RESUMEN
AIM: To assess the views and experience of the UK dentists specialising in paediatric dentistry (trainees) about molar incisor hypomineralisation (MIH) and compare the findings with the responses from a group of UK general dental practitioners. METHOD: A web-based questionnaire was sent to dentists undergoing specialist training in paediatric dentistry. The same questionnaire was completed by a group of general dentists who stated an interest in treating children, with various levels of experience. The questionnaire sought information on clinical experience and the views of the dentists on the impact of MIH on children and families. RESULTS: Specialty trainees (37) from different paediatric dental departments in the UK completed the online survey, giving a total response rate of 71%. The questionnaire was also completed by 31 general dental practitioners. There was difficulty in distinguishing MIH from other conditions for both groups. Increased sensitivity of affected teeth was the most frequently encountered problem with 51% of the trainees and 76% of the dentists saying this was often or always a challenge. The trainees were particularly concerned about the pain children experienced and about the appearance of the condition. Both groups felt that parental anxiety occurred in almost all cases. CONCLUSIONS: Both groups felt that MIH presents several clinical challenges and has a negative effect on the quality of life of the affected children and their families. There were significant differences in the views and perceptions between the two groups.
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Hipoplasia del Esmalte Dental/terapia , Odontología Pediátrica , Niño , Competencia Clínica , Restauración Dental Permanente , Odontólogos , Conocimientos, Actitudes y Práctica en Salud , Humanos , Incisivo , Diente Molar , Calidad de Vida , Reino UnidoRESUMEN
Genetic and immunological analysis of host-pathogen interactions can reveal fundamental mechanisms of susceptibility and resistance to infection. Modeling human infectious diseases among inbred mouse strains is a proven approach but is limited by naturally occurring genetic diversity. Using N-ethyl-N-nitrosourea mutagenesis, we created a recessive loss-of-function point mutation in Unc93b1 (unc-93 homolog B1 (C. elegans)), a chaperone for endosomal Toll-like receptors (TLR)3, TLR7 and TLR9, which we termed Letr for 'loss of endosomal TLR response'. We used Unc93b1(Letr/Letr) mice to study the role of Unc93b1 in the immune response to influenza A/PR/8/34 (H1N1), an important global respiratory pathogen. During the early phase of infection, Unc93b1(Letr/Letr) mice had fewer activated exudate macrophages and decreased expression of CXCL10, interferon (IFN)-γ and type I IFN. Mutation of Unc93b1 also led to reduced expression of the CD69 activation marker and a concomitant increase in the CD62L naive marker on CD4(+) and CD8(+) T cells in infected lungs. Finally, loss of endosomal TLR signaling resulted in delayed viral clearance that coincided with increased tissue pathology during infection. Taken together, these findings establish a role for Unc93b1 and endosomal TLRs in the activation of both myeloid and lymphoid cells during the innate immune response to influenza.
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Activación de Linfocitos , Activación de Macrófagos , Proteínas de Transporte de Membrana/genética , Mutación , Infecciones por Orthomyxoviridae/inmunología , Empalme Alternativo , Animales , Linfocitos T CD8-positivos/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Endosomas/metabolismo , Etilnitrosourea , Inmunidad Innata , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Selectina L/genética , Selectina L/metabolismo , Pulmón/metabolismo , Pulmón/patología , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
Experimental models of lung fibrosis have been disappointing in predicting therapeutic responses to a wide variety of interventions in clinical fibrosing lung diseases. There are multiple potential reasons, but this fundamentally calls into question the validity of the models and their fidelity to clinical syndromes. We propose that the clinical diseases associated with pulmonary fibrosis, although manifesting a broad array of widely different clinical presentations and features, result in essentially two distinct phenotypes of fibrosis that we will describe. The most common and problematic of these are not effectively modeled experimentally. In this review, we present several clinical entities as examples of the phenotypic distinctions. The first two represent the extremes: postinflammatory fibrosis observed in hypersensitivity pneumonitis (HP) and dysregulated matrix deposition as observed in idiopathic pulmonary fibrosis (IPF). We also present a third clinical entity, that of lung disease associated with rheumatoid arthritis (rheumatoid lung), representing a condition that can manifest as either phenotype, and offering a potential opportunity to explore the mechanisms underlying the pathogenesis of the two distinct fibrotic phenotypes.
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Alveolitis Alérgica Extrínseca/patología , Artritis Reumatoide/patología , Fibrosis Pulmonar Idiopática/patología , Neumonía/patología , Animales , Autoinmunidad , Fibrosis , Humanos , Modelos Animales , Fenotipo , SíndromeRESUMEN
Unnecessary variation in clinical care and clinical research reduces our ability to determine what healthcare interventions are effective. Reducing this unnecessary variation could lead to further healthcare quality improvement and more effective clinical research. We have developed and used electronic decision support tools (eProtocols) to reduce unnecessary variation. Our eProtocols have progressed from a locally developed mainframe computer application in one clinical site (LDS Hospital) to web-based applications available in multiple languages and used internationally. We use eProtocol-insulin as an example to illustrate this evolution. We initially developed eProtocol-insulin as a local quality improvement effort to manage stress hyperglycemia in the adult intensive care unit (ICU). We extended eProtocol-insulin use to translate our quality improvement results into usual clinical care at Intermountain Healthcare ICUs. We exported eProtocol-insulin to support research in other US and international institutions, and extended our work to the pediatric ICU. We iteratively refined eProtocol-insulin throughout these transitions, and incorporated new knowledge about managing stress hyperglycemia in the ICU. Based on our experience in the development and clinical use of eProtocols, we outline remaining challenges to eProtocol development, widespread distribution and use, and suggest a process for eProtocol development. Technical and regulatory issues, as well as standardization of protocol development, validation and maintenance, need to be addressed. Resolution of these issues should facilitate general use of eProtocols to improve patient care.
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Sistemas de Apoyo a Decisiones Administrativas/organización & administración , Quimioterapia Asistida por Computador/métodos , Hiperglucemia/diagnóstico , Hiperglucemia/tratamiento farmacológico , Insulina/administración & dosificación , Internet , Lenguajes de Programación , Adulto , Investigación Biomédica/métodos , Humanos , Sensibilidad y Especificidad , Estados UnidosRESUMEN
MicroRNAs (miRNAs) have recently emerged as an important new class of cellular regulators that control various cellular processes and are implicated in human diseases, including cancer. Here, we show that loss of let-7 function enhances lung tumor formation in vivo, strongly supporting the hypothesis that let-7 is a tumor suppressor. Moreover, we report that exogenous delivery of let-7 to established tumors in mouse models of non-small-cell lung cancer (NSCLC) significantly reduces the tumor burden. These results demonstrate the therapeutic potential of let-7 in NSCLC and point to miRNA replacement therapy as a promising approach in cancer treatment.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/administración & dosificación , ARN sin Sentido/administración & dosificación , ARN sin Sentido/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga TumoralRESUMEN
A 39-year-old white woman with longstanding Crohn's disease presented with the rare complication of granulomatous bronchiolitis. Rapid resolution after inhaled budesonide is highlighted, as this is the first case described in the literature successfully treated without the need for systemic therapy. This less toxic approach to therapy is warranted in granulomatous bronchiolitis of Crohn's disease to avoid unwanted side effects of steroids and infliximab.
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Bronquiolitis/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Budesonida/uso terapéutico , Enfermedad de Crohn/complicaciones , Glucocorticoides/uso terapéutico , Granuloma del Sistema Respiratorio/tratamiento farmacológico , Adulto , Antiinflamatorios/uso terapéutico , Bronquiolitis/diagnóstico por imagen , Bronquiolitis/etiología , Femenino , Granuloma del Sistema Respiratorio/diagnóstico por imagen , Granuloma del Sistema Respiratorio/etiología , Humanos , Tomografía Computarizada por Rayos XRESUMEN
SYBYL line notation (SLN) is a powerful way to represent molecular structures, reactions, libraries of structures, molecular fragments, formulations, molecular queries, and reaction queries. Nearly any chemical structure imaginable, including macromolecules, pharmaceuticals, catalysts, and even combinatorial libraries can be represented as an SLN string. The language provides a rich syntax for database queries comparable to SMARTS. It provides full Markush, R-Group, reaction, and macro atom capabilities in a single unified notation. It includes the ability to specify 3D conformations and 2D depictions. All the information necessary to recreate the structure in a modeling or drawing package is present in a single, concise string of ASCII characters. This makes SLN ideal for structure communication over global computer networks between applications sitting at remote sites. Unlike SMILES and its derivatives, SLN accomplishes this within a single unified syntax. Structures, queries, compounds, reactions, and virtual libraries can all be represented in a single notation.
RESUMEN
In critically ill patients control of blood sugar levels with IV insulin has been shown to improve clinical outcomes in the intensive care units. We have developed an analytical framework with which to evaluate and compare IV insulin-treatment models and protocols. Performance of the analytical framework is demonstrated using protocols published by others and new protocols under development by our group.
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Cuidados Críticos/métodos , Enfermedad Crítica/terapia , Sistemas de Apoyo a Decisiones Clínicas , Quimioterapia Asistida por Computador/métodos , Hiperglucemia/tratamiento farmacológico , Insulina/administración & dosificación , Sistemas de Registros Médicos Computarizados , Evaluación de Resultado en la Atención de Salud/métodos , Humanos , Inyecciones Intravenosas , Resultado del Tratamiento , UtahRESUMEN
Constantly changing diabetes care standards makes it challenging to deliver care adapted to the unique condition of the individual patient. The availability of large amounts of data from patient's electronic medical records makes it possible to individualize diabetes management. Initial design of a "patient-specific" hybrid system (physiological-causal probabilistic) of adaptive diabetes models and insulin treatment algorithms will be presented. The system is uniquely derived and tested using a diabetes data mart of about 33,000 patients.
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Sistemas de Apoyo a Decisiones Clínicas , Diabetes Mellitus/tratamiento farmacológico , Quimioterapia Asistida por Computador/métodos , Insulina/uso terapéutico , Sistemas de Registros Médicos Computarizados/estadística & datos numéricos , Medicina de Precisión/métodos , Atención Dirigida al Paciente/métodos , UtahRESUMEN
PURPOSE: Implementation of evidence-based techniques, such as explicit computerized protocols, has achieved limited success among clinicians. In this study, we describe the development and validation of an instrument for assessing clinicians' perceptions about use of explicit computerized protocols. METHODS: Qualitative assessment of semi-structured interviews with clinicians gave rise to a cognitive model evaluating the factors that motivate clinicians to use explicit computerized protocols. Using these constructs we developed a 35-item instrument which was administered to 240 clinicians (132 nurses, 53 physicians and 55 respiratory therapists), in three health-care institutions. RESULTS: Factor analysis identified nine factors that accounted for 66% of the total variance cumulatively. Factors identified were: Beliefs regarding Self-Efficacy, Environmental Support, Role Relevance, Work Importance, Beliefs regarding Control, Attitude towards Information Quality, Social Pressure, Culture, and Behavioral Intention. The strongest predictor was Beliefs regarding Self-Efficacy, which accounted for 26% of the total variance of intention to use explicit computerized protocols. Results supported the reliability and construct validity of the instrument. CONCLUSIONS: Clinicians' perceptions play a critical role in determining their intention to use explicit computerized protocols in routine clinical practice. Behavioral theories will help us understand factors predicting clinicians' intention to use explicit computerized protocols and recognize the implications of these factors in the design and implementation of these protocols.
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Actitud del Personal de Salud , Actitud hacia los Computadores , Protocolos Clínicos , Sistemas de Apoyo a Decisiones Clínicas/estadística & datos numéricos , Sistemas de Información/estadística & datos numéricos , Humanos , Modelos PsicológicosRESUMEN
The case of a 52-yr-old female with rheumatoid arthritis and HIV who developed massive, progressive, cavitary pulmonary nodules is described. Multiple diagnostic bronchoscopies and lung biopsies failed to demonstrate the presence of any microorganisms. Pathological analysis showed palisading histiocytes with necrobiosis consistent with rheumatoid nodules. The effect of co-existing HIV infection on the course and prognosis of rheumatoid arthritis is discussed, and it is concluded that the complex relationship between these two disease processes warrants further investigation.
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Infecciones por VIH/complicaciones , Pulmón/patología , Nódulo Reumatoide/patología , Femenino , Humanos , Pulmón/diagnóstico por imagen , Persona de Mediana Edad , Radiografía , Nódulo Reumatoide/complicaciones , Nódulo Reumatoide/diagnóstico por imagenRESUMEN
We describe a cognitive approach to evaluating the factors that motivate clinicians to use computerized protocols. Using Value-Expectancy theories we developed an open-ended interview to assess clinicians' beliefs and experiences about the use of computerized protocols. Using a qualitative methodology, 3 reviewers independently identified key concepts raised by 13 interviewees. These concepts were aggregated and independently sorted into 39 categories. Then final categories were chosen by consensus. Analysis of the concepts showed consistency across clinician specialties of physicians, nurses and respiratory therapists. Inter-rater reliability calculated using Cohen's Kappa was 0.474. Identified constructs from Value-Expectancy and Intrinsic Motivation theories were: Work Importance, Perception of Situation, Role Relevance, Beliefs regarding Control, Beliefs regarding Normative Expectations, Beliefs regarding Self-Efficacy, Attitude, Habit, Environmental Support and Pre-Behavior. This model will form the basis for an instrument to assess the beliefs and expectations of clinical use regarding the use of computerized protocols.
Asunto(s)
Actitud del Personal de Salud , Actitud hacia los Computadores , Sistemas de Apoyo a Decisiones Clínicas/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Medicina Clínica , Cognición , Toma de Decisiones , Estudios de Evaluación como Asunto , Humanos , Modelos Psicológicos , Motivación , Personal de Hospital/psicología , Teoría Psicológica , Encuestas y CuestionariosRESUMEN
Noninflammatory structural alterations, variously referred to as airway remodeling, are well documented in the asthmatic airway. However, the pathogenesis of these alterations, the importance of airway remodeling in generating the asthma phenotype, and the natural history of airway remodeling responses have not been adequately defined. Because exaggerated cytokine production is a characteristic feature of the asthmatic airway, we used constitutive and inducible overexpression transgenic systems to investigate the contributions that interleukin 11 (IL-11) and IL-13 might make to airway remodeling responses. These studies demonstrated that both cytokines produce responses in the murine airway with features similar to those in human asthmatic tissues. IL-11 caused airway fibrosis with the enhanced accumulation of interstitial collagens, myocytes, and myofibroblasts. IL-13 caused mucous metaplasia, enhanced mucin gene expression, enhanced tissue hyaluronic acid accumulation, and subepithelial fibrosis. Importantly, IL-11 was detected most readily in tissues from asthmatic subjects with severe airway remodeling that was similar to that seen in the IL-11 transgenic mice. In addition, IL-11 was shown to inhibit asthma-like inflammation while stimulating airway fibrosis. This suggests that IL-11 elaboration is, in part, an attempt at airway healing. Last, a novel triple transgenic system is described that allows transgene expression to be regulated in a true "on/off" manner. This system may be useful in defining the reversibility of transgene-induced airway remodeling responses.
Asunto(s)
Asma/genética , Asma/patología , Interleucina-11/fisiología , Interleucina-13/fisiología , Pulmón/patología , Animales , Antibacterianos/farmacología , Asma/fisiopatología , Enfermedad Crónica , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inflamación/genética , Inflamación/patología , Interleucina-11/genética , Interleucina-13/genética , Pulmón/metabolismo , Ratones , Ratones Transgénicos , Fenotipo , ARN Mensajero/análisis , Tetraciclina/farmacología , Transcripción GenéticaRESUMEN
The evolution of our understanding of IL-11 mirrors, in many ways, the problems that are faced by investigators in the post-genome era and the types of techniques that might need to be used to deal with these issues. IL-11 was discovered as a soluble factor in fibroblast supernatants that stimulated the proliferation of "IL-6-dependent" plasmacytoma cells. It was subsequently demonstrated to be an important stimulator of platelet reconstitution and a pleiotropic regulator of nonrespiratory tissues. In the lung, IL-11 is produced by a variety of structural cells and eosinophils in response to a variety of stimuli, including TGF-beta, major basic proteins, and viruses. IL-11 is also detected in exaggerated quantities at sites of virus infection. Its potential effector functions at these sites were defined with constitutive and inducible overexpression transgenic modeling systems which demonstrated that IL-11 causes nodular mononuclear infiltrates, airway remodeling with subepithelial fibrosis, airways obstruction, and airways hyperresponsiveness and can block alveolar development when expressed during development. In accord with these murine findings, IL-11 is selectively expressed in eosinophils and epithelial cells in patients with moderate and severe asthma where expression correlates directly with disease severity and inversely with FEV(1). Studies using transgenic mice also demonstrated that IL-11 inhibits antigen-induced tissue inflammation. Thus IL-11 might be an important regulator of inflammatory and remodeling responses in the asthmatic airway.
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Asma/etiología , Interleucina-11/inmunología , Sistema Respiratorio/inmunología , Animales , Asma/inmunología , Humanos , Interleucina-11/biosíntesis , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11 , Ratones , Ratones Transgénicos , Receptores de Interleucina/metabolismo , Receptores de Interleucina-11RESUMEN
Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-beta. To test this hypothesis we compared the regulation of TGF-beta in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-beta(1) production in transgenic animals and macrophages were the major site of TGF-beta(1) production and deposition in these tissues. IL-13 also activated TGF-beta(1) in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-beta-binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-beta(1) activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13-induced fibrosis was also significantly ameliorated by treatment with the TGF-beta antagonist soluble TGFbetaR-Fc (sTGFbetaR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-beta(1) in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-beta pathway.
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Interleucina-13/inmunología , Fibrosis Pulmonar/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Receptores de Hialuranos/fisiología , Interleucina-13/genética , Metaloproteinasa 9 de la Matriz/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1 , Activador de Plasminógeno de Tipo Uroquinasa/fisiologíaRESUMEN
The doxycycline-inducible reverse tetracycline transactivator (rtTA) is frequently used to overexpress transgenes in a temporally regulated fashion in vivo. These systems are, however, often limited by the levels of transgene expression in the absence of dox administration. The tetracycline-controlled transcriptional silencer (tTS), a fusion protein containing the tet repressor and the KRAB-AB domain of the kid-1 transcriptional repressor, is inhibited by doxycycline. We hypothesized that tTS would tighten control of transgene expression in rtTA-based systems. To test this hypothesis we generated mice in which the CC10 promoter targeted tTS to the lung, bred these mice with CC10-rtTA-interleukin 13 (IL-13) mice in which IL-13 was overexpressed in an inducible lung-specific fashion, and compared the IL-13 production and phenotypes of parental mice and the triple transgenic CC10-rtTA/tTS-IL-13 progeny of these crosses. In the CC10-rtTA-IL-13 mice, IL-13, mucus metaplasia, inflammation, alveolar enlargement, and enhanced lung volumes were noted at base line and increased greatly after doxycycline administration. In the triple transgenic tTS animals, IL-13 and the IL-13-induced phenotype could not be appreciated without doxycycline. In contrast, tTS did not alter the induction of IL-13 or the generation of the IL-13 phenotype by doxycycline. Thus, tTS effectively eliminated the baseline leak without altering the inducibility of rtTA-regulated transgenes in vivo. Optimal "off/on" regulation of transgene expression can be accomplished with the combined use of tTS and rtTA.
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Doxiciclina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Represoras/farmacología , Tetraciclina , Factores de Transcripción , Transgenes , Animales , Proteínas de Unión al ADN/genética , Interleucina-13/biosíntesis , Pulmón/efectos de los fármacos , Ratones , Ratones Transgénicos , Fenotipo , Proteínas Recombinantes/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
Airway eosinophilia in asthma is dependent on cytokines secreted by Th2 cells, including IL-5 and IL-4. In these studies we investigated why the absence of IL-4 led to a reduction in airway, but not lung tissue, eosinophils. Using adoptively transferred, in vitro-generated TCR-transgenic Th2 cells deficient in IL-4, we show that this effect is independent of IL-5 and Th2 cell generation. Airway eosinophilia was no longer inhibited when IL-4(-/-) Th2 cells were transferred into IFN-gammaR(-/-) mice, indicating that IFN-gamma was responsible for reducing airway eosinophils in the absence of IL-4. Intranasal administration of IFN-gamma to mice after IL-4(+/+) Th2 cell transfer also caused a reduction in airway, but not lung parenchymal, eosinophils. These studies show that IL-4 indirectly promotes airway eosinophilia by suppressing the production of IFN-gamma. IFN-gamma reduces airway eosinophils by engaging its receptor on hemopoietic cells, possibly the eosinophil itself. These studies capitalize on the complex counterregulatory effects of Th1 and Th2 cytokines in vivo and clarify how IL-4 influences lung eosinophilia. We define a new regulatory role for IFN-gamma, demonstrating that eosinophilic inflammation is differentially regulated at distinct sites within the respiratory tract.
Asunto(s)
Bronquios/patología , Regulación hacia Abajo/inmunología , Interferón gamma/antagonistas & inhibidores , Interferón gamma/fisiología , Interleucina-4/fisiología , Eosinofilia Pulmonar/inmunología , Hipersensibilidad Respiratoria/inmunología , Administración Cutánea , Administración Intranasal , Traslado Adoptivo , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Movimiento Celular/genética , Movimiento Celular/inmunología , Regulación hacia Abajo/genética , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Inflamación/genética , Inflamación/inmunología , Inflamación/prevención & control , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Interleucina-13/biosíntesis , Interleucina-4/deficiencia , Interleucina-4/genética , Interleucina-5/biosíntesis , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/patología , Eosinofilia Pulmonar/prevención & control , Receptores de Interferón/fisiología , Hipersensibilidad Respiratoria/genética , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/prevención & control , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplante , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Receptor de Interferón gammaRESUMEN
Chronic inflammation containing CD8(+) lymphocytes, neutrophils, and macrophages, and pulmonary emphysema coexist in lungs from patients with chronic obstructive pulmonary disease. Although this inflammatory response is believed to cause the remodeling that is seen in these tissues, the mechanism(s) by which inflammation causes emphysema have not been defined. Here we demonstrate that interferon gamma (IFN-gamma), a prominent product of CD8(+) cells, causes emphysema with alveolar enlargement, enhanced lung volumes, enhanced pulmonary compliance, and macrophage- and neutrophil-rich inflammation when inducibly targeted, in a transgenic fashion, to the adult murine lung. Prominent protease and antiprotease alterations were also noted in these mice. They included the induction and activation of matrix metalloproteinase (MMP)-12 and cathepsins B, H, D, S, and L, the elaboration of MMP-9, and the selective inhibition of secretory leukocyte proteinase inhibitor. IFN-gamma causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues.
Asunto(s)
Interferón gamma/biosíntesis , Pulmón/inmunología , Enfisema Pulmonar/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Catepsinas/genética , Cisteína Endopeptidasas/biosíntesis , Inducción Enzimática , Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Pulmón/patología , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Transgénicos , Enfisema Pulmonar/patología , Distribución Tisular , TransgenesRESUMEN
Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.
Asunto(s)
Catepsinas/metabolismo , Enfisema/enzimología , Enfisema/etiología , Interleucina-13/metabolismo , Pulmón/inmunología , Metaloproteinasas de la Matriz/metabolismo , Animales , Asma/complicaciones , Secuencia de Bases , Catepsinas/antagonistas & inhibidores , Catepsinas/genética , Cartilla de ADN/genética , Enfisema/inmunología , Humanos , Interleucina-13/genética , Pulmón/enzimología , Pulmón/patología , Enfermedades Pulmonares Obstructivas/enzimología , Enfermedades Pulmonares Obstructivas/etiología , Enfermedades Pulmonares Obstructivas/inmunología , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Transgénicos , Inhibidores de Proteasas/farmacología , Fumar/efectos adversosRESUMEN
Chronic Th2-dominated inflammation and exaggerated IL-6 production are characteristic features of the asthmatic airway. To understand the processes that are responsible for the chronicity of this response and the role(s) of IL-6 in the regulation of airway Th2 inflammation, we compared the responses induced by OVA in sensitized wild-type mice, IL-6 deficient (-/-) mice, and transgenic mice in which IL-6 was overexpressed in the airway (CC10-IL-6 mice). When compared with wild-type mice, IL-6-/- mice manifest exaggerated inflammation and eosinophilia, increased levels of IL-4, IL-5, and IL-13 protein and mRNA, exaggerated levels of eotaxin, JE/monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and -2, and mRNA, increased bronchoalveolar lavage (BAL) TGF-beta1, and exaggerated airway responses to aerosolized methacholine. In contrast, CC10-IL-6 mice, on both C57BL/6 and BALB/c backgrounds, manifest diminished inflammation and eosinophilia, decreased levels of IL-4, IL-5, and IL-13 protein and mRNA, and decreased levels of bronchoalveolar lavage TGF-beta1. IL-6 also decreased the expression of endothelial VCAM-1 and airway responsiveness to methacholine in these animals. These alterations in the IL-6-/- and CC10-IL-6 mice were not associated with significant decreases or increases in the levels of IFN-gamma, respectively. These studies demonstrate that endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation and that this inhibition is not mediated by regulatory effects of IFN-gamma. IL-6 may be an important anti-inflammatory, counterregulatory, and healing cytokine in the airway.