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1.
Sci Rep ; 11(1): 23205, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34853380

RESUMEN

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Tratamiento Farmacológico de COVID-19 , Hidroxicloroquina/efectos adversos , Enfermedades Pulmonares/patología , Metaloproteinasa 9 de la Matriz/metabolismo , SARS-CoV-2/efectos de los fármacos , Carga Viral , Adenosina Monofosfato/efectos adversos , Anciano , Alanina/efectos adversos , Formación de Anticuerpos , Antimaláricos/efectos adversos , Antivirales/efectos adversos , Antivirales/uso terapéutico , COVID-19/virología , Femenino , Hospitalización , Humanos , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/virología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
2.
Cells ; 10(12)2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34944053

RESUMEN

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.


Asunto(s)
Enfermedades Pulmonares/enzimología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Alveolitis Alérgica Extrínseca/complicaciones , Activación Enzimática , Humanos , Pulmón/metabolismo , Pulmón/patología , Enfermedades Pulmonares/patología , Linfangioleiomiomatosis/complicaciones , Linfangioleiomiomatosis/patología , Países Bajos , Fosforilación , Sarcoidosis/complicaciones , Sarcoidosis/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Vasculitis/complicaciones
3.
Int J Mol Sci ; 22(23)2021 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-34884674

RESUMEN

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.


Asunto(s)
Enfermedades por Almacenamiento Lisosomal/inmunología , Esfingomielina Fosfodiesterasa/deficiencia , Animales , Terapia de Reemplazo Enzimático , Humanos , Enfermedades Pulmonares/enzimología , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/terapia , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/inmunología
4.
J Cell Physiol ; 236(3): 1628-1637, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32780450

RESUMEN

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a subtype of the NOX family, which is mainly expressed in the pulmonary vasculature and pulmonary endothelial cells in the respiratory system. NOX4 has unique characteristics, and is a constitutively active enzyme that primarily produces hydrogen peroxide. The signaling pathways associated with NOX4 are complicated. Negative and positive feedback play significant roles in regulating NOX4 expression. The role of NOX4 is controversial because NOX4 plays a protective or damaging role in different respiratory diseases. This review summarizes the structure, enzymatic properties, regulation, and signaling pathways of NOX4. This review then introduces the roles of NOX4 in different diseases in the respiratory system, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis.


Asunto(s)
Enfermedades Pulmonares/enzimología , NADPH Oxidasa 4/metabolismo , Animales , Humanos , Enfermedades Pulmonares/patología , Modelos Biológicos , Transducción de Señal
5.
Curr Opin Pharmacol ; 51: 50-58, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32836013

RESUMEN

Asthma is an obstructive inflammatory airway disease. Airway obstruction is mediated by hyperresponsive airway smooth muscle cell contraction, which is induced and compounded by inflammation caused by T lymphocytes. One important signal transduction pathway that is involved in the activation of these cell types involves the generation of a lipid second messenger known as diacylglycerol (DAG). DAG levels are controlled in cells by a negative regulator known as DAG kinase (DGK). In this review, we discuss how the DAG signaling pathway attenuates the pathological function of immune cells and airway smooth muscle cells in allergic airway disease and asthma. Furthermore, we discuss how the enhancement of the DAG signaling pathway through the inhibition of DGK may represent a novel therapeutic strategy for these diseases.


Asunto(s)
Diacilglicerol Quinasa/metabolismo , Hipersensibilidad/enzimología , Enfermedades Pulmonares/enzimología , Miocitos del Músculo Liso/enzimología , Linfocitos T/enzimología , Animales , Antiasmáticos/administración & dosificación , Diacilglicerol Quinasa/inmunología , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/inmunología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
6.
Nat Nanotechnol ; 15(9): 792-800, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32690884

RESUMEN

Human breath contains many volatile metabolites. However, few breath tests are currently used in the clinic to monitor disease due to bottlenecks in biomarker identification. Here we engineered breath biomarkers for respiratory disease by local delivery of protease-sensing nanoparticles to the lungs. The nanosensors shed volatile reporters upon cleavage by neutrophil elastase, an inflammation-associated protease with elevated activity in lung diseases such as bacterial infection and alpha-1 antitrypsin deficiency. After intrapulmonary delivery into mouse models with acute lung inflammation, the volatile reporters are released and expelled in breath at levels detectable by mass spectrometry. These breath signals can identify diseased mice with high sensitivity as early as 10 min after nanosensor administration. Using these nanosensors, we performed serial breath tests to monitor dynamic changes in neutrophil elastase activity during lung infection and to assess the efficacy of a protease inhibitor therapy targeting neutrophil elastase for the treatment of alpha-1 antitrypsin deficiency.


Asunto(s)
Biomarcadores/análisis , Pruebas Respiratorias/métodos , Elastasa de Leucocito/metabolismo , Deficiencia de alfa 1-Antitripsina/enzimología , Animales , Pruebas Respiratorias/instrumentación , Simulación por Computador , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Femenino , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Elastasa de Leucocito/antagonistas & inhibidores , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/microbiología , Espectrometría de Masas , Ratones Endogámicos , Ratones Noqueados , Nanoestructuras/química , Polietilenglicoles/química , Infecciones por Pseudomonas/enzimología , Sulfonamidas/farmacología , Compuestos Orgánicos Volátiles/análisis , Compuestos Orgánicos Volátiles/química , Compuestos Orgánicos Volátiles/metabolismo , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/genética
7.
Eur Respir Rev ; 29(156)2020 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-32350087

RESUMEN

Chitotriosidase (CHIT1) is a highly conserved and regulated chitinase secreted by activated macrophages; it is a member of the 18-glycosylase family (GH18). CHIT1 is the most prominent chitinase in humans, can cleave chitin and participates in the body's immune response and is associated with inflammation, infection, tissue damage and remodelling processes. Recently, CHIT1 has been reported to be involved in the molecular pathogenesis of pulmonary fibrosis, bronchial asthma, COPD and pulmonary infections, shedding new light on the role of these proteins in lung pathophysiology. The potential roles of CHIT1 in lung diseases are reviewed in this article.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Hexosaminidasas/metabolismo , Enfermedades Pulmonares/enzimología , Pulmón/enzimología , Animales , Humanos , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Transducción de Señal
8.
Virchows Arch ; 477(4): 557-563, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32270298

RESUMEN

Surfactant protein B (SP-B) is a key component of pulmonary surfactant. SP-B is processed to a mature, surface-active protein from a pro-peptide by two distinct cleavage events in its N-terminal and C-terminal regions. Napsin A, a protease expressed in type II pneumocytes, is responsible for the N-terminal cleavage event. Here, for the first time, we have evaluated the expression of Napsin A in normal fetal lungs at different gestational ages and in lungs from fetuses and neonates with congenital and acquired pathological pulmonary conditions. Lung samples were collected from fetal and neonatal autopsies at the Department of Medicine and Surgery's Pathology Unit of Parma University (Italy). Immunohistochemical analysis was performed using a primary anti-Napsin A (clone IP64 clone) monoclonal antibody. A section of lung adenocarcinoma was used as an external positive control. Napsin A was expressed early in normal fetal lungs throughout the epithelium of the distal pseudoglandular tracts. In fetuses at 30 weeks of gestation and term newborns, Napsin A was already expressed only in isolated cells within the alveolar epithelium, similar to adult subjects. Furthermore, increased expression of Napsin A compared with a control group was observed in lung tissue from fetuses and a newborn with pathological conditions (inflammatory diseases and pulmonary hypoplasia). In conclusion, this study demonstrates that Napsin A is produced early in fetal life, and that its production is increased in many diseases, presumably in an effort to remedy functional pulmonary failure.


Asunto(s)
Células Epiteliales Alveolares/enzimología , Ácido Aspártico Endopeptidasas/análisis , Inmunohistoquímica , Enfermedades Pulmonares/enzimología , Pulmón/enzimología , Autopsia , Biomarcadores/análisis , Edad Gestacional , Humanos , Recién Nacido , Pulmón/anomalías , Enfermedades Pulmonares/congénito , Enfermedades Pulmonares/mortalidad , Valor Predictivo de las Pruebas , Regulación hacia Arriba
9.
Mol Genet Metab ; 130(1): 16-26, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32088119

RESUMEN

Acid Sphingomyelinase Deficiency (ASMD), or Niemann-Pick type A/B disease, is a rare lipid storage disorder leading to accumulation of sphingomyelin and its precursors primarily in macrophages. The disease has a broad phenotypic spectrum ranging from a fatal infantile form with severe neurological involvement (the infantile neurovisceral type) to a primarily visceral form with different degrees of pulmonary, liver, spleen and skeletal involvement (the chronic visceral type). With the upcoming possibility of treatment with enzyme replacement therapy, the need for biomarkers that predict or reflect disease progression has increased. Biomarkers should be validated for their use as surrogate markers of clinically relevant endpoints. In this review, clinically important endpoints as well as biochemical and imaging markers of ASMD are discussed and potential new biomarkers are identified. We suggest as the most promising biomarkers that may function as surrogate endpoints in the future: diffusion capacity measured by spirometry, spleen volume, platelet count, low-density lipoprotein cholesterol, liver fibrosis measured with a fibroscan, lysosphingomyelin and walked distance in six minutes. Currently, no biomarkers have been validated. Several plasma markers of lipid-laden cells, fibrosis or inflammation are of high potential as biomarkers and deserve further study. Based upon current guidelines for biomarkers, recommendations for the validation process are provided.


Asunto(s)
Enfermedad de Niemann-Pick Tipo A/sangre , Enfermedad de Niemann-Pick Tipo A/diagnóstico por imagen , Enfermedad de Niemann-Pick Tipo B/sangre , Enfermedad de Niemann-Pick Tipo B/diagnóstico por imagen , Esfingolípidos/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Enfermedades Óseas/inmunología , Enfermedades Óseas/metabolismo , Enfermedades Cardiovasculares/sangre , LDL-Colesterol/sangre , Humanos , Hepatopatías/sangre , Hepatopatías/diagnóstico por imagen , Hepatopatías/enzimología , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/metabolismo , Macrófagos/enzimología , Macrófagos/inmunología , Macrófagos/metabolismo , Enfermedad de Niemann-Pick Tipo A/fisiopatología , Enfermedad de Niemann-Pick Tipo B/fisiopatología , Bazo/diagnóstico por imagen , Bazo/crecimiento & desarrollo , Bazo/patología
10.
Expert Opin Ther Pat ; 29(7): 555-578, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31204543

RESUMEN

INTRODUCTION: Human neutrophil elastase (HNE) is involved in a variety of serious chronic diseases, especially cardiopulmonary pathologies. For this reason, the regulation of HNE activity represents a promising therapeutic approach, which is evident by the development of a number of new and selective HNE inhibitors, both in the academic and pharmaceutical environments. AREAS COVERED: The present review analyzes and summarizes the patent literature regarding human neutrophil elastase inhibitors for the treatment of cardiopulmonary diseases over 2014-2018. EXPERT OPINION: HNE is an interesting and defined target to treat various inflammatory diseases, including a number of cardiopulmonary pathologies. The research in this field is quite active, and a number of HNE inhibitors are currently in various stages of clinical development. In addition, new opportunities for HNE inhibitor development stem from recent studies demonstrating the involvement of HNE in many other inflammatory pathologies, including rheumatoid arthritis, inflammatory bowel disease, skin diseases, and cancer. Furthermore, the development of dual HNE/proteinase 3 inhibitors is being pursued as an innovative approach for the treatment of neutrophilic inflammatory diseases. Thus, these new developments will likely stimulate new and increased interest in this important therapeutic target and for the development of novel and selective HNE inhibitors.


Asunto(s)
Desarrollo de Medicamentos/métodos , Elastasa de Leucocito/efectos de los fármacos , Proteínas Inhibidoras de Proteinasas Secretoras/farmacología , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/fisiopatología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Elastasa de Leucocito/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/fisiopatología , Patentes como Asunto
11.
Exp Lung Res ; 45(5-6): 135-150, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31190576

RESUMEN

Abrin, a highly toxic plant protein found in the seeds of Abrus precatorius plant. To date, there is no antidote against abrin intoxication. Abrin is toxic by all routes of exposure, but inhalation exposure is the most toxic of all routes. Present study was conducted to evaluate the acute inhalation toxicity of aerosolized abrin in BALB/c mice. Animals were exposed to 0.2 and 0.8LC50 doses of aerosolized abrin and evaluated at 1 and 3 day post toxin exposure. Bronchoalveolar fluid from lungs was used for evaluation of markers for lung injury. Abrin inhalation exposure caused rise in LDH activity, protein content, increase in ß-glucuronidase and myeloperoxidase activity. Increase in CRP activity, MMP-9 expression and recruitment of CD11b + inflammatory cells in lungs was also observed which was associated with severe inflammation and lung damage. Histopathological findings support the lung damage after abrin exposure. Our results indicate lung injury after single aerosol inhalation exposure, associated with excessive inflammation, oxidative stress, pulmonary edema followed by lung damage. These results could supplement treatment strategies and planning for therapeutic approaches against aerosolized abrin inhalation exposure.


Asunto(s)
Abrina/toxicidad , Exposición por Inhalación/efectos adversos , Enfermedades Pulmonares/inducido químicamente , Pulmón/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar/química , Proteína C-Reactiva/metabolismo , Antígeno CD11b/metabolismo , Catalasa/metabolismo , Glucuronidasa/metabolismo , Glutatión/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Pulmón/enzimología , Pulmón/inmunología , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/inmunología , Ratones Endogámicos BALB C , Activación Neutrófila , Peroxidasa/metabolismo
12.
Pharmacol Ther ; 197: 225-242, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30759374

RESUMEN

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, affect millions of people all over the world. Cyclic adenosine monophosphate (cAMP) which is one of the most important second messengers, plays a vital role in relaxing airway smooth muscles and suppressing inflammation. Given its vast role in regulating intracellular responses, cAMP provides an attractive pharmaceutical target in the treatment of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and help control cyclic nucleotide signals in a compartmentalized manner. Currently, the selective PDE4 inhibitor, roflumilast, is used as an add-on treatment for patients with severe COPD associated with bronchitis and a history of frequent exacerbations. In addition, other novel PDE inhibitors are in different phases of clinical trials. The current review provides an overview of the regulation of various PDEs and the potential application of selective PDE inhibitors in the treatment of COPD and asthma. The possibility to combine various PDE inhibitors as a way to increase their therapeutic effectiveness is also emphasized.


Asunto(s)
Enfermedades Pulmonares/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Humanos , Enfermedades Pulmonares/enzimología
13.
Respir Res ; 19(1): 180, 2018 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-30236095

RESUMEN

Chronic Obstructive Pulmonary Disease (COPD) is a common, multifactorial lung disease which results in significant impairment of patients' health and a large impact on society and health care burden. It is believed to be the result of prolonged, destructive neutrophilic inflammation which results in progressive damage to lung structures. During this process, large quantities of neutrophil serine proteinases (NSPs) are released which initiate the damage and contribute towards driving a persistent inflammatory state.Neutrophil elastase has long been considered the key NSP involved in the pathophysiology of COPD. However, in recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response.This review summarises what is presently known about PR3, explores its involvement particularly in the development of COPD, and indicates areas requiring further investigation.


Asunto(s)
Sistemas de Liberación de Medicamentos , Mieloblastina/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Antiinflamatorios/administración & dosificación , Enfermedad Crónica , Sistemas de Liberación de Medicamentos/tendencias , Inhibidores Enzimáticos/administración & dosificación , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/enzimología , Mieloblastina/antagonistas & inhibidores , Mieloblastina/química , Estructura Secundaria de Proteína
14.
Eur J Anaesthesiol ; 35(9): 702-709, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29957706

RESUMEN

BACKGROUND: Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE: To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. SETTING: Operating rooms of six hospitals in Europe and USA. DESIGN: Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS: Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS: Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES: We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. RESULTS: In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml; P < 0.001), IL-6 (2.3 [1.5 to 4.0] vs. 4.0 [2.9 to 6.5] pg ml; P < 0.001) and IL-8 (4.7 [3.1 to 8.1] vs. 8.1 [6.0 to 13.9] pg ml; P < 0.001). Phenotype 2 patients had the highest incidence of PPC (69.8 vs. 34.2% in type 1; P < 0.001). There was no interaction between phenotype and PEEP level for the development of PPCs (43.2% in high PEEP vs. 25.6% in low PEEP in phenotype 1, and 73.6% in high PEEP and 65.7% in low PEEP in phenotype 2; P for interaction = 0.503). CONCLUSION: Patients at risk of PPCs and undergoing open abdominal surgery can be clustered based on pre-operative plasma biomarker concentrations. The two identified phenotypes have different incidences of PPCs. Biologic phenotyping could be useful in future randomised controlled trials of intra-operative ventilation. TRIAL REGISTRATION: The PROtective Ventilation with HIgh or LOw PEEP trial, including the substudy from which data were used for the present analysis, was registered at ClinicalTrials.gov (NCT01441791).


Asunto(s)
Mediadores de Inflamación/sangre , Enfermedades Pulmonares/sangre , Fenotipo , Respiración con Presión Positiva/tendencias , Complicaciones Posoperatorias/sangre , Cuidados Preoperatorios/tendencias , Anciano , Biomarcadores/sangre , Análisis por Conglomerados , Femenino , Humanos , Internacionalidad , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/enzimología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Cuidados Preoperatorios/métodos
15.
Biol Chem ; 399(9): 959-971, 2018 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-29604204

RESUMEN

Human tissue kallikreins (KLKs) are 15 members of the serine protease family and are present in various healthy human tissues including airway tissues. Multiple studies have revealed their crucial role in the pathophysiology of a number of chronic, infectious and tumour lung diseases. KLK1, 3 and 14 are involved in asthma pathogenesis, and KLK1 could be also associated with the exacerbation of this inflammatory disease caused by rhinovirus. KLK5 was demonstrated as an influenza virus activating protease in humans, and KLK1 and 12 could also be involved in the activation and spread of these viruses. KLKs are associated with lung cancer, with up- or downregulation of expression depending on the KLK, cancer subtype, stage of tumour and also the microenvironment. Functional studies showed that KLK12 is a potent pro-angiogenic factor. Moreover, KLK6 promotes malignant-cell proliferation and KLK13 invasiveness. In contrast, KLK8 and KLK10 reduce proliferation and invasion of malignant cells. Considering the involvement of KLKs in various physiological and pathological processes, KLKs appear to be potential biomarkers and therapeutic targets for lung diseases.


Asunto(s)
Calicreínas/metabolismo , Enfermedades Pulmonares/enzimología , Proliferación Celular , Humanos , Enfermedades Pulmonares/patología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología
16.
Eur Respir Rev ; 26(146)2017 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-29070579

RESUMEN

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) play a fundamental role in the embryonic development of the lung. Aberrant PDGF signalling has been documented convincingly in a large variety of pulmonary diseases, including idiopathic pulmonary arterial hypertension, lung cancer and lung fibrosis. Targeting PDGF signalling has been proven to be effective in these diseases. In clinical practice, the most effective way to block PDGF signalling is to inhibit the activity of the intracellular PDGFR kinases. Although the mechanism of action of such drugs is not specific for PDGF signalling, the medications have a broad therapeutic index that allows clinical use. The safety profile and therapeutic opportunities of these and future medications that target PDGFs and PDGFRs are reviewed.


Asunto(s)
Enfermedades Pulmonares/tratamiento farmacológico , Pulmón/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Humanos , Pulmón/enzimología , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Terapia Molecular Dirigida , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
17.
Physiol Genomics ; 49(11): 682-689, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28939643

RESUMEN

G protein-coupled receptor kinase-6 (GRK6) is a serine/threonine kinase that is important in inflammatory processes. In this study, we examined the role of GRK6 in Escherichia coli-induced lung infection and inflammation using GRK6 knockout (KO) and wild-type (WT) mice. Intratracheal instillation of E. coli significantly enhanced bacterial load in the bronchoalveolar lavage (BAL) of KO compared with WT mice. Reduced bacterial clearance in the KO mice was not due to an intrinsic defect in neutrophil phagocytosis or killing but as a result of reduced neutrophil numbers in the KO BAL. Interestingly, neutrophil numbers in the lung were increased in the KO compared with WT mice, suggesting a potential dysfunction in transepithelial migration of neutrophils from the lungs to the bronchoalveolar space. This effect was selective for lung tissue because peritoneal neutrophil numbers were similar between the two genotypes following peritoneal infection. Although neutrophil expression of CXCR2/CXCR3 was similar between WT and KO, IL-17A expression was higher in the KO compared with WT mice. These results suggest that enhanced neutrophil count in the KO lungs but reduced numbers in BAL are likely due to transepithelial migration defect and/or altered chemokines/cytokines. Together, our studies suggest a previously unrecognized and novel role for GRK6 in neutrophil migration specific to pulmonary tissue during bacterial infection.


Asunto(s)
Infecciones por Escherichia coli/enzimología , Infecciones por Escherichia coli/microbiología , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/microbiología , Animales , Apoptosis/genética , Carga Bacteriana , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/patología , Regulación de la Expresión Génica , Inflamación/genética , Inflamación/patología , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Viabilidad Microbiana , Neutrófilos/metabolismo , Fagocitosis , Receptores de Quimiocina/metabolismo
18.
J Med Chem ; 60(10): 4403-4423, 2017 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-28471663

RESUMEN

LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-molecule LOXL2 inhibitor to enter clinical development.


Asunto(s)
Aminoácido Oxidorreductasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piridinas/química , Piridinas/farmacología , Administración Oral , Aminoácido Oxidorreductasas/metabolismo , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Fibrosis , Halogenación , Humanos , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/patología , Masculino , Metilación , Ratones Endogámicos C57BL , Modelos Moleculares , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Relación Estructura-Actividad
19.
Chest ; 152(2): 249-262, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28442313

RESUMEN

In many respiratory diseases characterized by an intense inflammatory response, the balance between proteolytic enzymes (proteases, including elastases) and their inhibitors (proteinases inhibitors) is not neutral. Excess activity of neutrophil elastase (NE) and similar proteases has been reported to cause tissue damage and to alter the remodeling process in many clinical conditions such as pneumonia, respiratory distress, and acute lung injury (ALI). Several experimental NE inhibitors have been tested in preclinical and clinical studies of different conditions of inflammatory lung injury such as ALI and pneumonia, with contrasting results. This study reviews the literature regarding NE inhibitors in the field of respiratory diseases and reflects on possible future developments. In particular, we highlight potential gaps in the scientific evidence and discuss potential strategies for focusing investigation on antielastases in clinical practice through the selection of targeted populations and proper outcomes.


Asunto(s)
Enfermedades Pulmonares/tratamiento farmacológico , Proteínas Inhibidoras de Proteinasas Secretoras/farmacología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/enzimología , Animales , Bronquiectasia/tratamiento farmacológico , Bronquiectasia/enzimología , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/enzimología , Modelos Animales de Enfermedad , Humanos , Elastasa de Leucocito/fisiología , Enfermedades Pulmonares/enzimología , Proteínas Inhibidoras de Proteinasas Secretoras/fisiología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/enzimología
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