Occupational exposure to crystalline silica (CS) particles leads to silicosis, which is characterized by chronic inflammation and abnormal tissue repair. Alveolar macrophages (AMs) play a crucial role in the process of silicosis. Previously, we demonstrated positive effect of dioscin on silicosis through modulating macrophage-elicited innate immune response. However, the concrete molecular mechanism remains to be discovered.

The relationship between ambient air pollution exposure and mortality of cardiovascular and cerebrovascular diseases in human is controversial, and there is little information about how exposures to ambient air pollution contribution to the mortality of cardiovascular and cerebrovascular diseases among Chinese. The aim of the present study was to examine whether exposure to ambient-air pollution increases the risk for cardiovascular and cerebrovascular disease. We conducted a retrospective cohort study among humans to examine the association between compound-air pollutants [particulate matter <10 µm in aerodynamic diameter (PM₁₀), sulfur dioxide (SO₂) and nitrogen dioxide (NO₂)] and mortality in Shenyang, China, using 12 years of data (1998–2009). Also, stratified analysis by sex, age, education, and income was conducted for cardiovascular and cerebrovascular mortality. The results showed that an increase of 10 µg/m³ in a year average concentration of PM₁₀ corresponds to 55% increase in the risk of a death cardiovascular disease (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.51 to 1.60) and 49% increase in cerebrovascular disease (HR, 1.49; 95% CI, 1.45 to 1.53), respectively. The corresponding figures of adjusted HR (95%CI) for a 10 µg/m³ increase in NO₂ was 2.46 (2.31 to 2.63) for cardiovascular mortality and 2.44 (2.27 to 2.62) for cerebrovascular mortality, respectively. The effects of air pollution were more evident in female that in male, and nonsmokers and residents with BMI<18.5 were more vulnerable to outdoor air pollution. Long-term exposure to ambient air pollution is associated with the death of cardiovascular and cerebrovascular diseases among Chinese populations.

Silicosis is an occupational lung disease caused by inhalation of silica dust characterized by lung inflammation and fibrosis. Previous study showed that Th1 and Th2 cytokines are involved in silicosis, but Th1/Th2 polarization during the development of silicosis is still a matter of debate. Regulatory T cells (Treg cells) represent a crucial role in modulation of immune homeostasis by regulating Th1/Th2 polarization, but their possible implication in silicosis remains to be explored. To evaluate the implication of Treg cells in the development of silicosis, we generated the Treg-depleted mice model by administration of anti-CD25 mAbs and mice were exposed to silica by intratracheal instillation to establish experimental model of silica-induced lung fibrosis. The pathologic examinations show that the Treg-depleted mice are susceptive to severer inflammation in the early stage, with enhanced infiltration of inflammatory cells. Also, depletion of Treg cells causes a delay of the progress of silica-induced lung fibrosis in mice model. Further study of mRNA expression of cytokines reveals that depletion of Tregs leads to the increased production of Th1-cytokines and decreased production of Th2-cytokine. The Flow Cytometry and realtime PCR study show that Treg cells exert the modulation function both directly by expressing CTLA-4 at the inflammatory stage, and indirectly by secreting increasing amount of IL-10 and TGF-β during the fibrotic stage in silica-induced lung fibrosis. Our study suggests that depletion of Tregs may attenuate the progress of silica-induced lung fibrosis and enhance Th1 response and decelerate Th1/Th2 balance toward a Th2 phenotype in silica-induced lung fibrosis. The regulatory function of Treg cells may depend on direct mechanism and indirect mechanism during the inflammatory stage of silicosis.

Inhalation of crystalline silica particles leads to pulmonary fibrosis, eventually resulting in respiratory failure and death. There are few effective drugs that can delay the progression of this disease; thus, patients with silicosis are usually only offered supportive care. Dioscin, a steroidal saponin, exhibits many biological activities and health benefits including its protective effects against hepatic fibrosis. However, the effect of dioscin on silicosis is unknown.

Silicosis is pneumoconiosis of the lung, usually resulting from prolonged exposure to crystalline silica (CS). The hallmark of silicosis is excessive extracellular matrix (ECM) deposition produced by activated fibroblasts. Recent work demonstrated that excessive ECM-forming mechanical cues play an essential role in promoting fibroblast activation and perpetuating fibrotic pathologies. However, the detailed molecular mechanism still needs to be uncovered. Methods: NIH-3T3 fibroblasts were cultured on either 1 kappa (soft) or 60 kappa (stiff) gel-coated coverslips. A series of knockdown and reverse experiments in vitro were performed to establish the signaling for mechanics-induced fibroblast activation. An experimental model of silicosis was established by one-time intratracheal instillation of CS suspension. The cluster of differentiation 44 (CD44) antibody (IM7), dihydrotanshinone I (DHI) and verteporfin (VP) were used to explore the effect of CD44-RhoA-YAP signaling blockade on mechanics-induced fibroblast activation and CS-induced pulmonary fibrosis. Results: Matrix stiffness could induce nuclear translocation of the Yes-associated protein (YAP) through CD44 in fibroblasts. This effect required RhoA activity and F-actin cytoskeleton polymerization but was independent of Hippo pathway kinases, Mst 1 and Lats 1, forming CD44-RhoA-YAP signaling pathway. Pharmacological upstream blocking by CD44 antibody or downstream blockade of YAP by DHI or VP could attenuate fibroblast migration, invasion, proliferation, and collagen deposition. Furthermore, CD44-RhoA-YAP signaling blockade could alleviate CS-induced fibrosis and improve pulmonary function in vivo. Conclusion: CD44-RhoA-YAP signaling mediates mechanics-induced fibroblast activation. Targeting this pathway could ameliorate crystalline silica-induced silicosis and provide a potential therapeutic strategy to mitigate fibrosis.

Background: In China, both the levels and patterns of outdoor air pollution have altered dramatically with the rapid economic development and urbanization over the past two decades. However, few studies have investigated the association of outdoor air pollution with respiratory mortality, especially in the high pollution range. Objective: We conducted a retrospective cohort study of 9,941 residents aged ≥35 years old in Shenyang, China, to examine the association between outdoor air pollutants [particulate matter <10 µm in aerodynamic diameter (PM₁₀), sulfur dioxide (SO₂) and nitrogen dioxide (NO₂)] and mortality using 12 years of data. Methods: We applied extended Cox proportional hazards modeling with time-dependent covariates to respiratory mortality. Analyses were also stratified by age, sex, educational level, smoking status, personal income, occupational exposure and body mass index (BMI) to examine the association of air pollution with mortality. Results: We found significant associations between PM₁₀ and NO₂ levels and respiratory disease mortality. Our analysis found a relative risk of 1.67 [95% confidence interval (CI) 1.60–1.74] and 2.97 (95% CI 2.69–3.27) for respiratory mortality per 10 µg/m³ increase in PM₁₀ and NO₂, respectively. The effects of air pollution were more apparent in women than in men. Age, sex, educational level, smoking status, personal income, occupational exposure, BMI and exercise frequency influenced the relationship between outdoor PM₁₀ and NO₂ and mortality. For SO₂, only smoking, little regular exercise and BMI above 18.5 influenced the relationship with mortality. Conclusion: These data contribute to the scientific literature on the long-term effects of air pollution for the high-exposure settings typical in developing countries.