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1.
Cells ; 13(13)2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38995005

RESUMEN

Space travel presents multiple risks to astronauts such as launch, radiation, spacewalks or extravehicular activities, and microgravity. The lungs are composed of a combination of air, blood, and tissue, making it a complex organ system with interactions between the external and internal environment. Gravity strongly influences the structure of the lung which results in heterogeneity of ventilation and perfusion that becomes uniform in microgravity as shown during parabolic flights, Spacelab, and Skylab experiments. While changes in lung volumes occur in microgravity, efficient gas exchange remains and the lungs perform as they would on Earth; however, little is known about the cellular response to microgravity. In addition to spaceflight and real microgravity, devices, such as clinostats and random positioning machines, are used to simulate microgravity to study cellular responses on the ground. Differential expression of cell adhesion and extracellular matrix molecules has been found in real and simulated microgravity. Immune dysregulation is a known consequence of space travel that includes changes in immune cell morphology, function, and number, which increases susceptibility to infections. However, the majority of in vitro studies do not have a specific respiratory focus. These studies are needed to fully understand the impact of microgravity on the function of the respiratory system in different conditions.


Asunto(s)
Pulmón , Vuelo Espacial , Ingravidez , Humanos , Pulmón/fisiología , Ingravidez/efectos adversos , Animales
4.
Transplantation ; 105(12): 2546-2553, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34793112

RESUMEN

BACKGROUND: Lung transplantation provides a unique opportunity to investigate the constituents and temporal dynamics of the human pulmonary microbiome after lung transplantation. For methodological reasons, prior studies using metagenomics have detected DNA viruses but not demonstrated the presence of RNA viruses, including those that are common community acquired. In this proof-of-concept study, we aimed to further characterize the pulmonary microbiome after lung transplantation by using metagenomic next-generation sequencing (mNGS), with a particular focus on the RNA virome. METHODS: We performed a single-center longitudinal study of lower respiratory tract RNA viruses and bacteria using bronchoalveolar lavage at postoperative day 1 and week 6 analyzed with total RNA sequencing (metatranscriptomics). Five primary and 5 repeat transplant recipients were recruited. RESULTS: mNGS identified 5 RNA viruses (nil in the normal saline control), including 4 species of human rhinovirus not previously reported in Australia: A7 (HRV-A7), C22 (HRV-C22), B52 (HRV-B52), and B72 (HRV-B72). Overall, 12/20 specimens were virus positive in 7/10 cases. Human parainfluenza virus 3 was the most frequent virus in 7/20 specimens in 5/10 cases. In this small study, we did not detect a significant difference in abundance and diversity of RNA viruses and bacteria at postoperative day 1 and 6 wk, nor differences between retransplant recipients and primary lung transplant recipients. CONCLUSIONS: Our study demonstrates how mNGS can also identify RNA viruses within the human pulmonary virome, including novel RNA viruses, and paves the way for a greater understanding of the complex relationships among the constituents of the pulmonary infectome.


Asunto(s)
Trasplante de Pulmón , ARN , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios Longitudinales , Pulmón , Trasplante de Pulmón/efectos adversos , Viroma/genética
5.
Chem Biol Interact ; 348: 109637, 2021 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-34506765

RESUMEN

Both communicable and non-communicable chronic respiratory conditions have accorded for suffering of millions of people of all ages and stated to be leading cause of death, morbidity, economic and social pressures, and disability-adjusted life-years (DALYs) worldwide. These illnesses impair patient's health and negatively impacts families and society, particularly in low and middle-income countries. Chronic respiratory diseases (CRDs) affect different organs of respiratory system, involving airways, parenchyma, and pulmonary vasculature. As the number of respiratory diseases are exponentially escalating but still the stakeholders are not paying attention towards its serious complications. Currently, the treatment being used primarily focusses only on alleviating symptoms of these illness rather delivering the therapeutic agent at target site for optimal care and/or prevention. Lately, extensive research is being conducted on airways and systemic inflammation, oxidative stress, airway, or parenchymal rehabilitation. From which macrophages, neutrophils, and T cells, as well as structural cells as fibroblasts, epithelial, endothelial, and smooth muscle cells have been found to be active participants that are involved in these chronic respiratory diseases. The pathogenesis of all these chronic respiratory diseases gets caused differently via mediators and proteins, including cytokines, chemokines, growth factors and oxidants. Presently, the target of prescription therapies is to reduce the inflammation of airways and relieve the airway contraction. In all studies, cytokines have been found to play an imperative role in fostering chronic airway inflammation and remodelling. Owing to the limitations of conventional treatments, the current review aims to summarize the current knowledge about the chronic respiratory disease and discuss further about the various conventional methods that can be used for treating this ailment. Additionally, it also highlights and discusses about the advanced drug delivery system that are being used for targeting the interleukins for the treatment of CRDs.


Asunto(s)
Interleucinas/metabolismo , Terapia Molecular Dirigida/métodos , Nanomedicina/métodos , Enfermedades Respiratorias/tratamiento farmacológico , Enfermedad Crónica , Humanos
6.
Thorax ; 76(5): 508-511, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33273021

RESUMEN

COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis.


Asunto(s)
Senescencia Celular/fisiología , Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Proliferación Celular , Células Cultivadas , Daño del ADN , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Pulmón/metabolismo , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/patología
7.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L63-L72, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33084360

RESUMEN

Tobacco smoke has harmful effects on a multiorgan level. Exposure to smoke, whether in utero or environmental, significantly increases susceptibility. This susceptibility has been identified to be divergent between males and females. However, there remains a distinct lack of thorough research into the relationship between sex and exposure to tobacco. Females tend to generate a more significant response than males during adulthood exposure. The intrauterine environment is meticulously controlled, and exposure to tobacco presents a significant factor that contributes to poor health outcomes and susceptibility later in life. Analysis of these effects in relation to the sex of the offspring is yet to be holistically reviewed and summarized. In this review, we will delineate the time-dependent relationship between tobacco smoke exposure and sex-specific disease susceptibility. We further outline possible biological mechanisms that may contribute to the identified pattern.


Asunto(s)
Efectos Tardíos de la Exposición Prenatal/etiología , Contaminación por Humo de Tabaco/efectos adversos , Adulto , Femenino , Humanos , Masculino , Embarazo , Factores Sexuales
8.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L48-L60, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32460521

RESUMEN

Chronic obstructive pulmonary disease (COPD) is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO)-COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether this is also present in relatively young SEO-COPD patients is unknown. Therefore, we aimed to determine markers of aging in (SEO)-COPD-derived lung fibroblasts and investigate the impact on ECM. Aging hallmarks and ECM markers were analyzed in lung fibroblasts from SEO-COPD and older COPD patients and compared with fibroblasts from matched non-COPD groups (n = 9-11 per group), both at normal culture conditions and upon Paraquat-induced senescence. COPD-related differences in senescence and ECM expression were validated in lung tissue. Higher levels of cellular senescence, including senescence-associated ß-galactosidase (SA-ß-gal)-positive cells (19% for COPD vs. 13% for control) and p16 expression, DNA damage (γ-H2A.X-positive nuclei), and oxidative stress (MGST1) were detected in COPD compared with control-derived fibroblasts. Most effects were also different in SEO-COPD, with SA-ß-gal-positive cells only being significant in SEO-COPD vs. matched controls. Lower decorin expression in COPD-derived fibroblasts correlated with higher p16 expression, and this association was confirmed in lung tissue. Paraquat treatment induced cellular senescence along with clear changes in ECM expression, including decorin. Fibroblasts from COPD patients, including SEO-COPD, display higher levels of cellular senescence, DNA damage, and oxidative stress. The association between cellular senescence and ECM expression changes may suggest a link between accelerated aging and ECM dysregulation in COPD.


Asunto(s)
Senescencia Celular , Matriz Extracelular/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Adulto , Edad de Inicio , Biomarcadores/metabolismo , Células Cultivadas , Daño del ADN , Proteínas de Dominio Doblecortina , Femenino , Fibroblastos/patología , Regulación de la Expresión Génica , Humanos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Neuropéptidos/genética , Neuropéptidos/metabolismo , Estrés Oxidativo , Paraquat/toxicidad , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología
9.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1222-L1228, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32320267

RESUMEN

Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRMEmph) and small airway disease (PRMfSAD). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRMEmph in the lungs. One hundred thirty-three genes were identified to be associated with PRMEmph. Among the most significantly associated genes, CXCL11 is a potent chemokine involved with CD8+ T cell activation during inflammation in COPD, indicating that it may play an essential role in the development of emphysema. The PRMEmph signature was then replicated in two independent data sets. Pathway analysis showed that the PRMEmph signature is associated with proinflammatory and notch signaling pathways. Together these findings indicate that airway epithelium may play a role in the development of emphysema and/or may act as a biomarker for the presence of emphysema. In contrast, its role in relation to functional small airways disease is less clear.


Asunto(s)
Bronquios/diagnóstico por imagen , Bronquios/patología , Perfilación de la Expresión Génica , Procesamiento de Imagen Asistido por Computador , Enfisema Pulmonar/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano , Bronquios/fisiopatología , Femenino , Volumen Espiratorio Forzado , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/patología , Enfisema Pulmonar/fisiopatología
10.
J Heart Lung Transplant ; 37(9): 1111-1118, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30173825

RESUMEN

BACKGROUND: Lung transplantation provides a unique opportunity to investigate the dynamics of the human pulmonary virome that is transplanted within the donor lungs. The pulmonary virome comprises both "resident" and "transient" viruses. In this study we aimed to analyze the dynamics of the "transient" members. METHODS: We conducted a single-center, prospective, longitudinal investigation of community-acquired respiratory viruses detected in nasopharyngeal swabs, swabs of explanted and donor lungs, and serial bronchoalveolar lavages post-transplant. RESULTS: Fifty-two consecutive lung transplant recipients were recruited (bilateral:heart‒lung:bilateral lung-liver = 48:2:2) (age [mean ± SD] 48 ± 15 years, range 20 to 63 years; 27 males and 25 females). Follow-up was 344 ± 120 (range 186 to 534) days. Seventeen of 45 explanted lungs were positive for influenza A and/or B (A = 14, B = 2, A+B = 1), despite recipient vaccination and negative nasal swabs, and 4 of 45 had human rhinovirus and 2 of 45 parainfluenza. Donor swabs showed influenza (A = 1, B = 1) and rhinovirus (n = 3). Day 1 lavage showed influenza A (n = 28), rhinovirus (n = 9), and parainfluenza (n = 1). Forty-seven of 52 recipients had a positive lavage for virus (38 of 47 on multiple lavages). Influenza persisted for 59 ± 38 (range 4 to 147) days in 27 of 52, and 14 had a single isolate. Rhinovirus persisted for 95 ± 84 (range 22 to 174) days in 13 of 52, and 13 had a single isolate. Analysis of 118 paired transbronchial biopsies and lavage demonstrated no association between viruses and acute cellular rejection (Fisher's exact test, 2 tailed, p = 1.00). CONCLUSIONS: Using a sensitive uniplex polymerase chain reaction we found that the transplanted pulmonary virome often includes community-acquired respiratory viruses, including influenza, which are variably persistent but not associated with acute rejection.


Asunto(s)
Trasplante de Pulmón , Pulmón/virología , Neumonía Viral/cirugía , Neumonía Viral/virología , Adulto , Líquido del Lavado Bronquioalveolar/virología , Femenino , Estudios de Seguimiento , Trasplante de Corazón-Pulmón , Humanos , Gripe Humana/cirugía , Gripe Humana/virología , Trasplante de Hígado , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Donantes de Tejidos , Receptores de Trasplantes , Adulto Joven
11.
BMC Pulm Med ; 18(1): 84, 2018 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-29788952

RESUMEN

BACKGROUND: Bronchiectasis is a chronic respiratory condition. Persistent bacterial colonisation in the stable state with increased and sometimes altered bacterial burden during exacerbations are accepted as key features in the pathophysiology. The extent to which respiratory viruses are present during stable periods and in exacerbations is less well understood. METHODS: This study aimed to determine the incidence of respiratory viruses within a cohort of bronchiectasis patients with acute exacerbations at a teaching hospital and, separately, in a group of patients with stable bronchiectasis. In the group of stable patients, a panel of respiratory viruses were assayed for using real time quantitative PCR in respiratory secretions and exhaled breath. The Impact of virus detection on exacerbation rates and development of symptomatic infection was evaluated. RESULTS: Routine hospital-based viral PCR testing was only requested in 28% of admissions for an exacerbation. In our cohort of stable bronchiectasis patients, viruses were detected in 92% of patients during the winter season, and 33% of patients during the summer season. In the 2-month follow up period, 2 of 27 patients presented with an exacerbation. CONCLUSIONS: This pilot study demonstrated that respiratory viruses are commonly detected in patients with stable bronchiectasis. They are frequently detected during asymptomatic viral periods, and multiple viruses are often present concurrently.


Asunto(s)
Bronquiectasia/fisiopatología , Bronquiectasia/virología , Pulmón/fisiopatología , Pulmón/virología , Virosis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/virología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Retrospectivos , Estaciones del Año , Espirometría , Virosis/complicaciones , Virosis/diagnóstico , Virus/genética , Adulto Joven
12.
Artículo en Inglés | MEDLINE | ID: mdl-29541629

RESUMEN

Chronic rhinosinusitis (CRS) is an inflammatory condition that affects up to 12% of the human population in developed countries. Previous studies examining the potential role of the sinus bacterial microbiota within CRS infections have found inconsistent results, possibly because of inconsistencies in sampling strategies. The aim of this study was to determine whether the sinus microbiome is altered in CRS and additionally if the middle meatus is a suitable representative site for sampling the sinus microbiome. Swab samples were collected from 12 healthy controls and 21 CRS patients, including all eight sinuses for CRS patients and between one and five sinuses for control subjects. The left and right middle meatus and nostril swabs were also collected. Significant differences in the sinus microbiomes between CRS and control samples were revealed using high-throughput 16S rRNA gene sequencing. The genus Escherichia was over-represented in CRS sinuses, and associations between control patients and Corynebacterium and Dolosigranulum were also identified. Comparisons of the middle meatuses between groups did not reflect these differences, and the abundance of the genus Escherichia was significantly lower at this location. Additionally, intra-patient variation was lower between sinuses than between sinus and middle meatus, which together with the above results suggests that the middle meatus is not an effective representative sampling site.


Asunto(s)
Enfermedad Crónica , Disbiosis/microbiología , Microbiota/fisiología , Rinitis/microbiología , Sinusitis/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Biodiversidad , Carnobacteriaceae/clasificación , Carnobacteriaceae/aislamiento & purificación , ADN Bacteriano/aislamiento & purificación , Escherichia/clasificación , Escherichia/aislamiento & purificación , Humanos , Microbiota/genética , Cavidad Nasal/microbiología , Senos Paranasales/microbiología , ARN Ribosómico 16S/genética , Análisis de Secuencia
13.
J Drug Target ; 25(4): 342-349, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27822974

RESUMEN

The epithelial barrier in the respiratory system is a major obstacle for drug delivery to the systemic circulation in the lung. Epithelial barrier hinders the transport of large macromolecules or polar drugs. Essential components of this epithelial fence are physical intercellular structures termed tight junctions. Therefore, modulating tight junctions can enhance paracellular transport across epithelial barrier. In this study, the effect of some of non-specific tight junction modulators (TJMs); (Sodium (Na) decanoate, oleic acid and ethyleneglycol-bis-(ß-aminoethyl ether)-N, N'-tetraacetic acid (EGTA)) with established effect on intestinal tight junctions was evaluated for its effects on bronchial epithelial cells (Calu-3 cells). It was demonstrated that the effect of TJMs especially Na decanoate resulted in a reversible opening of tight junctions evidenced by the decrease in the transepithelial resistance. It was also demonstrated that this reduction of TEER upon exposing the epithelial cells to the TJMs resulted in a significant increase in Flu-Na (paracellular marker) and PXS25 (anti-fibrotic compound) transepithelial transport through this barrier. In conclusion, among the investigated non-specific TJMs, Na decanoate fulfilled the requirements of an effective, non-toxic and reversible tight junction modulator for Calu-3 lung epithelial cells.


Asunto(s)
Bronquios/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Uniones Estrechas/efectos de los fármacos , Transporte Biológico , Biomarcadores/metabolismo , Bronquios/citología , Línea Celular , Células Epiteliales/metabolismo , Humanos , Manosafosfatos/metabolismo
14.
Am J Respir Crit Care Med ; 194(12): 1458-1464, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27653942

RESUMEN

Despite the dominant role of community-acquired respiratory viruses as etiological agents of disease, there has been little focus to date on the translation of rapidly developing diagnostic modalities, such as next-generation sequencing techniques in the examination of lower respiratory tract samples. When applied, these techniques should inform strategies to both understand the nexus between health and disease states of the respiratory virome, and drive a paradigm shift in how the practicing pulmonologist views the conceptual framework of respiratory infections. The lower respiratory tract was once thought to be a sanctuary site from microbiological colonization owing to the efficacy of upper airway-protective mechanisms and the host mucosal barrier function of the lower airways, combined with both innate and adaptive immune responses. As a small number of recent studies confirm, this is a naive vision of the lung, the viral component of which parallels recent revelations from respiratory microbiome studies. Hence, it is now timely to revise our thinking regarding the constituents, diversity, and changing nature of the respiratory virome in health and disease. One area worthy of focus is the interface between community-acquired respiratory viruses and the respiratory virome to better understand the dynamics in acute infection, as well as the factors that may lead to viral persistence and chronic disease. Given recent advances in metagenomics, the tools are now at hand to accomplish these goals.


Asunto(s)
Microbiota/fisiología , Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/virología , Investigación Biomédica Traslacional/métodos , Humanos
15.
Respiration ; 92(1): 34-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27355358

RESUMEN

BACKGROUND: Transbronchial lung biopsy using a cryoprobe is a novel way of sampling lung parenchyma. Correlation of freezing time with biopsy size and complications has not been evaluated in vivo. OBJECTIVES: The primary aim of the study is to evaluate the correlation between transbronchial cryobiopsy freezing time and size. The secondary aims are to evaluate histological quality of the biopsy and evaluate procedure-associated complications. METHODS: Transbronchial lung cryobiopsies were obtained from two anaesthetised sheep using a 1.9-mm cryoprobe inserted into a flexible bronchoscope under fluoroscopic guidance. Freezing times ranged from 1 to 6 s (n = 49). The cryobiopsies were evaluated histologically with respect to their size and quality. Complications of bleeding and pneumothorax were recorded. RESULTS: The mean cross-sectional area of the cryobiopsy ranged from 4.7 ± 2.1 to 15.7 ± 15.3 mm2. There was a significant positive correlation between increasing freezing time and cryobiopsy cross-sectional area (p = 0.028). All biopsies contained lung tissue with preserved parenchyma. Crush and freeze artefacts were not observed and tissue architecture was intact in all specimens. Small blood vessels and terminal bronchioles were observed in 88% of specimens. All cryobiopsies caused nil or mild haemorrhage with the exception of only 1 episode of severe haemorrhage at 6 s freezing time. Pneumothoraces occurred at 2, 5 and 6 s freezing time and required chest tube insertion. The most significant haemorrhage and pneumothoraces occurred at 5 and 6 s. Our results suggest an initial freezing time of 3 s can provide the maximal biopsy size while minimising major complications. CONCLUSION: The optimal transbronchial cryobiopsy freezing time is initially 3 s. This time is associated with minimal complications and large artefact-free biopsies.


Asunto(s)
Broncoscopía/métodos , Congelación , Pulmón/patología , Animales , Biopsia/efectos adversos , Biopsia/métodos , Broncoscopía/efectos adversos , Ovinos , Factores de Tiempo
17.
Am J Physiol Lung Cell Mol Physiol ; 309(10): L1093-102, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26342086

RESUMEN

Altered ECM protein deposition is a feature in asthmatic airways. Fibronectin (Fn), an ECM protein produced by human bronchial epithelial cells (HBECs), is increased in asthmatic airways. This study investigated the regulation of Fn production in asthmatic or nonasthmatic HBECs and whether Fn modulated HBEC proliferation and inflammatory mediator secretion. The signaling pathways underlying transforming growth factor (TGF)-ß1-regulated Fn production were examined using specific inhibitors for ERK, JNK, p38 MAPK, phosphatidylinositol 3 kinase, and activin-like kinase 5 (ALK5). Asthmatic HBECs deposited higher levels of Fn in the ECM than nonasthmatic cells under basal conditions, whereas cells from the two groups had similar levels of Fn mRNA and soluble Fn. TGF-ß1 increased mRNA levels and ECM and soluble forms of Fn but decreased cell proliferation in both cells. The rate of increase in Fn mRNA was higher in nonasthmatic cells. However, the excessive amounts of ECM Fn deposited by asthmatic cells after TGF-ß1 stimulation persisted compared with nonasthmatic cells. Inhibition of ALK5 completely prevented TGF-ß1-induced Fn deposition. Importantly, ECM Fn increased HBEC proliferation and IL-6 release, decreased PGE2 secretion, but had no effect on VEGF release. Soluble Fn had no effect on cell proliferation and inflammatory mediator release. Asthmatic HBECs are intrinsically primed to produce more ECM Fn, which when deposited into the ECM, is capable of driving remodeling and inflammation. The increased airway Fn may be one of the key driving factors in the persistence of asthma and represents a novel, therapeutic target.


Asunto(s)
Asma/metabolismo , Células Epiteliales/metabolismo , Fibronectinas/metabolismo , Asma/patología , Bronquios/patología , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Fibronectinas/genética , Expresión Génica , Humanos , Mucosa Respiratoria/patología , Factor de Crecimiento Transformador beta1/fisiología
18.
Curr Drug Deliv ; 12(1): 9-15, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-24909291

RESUMEN

There is an enormous drive to refine therapeutic designs and delivery systems, but in this review we ask if this is always the right direction? We choose to play devil's advocate, and argue that refining drug design is not always needed, and what is actually needed is a greater understanding of the biology of the disease. Here we focus on asthma and the ß2-agonist group of bronchodilators as an example of how a class of therapeutic has been developed and continues to be developmentally refined. In this review, we define viral-induced exacerbations as the greatest cause of lung attacks and the most crucial time ß2-agonist therapy is needed. We explore the reasons why ß2-agonist therapy fails in patients with rhinovirus-induced exacerbations, and explain why further "engineered" ß2-agonist therapies are likely to continue to fail in this subset of asthmatic population. We justify our perspective by returning to the biology that underlies the cause of disease and highlight the need for "more research" into alternative therapies for this population of asthmatic patients.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Diseño de Fármacos , Pulmón/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/química , Animales , Antiasmáticos/efectos adversos , Antiasmáticos/química , Asma/diagnóstico , Asma/fisiopatología , Asma/virología , Broncodilatadores/efectos adversos , Broncodilatadores/química , Progresión de la Enfermedad , Humanos , Pulmón/fisiopatología , Pulmón/virología , Infecciones por Picornaviridae/virología , Infecciones del Sistema Respiratorio/virología , Rhinovirus/patogenicidad , Resultado del Tratamiento
19.
Eur Respir J ; 44(6): 1666-81, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25234802

RESUMEN

Asthma is a chronic inflammatory disease of the airways in which the majority of patients respond to treatment with corticosteroids and ß2-adrenoceptor agonists. Acute exacerbations of asthma substantially contribute to disease morbidity, mortality and healthcare costs, and are not restricted to patients who are not compliant with their treatment regimens. Given that respiratory viral infections are the principal cause of asthma exacerbations, this review article will explore the relationship between viral infections and asthma, and will put forward hypotheses as to why virus-induced exacerbations occur. Potential mechanisms that may explain why current therapeutics do not fully inhibit virus-induced exacerbations, for example, ß2-adrenergic desensitisation and corticosteroid insensitivity, are explored, as well as which aspects of virus-induced inflammation are likely to be attenuated by current therapy.


Asunto(s)
Asma/inmunología , Virosis/inmunología , Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/complicaciones , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Progresión de la Enfermedad , Humanos , Inflamación/inmunología , Infecciones del Sistema Respiratorio , Virosis/complicaciones
20.
Eur Respir J ; 44(3): 634-46, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24969654

RESUMEN

We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-ß1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD.


Asunto(s)
Bronquios/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/etiología , Fumar/efectos adversos , Remodelación de las Vías Aéreas (Respiratorias) , Línea Celular , Movimiento Celular , Supervivencia Celular , Colágeno Tipo VIII/metabolismo , Ensayo de Inmunoadsorción Enzimática , Matriz Extracelular/metabolismo , Fluoresceínas/química , Humanos , Inmunohistoquímica , Inflamación , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Sistema Respiratorio/efectos de los fármacos , Nicotiana/efectos adversos , Cloruro de Tolonio/química , Factor de Transcripción AP-1/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Cicatrización de Heridas
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