Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis

doi:10.1378/chest.08-2209

Chest

Volume 135, Issue 6, June 2009, Pages 1557-1563

https://doi.org/10.1378/chest.08-2209 Get rights and content

Background

Serum surfactant protein A and SP-D had prognostic value for mortality in patients with idiopathic pulmonary fibrosis in prior studies before the reclassification of the idiopathic interstitial pneumonias. We hypothesized that baseline serum SP-A and SP-D concentrations would be independently associated with mortality among patients with biopsy-proven IPF and would improve a prediction model for mortality.

Methods

We evaluated the association between serum SP-A and SP-D concentrations and mortality in 82 patients with surgical lung biopsy-proven IPF. Regression models with clinical predictors alone and clinical and biomarker predictors were used to predict mortality at 1 year.

Results

After controlling for known clinical predictors of mortality, we found that each increase of 49 ng/mL in baseline SP-A level was associated with a 3.3-fold increased risk of mortality in the first year after presentation. We did not observe a statistically significant association between serum SP-D and mortality (adjusted hazard ratio, 2.04; p = 0.053). Regression models demonstrated a significant improvement in the 1-year mortality prediction model when serum SP-A and SP-D (area under the receiving operator curve [AROC], 0.89) were added to the clinical predictors alone (AROC, 0.79; p = 0.03).

Conclusions

Increased serum SP-A level is a strong and independent predictor of early mortality among patients with IPF. A prediction model containing SP-A and SP-D was substantially superior to a model with clinical predictors alone.

Section snippets

Study Patients

The study cohort consisted of 82 patients with IPF and a pathologic pattern of UIP seen on a surgical lung biopsy specimen prospectively enrolled into a specialized center of research study at the National Jewish Medical and Research Center (Denver, CO) between 1982 and 1996. The cohort also included a subset of patients (n = 78) previously evaluated by Greene et al¹⁹ (n = 111). The remainder of the cohort in the study by Greene et al¹⁹ was excluded because these patients did not have a

Results

Among the 82-patient study sample, the mean age was 62 years; 62% were men, and 90% were white. Sixty-two percent of patients were either current or former smokers. The mean serum SP-A level was 106 ng/mL (range, 27 to 276 ng/mL), and the mean serum SP-D level was 641 ng/mL (range, 82 to 2,404 ng/mL). Exploratory analyses revealed that serum SP-A level, but not SP-D level, was associated with early mortality; thus, the baseline characteristics are shown in relation to serum SP-A tertiles (Table

Discussion

This study examined the association of serum SP-A and SP-D levels with survival in a relatively large and well-characterized cohort of patients with biopsy-proven IPF through long-term and comprehensive follow-up. We demonstrated that serum SP-A levels obtained at the time of initial diagnosis among patients with IPF (confirmed by use of the current consensus pathologic definition) is independently and strongly associated with death or lung transplant within 1 year after presentation. This

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An extended-gate field-effect transistor (EG-FET) signal transducing combined with epitope molecular imprinting for selective chemosensing of chosen idiopathic pulmonary fibrosis (IPF) biomarkers
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We propose a relatively rapid and straightforward procedure for the determination of chosen idiopathic pulmonary fibrosis (IPF) predictive protein biomarkers, vis., matrix metalloproteinase-1 (MMP-1) and surfactant-associated protein-A (SP-A), suitable for their determination in bodily fluids. IPF is a lethal lung disease, annually causing nearly as many deaths as breast cancer. Moreover, the coronavirus recently triggered acute exacerbation of patients suffering from IPF. Here, epitopes specific to the chosen IPF biomarkers were molecularly imprinted in a polymer as an alternative to imprinting fragile whole biomarkers’ molecules. A thin molecularly imprinted polymer (MIP) film-based recognition units were integrated by electropolymerization with gates of extended-gate field-effect transistors (EG-FETs) to fabricate biomarker-selective chemical sensors suitable as point-of-care testing (POCT) diagnostic devices. Either AQDDIDGIQAI or FKGNKYWAVQGQNV single-epitope imprinting allowed determining the MMP-1 biomarker in the 10 to 250 nM linear dynamic concentration range with a LOD of 7.5 or 2 nM, respectively. Simultaneous imprinting of three MMP-1 epitopes, vis., MIAHDFPGIGHK, HGYPKDIYSS, and FKGNKYWAVQGQNV, decreased this LOD to 0.1 nM, allowing for determining this biomarker in serum. Moreover, by FSSNGQSIT or YSDGTPVNYTNWYR single-epitope imprinting, chemosensors for SP-A were fabricated to show the versatility of epitope imprinting. These chemosensors selectively determined the SP-A biomarker with the LOD of 1.9 or 2.9 nM, allowing its determination in bodily fluids.
Precision medicine advances in idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous, unpredictable and ultimately lethal chronic lung disease. Over the last decade, two anti-fibrotic agents have been shown to slow disease progression, however, both drugs are administered uniformly with minimal consideration of disease severity and inter-individual molecular, genetic, and genomic differences. Advances in biological understanding of disease endotyping and the emergence of precision medicine have shown that “a one-size-fits-all approach” to the management of chronic lung diseases is no longer appropriate. While precision medicine approaches have revolutionized the management of other diseases such as lung cancer and asthma, the implementation of precision medicine in IPF clinical practice remains an unmet need despite several reports demonstrating a large number of diagnostic, prognostic and theragnostic biomarker candidates in IPF. This review article aims to summarize our current knowledge of precision medicine in IPF and highlight barriers to translate these research findings into clinical practice.
Synergistic effect of constituent drugs of Baibutang on improving Yin-deficiency pulmonary fibrosis in rats
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Baibutang (BBT) is an ancient prescription for the treatment of pulmonary fibrosis. Previous experiments have shown that BBT had a good therapeutic effect on pulmonary fibrosis. However, there had been no study on the synergy between drugs composed of BBT. Due to the interaction between the constituent drugs, exploring their synergy profile is of great significance for explaining the essence of BBT's efficacy in improving pulmonary fibrosis.
Based on the pharmacodynamic value, this study aimed to explore a method for the evaluation of the synergy profile between constituent drugs in traditional Chinese medicine (TCM) compounds.
Nine herbs of BBT were divided into Zhikeqingre (ZK), Yangyinyiqi (YY) and Lishijianpi (LS) groups. A rat model of Yin-deficiency pulmonary fibrosis induced by thyroxine-bleomycin was used to evaluate the effects of BBT and the three groups. The pathological changes of lung tissue and the changes of biomarkers associated with fibrosis, Yin-deficiency and water-fluid metabolism were detected. After standardization of pharmacodynamics value (PV), the compatibility coefficient (CC) of the three groups, the relative PV (RPV) and contribution value (CV) of each group on every index were calculated.
The average CC on fibrosis indexes was 0.44, indicating that 44% of the efficacy of BBT came from the synergistic effect of the three groups. ZK group had the highest RPV (0.80) in improving fibrosis indexes such as histopathological changes, α-SMA, collagen-I and renin-angiotensin system. The average CC on Yin-deficiency indexes was 0.25, and YY group had the highest RPV (0.96) in improving deficiency indexes such as body temperature, cAMP/cGMP ratio, and PDEs, PGE2 and COX-2 levels. The average CC on water-fluid metabolism indexes was 0.15, and LS group had the highest RPV (1.52) in improving water-fluid metabolism indexes such as aquaporins, mucins, and surfactant proteins. The results also showed that 29% of the improvement effect of BBT on all indexes came from the synergistic effect of the three groups, and the contribution of ZK, YY and LS groups to the efficacy of BBT were 25%, 25% and 21%, respectively.
The established semiquantitative method can clearly and simply evaluate the synergy of the three groups in BBT, which will help to promote the research on the synergy of TCM compounds and other multiple-components combinations.
Improved targeting delivery of WED-load immunoliposomes modified with SP-A mAb for the treatment of pulmonary fibrosis
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The epithelial-mesenchymal transition (EMT) of type Ⅱ alveolar epithelial cells (AECS Ⅱ) induced by transforming growth factor (TGF-β1) is a primary pathogenesis of pulmonary fibrosis (PF). To augment the therapeutic potency of wedelolactone (WED) for PF, herein, pulmonary surfactant protein A (SP-A) specifically expressed on AECS Ⅱ was selected as the targeted receptor. Immunoliposomes modified with SP-A monoclonal antibody (SP-A mAb), novel anti-PF drug delivery systems, were developed and investigated in vivo and in vitro. In vivo fluorescence imaging technique was performed to evaluate the pulmonary-targeting effects of immunoliposomes. The result showed that immunoliposomes accumulated more in the lung, compared with non-modified nanoliposomes. Fluorescence detection methods and flow cytometry were used to investigate the function of SP-A mAb and the cellular uptake efficiency of WED-ILP in vitro. SP-A mAb enabled the immunoliposomes to specifically target the A549 cells and increased uptake more effectively. The mean fluorescence intensity (MFI) of cells treated with the targeted immunoliposomes was about 1.4-fold higher than that of cells treated with regular nanoliposomes. The cytotoxicity of nanoliposomes was assessed by the MTT assay, which demonstrated that blank nanoliposomes have no significant effect on A549 cell proliferation even at the SPC concentration of 1000 µg/mL. Additionally, in vitro pulmonary fibrosis model was established to further investigate the anti-pulmonary fibrosis effect of WED-ILP. WED-ILP significantly (**P < 0.01) inhibited the proliferation of A549 cells stimulated by TGF-β1 indicating that WED-ILP has great potential for the clinical treatment of PF.
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Citation Excerpt :
Traditional methods to predict survival in IPF relies on the clinician integrating the clinical, laboratory, radiologic, and/or pathologic data to make a clinical-radiologic-pathologic correlation.5,10 Current IPF biomarkers include Mucin protein 1 (MUC-1),11 CC chemokine ligand 18 (CCL18),12 serum surfactant proteins A (SP-A)13 and chitinase-like glycoprotein YKL-40.14 However, most biomarker studies are limited by the scale of candidate biomarkers, cohort size, and lack replication.8
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology that poses significant challenges in early diagnosis and prediction of progression. Analyses of microRNA and gene expression in IPF have yielded potentially predictive information. However, the relationship between microRNA/gene expression and quantitative phenotypic value in IPF remains controversial, as is the added value of this approach to current molecular signatures in IPF. To identify biomarkers predictive of survival in IPF via a microRNA-driven strategy. We profiled microRNA and protein-coding gene expression in peripheral blood mononuclear cells from 70 IPF subjects in a discovery cohort. We linked the microRNA/gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide and the forced vital capacity percent predicted. In silico analyses of expression profiles and quantitative phenotypic data allowed the generation of 2 sets of IPF molecular signatures (unique for microRNAs and protein-coding genes) that predict IPF survival. Each signature performed well in a validation cohort comprised of IPF patients aggregated from distinct patient populations recruited from different sites. Resampling test suggests that the protein-coding gene based signature is comparable and potentially superior to published IPF prognostic gene signatures. In conclusion, these results highlight the utility of microRNA-driven peripheral blood molecular signatures as valuable and novel biomarkers associated to individuals at high survival risk and for potentially facilitating individualized therapies in this enigmatic disorder.

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This work was supported by a National Institutes of Health T32 training grant and a Clinical Research Loan Repayment Grant (to Dr. Kinder); National Heart, Lung, and Blood Institute Specialized Center of Research (SCOR) grants No. HL-27353 and No. HL-67671; and a Dean's Scholars Clinical Research grant from the University of Cincinnati (to Dr. Kinder).

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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Chest

Original ResearchInterstitial Lung DiseaseSerum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis

Background

Methods

Results

Conclusions

Section snippets

Study Patients

Results

Discussion

Chest

Chest

Chest

Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality

Am J Respir Crit Care Med

Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia

Am J Respir Crit Care Med

International multidisciplinary consensus classification of the idiopathic interstitial pneumonias

Am J Respir Crit Care Med

A placebo-controlled trial of interferon γ-1b in patients with idiopathic pulmonary fibrosis

N Engl J Med

High-dose acetylcysteine in idiopathic pulmonary fibrosis

N Engl J Med

The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis

Am J Respir Crit Care Med

Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test

Am J Respir Crit Care Med

Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model

Am J Respir Crit Care Med

Original Research
Interstitial Lung Disease
Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis