RESUMO
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.
Assuntos
Linfangioleiomiomatose , Proteína 2 do Complexo Esclerose Tuberosa , Esclerose Tuberosa , Proteínas Supressoras de Tumor , Animais , Humanos , Lactente , Camundongos , Células Endoteliais/metabolismo , Pulmão/metabolismo , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mesoderma/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Remodelação Vascular/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Técnicas In VitroRESUMO
The omnipresence of microplastics (MPs) in marine and terrestrial environments as a pollutant of concern is well established and widely discussed in the literature. However, studies on MP contamination in commercial food sources like salts from the terrestrial environment are scarce. Thus, this is the first study to investigate various varieties of Australian commercial salts (both terrestrial and marine salts) as a source of MPs in the human diet, and the first to detect MPs in black salt. Using Nile red dye, the MPs were detected and counted under light microscopy, further characterised using attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM-EDS). Of all the 90 suspected particles, 78.8% were identified as MPs with a size ranging between 23.2 µm and 3.9 mm. The fibres and fragments constituted 75.78% and 24.22% respectively. Among the tested samples, Himalayan pink salt (coarse) from terrestrial sources was found to have the highest MP load, i.e. 174.04 ± 25.05 (SD) particle/kg, followed by black salt at 157.41 ± 23.13 particle/kg. The average concentration of detected MPs in Australian commercial salts is 85.19 ± 63.04 (SD) per kg. Polyamide (33.8%) and polyurethane (30.98%) were the dominant MP types. Considering the maximum recommended (World Health Organization) salt uptake by adults daily at 5 g, we interpret that an average person living in Australia may be ingesting approximately 155.47 MPs/year from salt uptake. Overall, MP contamination was higher in terrestrial salts (such as black and Himalayan salt) than the marine salt. In conclusion, we highlight those commercial salts used in our daily lives serve as sources of MPs in the diet, with unknown effects on human health.
Assuntos
Microplásticos , Poluentes Químicos da Água , Humanos , Plásticos , Sais/química , Monitoramento Ambiental/métodos , Austrália , Cloreto de Sódio na Dieta/análise , Dieta , Poluentes Químicos da Água/análiseRESUMO
Workers in the mining and construction industries are at increased risk of respiratory and other diseases as a result of being exposed to harmful levels of airborne particulate matter (PM) for extended periods of time. While clear links have been established between PM exposure and the development of occupational lung disease, the mechanisms are still poorly understood. A greater understanding of how exposures to different levels and types of PM encountered in mining and construction workplaces affect pathophysiological processes in the airways and lungs and result in different forms of occupational lung disease is urgently required. Such information is needed to inform safe exposure limits and monitoring guidelines for different types of PM and development of biomarkers for earlier disease diagnosis. Suspended particles with a 50% cut-off aerodynamic diameter of 10â µm and 2.5â µm are considered biologically active owing to their ability to bypass the upper respiratory tract's defences and penetrate deep into the lung parenchyma, where they induce potentially irreversible damage, impair lung function and reduce the quality of life. Here we review the current understanding of occupational respiratory diseases, including coal worker pneumoconiosis and silicosis, and how PM exposure may affect pathophysiological responses in the airways and lungs. We also highlight the use of experimental models for better understanding these mechanisms of pathogenesis. We outline the urgency for revised dust control strategies, and the need for evidence-based identification of safe level exposures using clinical and experimental studies to better protect workers' health.
Assuntos
Pneumopatias , Doenças Profissionais , Exposição Ocupacional , Carvão Mineral/efeitos adversos , Poeira/análise , Humanos , Pulmão , Pneumopatias/induzido quimicamente , Pneumopatias/etiologia , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Qualidade de Vida , Dióxido de Silício/efeitos adversosRESUMO
Particulate matter (PM) is a complex mixture of solid particles and liquid droplets suspended in the air with varying size, shape, and chemical composition which intensifies significant concern due to severe health effects. Based on the well-established human health effects of outdoor PM, health-based standards for outdoor air have been promoted (e.g., the National Ambient Air Quality Standards formulated by the U.S.). Due to the exchange of indoor and outdoor air, the chemical composition of indoor particulate matter is related to the sources and components of outdoor PM. However, PM in the indoor environment has the potential to exceed outdoor PM levels. Indoor PM includes particles of outdoor origin that drift indoors and particles that originate from indoor activities, which include cooking, fireplaces, smoking, fuel combustion for heating, human activities, and burning incense. Indoor PM can be enriched with inorganic and organic contaminants, including toxic heavy metals and carcinogenic volatile organic compounds. As a potential health hazard, indoor exposure to PM has received increased attention in recent years because people spend most of their time indoors. In addition, as the quantity, quality, and scope of the research have expanded, it is necessary to conduct a systematic review of indoor PM. This review discusses the sources, pathways, characteristics, health effects, and exposure mitigation of indoor PM. Practical solutions and steps to reduce exposure to indoor PM are also discussed.