RESUMO
OBJECTIVE: The aim of this study is to assess the impact of Liver X receptors (LXRs) on airway inflammation, airway remodeling, and lipid deposition induced by cigarette smoke and lipopolysaccharide (LPS) exposure in the lung. METHODS: Wild mice and LXR-deficient mice were exposed to cigarette smoke and LPS to induce airway inflammation and remodeling. In addition, some wild mice received intraperitoneal treatment with the LXR agonist GW3965 before exposure to cigarette smoke and LPS. Lung tissue and bronchoalveolar lavage fluid were collected to evaluate airway inflammation, airway remodeling and lipid deposition. RESULTS: Exposure to cigarette smoke and LPS resulted in airway inflammation, emphysema and lipid accumulation in wild mice. These mice also exhibited downregulated LXRα and ABCA1 in the lung. Treatment with GW3965 mitigated inflammation, remodeling and lipid deposition, while the deletion of LXRs exacerbated these effects. Furthermore, GW3965 treatment following exposure to cigarette smoke and LPS increased LXRα and ABCA1 expression and attenuated MyD88 expression in wild mice. CONCLUSION: LXRs demonstrate the potential to mitigate cigarette smoke and LPS- induced airway inflammation, emphysema and lipid disposition in mice.
Assuntos
Benzoatos , Benzilaminas , Fumar Cigarros , Enfisema , Enfisema Pulmonar , Animais , Camundongos , Remodelação das Vias Aéreas , Líquido da Lavagem Broncoalveolar , Fumar Cigarros/efeitos adversos , Enfisema/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Receptores X do Fígado/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Lipofibroblasts form a sub-population of fibroblasts located in the mesenchymal alveolar stem cell niche. They show close proximity with alveolar epithelial type 2 cells and play a key role in alveolar development and lung homeostasis. Their role in various diseases such as acute respiratory distress syndrome, pulmonary fibrosis and emphysema is progressively better understood. Through the activation of signaling pathways such as PPARg lipofibroblasts may help to induce endogenous alveolar regeneration.
Assuntos
Enfisema , Enfisema Pulmonar , Adulto , Humanos , Alvéolos Pulmonares , Pulmão/fisiologia , Enfisema/metabolismo , Regeneração/fisiologiaRESUMO
Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.
Assuntos
Enfisema , Enfisema Pulmonar , Transdução de Sinais , Animais , Humanos , Camundongos , Células Epiteliais Alveolares/metabolismo , Enfisema/metabolismo , Pulmão/metabolismo , Enfisema Pulmonar/genética , Transdução de Sinais/fisiologia , Proteína Smad1/genética , Proteína Smad1/metabolismoRESUMO
Objetivo: Investigar si los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) con un mismo grado de limitación ventilatoria, pero diferente fenotipo clínico, presentan diferencias en el grado de respuesta inflamatoria pulmonar y/o sistémica. Pacientes y métodos: Se estudió a 15 varones fumadores sin EPOC (grupo control) y a 39 varones con EPOC en situación clínica estable. Usando la relación factor de transferencia de monóxido de carbono/volumen alveolar (TLCO/VA%), se dividió a los pacientes con EPOC en 2 grupos: a) EPOC de predominio enfisema (EPOC-A; n = 15), y b) EPOC de predominio bronquitis crónica (EPOC-B; n = 24). La correcta clasificación de los pacientes se confirmó analizando aspectos clínicos y técnicas de imagen. Resultados: Las concentraciones medias ± DE de interleucina-8 (IL-8) y de 8-isoprostano en el condensado de aire exhalado (CAE) fueron significativamente menores (p < 0,05 para la IL-8 y p < 0,01 para el 8-isoprostano) en los pacientes con predominio enfisematoso (IL-8: 0,34 ± 0,70 pg/ml; 8-isoprostano: 0,07 ± 0,26 pg/ml) que en los pacientes con bronquitis crónica (IL-8: 2,32 ± 3,10 pg/ml; 8-isoprostano: 1,77 ± 2,98 pg/ml) o que en los controles (IL-8: 3,14 ± 4,59 pg/ml; 8-isoprostano: 1,92 ± 2,84 pg/ml). Los valores de IL-8, leucotrieno B4 y 8-isoprostano en el CAE se relacionaron significativamente con los valores de TLCO/VA% (r = 0,30, p < 0,05; r = 0,29, p ≤ 0,05, y r = 0,46; p < 0,01, respectivamente), pero no con el volumen espiratorio forzado en el primer segundo. Existió una relación negativa entre los valores de IL-8 (r = -0,31; p < 0,05) y 8-isoprostano (r = -0,51; p < 0,001) en suero y CAE. Sin embargo, esta correlación no fue significativa para el leucotrieno B4. No se observaron diferencias significativas entre fumadores activos y ex fumadores para IL-8, leucotrieno B4 y 8-isoprostano en suero y CAE. Conclusiones: Los resultados de este estudio indican que en pacientes con EPOC la presencia de un fenotipo enfisematoso se acompaña de una menor respuesta inflamatoria y menor estrés oxidativo en el pulmón
Objective: To study whether patients with chronic obstructive pulmonary disease (COPD) at the same level of flow limitation but with different clinical phenotypes present different degrees of systemic and/or pulmonary inflammation. Patients and methods: We studied 15 male smokers without COPD (control group) and 39 males with COPD in stable clinical condition. The COPD patients were assigned to 2 groups based on the ratio of carbon monoxide diffusing capacity (DLCO) to alveolar volume (DLCO/VA) expressed as a percentage as follows: a) mainly emphysema (n=15) and b) mainly chronic bronchitis (n=24). Classification was determined by comparing both clinical features and diagnostic images. Results: Mean (SD) concentrations of interleukin 8 (IL-8) and 8-isoprostane in exhaled breath condensate (EBC) were significantly lower in patients with mainly emphysema (IL-8, 0.34 [0.70] pg/mL; 8-isoprostane, 0.07 [0.26] pg/mL) than in patients with chronic bronchitis (IL-8, 2.32 [3.10] pg/mL; 8-isoprostane, 1.77 [2.98] pg/mL) or in the controls (IL-8, 3.14 [4.59] pg/mL; 8-isoprostane, 1.92 [2.84] pg/mL); P<.05 for IL-8 comparisons and P<.01 for 8-isoprostane. IL-8, leukotriene B4, and 8-isoprostano in EBC correlated significantly with DLCO/VA (% of predicted) (r=0.30, P<.05; r=0.29, P≤.05; and r=0.46, P<.01, respectively) but not with forced expiratory volume in 1 second. There was a negative correlation between EBC and serum levels of both IL-8 (r=-0.31; P<.05) and 8-isoprostane (r=-0.51; P<.001). The correlation between leukotriene B4 concentrations in EBC and serum was not significant, however. No significant differences were found between smokers' and ex-smokers' serum levels of IL-8, leukotriene B4, 8-isoprostane in serum or EBC. Conclusions: The results indicate that COPD patients with an emphysematous phenotype have a less intense inflammatory response and less oxidative stress in the lung