Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions

Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis

Amisha V. Barochia, Maryann Kaler, Nargues Weir, Elizabeth M. Gordon, Debbie M. Figueroa, Xianglan Yao, Merte Lemma WoldeHanna, Maureen Sampson, Alan T. Remaley, Geraldine Grant, Scott D. Barnett, Steven D. Nathan, Stewart J. Levine
European Respiratory Journal 2021 58: 2004053; DOI: 10.1183/13993003.04053-2020
Amisha V. Barochia
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Amisha V. Barochia
  • For correspondence: barochiaav@nhlbi.nih.gov
Maryann Kaler
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nargues Weir
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
2Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth M. Gordon
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Debbie M. Figueroa
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xianglan Yao
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Xianglan Yao
Merte Lemma WoldeHanna
2Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maureen Sampson
3Clinical Center, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan T. Remaley
4Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geraldine Grant
5Dept of Biology, George Mason University, Manassas, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Scott D. Barnett
2Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven D. Nathan
2Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stewart J. Levine
1Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stewart J. Levine
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Background Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF.

Methods Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses.

Results Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLPNMR) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLPNMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLPNMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-μmol·L−1 increase in S-HDLPNMR, p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects.

Conclusions Higher serum levels of S-HDLPNMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLPNMR may modify mortality risk in patients with IPF.

Abstract

This is the first study showing that higher serum levels of small HDL particles correlate with a lower risk of death or lung transplantation in patients with idiopathic pulmonary fibrosis, suggesting that they may be important in IPF pathobiology https://bit.ly/2RG4UGS

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease, characterised by fibrosis within the lung parenchyma leading to lung function decline, with an incidence of 2.8–18 per 100 000 persons per year in Europe and North America [1]. The pathogenesis of IPF reflects complex host–environment interactions with a maladaptive reparative response to alveolar epithelial injury causing fibroblast activation and proliferation, deposition of excessive extracellular matrix and remodelling of the lung interstitium. New treatments, namely nintedanib and pirfenidone slow disease progression, but despite recent advances morbidity and mortality from IPF remain higher than many malignancies.

Lipids and lipoproteins play important roles both in normal lung health and in pulmonary diseases such as acute lung injury, asthma, emphysema and pulmonary hypertension [2–4]. High-density lipoproteins (HDL), a complex, heterogeneous group of lipoprotein particles of varying composition, size and function mediates reverse cholesterol transport out of cells, and has anti-inflammatory, anti-thrombotic and anti-oxidative properties [5]. However, modifications to HDL composition and function may influence its role in health and disease. Several studies have also suggested a role for apolipoprotein AI (APOA1), the major protein component of HDL, in modifying disease severity in IPF. Bronchoalveolar lavage fluid (BALF) proteome analysis identified that APOA1 concentrations were lower in IPF subjects than healthy controls, and correlated negatively with the percentage of foamy, lipid-laden macrophages and fibrosis scores [6]. BALF APOA1 levels were also reduced in bleomycin-challenged mice, and administration of human APOA1 abrogated both inflammation and fibrosis in a dose-dependent manner [6]. In a silica-induced model of pulmonary fibrosis, transgenic mice with inducible overexpression of human APOA1 under the control of the human surfactant protein C promoter had fewer fibrotic nodules, less soluble collagen, lower inflammatory cell counts and decreased levels of transforming growth factor (TGF)β-1, interleukin-1β and tumour necrosis factor-α than control mice [7]. Furthermore, treatment of human alveolar epithelial cells with human APOA1 or with D4F, a synthetic APOA1 mimetic peptide, inhibited TGFβ-1-mediated epithelial–mesenchymal transformation [8, 9].

These observations led us to hypothesise that circulating serum lipoproteins and lipids, and in particular HDL, may be associated with clinically important measures of disease severity in IPF. Specifically, we examined if relationships exist between serum lipids, measured by standard and nuclear magnetic resonance (NMR) spectroscopy assays and the forced vital capacity (FVC), 6-min walk distance (6MWD) and gender age physiology (GAP) index, as well as GAP predicted mortality, and the composite outcome measure of observed mortality or lung transplantation in IPF subjects.

Methods

Study population

This study was conducted in accordance with the amended Declaration of Helsinki. The National Heart, Lung, and Blood Institute institutional review board (IRB) and the Inova human research protection programme independently approved the protocols (15-H-0017 and 09.147, respectively). To be included in the study, subjects provided written informed consent, and had serum samples collected within 100 days of pulmonary function and 6-min walk tests. All IPF subjects had their diagnosis confirmed either by lung biopsy and/or radiographic imaging on high-resolution computed tomography (CT) scans of the chest and clinical features consistent with IPF upon evaluation by a multidisciplinary team specialising in care of patients with interstitial lung diseases. Patients with other primary lung diseases were excluded. Healthy controls had no history of lung disease and a normal chest radiograph at the time of sample collection. The discovery cohort consisted of 102 subjects: 56 IPF subjects were evaluated at the Advanced Lung Disease and Transplant Clinic at Inova Fairfax Hospital (Fairfax, VA, USA) between January 2010 and August 2016. 56 race- and age (±10 years)-matched, healthy volunteers and three IPF subjects were enrolled at the National Institutes of Health Clinical Center (Bethesda, MD, USA) between January 2015 and November 2016. Healthy controls were included as a comparator for the discovery cohort to assess whether relationships observed between lung function and serum lipids and lipoproteins were specific to the IPF cohort or were also present in healthy subjects. The independent validation cohort consisted of 207 randomly selected (using SAS procedure) IPF subjects enrolled in the Pulmonary Fibrosis Foundation (PFF) patient registry between 2016 and 2018 who fulfilled the study inclusion criteria and for whom clinical data and stored serum samples were available [10]. We excluded subjects from the validation cohort that were already present in the discovery cohort, since Inova Fairfax Hospital is a participating PFF site. The PFF registry protocol, consent documents and questionnaires were approved by the IRB for the coordinating centre at the University of Michigan and by each participating centre's IRB (see appendix for list of participating sites). Details about the multicentre PFF patient registry, including eligibility criteria, can be found at www.pulmonaryfibrosis.org/pff-registry and in the publication by Wang et al. [10].

Details about lipid measurements are provided in the supplementary material.

Statistical methods

All analyses were performed using SAS Enterprise Guide version 7.15 (SAS Institute, Cary, NC, USA). The null hypotheses were that 1) there were no significant differences in serum lipid levels by standard assay or NMR spectroscopy between the discovery IPF cohort and the healthy controls and 2) there were no significant correlations between serum lipid parameters (total cholesterol, HDL cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides and subgroups of HDL particles measured using NMR spectroscopy, as well as APOA1 and APOB concentrations) and clinical end-points (FVC, 6MWD, GAP index) in the discovery IPF cohort.

Non-normally distributed variables were log-transformed prior to analysis. Comparisons of raw means between groups were based on one-way ANOVA (Bonferroni method). GAP index and predicted mortality were calculated as described previously [11]. Correlation analyses were performed using Pearson correlation method. Linear models using the variables age, sex, race, body mass index (BMI) and C-reactive protein (CRP) levels, determined a priori as potential factors that might influence serum lipid levels, were fitted in multivariable regression analyses to assess relationships between serum lipid parameters and FVC, 6MWD and GAP index. Based on the results of the analyses performed on the discovery cohort, we calculated that a sample size of 194–221 subjects for the validation cohort provided 85–90% power to detect statistically significant correlations of ⩾0.2 (β=0.1–0.15, α=0.05; two-tailed). Correlation and multivariable regression analyses were replicated in the validation cohort, but limited to those variables that were significant in the discovery cohort.

Based upon the results of the a priori statistical analysis plan, additional analyses were performed to assess whether small HDL particles measured using NMR (S-HDLPNMR) were associated with a composite end-point of mortality or lung transplantation. The discovery and validation cohorts of IPF subjects were analysed as a single group to generate a larger cohort in order to assess the relationship between S-HDLPNMR and the composite end-point of observed death or lung transplantation. Since this is a cross-sectional observational study of patients at a single point in their disease course, an adjustment for disease severity at the time of study participation was required to analyse associations between lipoproteins and observed death or lung transplantation. Therefore, predicted mortality at 1, 2 and 3 years as determined by the GAP calculator was used to adjust for disease severity. The GAP models have been developed as a multidimensional prognostic staging system for IPF, and incorporate age, sex, FVC and diffusing capacity of the lung for carbon monoxide (DLCO) to predict death at 1, 2 or 3 years from the time of measurement of these variables. The GAP calculator derived predicted mortality provides a more precise estimate of individual risk that could be helpful in clinical decision-making above and beyond a simple GAP score [11]. Logistic regression analyses were performed to determine whether S-HDLPNMR levels were associated with the composite outcome of observed death or lung transplantation, using race, GAP predicted mortality, BMI and treatment status (with anti-fibrotic and lipid-lowering medications) as additional variables. Since age, sex, and lung function (FVC and DLCO) are already incorporated into the GAP calculator, these were not again included as variables in the logistic regression models. All subjects were included who had either met the composite outcome (death or lung transplantation) or had a minimum follow-up period corresponding to 1, 2 or 3 years from the time of sample collection.

Significance level was set at 0.05 for α-errors; all statistical tests were two-tailed. No adjustment was made for multiple comparisons for global hypothesis testing. The number of variables analysed in the validation cohort were limited based on the results from the discovery cohort. All multivariable analyses were performed with included variables selected a priori, following a backwards stepwise selection method (significance level for keeping a variable in the model was set at p≤0.2).

Results

Demographic analysis showed that the 59 IPF subjects from the discovery cohort were significantly older, with lower FVC, DLCO and 6MWD, but higher CRP levels and lipid-lowering medication use, than the 56 healthy control subjects (table 1). The validation cohort of 207 IPF subjects was similar to the discovery cohort of IPF patients, except for a lower 6MWD and higher anti-fibrotic medication use. Significantly fewer IPF patients died or had lung transplants in the validation cohort than the discovery cohort (table 1). Serum lipid and lipoprotein levels for all subjects are shown in supplementary table S1. The number of subjects with missing data are shown in supplementary table 2.

View this table:
  • View inline
  • View popup
TABLE 1

Demographic characteristics of healthy controls and subjects with idiopathic pulmonary fibrosis (IPF) (discovery and validation cohorts)

View this table:
  • View inline
  • View popup
TABLE 2

Multivariable analysis (reduced linear models incorporating age, sex, race, body mass index and C-reactive protein levels; SAS, Cary, NC, USA) to examine associations between lipids/lipoproteins and forced vital capacity (FVC), 6-min walk distance (6MWD) and gender age physiology (GAP) index in the discovery cohort of idiopathic pulmonary fibrosis subjects

Pearson correlation analyses were performed to determine whether serum lipid and lipoprotein values were significantly associated with the clinical end-points of FVC, 6MWD and GAP index in the discovery cohort of IPF patients. Total cholesterol (TCNMR), LDL-CNMR and S-HDLPNMR, all measured using NMR spectroscopy, correlated positively with FVC and 6MWD, and negatively with GAP index (figure 1). Negative correlations were also observed between total cholesterol from the standard lipid assay, as well as NMR-derived APOB particle concentrations and the GAP index. These associations were absent in healthy controls (supplementary table S3).

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Scatter plots showing Pearson correlations between total cholesterol (TCNMR), low-density lipoprotein cholesterol (LDL-CNMR) and small high-density lipoprotein particles (S-HDLPNMR) as measured by nuclear magnetic resonance spectroscopy, and the clinical end-points (forced vital capacity (FVC), 6-min walk distance (6MWD) and gender age physiology (GAP) index) in subjects with idiopathic pulmonary fibrosis in the discovery cohort.

Next, multivariable analyses focused on the lipid parameters (TCNMR, LDL-CNMR and S-HDLPNMR) that were significantly correlated with all three of the pre-specified clinical end-points, FVC, 6MWD and GAP. The positive correlations between TCNMR, LDL-CNMR and S-HDLPNMR with FVC and 6MWD remained significant in the discovery cohort after adjusting for age, sex, race, BMI and CRP levels. In addition, the negative correlations between the GAP index and TCNMR and LDL-CNMR remained significant, while that with S-HDLPNMR trended toward significance (p=0.09; table 2).

We then assessed whether these correlations could be replicated in the validation cohort of IPF patients and found that TCNMR and LDLNMR were not significantly correlated with either FVC or 6MWD, although the correlations with GAP score approached significance (p=0.06 for both by Pearson correlation; supplementary table S3). S-HDLPNMR levels were significantly correlated with both FVC and the GAP index (p=0.003), and the relationship with 6MWD approached significance (p=0.06; figure 2 and supplementary table S3). On multivariable regression, only the inverse relationship between S-HDLPNMR and GAP index remained significant in the validation cohort (estimate −0.33, 95% CI −0.65–−0.009; p=0.04). Taken collectively, analyses of two independent cohorts of IPF subjects identified a negative association between S-HDLPNMR and the GAP index, which is a predictor of mortality in IPF. A post hoc analysis showed that S-HDLPNMR concentrations correlated positively with DLCO in both the discovery and the validation cohorts (p=0.01 for both). While DLCO remained significantly associated with S-HDLPNMR by multivariable analysis in the discovery cohort (p=0.04), it was not so in the validation cohort (p=0.18; reduced linear models).

FIGURE 2
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 2

Scatter plots showing Pearson correlations between small high-density lipoprotein particles as measured by nuclear magnetic resonance spectroscopy (S-HDLPNMR) and the clinical end-points (forced vital capacity (FVC), 6-min walk distance (6MWD) and gender age physiology (GAP) index), in subjects with idiopathic pulmonary fibrosis in the validation cohort.

Subsequent analyses focused on assessing the association between S-HDLPNMR and mortality in the combined cohort of all IPF subjects. Logistic regression analyses showed that S-HDLPNMR was associated with a lower risk of the composite outcome of observed death or lung transplantation at 1, 2 and 3 years, which remained significant after adjusting for predicted mortality (as a measure of disease severity), race, and anti-fibrotic and lipid-lowering drug use (figure 3). Each 1-μmol·L−1 increase in S-HDLPNMR was associated with a decrease in the risk of death or lung transplantation by ∼10% (OR 0.9) at 1, 2 and 3 years from the time of sample collection. Although the lipid profiles of IPF subjects taking lipid-lowering medication differed from those not taking these medications as expected (supplementary table S1), treatment status did not change the relationship between S-HDLPNMR and observed death or lung transplantation. Furthermore, these associations remained significant even after adjusting for BMI, which could potentially influence outcomes and lipid levels in IPF patients.

FIGURE 3
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 3

Forest plots showing the odds ratios of the composite outcome of death or lung transplantation at 1, 2 and 3 years from study entry associated with each unit increase in small high-density lipoprotein particles as measured by nuclear magnetic resonance spectroscopy (S-HDLPNMR), from logistic regression models (SAS, Cary, NC, USA). Variables for the adjusted odds ratio models included race, treatment status, body mass index and gender age physiology (GAP)-calculated predicted mortality which also incorporates age, sex, forced vital capacity and diffusing capacity of the lung for carbon monoxide.

Discussion

The role of lipids and lipoproteins in the pathogenesis of IPF is yet to be completely defined. Here, we found that the serum concentration of S-HDLPNMR correlated negatively with the GAP index in a discovery cohort of IPF subjects from a single centre, and validated this in a larger, multicentre cohort of IPF patients. These relationships remained largely significant after adjusting for BMI, sex, age, race and CRP levels. Furthermore, higher serum S-HDLPNMR levels were associated with a lower risk of observed death or lung transplantation, irrespective of disease severity, race, or treatment status with either anti-fibrotics or lipid-lowering medications.

Experimental murine studies have identified both harmful and protective roles for lipids and lipoproteins in IPF pathobiology [3]. For example, Apoe−/− mice fed a high-fat or Western diet develop hypercholesterolaemia with resultant systemic inflammation, oxidative stress and lipid accumulation in the lung, causing pulmonary fibrosis [3]. A paracrine lipid-signalling axis in the mouse lung has been described, linking epithelial injury with macrophage activation and pulmonary fibrosis [12]. Additionally, serum lipids and lipoproteins might modify the composition or function of pulmonary surfactant in IPF; as circulating lipids affect the content and characteristics of pulmonary surfactant both in health and disease [13–15].

HDL cholesterol was long considered protective and thus a therapeutic target for mitigating cardiovascular risk; however, simply raising HDL cholesterol levels in blood failed to deliver better cardiovascular outcomes [16]. The HDL fraction is composed of a heterogeneous group of particles varying in not only size (7.3–8.2 nm for small, 8.2–8.8 nm for medium and 8.8–13.0 nm for large HDL particles), but also in composition [17]. More than 550 proteins have been reported to be associated with HDL particles, which may vary by disease state and alter its biological function [18]. APOA1, which is the most abundant HDL-associated protein, is known to have significant anti-inflammatory and antioxidant properties. However, APOA1 did not correlate with the clinical end-points in our study, suggesting that other protein or lipid components of small HDL particles may be more important in IPF.

Small HDL particles have been shown to be associated with cardioprotection, based on their ability to accept cholesterol from foam cells by ABCA1, and have anti-oxidant, anti-inflammatory and anti-apoptotic properties [19]. Sphingosine-1-phosphate (S1P), a bioactive lipid that acts through G-protein coupled S1P receptors and regulates cell proliferation, motility, apoptosis, angiogenesis, immune response and wound healing, is enriched in small dense HDL particles [20, 21]. Serum and bronchoalveolar lavage levels of S1P are higher in IPF subjects compared to healthy volunteers, and associated with epithelial to mesenchymal transition [22]. S1P has been shown to have both pro-fibrotic and anti-fibrotic effects, depending on the site of action (intracellular versus extracellular) [23]. Levels of serum amyloid A, which is primarily associated with HDL particles, are also increased in IPF patients as compared to healthy controls, and are negatively correlated with HDL cholesterol levels and FVC [24]. Moreover, HDL function is not static; HDL subfractions have been shown to change from being anti-inflammatory to pro-inflammatory in specific disease conditions such as diabetes or metabolic syndrome [25–28]. Therefore, further investigations to elucidate the lipid and protein components of small HDL particles and their role in IPF are indicated.

NMR spectroscopy lipid profiles are being increasingly studied regarding their association with disease risk, severity, or outcome, particularly in cardiovascular and metabolic disorders such as diabetes. In particular, assessment of HDL particle number and HDL particle profile by NMR spectroscopy has been proposed to be superior to HDL-C as a predictor of cardiovascular disease risk and mortality, which may reflect that measurement of HDL particle number by NMR is more accurate and reliable [29–31]. NMR spectroscopy lipid profiles have also been studied in lung disease. Plasma levels of the small-HDL subclass HDL-4 have been inversely related to survival in patients with pulmonary arterial hypertension [32]. A positive correlation has been found between forced expiratory volume in 1 s and HDLNMR particle size, as well as the concentration of large HDLNMR particles in asthmatics [33]. Similarly, the concentration of large HDLNMR particles was negatively correlated with blood eosinophils, a biomarker of type 2 inflammation, while serum periostin levels were inversely associated with the concentration of total HDLNMR particles in asthmatics [34]. Of note, the association between death or lung transplantation and S-HDLPNMR was not seen with HDL-C in our study. This may in part reflect that quantification of HDL subspecies by different methodologies are not directly comparable, as well as differences in HDL function and composition [29].

Associations between serum lipoproteins and radiographic abnormalities in the lungs were also present in subjects enrolled in the Multi-Ethnic Study of Atherosclerosis [35]. This study investigated the progression of subclinical cardiovascular disease over time in asymptomatic individuals aged 45–84 years who were not pre-selected based on lung disease. Cardiac CT images were analysed by automated quantitative CT densitometry to measure high attenuation areas (HAA) and visual inspection to detect interstitial lung abnormalities. Higher serum levels of total cholesterol, HDL-C, LDL-C, APOA1 and triglycerides were associated with lower HAA, and the association of HAA with HDL-C and APOA1 remained significant after adjusting for left ventricular function. HDL-C and APOA1 were also inversely associated with matrix metalloproteinase 7 and surfactant protein A, two potential biomarkers of lung inflammation and extracellular matrix remodelling. These observations, linking serum lipid and lipoprotein levels with disease risk, severity or outcomes support further investigations to delineate the possible role of HDL and other lipoproteins in lung disease.

One shortcoming of the current study is the relatively small sample size. In addition, the results of this cross-sectional study only characterise an association between serum lipoproteins and clinical outcomes in a cohort of IPF patients; this does not prove that a causal relationship exists between serum lipoproteins and IPF, nor does it establish S-HDLPNMR as a biomarker for disease severity in IPF. These findings would first have to be reproduced in well-designed, prospective studies with the specific aim of biomarker development, and the exact role of these lipoprotein particles in IPF pathobiology would have to be elucidated at a molecular level. However, to counterbalance these shortcomings, particular strengths of our study design include the well-defined clinical phenotyping of subjects and controls in the discovery cohort, the confirmation of our primary finding in the independent multicentre validation cohort, as well as the choice of outcomes analysed. To the best of our knowledge, this is the first study to show a relationship between NMR spectroscopy-derived lipid measurements with clinically important end-points, including mortality, in an IPF cohort.

Although the overall prognosis for IPF is poor, with a median survival of 2–4 years, disease course and progression varies significantly between individual patients [1, 36]. The GAP index and system of staging, and the GAP calculator of predicted mortality, were developed and validated for use in individual IPF patients with applicability to both clinical care (i.e. guiding decision making, such as timing of lung transplantation or hospice referral) and clinical research [11]. It must be pointed out that the GAP calculator was developed and validated prior to the era of anti-fibrotic medication use in IPF, and thus it is not known whether it accurately predicts mortality in IPF patients who are taking these medications. However, we were able to show that S-HDLPNMR levels were associated with a lower risk of observed death or lung transplantation at 1, 2 and 3 years of follow up irrespective of anti-fibrotic medication use, which was included as a variable in the logistic regression models.

In conclusion, we show that serum concentrations of S-HDLPNMR were inversely correlated to disease severity as represented by GAP index as well as observed mortality, or its competing outcome, lung transplantation, in subjects with IPF. This finding that circulating lipids are associated with important clinical indicators of disease severity and mortality in IPF adds new evidence supporting further investigations to evaluate the role of lipids and lipoproteins in IPF pathobiology.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material: Laboratory measurements of lipid panels ERJ-04053-2020.Methods

Supplementary tables S1 and S2 ERJ-04053-2020.Tables_1

Supplementary table S3 ERJ-04053-2020.Tables_3

Appendix: List of Pulmonary Fibrosis Foundation Care Center Network sites that enrolled patients in the Pulmonary Fibrosis Foundation Patient Registry ERJ-04053-2020.Appendix

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-04053-2020.Shareable

Acknowledgements

We thank all the IPF patients and healthy individuals who participated in this study. We also thank the Pulmonary Fibrosis Foundation and participating academic centres (listed in the appendix) for providing clinical data and serum samples for the validation cohort of IPF patients.

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • An abstract reporting preliminary results was presented at the 2018 International American Thoracic Society meeting in San Diego, CA, USA (20 May 2018, Session A21: clinical and mechanistic studies of lung fibrosis; poster 912).

  • Author contributions: A.V. Barochia, N. Weir, M. Kaler, A.T. Remaley, G. Grant, S.D. Nathan and S.J. Levine conceived the study; A.V. Barochia, M. Kaler, N. Weir and M. Lemma WoldeHanna collected the data; A.V. Barochia, E.M. Gordon, D.M. Figueroa, X. Yao and M. Sampson performed the assays; A.V. Barochia, S.D. Barnett, N. Weir, S.D. Nathan, G. Grant, A.T. Remaley and S.J. Levine analysed the data; A.V. Barochia and S.J. Levine wrote the manuscript. All authors provided critical review of the manuscript and approved of its contents and submission. A.V. Barochia takes responsibility for the content of the manuscript, including the data and analysis.

  • Conflict of interest: A.V. Barochia has nothing to disclose.

  • Conflict of interest: M. Kaler has nothing to disclose.

  • Conflict of interest: N. Weir has nothing to disclose.

  • Conflict of interest: E.M. Gordon has nothing to disclose.

  • Conflict of interest: D.M. Figueroa has nothing to disclose.

  • Conflict of interest: X. Yao has nothing to disclose.

  • Conflict of interest: M. Lemma WoldeHanna has nothing to disclose.

  • Conflict of interest: M. Sampson has nothing to disclose.

  • Conflict of interest: A.T. Remaley has nothing to disclose.

  • Conflict of interest: G. Grant has nothing to disclose.

  • Conflict of interest: S.D. Barnett has nothing to disclose.

  • Conflict of interest: S.D. Nathan is a consultant and is on the speakers’ bureau for Roche-Genentech and Boehringer Ingelheim, and has received research funding from both companies.

  • Conflict of interest: S.J. Levine has nothing to disclose.

  • Support statement: This work was funded by the Division of Intramural Research at the National Heart, Lung, and Blood Institute (NIH, Bethesda, MD, USA). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received November 3, 2020.
  • Accepted April 13, 2021.
  • The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2021. For commercial reproduction rights and permissions contact permissions{at}ersnet.org
https://www.ersjournals.com/user-licence

References

  1. ↵
    1. Richeldi L,
    2. Collard HR,
    3. Jones MG
    . Idiopathic pulmonary fibrosis. Lancet 2017; 389: 1941–1952. doi:10.1016/S0140-6736(17)30866-8
    OpenUrlCrossRefPubMed
  2. ↵
    1. Gordon EM,
    2. Figueroa DM,
    3. Barochia AV, et al.
    High-density lipoproteins and apolipoprotein A-I: potential new players in the prevention and treatment of lung disease. Front Pharmacol 2016; 7: 323. doi:10.3389/fphar.2016.00323
    OpenUrlCrossRef
  3. ↵
    1. Yao X,
    2. Gordon EM,
    3. Figueroa DM, et al.
    Emerging roles of apolipoprotein E and apolipoprotein A-I in the pathogenesis and treatment of lung disease. Am J Respir Cell Mol Biol 2016; 55: 159–169. doi:10.1165/rcmb.2016-0060TR
    OpenUrlCrossRef
  4. ↵
    1. Fessler MB
    . A new frontier in immunometabolism. Cholesterol in lung health and disease. Ann Am Thorac Soc 2017; 14: Suppl. 5, S399–S405. doi:10.1513/AnnalsATS.201702-136AW
    OpenUrl
  5. ↵
    1. Navab M,
    2. Reddy M,
    3. Van Lenten ST, et al.
    HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 2011; 8: 222–232. doi:10.1038/nrcardio.2010.222
    OpenUrlCrossRefPubMed
  6. ↵
    1. Kim TH,
    2. Lee YH,
    3. Kim KH, et al.
    Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis: antiinflammatory and antifibrotic effect on experimental lung injury and fibrosis. Am J Respir Crit Care Med 2010; 182: 633–642. doi:10.1164/rccm.200905-0659OC
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Lee E,
    2. Lee EJ,
    3. Kim HJ, et al.
    Overexpression of apolipoprotein A1 in the lung abrogates fibrosis in experimental silicosis. PLoS One 2013; 8: e55827. doi:10.1371/journal.pone.0055827
    OpenUrl
  8. ↵
    1. You J,
    2. Wang J,
    3. Xie L, et al.
    D-4F, an apolipoprotein A-I mimetic, inhibits TGF-β1 induced epithelial-mesenchymal transition in human alveolar epithelial cell. Exp Toxicol Pathol 2016; 68: 533–541. doi:10.1016/j.etp.2016.07.005
    OpenUrlPubMed
  9. ↵
    1. Baek AR,
    2. Lee JM,
    3. Seo HJ, et al.
    Apolipoprotein A1 inhibits TGF-β1-induced epithelial-to-mesenchymal transition of alveolar epithelial cells. Tuberc Respir Dis 2016; 79: 143–152. doi:10.4046/trd.2016.79.3.143
    OpenUrl
  10. ↵
    1. Wang BR,
    2. Edwards R,
    3. Freiheit EA, et al.
    The Pulmonary Fibrosis Foundation patient registry: rationale, design, and methods. Ann Am Thorac Soc 2020; 17: 1620–1628. doi:10.1513/AnnalsATS.202001-035SD
    OpenUrl
  11. ↵
    1. Ley B,
    2. Ryerson CJ,
    3. Vittinghoff E, et al.
    A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012; 156: 684–691. doi:10.7326/0003-4819-156-10-201205150-00004
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Romero F,
    2. Shah D,
    3. Duong M, et al.
    A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis. Am J Respir Cell Mol Biol 2015; 53: 74–86. doi:10.1165/rcmb.2014-0343OC
    OpenUrlCrossRefPubMed
  13. ↵
    1. Fessler MB,
    2. Summer RS
    . Surfactant lipids at the host-environment interface. Metabolic sensors, suppressors, and effectors of inflammatory lung disease. Am J Respir Cell Mol Biol 2016; 54: 624–635. doi:10.1165/rcmb.2016-0011PS
    OpenUrlCrossRefPubMed
    1. Mallampalli RK,
    2. Ryan AJ,
    3. Carroll JL, et al.
    Lipid deprivation increases surfactant phosphatidylcholine synthesis via a sterol-sensitive regulatory element within the CTP: phosphocholine cytidylyltransferase promoter. Biochem J 2002; 362: 81–88. doi:10.1042/bj3620081
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Ryan AJ,
    2. Medh JD,
    3. McCoy DM, et al.
    Maternal loading with very low-density lipoproteins stimulates fetal surfactant synthesis. Am J Physiol Lung Cell Mol Physiol 2002; 283: L310–L318. doi:10.1152/ajplung.00021.2002
    OpenUrlCrossRefPubMed
  15. ↵
    1. Kingwell BA,
    2. Chapman MJ,
    3. Kontush A, et al.
    HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov 2014; 13: 445–464. doi:10.1038/nrd4279
    OpenUrlCrossRefPubMed
  16. ↵
    1. Kontush A,
    2. Lindahl M,
    3. Lhomme M, et al.
    Structure of HDL: particle subclasses and molecular components. Handb Exp Pharmacol 2015; 224: 3–51. doi:10.1007/978-3-319-09665-0_1
    OpenUrlCrossRefPubMed
  17. ↵
    1. Ronsein GE,
    2. Vaisar T
    . Deepening our understanding of HDL proteome. Expert Rev Proteomics 2019; 16: 749–760. doi:10.1080/14789450.2019.1650645
    OpenUrl
  18. ↵
    1. Kim DS,
    2. Li YK,
    3. Bell GA, et al.
    Concentration of smaller high-density lipoprotein particle (HDL-P) is inversely correlated with carotid intima media thickening after confounder adjustment: the Multi Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc 2016; 5: e002977. doi:10.1161/JAHA.115.002977
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Kontush A,
    2. Therond P,
    3. Zerrad A, et al.
    Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities. Arterioscler Thromb Vasc Biol 2007; 27: 1843–1849. doi:10.1161/ATVBAHA.107.145672
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Perségol L,
    2. Darabi M,
    3. Dauteuille C, et al.
    Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate. J Lipid Res 2018; 59: 25–34. doi:10.1194/jlr.M076927
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Milara J,
    2. Navarro R,
    3. Juan G, et al.
    Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition. Thorax 2012; 67: 147–156. doi:10.1136/thoraxjnl-2011-200026
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Schwalm S,
    2. Pfeilschifter J,
    3. Huwiler A
    . Sphingosine-1-phosphate: a Janus-faced mediator of fibrotic diseases. Biochim Biophys Acta 2013; 1831: 239–250. doi:10.1016/j.bbalip.2012.07.022
    OpenUrlPubMedWeb of Science
  23. ↵
    1. Vietri L,
    2. Bennett D,
    3. Cameli P, et al.
    Serum amyloid A in patients with idiopathic pulmonary fibrosis. Respir Investig 2019; 57: 430–434. doi:10.1016/j.resinv.2019.03.010
    OpenUrl
  24. ↵
    1. Liao KP,
    2. Playford MP,
    3. Frits M, et al.
    The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 2015; 4: e001588. doi:10.1161/JAHA.114.001588
    OpenUrlAbstract/FREE Full Text
    1. Vaisar T,
    2. Couzens E,
    3. Hwang A, et al.
    Type 2 diabetes is associated with loss of HDL endothelium protective functions. PLoS One 2018; 13: e0192616. doi:10.1371/journal.pone.0192616
    OpenUrlPubMed
    1. Keul P,
    2. Polzin A,
    3. Kaiser K, et al.
    Potent anti-inflammatory properties of HDL in vascular smooth muscle cells mediated by HDL-S1P and their impairment in coronary artery disease due to lower HDL-S1P: a new aspect of HDL dysfunction and its therapy. FASEB J 2019; 33: 1482–1495. doi:10.1096/fj.201801245R
    OpenUrl
  25. ↵
    1. Sposito AC,
    2. de Lima-Junior JC,
    3. Moura FA, et al.
    Reciprocal multifaceted interaction between HDL (high-density lipoprotein) and myocardial infarction. Arterioscler Thromb Vasc Biol 2019; 39: 1550–1564. doi:10.1161/ATVBAHA.119.312880
    OpenUrl
  26. ↵
    1. Connelly MA,
    2. Shalaurova I,
    3. Otvos JD
    . High-density lipoprotein and inflammation in cardiovascular disease. Transl Res 2016; 173: 7–18. doi:10.1016/j.trsl.2016.01.006
    OpenUrl
    1. Matyus SP,
    2. Braun PJ,
    3. Wolak-Dinsmore J, et al.
    HDL particle number measured on the Vantera®, the first clinical NMR analyzer. Clin Biochem 2015; 48: 148–155. doi:10.1016/j.clinbiochem.2014.11.017
    OpenUrlCrossRefPubMed
  27. ↵
    1. deGoma EM,
    2. Rader DJ
    . High-density lipoprotein particle number: a better measure to quantify high-density lipoprotein? J Am Coll Cardiol 2012; 60: 517–520. doi:10.1016/j.jacc.2012.03.058
    OpenUrlFREE Full Text
  28. ↵
    1. Harbaum L,
    2. Ghataorhe P,
    3. Wharton J, et al.
    Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension. Thorax 2019; 74: 380–389. doi:10.1136/thoraxjnl-2018-212144
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Barochia AV,
    2. Kaler M,
    3. Cuento RA, et al.
    Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. Am J Respir Crit Care Med 2015; 191: 990–1000. doi:10.1164/rccm.201411-1990OC
    OpenUrlCrossRefPubMed
  30. ↵
    1. Barochia AV,
    2. Gordon EM,
    3. Kaler M, et al.
    High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics. J Lipid Res 2017; 58: 1713–1721. doi:10.1194/jlr.P077776
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Podolanczuk AJ,
    2. Raghu G,
    3. Tsai MY, et al.
    Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study. Thorax 2017; 72: 472–474. doi:10.1136/thoraxjnl-2016-209568
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Kim DS,
    2. Collard HR,
    3. King TE Jr.
    . Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006; 3: 285–292. doi:10.1513/pats.200601-005TK
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
View this article with LENS
Vol 58 Issue 6 Table of Contents
European Respiratory Journal: 58 (6)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis
Amisha V. Barochia, Maryann Kaler, Nargues Weir, Elizabeth M. Gordon, Debbie M. Figueroa, Xianglan Yao, Merte Lemma WoldeHanna, Maureen Sampson, Alan T. Remaley, Geraldine Grant, Scott D. Barnett, Steven D. Nathan, Stewart J. Levine
European Respiratory Journal Dec 2021, 58 (6) 2004053; DOI: 10.1183/13993003.04053-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis
Amisha V. Barochia, Maryann Kaler, Nargues Weir, Elizabeth M. Gordon, Debbie M. Figueroa, Xianglan Yao, Merte Lemma WoldeHanna, Maureen Sampson, Alan T. Remaley, Geraldine Grant, Scott D. Barnett, Steven D. Nathan, Stewart J. Levine
European Respiratory Journal Dec 2021, 58 (6) 2004053; DOI: 10.1183/13993003.04053-2020
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Supplementary material
    • Shareable PDF
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Interstitial and orphan lung disease
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Original Research Articles

  • Oxidised IL-33 and RAGE/EGFR signalling complex in COPD
  • From pre-COPD to COPD: SLIM risk calculator
  • Effects of sotatercept on haemodynamics and right heart function
Show more Original Research Articles

Interstitial lung disease

  • Use of statins and risk of ILD/IPF
  • Rituximab and mycophenolate mofetil in ILD
  • Incidence of interstitial lung abnormalities
Show more Interstitial lung disease

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society