Loss of ZNF451 mediates fibroblast activation and promotes lung fibrosis.

BACKGROUND: No effective therapies for pulmonary fibrosis (PF) exist because of the unclear molecular pathogenesis and the lack of effective therapeutic targets. Zinc finger protein 451 (ZNF451), a transcriptional regulator, plays crucial roles in the pathogenesis of several diseases. However, its expression pattern and function in PF remain unknown. This study was designed to investigate the role of ZNF451 in the pathogenesis of lung fibrosis. METHODS: GEO dataset analysis, RT‒PCR, and immunoblot assays were used to examine the expression of ZNF451 in PF; ZNF451 knockout mice and ZNF451-overexpressing lentivirus were used to determine the importance of ZNF451 in PF progression; and migration assays, immunofluorescence staining, and RNA-seq analysis were used for mechanistic studies. RESULTS: ZNF451 is downregulated and negatively associated with disease severity in PF. Compared with wild-type (WT) mice, ZNF451 knockout mice exhibited much more serious PF changes. However, ZNF451 overexpression protects mice from BLM-induced pulmonary fibrosis. Mechanistically, ZNF451 downregulation triggers fibroblast activation by increasing the expression of PDGFB and subsequently activating PI3K/Akt signaling. CONCLUSION: These findings uncover a critical role of ZNF451 in PF progression and introduce a novel regulatory mechanism of ZNF451 in fibroblast activation. Our study suggests that ZNF451 serves as a potential therapeutic target for PF and that strategies aimed at increasing ZNF451 expression may be promising therapeutic approaches for PF.

Prevalence and prognostic value of malnutrition in patients with IPF using three scoring systems.

BACKGROUND: To describe the nutritional status of IPF patients, report clinical associations and evaluate the prognostic value of them in IPF. METHODS: 264 IPF patients diagnosed with IPF at the Second Xiangya Hospital of Central South University between January 2011 and January 2021 were recruited. Three different scoring systems, including nutritional risk index (NRI), controlling nutritional status (CONUT) score, and prognostic nutritional index (PNI) were used to describe the nutritional status of IPF patients. RESULT: This study investigated the prevalence of malnutrition in 264 IPF patients, of which the percentage with malnutrition varied from 37.5 % with the NRI, to 47.4 % with the CONUT score, and to 6.4 % with the PNI. The moderate to severe malnutrition ranged from 10.2 % to 31.1 % across these indices, with PNI identifying only 4.9 % in this category. Worsening malnutrition status was associated with significantly higher incidence of all-cause mortality and IPF death regard of the malnutrition index as NRI (p < 0.05). When the normal nutrition of NRI was used as a reference, patients in the moderate to severe risk remained at a higher risk of all-cause death (HR = 2.06(1.25-3.41)) and IPF death(HR = 2.36(1.35-4.15)). The adjusted multivariate analysis, identified age(HR = 1.13(1.08-1.20)), DLCO <60, % predicted (HR = 3.31(1,24-9.42)) and the use of anti-fibrotic drugs (HR = 0.25(0.10-0.60)) as independent predictors of mortality. CONCLUSIONS: Malnutrition is common among patients with IPF and the baseline as diagnosis of IPF is strongly related to increased mortality.

The prognostic role of high-density lipoprotein cholesterol/C- reactive protein ratio in idiopathic pulmonary fibrosis.

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF) patients is highly heterogeneous. Abnormalities in lipids and their metabolism play an important role in the development of IPF. AIM: To investigate the value of lipid parameters, C-reactive protein (CRP), and high-density lipoprotein cholesterol/C-reactive protein (HDL-C/CRP) ratio levels in the prognosis of IPF patients. DESIGN: An observational cohort study. METHODS: We collected baseline data of non-IPF controls and IPF patients, and IPF patients were followed up for 4 years. All-cause death or lung transplantation and IPF-related death were the outcome events. Receiver operating characteristic (ROC) curves and Cox proportional hazards models were used to analyze the predictive effect of lipid parameters, CRP and HDL-C/CRP ratio on the prognosis of IPF patients. RESULTS: IPF patients had lower HDL-C, HDL-C/CRP ratio and higher CRP compared to non-IPF controls. IPF patients who died or underwent lung transplantation were older and had worse pulmonary function, lower HDL-C, HDL-C/CRP ratio and higher CRP compared with surviving patients. HDL-C/CRP ratio was better than HDL-C and CRP in predicting all-cause death or lung transplantation. IPF patients with low HDL-C/CRP ratio had shorter survival times. HDL-C/CRP ratio and DLCO% of predicted were independent protective factors for all-cause death or lung transplantation and IPF-related death in IPF patients, while age and GAP stage ≥ 2 (HR = 4.927)were independent risk factors for all-cause death or lung transplantation. Age > 65 years (HR = 3.533) was an independent risk factor for IPF-related death. CONCLUSIONS: HDL-C/CRP ratio was a valid predictor of clinical outcomes in IPF patients, including all-cause death or lung transplantation and IPF-related death.