Background: Iron-catalyzed oxidative stress contributes to lung injury after exposure to various toxins, including cigarette smoke. An oxidant/antioxidant imbalance is considered to play a critical role in the pathogenesis of COPD. Ferritin is a key protein in iron homeostasis, and its capacity to oxidize and sequester the metal preventing iron prooxidant activity implicates its possible role in the alteration of antioxidant imbalance. We investigated the relationship among cigarette smoking, lung function, and serum ferritin concentration in a large cohort representative of the Korean adult population. Materials and methods: Among 50,405 participants of the Korean National Health and Nutrition Examination Survey from 2010 to 2014, 15,239 adult subjects older than 40 years with serum ferritin levels and spirometric data were selected for this study.
Results: The mean age was 56.5 years for men (43%) and 56.9 years for women (57%). The prevalence of airway obstruction was 13.4%, which was significantly higher in men than in women, and increased in former or current smokers. The median levels of serum ferritin were highest in the airway obstruction group, followed by the restrictive pattern group, and lowest in the normal lung function group. The median ferritin levels were increased by smoking status and amounts in each spirometric subgroup. In multivariable regression analysis, serum ferritin was positively associated with forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity, whereas the smoking amount was negatively associated with the adjustment with age, sex, height, and weight. Conclusion: Serum ferritin levels were increased in former or current smokers and were increased with smoking amount in all subgroups of participants categorized according to spirometric results. The result was also evident in the subgroups divided by obstructive severity. While smoking amount was inversely related to lung function, higher levels of serum ferritin were associated with enhanced spirometric results in a representative sample of the general Korean adult population. Future prospective studies will be needed to clarify the causality between serum ferritin and lung functions and their role in COPD morbidity.

Introduction: Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results regarding lung function. Therefore, we investigated the association between lung function and HDL-C levels in three cross-sectional studies conducted in the USA and South Korea. Methods: US National Health and Nutrition Examination Survey (NHANES) III, US NHANES 2007–2012, and Korea National Health and Nutrition Examination Survey (KNHANES) IV–VII performed spirometry and met the American Thoracic Society recommendations. Multiple linear regression models were used to determine the relationship between serum lipid levels and lung function. The models were adjusted for age, sex, household income, body mass index, smoking pack year, use of lipid-lowering medication and race. Serum HDL-C levels were classified into three groups to assess the dose–response relationship according to the guideline from the National Cholesterol Education Program-Adult Treatment Panel III. Results: The adult participants of the KNHANES (n=31 288), NHANES III (n=12 182) and NHANES 2007–2012 (n=9122) were analysed. Multivariate linear regression analysis of the serum cholesterol profiles revealed that only serum HDL-C was associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) in all three studies. A 1 SD increase in the HDL-C level increased the percent predicted FVC by 0.5%–1.5% p, and the per cent predicted FEV₁ by 0.5%–1.7% p. In terms of HDL-C levels, correlations between the HDL-C groups and the per cent predicted FVC and FEV₁ showed dose–response relationships. Compared with the normal group, high HDL-C levels increased FVC by 0.75%–1.79% p and FEV₁ by 0.55%–1.90% p, while low levels led to 0.74%–2.19% p and 0.86%–2.68% p reductions in FVC and FEV₁, respectively. Subgroup analyses revealed weaker associations in females from KNHANES and NHANES III. Conclusion: In the three nationwide cross-sectional studies, high HDL-C levels were associated with improved FVC and FEV₁. However, future studies are needed to confirm this correlation and elucidate the underlying mechanisms.

Background: We previously identified ezetimibe, an inhibitor of Niemann–Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis.Methods: Primary lung fibroblasts isolated from both humans and mice were employed for mechanisticin vitroexperiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examinein vivoefficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe.Results: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1–autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline.Conclusion: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.

Park Y, et al. Yonsei Med J. 2022 Jan;63(Suppl):S1-S13. https://doi.org/10.3349/ymj.2022.63.S1

So KH, et al. Nutr Res Pract. 2015 Aug;9(4):439-444. https://doi.org/10.4162/nrp.2015.9.4.439

Purpose Cholesterol regulation is essential to maintain pulmonary homeostasis. Studies suggest that increased high-density lipoprotein cholesterol (HDL-C) levels correlate with better lung function. However, the longitudinal association of HDL-C with lung function remains unknown. We aimed to analyze the long-term correlation of HDL-C with lung function decline in a population-based cohort study. Methods We included 7,652 participants from a prospective community-based cohort study in South Korea. Participants were categorized into five trajectory groups based on repeated HDL-C measurements. Generalized linear mixed models with random intercepts and slopes were used to examine the longitudinal relationship between HDL-C levels and lung function decline within these groups. Results In the five HDL-C trajectory group analyses, the very low HDL-C trajectory group (Group 1) showed faster declines in forced vital capacity (FVC) (−3.1 mL/year) and forced expiratory volume in one second (FEV₁) (−3.1 mL/year) than the middle HDL-C group (Group 3, the reference group) did. The low HDL-C trajectory group (Group 2) also exhibited faster FVC (−1.5 mL/year) and FEV₁ (−1.7 mL/year) declines than the middle HDL-C group; however, the estimated difference was smaller than that in Group 1. Faster lung function decline in the low HDL-C trajectory group was consistently observed even when the population was analyzed using three- or four-HDL-C trajectory groups instead of five. Conclusion Participants in the low HDL-C trajectory groups experienced a more rapid lung function decline over time than the reference groups, suggesting a negative longitudinal association between HDL-C and lung function decline.