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Rationale: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. Objectives: Define high-risk COPD subtypes using both genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics. Methods: We defined high-risk groups based on PRS and TRS quantiles by maximizing differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. Measurements and Main Results: We examined two high-risk omics-defined groups in non-overlapping test sets (n=1,133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "High activity" (low PRS/high TRS) and "severe risk" (high PRS/high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signaling processes compared to a low-risk (low PRS, low TRS) reference subgroup. "High activity" but not "severe risk" participants had greater prospective FEV 1 decline (COPDGene: -51 mL/year; ECLIPSE: - 40 mL/year) and their proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Conclusions: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.
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Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).
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Fibrosis Pulmonar Idiopática , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Resultado del Tratamiento , Método Doble Ciego , Inmunoglobulina GAsunto(s)
Ensayos Clínicos como Asunto , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Aprobación de Drogas , Desarrollo de Medicamentos , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/fisiopatología , Indoles/uso terapéutico , Evaluación del Resultado de la Atención al Paciente , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Calidad de Vida , Nivel de Atención , Capacidad Vital , Prueba de PasoRESUMEN
Hypersensitivity pneumonitis (HP) is a diffuse granulomatous lung disease resulting from inhalation of an antigen to which an individual has been previously sensitized. Hot tub lung is an increasingly common form of HP associated with inhalation of water aerosols containing Mycobacterium avium complex organisms that contaminate hot tub water. Granulomatous lung disorders, most classically sarcoidosis, have been associated with unregulated 1-α-hydroxylase expression by macrophages present in the granulomas, causing conversion of 25-OH-vitamin D to the active form of vitamin D, 1,25(OH)2 vitamin D, and, thus, hypercalcemia. To our knowledge, this is the first confirmed case of hypercalcemia secondary to elevated 1,25(OH)2 vitamin D levels associated with HP.
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Alveolitis Alérgica Extrínseca/diagnóstico , Alveolitis Alérgica Extrínseca/etiología , Baños/efectos adversos , Hipercalcemia/etiología , Infección por Mycobacterium avium-intracellulare/diagnóstico , Infección por Mycobacterium avium-intracellulare/etiología , Microbiología del Agua , Anciano , Alveolitis Alérgica Extrínseca/sangre , Alveolitis Alérgica Extrínseca/tratamiento farmacológico , Biopsia con Aguja , Disnea/diagnóstico , Disnea/etiología , Calor , Humanos , Hipercalcemia/tratamiento farmacológico , Hipercalcemia/fisiopatología , Inmunohistoquímica , Masculino , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Prednisona/uso terapéutico , Radiografía Torácica/métodos , Enfermedades Raras , Medición de Riesgo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Vitamina D/sangreRESUMEN
Recognition and clearance of a bacterial infection are a fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases.
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Subgrupos de Linfocitos B/inmunología , Infecciones por Escherichia coli/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunidad Innata , Peritonitis/inmunología , Sepsis/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Linaje de la Célula , Separación Celular , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Inmunoglobulina M/metabolismo , Inmunofenotipificación , Integrina alfa4beta1/inmunología , Integrina alfa4beta1/metabolismo , Lipopolisacáridos , Activación de Linfocitos , Antígeno-1 Asociado a Función de Linfocito/inmunología , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Parabiosis , Choque Séptico/inmunología , Bazo/inmunología , Receptor Toll-Like 4/inmunologíaRESUMEN
RATIONALE: Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied. OBJECTIVE: This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia. METHODS AND RESULTS: Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2. CONCLUSIONS: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.
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Proteínas de Fase Aguda/metabolismo , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/cirugía , Escherichia coli/patogenicidad , Lipocalinas/metabolismo , Trasplante de Células Madre Mesenquimatosas , Proteínas Oncogénicas/metabolismo , Neumonía Bacteriana/microbiología , Proteínas de Fase Aguda/biosíntesis , Animales , Modelos Animales de Enfermedad , Lipocalina 2 , Lipocalinas/biosíntesis , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ratones Endogámicos C57BL , Proteínas Oncogénicas/biosíntesis , Neumonía Bacteriana/cirugía , Análisis de Supervivencia , Tráquea , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke-induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress-dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-kappaB (NF-kappaB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-kappaB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke-induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury.
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Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Enfisema Pulmonar/inducido químicamente , Fumar/efectos adversos , Factores de Transcripción/fisiología , Animales , Activación Enzimática , Homeostasis , Humanos , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Alveolos Pulmonares/efectos de los fármacos , Enfisema Pulmonar/genética , Serina-Treonina Quinasas TOR , Factores de Transcripción/genéticaRESUMEN
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.
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Adenocarcinoma/patología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Elastasa de Leucocito/metabolismo , Neoplasias Pulmonares/patología , Adenocarcinoma/metabolismo , Animales , Línea Celular , Humanos , Hidrólisis , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , RatonesRESUMEN
Theories of emphysema traditionally revolved around proteolytic destruction of extracellular matrix. Models have recently been developed that show airspace enlargement with the induction of pulmonary cell apoptosis. The purpose of this study was to determine the mechanism by which a model of epithelial cell apoptosis caused airspace enlargement. Mice were treated with either intratracheal microcystin (MC) to induce apoptosis, intratracheal porcine pancreatic elastase (PPE), or their respective vehicles. Mice from all groups were inflated and morphometry was measured at various time points. Physiology measurements were performed for airway resistance, tissue elastance, and lung volumes. The groups were further analyzed by air-saline quasistatic measurements, surfactant staining, and surfactant functional studies. Mice treated with MC showed evidence of reversible airspace enlargement. In contrast, PPE-treated mice showed irreversible airspace enlargement. The airspace enlargement in MC-treated mice was associated with an increase in elastic recoil due to an increase in alveolar surface tension. PPE-treated mice showed a loss of lung elastic recoil and normal alveolar surface tension, a pattern more consistent with human emphysema. Airspace enlargement that occurs with the MC model of pulmonary epithelial cell apoptosis displays physiology distinct from human emphysema. Reversibility, restrictive physiology due to changes in surface tension, and alveolar enlargement associated with heterogeneous alveolar collapse are most consistent with a mild acute lung injury. Inflation near total lung capacity gives the appearance of enlarged alveoli as neighboring collapsed alveoli exert tethering forces.
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Lesión Pulmonar Aguda/etiología , Apoptosis/fisiología , Células Epiteliales/patología , Alveolos Pulmonares/efectos de los fármacos , Enfisema Pulmonar/etiología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/diagnóstico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/fisiopatología , Resistencia de las Vías Respiratorias , Animales , Apoptosis/efectos de los fármacos , Diagnóstico Diferencial , Modelos Animales de Enfermedad , Elasticidad , Femenino , Inflamación/inducido químicamente , Inflamación/fisiopatología , Mediciones del Volumen Pulmonar , Ratones , Ratones Endogámicos C57BL , Microcistinas/toxicidad , Modelos Biológicos , Elastasa Pancreática/toxicidad , Alveolos Pulmonares/patología , Enfisema Pulmonar/diagnóstico , Surfactantes Pulmonares , Tensión Superficial , Capacidad Pulmonar TotalRESUMEN
Respiratory tract dendritic cells (DCs) are juxtaposed to directly sample inhaled environmental particles. Processing and presentation of these airborne Ags could result in either the development of immunity or tolerance. The purpose of this study was to determine the consequences of cigarette smoke exposure on DC function in mice. We demonstrate that while cigarette smoke exposure decreased the number of DCs in the lungs, Ag-induced DC migration to the regional thoracic lymph nodes was unaffected. However, cigarette smoking suppressed DC maturation within the lymph nodes as demonstrated by reduced cell surface expression of MHC class II and the costimulatory molecules CD80 and CD86. Consequently, DCs from cigarette smoke-exposed animals had a diminished capacity to induce IL-2 production by T cells that was associated with diminished Ag-specific T cell proliferation in vivo. Smoke-induced defects in DC function leading to impaired CD4(+) T cell function could inhibit tumor surveillance and predispose patients with chronic obstructive pulmonary disease to infections and exacerbations.