Pneumoconiosis

BackgroundGlobally, silicosis accounts for 90% of all pneumoconiosis cases and is a serious public health issue. It is characterized by progressive inflammation and irreversible pulmonary fibrosis. A comprehensive analysis at temporal, spatial and population levels with the most updated data from GBD 2019 is provided in this study to estimate the disease burden of silicosis from 1990 to 2019 and make predictions to 2029.MethodsWe delineated silicosis data on incidence, prevalence, and disability-adjusted life years (DALYs) as well as age-standardized rates (ASRs) across 30 years from GBD 2019. Joinpoint regression analysis was employed to detect temporal changes and estimate annual percentage change (APC) of each trend segment. Measures were stratified by time, location, age, and sociodemographic index (SDI). Back propagation artificial neural network (BP-ANN) model was applied to elaborate ASR trends from 1990 to 2019 and projections to the next 10 years.ResultsGlobally, silicosis incident, prevalent cases, and DALYs increased by 64.6%, 91.4%, and 20.8%, respectively. However, all the corresponding ASRs showed overall downward trends with an estimated average APC (AAPC) of -0.5(-0.7 to -0.3), -0.2(-0.5 to 0.0), and - 2.0(-2.2 to -1.8), respectively. Middle and high-middle SDI regions carried the heaviest disease burden. The highest disease burden of silicosis was mainly transferred to the older from 1990 to 2019. The trend of ASRs demonstrated a rapid decline between 2005 and 2019, followed by a continuous decline until 2029.ConclusionThough disease burden of silicosis has been on a decline in general from 1990 to 2019, which shows a promising prospect but cannot be ignored. We should pay more attention to implementing preventive tactics and improving the life quality of present sufferers.

Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1hiMacs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7)-acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)-cardiolipin (CL) signaling pathway, which interferes with Spp1hiMac differentiation. We demonstrated that in SiO2-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

Silicosis is a progressive and life-threatening fibrotic lung disease caused by crystalline silica. However, targeted therapies remain unavailable due to its incompletely understood pathogenic mechanisms. Here, we identify ferritin as a pivotal mediator of silica-induced pulmonary fibrosis by integrating clinical exploration with experimental validation. We detected persistently elevated ferritin levels in lung tissues and serum from silicosis patients and silica-exposed mice, and demonstrated that exogenous ferritin administration exacerbates fibrosis in vivo. Multi-omics profiling and co-culture experiments revealed that macrophage-secreted ferritin promotes fibroblast-to-myofibroblast differentiation and pathological extracellular matrix (ECM) deposition via the PIK3R2/SMAD signaling axis. Importantly, genetic knockdown of ferritin in macrophages significantly suppressed myofibroblast differentiation and collagen accumulation both in vivo and in vitro. These findings underscore that ferritin functions not only as a potential clinical biomarker for silicosis surveillance but also as a pathogenic driver through macrophage-fibroblast crosstalk, and provide a theoretical foundation for developing integrated diagnostic and therapeutic strategies against silicosis.