Coal Workers’ Pneumoconiosis (CWP) is the primary occupational disease in China. However, information about the definite prevalence of CWP is only partially available. The aims of our study were to assess the prevalence characteristics of CWP in a state-owned coal mine, evaluate the effects of control measures and develop further preventive strategies for CWP. The total study population included 495 cases who were diagnosed with CWP from the construction of this coal mine to the end of October 2014. Individuals’ information, including duration of dust exposure, job titles, age as first diagnosis, stages of CWP, CWP progress, complications with pulmonary tuberculosis, death and others were collected and analyzed. The results showed that 71.11% of 495 CWP cases were stage I and 90.71% were involved in tunneling or coal mining. The mean dust exposure period in CWP patients was 26.7 years, the mean latent period was 29.3 years and the mean diagnosed age was 50.3 years old. The proportion of CWP diagnosed after ending dust exposure were remarkably increased with the time passing. Among the CWP cases, 36 (7.27%) were complicated with pulmonary tuberculosis. The mortality of patients with stage III was the highest (60.71%) (p < 0.0001). Our data obviously show that more strict policies to protect coal miners are needed to be implemented in China, especially for tunneling and mining workers.

The interleukin 17A (IL-17A) which is located on chromosome 6p and has been linked to chronic inflammation, is an important candidate gene conferring coal workers’ pneumoconiosis (CWP). The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL-17A and CWP in a Chinese population. We conducted a case–control study to investigate the role of four common SNPs in the IL-17A gene, and evaluated the relationship between these four SNPs and dust-exposure year, tobacco smoking and stages of CWP. A total of 1391 subjects was enrolled in this study, including 694 subjects in control group and 697 in case group. TaqMan based qRT-PCRs were taken to genotype rs2275913, rs3748067, rs4711998, and rs8193036 within the IL-17A gene. Luciferase assays were used to determine the effects of rs8193036 C > T alleles on the expression of IL-17A. Unconditional logistic regression analysis showed that the genotypes of rs3748067 AA (adjusted OR = 0.43, 95 % CI = 0.23–0.83) and rs8193036 TT (adjusted OR = 0.59, 95 % CI = 0.40–0.86) were associated with a decreased risk of CWP, particularly among subgroups of smokers (adjusted OR =0.34, 95 % CI = 0.13–0.86 for rs3748076; adjusted OR = 0.41, 95 % CI = 0.23–0.71 for 8193036) and CWP cases with stage I (adjusted OR = 0.45, 95 % CI = 0.21–0.98 for rs3748076; adjusted OR = 0.46, 95 % CI = 0.28–0.74 for 8193036). Furthermore, the polymorphism of rs3748067 significantly reduced the CWP risk among cases with over 27 years of dust exposure (adjusted OR = 0.42, 95 % CI = 0.18–0.97). The luciferase assays in two cell lines showed that the rs8193036 C > T substitution could reduce the expression of IL-17A, which was consistent with the findings of our association study. The rs3748067 G > A and rs8193036 C > T polymorphisms decrease CWP risk. These findings could be helpful in identifying individuals at decreased risk for CWP and further studies are warranted to validate them.

Coal workers’ pneumoconiosis (CWP) has been associated with abnormalities in the extracellular matrix remodeling, as well as aberrant matrix metalloproteinases (MMPs) in lung tissues. We investigated the association of three functional polymorphisms in MMP gene promoters (MMP1 rs1799750, MMP2 rs2285053 and MMP3 rs522616) with the risk of CWP. A total of 693 CWP cases and 690 controls were included in a case-control study. Genotype analysis was performed by the TaqMan method. Statistically significant differences were found in distributions of MMP3 rs522616 under a recessive model (p = 0.047) between CWP cases and controls. In the stratification analysis, individuals with MMP3 rs522616 GG genotype decreased the risk of CWP (adjusted OR = 0.72, 95% CI = 0.52–0.99) compared to those with AA/AG genotype obviously, particularly among subgroups of no smokers (adjusted OR = 0.64, 95% CI = 0.41–1.00). Furthermore, serum MMP3 protein levels measured with enzyme-linked immune-sorbent assay in the control group was significantly lower than that in the CWP groups (p = 0.02). Extremely lower MMP3 among subjects with the rs522616 GG or AG genotype compared with the AA genotype carriers (p < 0.05, p < 0.01 respectively) in the normal serum. These findings indicate that the MMP3 rs522616 polymorphism may contribute to the etiology of CWP in the Chinese population and MMP3 might be a potential diagnostic biomarker for CWP, additional independent studies are warranted to validate our findings in different populations as well as in a larger series.

Objectives: Susceptibility loci of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were also significantly associated with the predisposition of coal worker’s pneumoconiosis (CWP) in recent studies. However, only a few genes and loci were targeted in previous studies.Methods: To systematically evaluate the genetic associations between CWP and other respiratory traits, we reviewed the reported genome-wide association study loci of five respiratory traits and then conducted a Mendelian randomisation study and a two-stage genetic association study.Results: Interestingly, we found that for each SD unit, higher lung function was associated with a 66% lower risk of CWP (OR=0.34, 95% CI: 0.15 to 0.77, p=0.010) using conventional Mendelian randomisation analysis (inverse variance weighted method). Moreover, we found susceptibility loci of interstitial lung disease (rs2609255, OR=1.29, p=1.61×10⁻⁴) and lung function (rs4651005, OR=1.39, p=1.62×10⁻³; rs985256, OR=0.73, p=8.24×10⁻⁴ and rs6539952, OR=1.28, p=4.32×10⁻⁴) were also significantly associated with the risk of CWP. Functional annotation showed these variants were significantly associated with the expression of FAM13A (rs2609255, p=7.4 ×10⁻⁴), ANGPTL1 (rs4651005, p=5.4 ×10⁻⁷), SPATS2L (rs985256, p=1.1 ×10⁻⁵) and RP11-463O9.9 (rs6539952, p=7.1 ×10⁻⁶) in normal lung tissues, which were related to autophagy pathway simultaneously according to enrichment analysis.Conclusions: These results provided a deeper understanding of the genetic predisposition basis of CWP.

Silicosis is a chronic fibrotic pulmonary disease caused by consistent inhalation of respirable crystalline-free silica dust. The senescence of alveolar epithelial type II cells (ATII) is considered the initiation of pulmonary fibrosis. As a secreted protein, growth differentiation factor 15 (GDF15) was found intimately associated with the severity of lung diseases via senescence. Therefore, we speculate that GDF15 may involved in silica-induced pulmonary fibrosis. Co-culture was performed to observe the pro-fibrotic effect of GDF15, which is secreted from the silica-induced senescence ATII cells, on peripheral effector cells. We further explored GDF15-related signaling pathways via ChIP and IP assays. GDF15 siRNA lipid nanoparticles, anti-aging compound β-nicotinamide mononucleotide (NMN), and the Chinese traditional drug Bazibushen (BZBS) were used individually to intervene silicosis progress. SiO₂ and etoposide-stimulated MLE-12 cells showed senescence phenotype and secreted substantial GDF15, which is consistent with over-expressed GDF15 in lung tissues from silica-induced pulmonary fibrosis. The results further demonstrated that senescence ATII cells could facilitate co-cultured epithelial cell epithelial-mesenchymal transition (EMT) and fibroblast activation in a GDF15-dependent manner. Mechanistically, p53 regulates GDF15 transcription and secretion in senescence ATII cells. Moreover, secreted GFD15 performed its pro-fibrotic role by directly binding to TGF-βR via autocrine and paracrine manners. Also, lipid nanoparticles targeting GDF15 or cell senescence inhibitor NMN and BZBS showed efficient anti-fibrotic effects in vivo. Our results elucidate that senescence ATII cell-secreted GDF15 plays a vital role in promoting silicosis by influencing surrounding cells, and provides scientific clues for the selection of potential therapeutic drugs for silicosis.