vehicle, were analyzed to define the mechanism by which scuPA induces durable fibrinolysis. uPA activity was elevated in PFs of animals treated with scuPA, correlated with the ability to clear pleural loculations, and resisted (70-80%) inhibition by PAI-1. Alpha-macroglobulin (alphaM) but not urokinase receptor complexes immunoprecipitated from PFs of scuPA-treated rabbits retained uPA activity that resists PAI-1 and activates plasminogen. Conversely, little plasminogen activating or enzymatic activity resistant to PAI-1 was detectable in PFs of rabbits treated with Abbokinase or Activase. Consistent with these findings, PAI-1 interacts with scuPA much slower than with Activase or Abbokinase in vitro. An equilibrium between active and inactive scuPA (k(on) = 4.3 h(-1)) limits the rate of its inactivation by PAI-1, favoring formation of complexes with alphaM. These observations define a newly recognized mechanism that promotes durable intrapleural fibrinolysis via formation of alphaM/uPA complexes. These complexes promote uPA-mediated plasminogen activation in scuPA-treated rabbits with TCN-induced pleural injury.


Asunto(s)
Fibrinólisis/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/farmacología , Pleura/efectos de los fármacos , Tetraciclina/toxicidad , Activador de Plasminógeno de Tipo Uroquinasa/farmacología , alfa-Macroglobulinas/farmacología , Animales , Western Blotting , Femenino , Inmunoprecipitación , Pleura/metabolismo , Inhibidores de la Síntesis de la Proteína/toxicidad , Conejos , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Proteínas Recombinantes/farmacología , Activador de Tejido Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
7.
Exp Lung Res ; 35(8): 665-81, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19895321

RESUMEN

Intrapleural fibrin deposition and subsequent fibrosis characterize evolving empyema and contribute to the morbidity associated with this condition. Single-chain urokinase (scuPA) is proenzyme form of the urokinase plasminogen activator, which has recently been shown to effectively clear intrapleural loculation in tetracycline-induced pleurodesis in rabbits. The authors therefore hypothesized that scuPA could likewise improve intrapleural injury associated with empyema. The authors used a rabbit model of empyema induced by intrapleural administration of Pasturella multocida to test this hypothesis and determined the effects of intrapleural scuPA on pleural fluids indices of inflammation and intrapleural fibrosis. The authors found that intrapleural administration of scuPA was well tolerated, generated readily detectable fibrinolytic activity in the empyema fluids and did not induce intrapleural or systemic bleeding. Pleural fluid volume, intrapleural protein, and D-dimer concentrations were increased at 24 and 48 hours (P < .01, respectively) after induction of empyema. Intrapleural loculation did not occur in the scuPA- or vehicle control-treated animals and there was no significant change in the pleural empyema or thickening scores. These findings confirm that intrapleural scuPA generates fibrinolysis in empyema fluids but does not alter fibrotic repair at the pleural surface or the intensity of intrapleural inflammation in this empyema model.


Asunto(s)
Empiema Pleural/microbiología , Pasteurella multocida , Activador de Plasminógeno de Tipo Uroquinasa/farmacología , Animales , Empiema Pleural/enzimología , Empiema Pleural/etiología , Exudados y Transudados/química , Exudados y Transudados/efectos de los fármacos , Fibrinólisis/efectos de los fármacos , Inflamación , Pleura/patología , Conejos , Resultado del Tratamiento , Activador de Plasminógeno de Tipo Uroquinasa/administración & dosificación , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéutico
8.
J Autism Dev Disord ; 38(4): 764-70, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18058216

RESUMEN

The authors assessed the reliability of the Autism Diagnostic Interview (ADI-R). Seven Clinical Examiners evaluated a three and one half year old female toddler suspected of being on the Autism Spectrum. Examiners showed agreement levels of 94-96% across all items, with weighted kappa (K(w)) between .80 and .88. They were in 100% agreement on 74% of the items; in excellent agreement on 6% of the items (93-96%, with K(w) between .78 and .85); in good agreement on 7% (89-90%, with K(w) between .62 and 0.68); and in fair agreement on 3% (82 - 84%, with K(w) between .40 and .47). For the remaining 10% of ADI-R items, examiners showed poor agreement (50-81% with K(w )between -.67 and .37).


Asunto(s)
Trastorno Autístico/diagnóstico , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Variaciones Dependientes del Observador
9.
J Autism Dev Disord ; 48(4): 1301-1310, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29022174

RESUMEN

Most studies investigating the experiences and needs of individuals with ASD have largely focused on males. Hence, this study investigates parents' perspectives on the challenges that their daughters with ASD face. In total, 40 parents of 40 females with autism (age range = 4-29 years; mean = 15.9) participated in the study. Five separate, 2-h long focus groups were conducted, with 7-10 participants in each group. Field notes were analyzed using thematic analysis. Some of the issues parents discussed were similar to those experienced by males with ASD, such as challenges in social interactions. However, other issues discussed were of particular relevance to girls with ASD, including difficulties socializing with other girls, sex-specific puberty issues, barriers in accessing intervention and sexual vulnerability.


Asunto(s)
Trastorno Autístico/psicología , Núcleo Familiar/psicología , Relaciones Padres-Hijo , Padres/psicología , Factores Sexuales , Adolescente , Adulto , Niño , Preescolar , Femenino , Grupos Focales , Humanos , Relaciones Interpersonales , Conducta Social , Adulto Joven
10.
J Autism Dev Disord ; 44(12): 3154-60, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24996869

RESUMEN

In an earlier investigation, the authors assessed the reliability of the ADI-R when multiple clinicians evaluated a single case, here a female 3 year old toddler suspected of having an autism spectrum disorder (Cicchetti et al. in J Autism Dev Disord 38:764-770, 2008). Applying the clinical criteria of Cicchetti and Sparrow (Am J Men Def 86:127-137, 1981); and those of Cicchetti et al. (Child Neuropsychol 126-137, 1995): 74 % of the ADI-R items showed 100 % agreement; 6 % showed excellent agreement; 7 % showed good agreement; 3 % manifested average agreement; and the remaining 10 % evidenced poor agreement. In this follow-up investigation, the authors described and applied a novel method for determining levels of statistical significance of the reliability coefficients obtained in the earlier investigation. It is based upon a modification of the Z test for comparing a given level of inter-examiner reliability with a lower limit value of 70 % (Dixon and Massey in Introduction to statistical analysis. McGraw-Hill, New York, 1957). Results indicated that every item producing a clinically acceptable level of inter-examiner reliability was also statistically significant. However, the reverse was not true, since a number of the items with statistically significant reliability levels did not reach levels of agreement that were clinically meaningful. This indicated that clinical significance was an accurate marker of statistical significance. The generalization of these findings to other areas of diagnostic interest and importance is also examined.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/psicología , Escalas de Valoración Psiquiátrica/normas , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Variaciones Dependientes del Observador , Psicometría/normas , Reproducibilidad de los Resultados
11.
J Autism Dev Disord ; 41(2): 168-74, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20490646

RESUMEN

The objectives of this report are: (a) to trace the theoretical roots of the concept clinical significance that derives from Bayesian thinking, Marginal Utility/Diminishing Returns in Economics, and the "just noticeable difference", in Psychophysics. These concepts then translated into: Effect Size (ES), strength of agreement, clinical significance, and related concepts, and made possible the development of Power Analysis; (b) to differentiate clinical significance from statistical significance; and (c) to demonstrate the utility of measures of ES and related concepts for enhancing the meaning of Autism research findings. These objectives are accomplished by applying criteria for estimating clinical significance, and related concepts, to a number of areas of autism research.


Asunto(s)
Trastorno Autístico , Investigación Biomédica/estadística & datos numéricos , Interpretación Estadística de Datos , Análisis de Varianza , Teorema de Bayes , Investigación Biomédica/normas , Humanos , Reproducibilidad de los Resultados , Tamaño de la Muestra
12.
Shock ; 36(2): 128-37, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21478814

RESUMEN

Although aberrant fibrinolysis and plasminogen activator inhibitor 1 (PAI-1) are implicated in acute lung injury, the role of this serpin in the pathogenesis of wood bark smoke (WBS)-induced acute lung injury (SIALI) and its regulation in resident lung cells after exposure to smoke are unclear. A total of 22 mechanically ventilated pigs were included in this study. Immunohistochemical analyses were used to assess fibrin and PAI-1 in the lungs of pigs with SIALI in situ. Plasminogen activator inhibitor 1 was measured in bronchoalveolar lavage fluids by Western blotting. Induction of PAI-1 was determined at the protein and mRNA levels by Western and polymerase chain reaction analyses in primary porcine alveolar type II cells, fibroblasts, and pleural mesothelial cells. Plasminogen activator inhibitor 1 mRNA stability was determined by transcription chase studies. Gel shift analyses were used to characterize the mechanism regulating PAI-1 mRNA stability. Smoke-induced ALI induced PAI-1, with prominent extravascular fibrin deposition in large and small airways as well as alveolar and subpleural compartments. In pleural mesothelial cells, lung fibroblasts, and alveolar type II cells, PAI-1 mRNA was stabilized by WBS extract and contributed to induction of PAI-1. The mechanism involves dissociation of a novel 6-phospho-d-gluconate-NADP oxidoreductase-like PAI-1 mRNA binding protein from PAI-1 mRNA. Exposure to WBS induces prominent airway and mesothelial expression of PAI-1, associated with florid distribution of fibrin in SIALI in vivo Wood bark smoke components induce PAI-1 in vitro in part by stabilization of PAI-1 mRNA, a newly recognized pathway that may promote extravascular fibrin deposition and lung dysfunction in SIALI.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Pulmón/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Pleura/metabolismo , Humo/efectos adversos , Lesión Pulmonar Aguda/inducido químicamente , Animales , Células Cultivadas , Femenino , Fibrina/metabolismo , Pulmón/patología , Inhibidor 1 de Activador Plasminogénico/genética , Distribución Aleatoria , Porcinos
14.
Am J Physiol Lung Cell Mol Physiol ; 292(1): L25-32, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16980376

RESUMEN

Intrapleural fibrinolysins have been used to treat pleural loculations. However, the efficacy of clinically available agents has recently been questioned, providing a rationale for investigation of new interventions. Single-chain urokinase plasminogen activator resists inhibition by serpins, and repeated, daily intrapleural administration of this agent prevents intrapleural loculation more effectively than complexes of this proenzyme with its receptor (Idell S, Mazar A, Cines D, Kuo A, Parry G, Gawlak S, Juarez J, Koenig K, Azghani A, Hadden W, McLarty J, Miller E. Am J Respir Crit Care Med 166: 920-926, 2002). Understanding of the protective mechanism and intrapleural processing remains unclear. We speculated that single-chain urokinase could induce sustained local fibrinolysis and protection by selective administration either before, during, or following loculation after pleural injury induced by tetracycline in rabbits. Enzymography, immunoassays, histology, immunohistochemistry, morphology, and morphometry were used to test the efficacy, duration of protective effect, and processing of single-chain urokinase. Intrapleural single chain urokinase prevented loculation at 72 h after injury (P < 0.01) if given either before or during adhesion formation and was converted to two-chain high-molecular-weight urokinase, which remained active for at least 24 h within pleural fluids. The effect was dose dependent, and established loculations at 72 h after tetracycline-induced injury were reversed at 96 h by single-dose treatment. Single-chain urokinase bound and saturated intrapleural plasminogen activator inhibitory (PAI)-1-like activity and urokinase-related immunoreactivity of the mesothelium was comparable in treatment or vehicle-control groups. Adhesions recurred by 2 wk after treatment with recurrence of excess local PAI activity. Single-chain urokinase induces sustained local fibrinolysis and reversibly prevents pleural loculation for up to 48 h after intrapleural administration after tetracycline-induced injury.


Asunto(s)
Pleura/efectos de los fármacos , Pleura/lesiones , Tetraciclina/toxicidad , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/farmacología , Animales , Femenino , Fibrina/metabolismo , Fibrinólisis/efectos de los fármacos , Pleura/enzimología , Conejos , Adherencias Tisulares/inducido químicamente , Adherencias Tisulares/prevención & control , Activador de Plasminógeno de Tipo Uroquinasa/administración & dosificación
15.
Exp Lung Res ; 33(8-9): 419-40, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17994370

RESUMEN

The authors compared the ability of a single dose of the proenzyme single-chain urokinase (scuPA), low-molecular-weight urokinase, tissue plasminogen activator (tPA), or a mutant site-inactive scuPA to resolve intrapleural loculations at 72 to 96 hours after tetracycline-induced pleural injury in rabbits. Both scuPA and tPA reversed loculations at 96 hours after injury P < or = .001, whereas low-molecular-weight urokinase and the scuPA mutant were ineffective. scuPA and tPA generated inhibitor complexes, induced fibrinolytic activity, and quenched plasminogen activator-1 activity in pleural fluids. The authors conclude that scuPA reverses loculations as effectively as tPA at clinically applied intrapleural doses, whereas low-molecular-weight urokinase was ineffective.


Asunto(s)
Fibrinolíticos/administración & dosificación , Pleura/efectos de los fármacos , Tetraciclina/toxicidad , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Plasminógeno de Tipo Uroquinasa/administración & dosificación , Animales , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Pleura/química , Pleura/citología , Derrame Pleural/prevención & control , Pleuresia/prevención & control , Pleurodesia , Conejos , Adherencias Tisulares/prevención & control
16.
Am J Respir Crit Care Med ; 166(7): 920-6, 2002 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-12359647

RESUMEN

Intrapleural loculation can increase morbidity in hemothoraces or parapneumonic effusions. Intrapleural fibrin precedes visceral-parietal pleural adhesions. We speculated that single-chain urokinase plasminogen activator alone or bound to its receptor could prevent these adhesions by their relative resistance to local inhibition by plasminogen activator inhibitors. We found that recombinant human single-chain urokinase-bound rabbit pleural mesothelial cells or lung fibroblasts with kinetics similar to that reported for human cells (kD of approximately 5 nM). The receptor-bound fibrinolysin maintained in vitro fibrinolytic activity in the presence of pleural fluids from rabbits with tetracycline-induced pleural injury over 24 hours. In rabbits given intrapleural single-chain urokinase 24 and 48 hours after intrapleural tetracycline (n = 10 animals), adhesions were prevented, whereas the receptor-complexed form (n = 12) attenuated adhesions versus vehicle/tetracycline-treated rabbits (n = 22, p

Asunto(s)
Antibacterianos/efectos adversos , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Receptores de Superficie Celular/uso terapéutico , Tetraciclina/efectos adversos , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéutico , Animales , Biomarcadores/análisis , Líquidos Corporales/química , Líquidos Corporales/citología , Recuento de Células , Modelos Animales de Enfermedad , Epitelio/efectos de los fármacos , Femenino , Fibrina/efectos de los fármacos , Fibrina/metabolismo , Fibroblastos/efectos de los fármacos , Pleura/efectos de los fármacos , Derrame Pleural/inducido químicamente , Derrame Pleural/tratamiento farmacológico , Conejos , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Adherencias Tisulares/metabolismo
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