Objective To identify new potential drug targets for idiopathic pulmonary fibrosis (IPF) in order to improve the current situation where there are very few effective treatments for IPF. Methods This study integrates protein quantitative trait loci (pQTL) data from the deCODE cohort and the Atherosclerosis Risk in Communities (ARIC) study, expression quantitative trait loci (eQTL) data of whole blood from the GTEx-V8 and eQTLGen databases, and genome-wide association study (GWAS) data of IPF, and employs a multi-dimensional genetic epidemiology approach for analysis. Specifically, it includes: assessing the causal relationship between protein levels and IPF risk using two-sample Mendelian randomization (MR) methods; examining the potential associations between gene expression and IPF using summary-data-based Mendelian randomization (SMR) analysis; and determining the sharing of genetic variants between pQTL/eQTL and GWAS signals using Bayesian colocalization analysis. On this basis, a protein-protein interaction (PPI) network was further constructed, and target druggability assessment and potential drug prediction were performed to evaluate the biological significance and therapeutic potential of candidate targets. Results This study identified two proteins significantly associated with IPF: BRSK2 (β=1.222 7, P=1.12×10–10) and AP2A2 (β=2.854 3, P=1.22×10–7). The analysis suggests that these two proteins may participate in the occurrence and progression of IPF by affecting the balance of lung tissue injury and repair or by modulating fibrosis-related signaling pathways, and increased levels of both BRSK2 and AP2A2 proteins were significantly associated with an increased risk of IPF. Further Bayesian colocalization analysis indicated that AP2A2 shares genetic variant loci with IPF, with posterior probabilities of PPH0=1.49×10–11, PPH1=7.6×10–5, PPH2=1.99×10–10, PPH3=1.33×10–5, and PPH4=0.999 9, suggesting a high degree of genetic signal concordance between them. For external validation, analyses based on the ARIC and UK Biobank databases further supported a potential causal association between BRSK2 and IPF, showing that genetic variants leading to increased BRSK2 protein levels also increased the risk of developing IPF (P=0.004). Conclusions At the protein and gene expression levels, this study provides genetic evidence supporting a potential causal association of AP2A2 and BRSK2 with IPF. These proteins may participate in the pathogenesis and progression of IPF by influencing the balance of lung tissue injury and repair or fibrosis-related signaling pathways. They may also serve as potential therapeutic targets for IPF. However, their specific mechanisms of action require further elucidation.
Objective To investigate the effect of heme oxygenase-1 (HO-1) activity on rat liver transplantation model. Methods One hundred and thirty-seven rats were divided into 4 groups. Study control group (n＝44)： 24 h before operation, saline 5 ml/kg was infused into peritoneal cavity of donor rats; Hemin group (n＝44)： hemin 100 mg/kg was infused into peritoneal cavity of donor rats 24 h before operation, and hemin 100 mg/kg was infused into portal vein during the preserve time in 4 ℃ saline； ZnPP group (n＝44)： ZnPP 5 mg/kg was infused into peritoneal cavity of donor rats 24 h before operation, and ZnPP 5 mg/kg was infused into portal vein during the preserve time in 4 ℃ saline； Normal control group (n＝5)： normal rats as normal control group. Expressions of HO-1 protein and mRNA were detected with immunohistochemistry and RT-PCR technique respectively. The apoptosis rate of hepatocytes was analyzed by flow cytometry. Results Expression of HO-1 mRNA in the liver of hemin group after transplantation was higher than that in study control group obviously, serum ALT and AST levels were lower than those in study control group (P＜0.05); HO-1 mRNA expression in ZnPP group liver was lower than that in study control group, serum ALT and AST levels were higher than those in study control group (P＜0.05). About liver cell apoptosis rate 48 h after liver transplantation, ZnPP group was the highest, hemin group was the minimum, and there had a significant difference between two groups (P＜0.05). Seven days after transplantation, the survival ratios of control study group, hemin group and ZnPP group were 7/12, 9/12 and 4/12 in turn, the inter-group differences had statistical significance (P＜0.05). Conclusion Activity of HO-1 could be induced by the transplant operation. HO-1 increases the survival rate after liver transplantation which was related with reducing apoptotic ratio of hepatocyte and improve hepatic function.