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Erschienen in: Critical Care 6/2014

Open Access 01.12.2014 | Research

Dynamic gene expressions of peripheral blood mononuclear cells in patients with acute exacerbation of chronic obstructive pulmonary disease: a preliminary study

verfasst von: Xiaodan Wu, Xiaoru Sun, Chengshui Chen, Chunxue Bai, Xiangdong Wang

Erschienen in: Critical Care | Ausgabe 6/2014

Abstract

Introduction

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a serious event that is responsible for the progress of the disease, increases in medical costs and high mortality.

Methods

The aim of the present study was to identify AECOPD-specific biomarkers by evaluating the dynamic gene expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD on days 1, 3 and 10 after hospital admission and to compare the derived data with data from healthy controls or patients with stable COPD.

Results

We found that 14 genes were co–differentially upregulated and 2 downregulated greater than 10-fold in patients with COPD or AECOPD compared with the healthy individuals. Eight co–differentially upregulated genes and six downregulated genes were identified as a panel of AECOPD-specific genes. Downregulation of TCF7 in PBMCs was found to be associated with the severity of COPD. Dynamic changes of Aminolevulinate-delta-synthase 2 and carbonic anhydrase I had similar patterns of Digital Evaluation Score System scores and may serve as potential genes of interest during the course of AECOPD.

Conclusion

Thus, our findings indicate a panel of altered gene expression patterns in PBMCs that can be used as AECOPD-specific dynamic biomarkers to monitor the course of AECOPD.
Begleitmaterial
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13054-014-0508-y) contains supplementary material, which is available to authorized users.
Xiaodan Wu, Xiaoru Sun contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

XW carried out the study, participated in the data analysis and drafted the manuscript. XRS participated in the data mining and analysis. CSC and CXB participated in the study design and data analysis and helped to revise the manuscript. XDW conceived of the study, participated in its design and coordination and finalized the manuscript. All authors read and approved the final manuscript.
Abkürzungen
AE-1
Acute exacerbations of chronic obstructive pulmonary disease on day 1
AE-3
Acute exacerbations of chronic obstructive pulmonary disease on day 3
AE-10
Acute exacerbations of chronic obstructive pulmonary disease on day 10
AECOPD
Acute exacerbation of chronic obstructive pulmonary disease
ALAS2
Aminolevulinate, delta-, synthase 2
CA1
Carbonic anhydrase I
COPD
Chronic obstructive pulmonary disease
CXCL8
Chemokine (C-X-C motif) ligand 8
DESS
Digital evaluation score system
EPB42
Erythrocyte membrane protein band 4.2
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GO
Gene Ontology
IL
Interleukin
MHC
Major histocompatibility complex
MYH9
Myosin, heavy polypeptide 9, non-muscle
PBMC
Peripheral blood mononuclear cell
SCP2
Sterol carrier protein 2
SELENBP1
Selenium-binding protein 1
TCF7
Transcription factor 7
TFCP2L1
Transcription factor CP2-like 1

Introduction

Chronic obstructive pulmonary disease (COPD) is an inflammation-based syndrome characterized by progressive deterioration of pulmonary function and increasing airway obstruction [1]. COPD is a major and growing public health burden, ranking as the fourth leading cause of death in the world [2]. In China, it is the fourth leading cause of mortality in urban areas and the third leading cause in rural areas [3]. Patients with COPD often experience a sudden deterioration, termed acute exacerbations of chronic obstructive pulmonary disease (AECOPD), along with a progressive decline in lung function; AECOPD becomes more frequent and severe when the severity of disease increases [4],[5]. There is a great need for early and sensitive diagnosis and novel therapeutic targets for the disease, especially for patients with AECOPD in whom COPD is diagnosed in the late phase of disease, when they have significant or irreversible impairment [6].
The progress of COPD is accelerated by the occurrence of the exacerbation induced by multiple factors, including infection. AECOPD is a serious event that is related to decreased health status, increased medical and social costs and increased mortality [7]. Inflammatory cells (for example, lymphocytes, monocytes or macrophages, and their products) could interact with each other or with structural cells in the airways and the lung parenchymal and pulmonary vasculature, leading to the worsening of COPD [8]. Increased numbers of CD8+ lymphocytes were suggested as one of COPD’s characteristics, being present only in smokers who develop the disease [9]. Increased pulmonary inflammatory mediators in patients with COPD could attract inflammatory cells from the circulation, amplify the inflammatory process and induce structural changes [9].
Peripheral blood mononuclear cells (PBMCs) act as a critical component in the immune system to fight infection and adapt to intruders and play an important role in the development of AECOPD. Gene expression profiles of PBMCs were found to be disease-specific and associated with severity [10]. PBMC samples were suggested as easy to gather and important to the discovery of biomarkers for diagnosis and therapeutic management of COPD [11],[12], although gene expression changes in lung tissues were noted to be associated with COPD [13]-[15]. The aim of the present study was to determine AECOPD-specific biomarkers of PBMCs using the concept of clinical bioinformatics and integrating genomics, bioinformatics, clinical informatics and systems biology [16]-[18]. We translated all clinical measures, including patient complaints, history, therapies, clinical symptoms and signs, physician’s examinations, biochemical analyses, imaging profiles, pathologies and other measurements, into digital format using a digital evaluation scoring system. PBMCs were isolated from healthy volunteers and patients with stable COPD or AECOPD, and we investigated the disease specificity that we inferred from clinical informatics analysis to search for COPD- or AECOPD-specific genes and dynamic biomarkers for AECOPD.

Material and methods

Patient population

The present study was approved by the Ethical Evaluation Committee of Zhongshan Hospital and designed using a case–control approach. From among 220 candidates comprising blood donors (60 healthy controls), inpatients (80 patients with AECOPD) and outpatients (80 patients with stable COPD) in Zhongshan Hospital, patients with AECOPD, patients with stable COPD and healthy controls matched for age and sex were recruited into the study between October 2011 and March 2012. The inclusion criteria for patients with COPD were as follows: (1) forced expiratory volume in 1 second (FEV1) <80% of predicted value adjusted for age, weight and height, and (2) an improvement in FEV1 following bronchodilator inhalation <12% of baseline FEV1. Patients with asthma who had a persistent airflow obstruction were excluded. Stable COPD was defined according to American Thoracic Society/European Respiratory Society consensus criteria as no requirement for increased treatment above maintenance therapy, other than bronchodilators, for 30 days [1]. AECOPD was the reason for hospital admission and was characterized as a worsening of the patient’s respiratory symptoms that was beyond normal day-to-day variations and led to a change in medication [4],[19]. Healthy controls enrolled were blood donors at Zhongshan Hospital. Subjects with respiratory diseases, or any family history of lung disease, were excluded. PBMCs were harvested once from healthy controls and patients with stable COPD, as well as from patients with AECOPD, on the admission day and 3 and 10 days after the admission. Informed consent was given by the subjects themselves before they underwent lung function tests, high-resolution computed tomography and blood collection. The time points used in the present study were selected on the basis of our previous study for collecting plasma samples from healthy controls and from patients with stable COPD or AECOPD. The details of the study design are explained in Figure 1.

Digital evaluation score system

The Digital Evaluation Score System (DESS) is a score index used to translate clinical descriptions and information into clinical informatics, as described previously [20]. Using this instrument, we took into account patient symptoms and signs, biochemical analyses and clinical imaging for patients with stable COPD or AECOPD. Briefly, for the assessment of severity, each component was assigned a score of 0, 1, 2 or 4. The score of 4 as the maximum value indicates far above normal range or much severer condition, and 0 as the minimum value indicates within normal physiological range. After compiling patient data, we added the points for each variable. The DESS scores ranged from 0 to 256 points, with a higher score indicating a severer condition. Patients were scored on the day when their blood samples were collected.

Isolation of PBMC RNA

PBMCs were isolated by using BD Vacutainer CPT cell preparation tubes (Becton Dickinson, Franklin Lakes, NJ, USA) according to the manufacturer’s instructions. Approximately 4 ml of whole blood was collected from each subject. Following centrifugation, cells were lysed for RNA isolation. DNase-free total RNA preparation was performed using TRIzol reagent (Life Technologies, Carlsbad, CA, USA) and the RNeasy kit (QIAGEN, Valencia, CA, USA) according to the manufacturers’ recommendations. RNA concentrations were determined by using a NanoDrop ND-1000 spectrophotometer (NanoDrop, Wilmington, DE, USA). RNA quality was assessed on an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA), and samples with an RNA integrity number >6.0 were used.

Microarray analysis

The Human 12×135K Gene Expression Array (Roche NimbleGen Systems, Madison, WI, USA), with about 45,000+ human genes and transcripts represented with public domain annotations, was applied for this study. Sample labeling and array hybridization were performed according to the one-color microarray-based gene expression analysis protocol (Roche NimbleGen Systems). Double-stranded cDNA (ds-cDNA) was synthesized from 5 μg of total RNA using an Invitrogen SuperScript reverse transcriptase ds-cDNA synthesis kit (Life Technologies) in the presence of 100 pmol oligo(dT) primers. ds-cDNA was cleaned and labeled in accordance with the NimbleGen gene expression analysis protocol. Briefly, ds-cDNA was incubated with 4 μg of RNase A at 37°C for 10 minutes and cleaned using phenol:chloroform:isoamyl alcohol, followed by ice-cold absolute ethanol precipitation. The purified cDNA was quantified using the NanoDrop ND-1000 spectrophotometer. For Cy3 labeling of cDNA, the NimbleGen one-color DNA labeling kit was used according to the manufacturer’s guidelines as detailed in its gene expression analysis protocol. One microgram of ds-cDNA was incubated for 10 minutes at 98°C with 1 optical density of Cy3-9mer primer. Next, 100 pmol of deoxynucleoside triphosphates and 100 U of the Klenow fragment (New England Biolabs, Ipswich, MA, USA) were added, and the mix was incubated at 37°C for 2 hours. The reaction was stopped by adding 0.1 vol of 0.5 M ethylenediaminetetraacetic acid, and the labeled ds-cDNA was purified by isopropanol/ethanol precipitation. Microarrays were hybridized at 42°C for 16 to 20 hours with 4 μg of Cy3-labeled ds-cDNA in NimbleGen hybridization buffer/hybridization component A in a hybridization chamber. Following hybridization, washing was performed using the NimbleGen wash buffer kit. After being washed in an ozone-free environment, the slides were scanned using an Axon GenePix 4000B microarray scanner (Molecular Devices, Sunnyvale, CA, USA).

Data analysis

For clinical data, all values were expressed as mean ± SE. Analyses were performed using SPSS software (SPSS 18.0; SPSS, Chicago, IL, USA). For microarray analysis, slides were scanned at 5 μm/pixel resolution using the Axon GenePix 4000B microarray scanner piloted by GenePix Pro 6.0 software (Molecular Devices). Scanned images (in TIFF file format) were then imported into NimbleScan software (version 2.5) files for grid alignment and expression data analysis. Expression data were normalized through quantile normalization and the Robust Multi-array Average (RMA) algorithm included in the NimbleScan software. The probe-level (*_norm_RMA.pair) files and gene-level (*_RMA.calls) files were generated after normalization. All gene-level files were imported into GeneSpring GX software (version 11.5.1; Agilent Technologies) for further analysis. Differentially expressed genes between two samples were identified by fold change filtering. Hierarchical clustering was performed using the GeneSpring GX software. Gene Ontology (GO) database analysis and pathway analysis were performed using the standard enrichment computation method. The GO database covers three domains: biological process, cellular component and molecular function. Fisher’s exact test was used to find more overlaps between the descriptive list and the GO annotation list than would be expected by chance. The P-value denoted the significance of GO term enrichment in the descriptive genes. The gene expression data are publicly available in the Gene Expression Omnibus database [GEO:GSE60399] [21].

Results

Clinical informatics analysis

Clinical phenotypes are described in Table 1, including age, sex, smoking status, lung function test results and emphysema scores of the subjects. Control subjects were nonsmokers, and patients with stable COPD or AECOPD were ex-smokers. Because of the severity of disease, lung function tests were not performed at the onset of AECOPD; however, the baseline FEV1/forced vital capacity (FVC%) and FEV1/predicted percentage of patients with AECOPD were similar to those of patients with stable COPD. In addition, there was no significant difference in the extent of emphysema between patients with stable COPD and those with AECOPD (P = 0.47). DESS scores of subjects from each group are shown in Additional file 1. DESS values of patients with stable COPD or AECOPD were significantly higher than those of control subjects (P < 0.01), as shown in Table 2. DESS scores represented the severity of COPD and declined as the patient’s condition improved. DESS values of patients with AECOPD on day 1 of hospital admission (AE-1) were significantly higher than those on day 3 (AE-3) and day 10 (AE-10) (P < 0.05 and P < 0.01, respectively) (Table 2).
Table 1
Clinical phenotypes of healthy controls, patients with stable chronic obstructive pulmonary disease and patients with acute exacerbation of chronic obstructive pulmonary disease a
Groups
Subject no.
Age (yr)
Smoking status
FEV 1/FVC%
FEV 1/pred%
Goddard emphysema score
Control
1
56
Nonsmoker
75
85
0
 
2
53
Nonsmoker
80
87
0
 
3
62
Nonsmoker
77
91
0
 
4
68
Nonsmoker
81
83
0
 
5
58
Nonsmoker
79
81
0
 
6
67
Nonsmoker
76
90
0
Mean ± SE
 
60.7 ± 2.5
 
78.0 ± 1.0
86.2 ± 1.6
0.0 ± 0.0
Stable COPD
1
71
Ex-smoker
57
47
10
 
2
75
Ex-smoker
46
66
6
 
3
61
Ex-smoker
46
47
8
 
4
57
Ex-smoker
38
29
12
 
5
59
Ex-smoker
67
66
7
 
6
53
Ex-smoker
29
36
11
Mean ± SE
 
62.7 ± 3.5
 
47.2 ± 5.5
48.5 ± 6.2
9.0 ± 1.0
AECOPD
1
77
Ex-smoker
40
42
10
 
2
72
Ex-smoker
36
27
11
 
3
65
Ex-smoker
28
33
16
 
4
56
Ex-smoker
48
61
6
 
5
61
Ex-smoker
69
55
4
 
6
67
Ex-smoker
56
60
8
Mean ± SE
 
66.3 ± 3.1
 
46.2 ± 6.0
46.3 ± 5.9
9.2 ± 1.7
aAECOPD, Acute exacerbation of chronic obstructive pulmonary disease; COPD, Chronic obstructive pulmonary disease; FEV1, Forced expiratory volume in 1 second; FVC, Forced vital capacity; pred, Prediction. Data represent information gathered on days 1, 3 and 10 of hospital admission.
Table 2
Digital evaluation score system scores a
 
DESS scores
Patient no.
Control
Stable COPD
AE-1
AE-3
AE-10
1
0
30
100
78
43
2
4
27
81
66
46
3
8
35
86
76
36
4
4
55
70
51
30
5
3
38
80
71
35
6
0
47
97
81
30
Mean ± SE
3.2 ± 1.2
38.7 ± 4.3
85.7 ± 4.6
70.5 ± 4.5
36.7 ± 2.7
aAE-1, Day 1 of hospital admission; AE-3, Day 3 of hospital admission; AE-10, Day 10 of hospital admission; COPD, Chronic obstructive pulmonary disease; DESS, Digital evaluation score system.

Gene expression profiles

The quality of the genetic data obtained after filtering and the distribution of data sets were assessed and visualized by creating box plots, which showed that there were no significant differences in the distributions of log2 ratios among the groups (see Additional file 2: Figure S1). The variation or reproducibility of gene expression between arrays of different groups was visualized and assessed by creating scatterplots, which are shown in Figure 2. There was a significant variation in gene arrays between healthy controls and patients with stable COPD or AECOPD (Figures 2A to 2D) and between patients with stable COPD and AECOPD (Figures 2E to 2G). The variation in gene array data at AE-1 and AE-3 was significantly different from that at AE-10 (Figures 2I and 2J), whereas there was no difference between AE-1 and AE-3 (Figure 2H). The results of hierarchical clustering showed gene expression profiles similar to those revealed by the scatterplots shown in Figure S2 of Additional file 2.
To identify differentially expressed genes, a fold change filtering between each group pair was performed with a threshold fold change ≥2.0. There were ten comparison pairs with information for fold changes and regulation (that is, SEQ-ID, log fold change, log or absolute fold change, or regulation), normalized intensities or annotations (that is, GENE_NAME, synonyms, description, NCBI_GENE_ID, chromosome, GO, UniGene ID, The Institute of Genomic Research Database-TDB (TIGRID) or Ensembl ID), as shown in Additional file 3. Table 3 shows the number of genes overexpressed more than twofold, (for example, 4,508, 3,899, 4,167 and 3,488 genes of stable, AE-1, AE-3 and AE-10, respectively, above controls; 4,067, 5,063 or 5,451 genes of AE-1, AE-3 and AE-10, respectively, above stable COPD; 586 genes of AE-3 above AE-1; and 1,735 and 1,706 genes of AE-10, respectively, above AE-1 and AE-3). Tables 4, 5 and 6, respectively, list the genes overexpressed (above controls) in PBMCs from patients with stable COPD, AE-1, AE-3 or AE-10 by more than 30-fold (Table 4), between 20- and 30-fold (Table 5) and between 15- and 20-fold (Table 6). Tables 7, 8 and 9 list the genes overexpressed (above patients with stable COPD) in PBMCs from patients with AE-1, AE-3 or AE-10 by more than 30-fold (Table 7), between 20- and 30-fold (Table 8) and between 15- and 20-fold. Table 10 presents upregulated genes in PBMCs of patients at AE-1, AE-3 or AE-10.
Table 3
Genes upregulated in peripheral blood mononuclear cells a
 
Fold changes in upregulated genes ( n )
Comparisons
>2
>5
>8
>10
>15
>20
>30
>50
>100
Stable vs Con
4,508
671
217
145
49
27
9
1
0
AE-1 vs Con
3,899
734
334
221
136
86
40
18
3
AE-3 vs Con
4,167
742
358
259
149
97
51
17
5
AE-10 vs Con
3,488
677
331
238
116
74
35
10
1
AE-1 vs Stable
4,067
389
135
80
36
21
9
3
1
AE-3 vs Stable
5,063
620
221
146
56
24
10
1
0
AE-10 vs Stable
5,451
534
178
117
56
33
14
1
0
AE-3 vs AE-1
586
8
2
2
0
0
0
0
0
AE-10 vs AE-1
1,735
164
55
26
10
4
1
0
0
AE-10 vs AE-3
1,706
156
49
29
2
2
1
0
0
aData are number of upregulated genes expressed in peripheral blood mononuclear cells of healthy controls (Con) or of patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on hospital admission day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10).
Table 4
Genes upregulated >30-fold in peripheral blood mononuclear cells a
Stable vs control
AE-1 vs control
AE-3 vs control
AE-10 vs control
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
31.7
REXO1L2P
30.3
HP
30.1
FOS
30.8
EMP2
33.0
DEFA1
30.5
LOC152573
30.6
BPIL1
31.0
SEPP1
33.3
DUB3
31.2
INHBA
31.0
ARG1
31.0
FOLR1
37.2
LOC402207
31.4
COL6A3
31.6
N/A
31.1
GPX3
37.3
DUB3
32.4
MPO
31.9
LOC152573
31.2
SFTPB
40.5
LOC402110
32.6
ELF3
32.5
COL6A3
31.4
S100A14
43.1
LOC653600
34.4
CLDN4
32.9
TIMP3
33.1
FOLR1
43.5
N/A
34.9
DCN
33.5
FOS
33.4
CDH5
50.7
MGC45438
35.7
CTGF
34.4
KRT19
34.9
CAV1
  
35.7
MMP2
34.7
INHBA
35.4
DLC1
  
36.2
MFAP4
35.2
HP
35.6
FOSB
  
37.1
EPB42
35.6
CD177
36.1
KRT19
  
37.2
H19
36.5
LCN2
36.4
SUSD2
  
37.3
ATP1B1
36.9
CTGF
36.9
FN1
  
37.5
INHBA
37.9
MMP8
37.2
ADH1C
  
38.0
AZU1
38.3
ORM1
37.2
RNASE1
  
38.5
LCN2
38.8
ELF3
37.3
IL1RL1
  
39.6
CEACAM8
38.9
DCN
41.1
FOLR1
  
40.3
CALCA
39.0
CTSG
41.3
DHCR24
  
41.4
LOC387763
39.1
CLDN4
41.3
LOC387763
  
42.2
CEACAM3
39.3
CALCA
42.0
ADH1B
  
45.9
UNQ473
40.0
DCN
43.6
LAMA3
  
54.0
BPIL1
40.1
FOSB
45.0
GPX3
  
56.2
FN1
41.1
ATP1B1
47.9
DCN
  
56.7
CEACAM5
41.6
MFAP4
49.1
EPAS1
  
58.4
MMP8
41.8
FN1
50.9
CNN3
  
65.0
CALCA
42.0
MMP2
51.5
DCN
  
66.3
BPI
42.0
GPR97
54.5
LOC653509
  
68.7
DEFA1
42.2
INHBA
56.2
CXCL2
  
72.3
COL1A2
45.5
AZU1
58.2
MGC45438
  
77.2
CA1
46.0
BPI
58.5
CYP4B1
  
80.2
PLUNC
46.4
LOC387763
59.3
CTGF
  
83.0
CEACAM1
46.6
MPO
75.8
GPRC5A
  
83.9
DEFA4
50.0
HP
88.9
TIMP3
  
85.0
COL3A1
50.7
ORM2
149.5
MFAP4
  
96.1
DEFA1
53.1
UNQ473
  
  
99.4
CEACAM5
57.8
AQP9
  
  
101.2
CEACAM1
59.6
CEACAM5
  
  
115.8
LOC653600
59.6
BPIL1
  
  
140.3
DEFA4
61.0
CEACAM1
  
    
62.8
DEFA1
  
    
66.5
CEACAM1
  
    
72.6
DEFA4
  
    
82.5
PLUNC
  
    
86.7
DEFA1
  
    
92.9
COL1A2
  
    
100.8
CEACAM5
  
    
101.1
CALCA
  
    
109.4
LOC653600
  
    
111.5
COL3A1
  
    
165.7
DEFA4
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to healthy controls.
Table 5
Genes upregulated between 20- and 30-fold in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared with healthy control subjects a
Stable vs control
AE-1 vs control
AE-3 vs control
AE-10 vs control
Fold changes
Genes
Fold changes
Gene
Fold changes
Genes
Fold changes
Genes
20.1
P8
20.3
PLAU
20.0
ALPL
20.3
SCNN1A
20.1
REXO1L5P
21.0
COL6A3
20.1
MUC1
20.4
MGC45438
20.2
UNQ473
21.1
SLC25A37
20.2
SPDEF
20.7
FBLN1
20.2
DEFA1
21.1
HIG2
20.3
HIG2
20.7
CLDN4
20.5
LOC440015
21.2
GPRC5A
20.4
KLK11
20.9
SFTPA2
21.1
LOC391749
21.2
CFB
20.4
MGP
21.0
FKBP9
21.3
MGC45438
21.3
LTF
20.4
GPR109A
21.1
FAM107A
21.7
RP11-146D12.2
21.4
VSIG4
21.0
LOC653342
21.3
N/A
22.0
LOC399839
21.7
FOSB
21.1
CFB
21.4
C10orf10
22.9
SPDEF
21.9
SLC25A37
21.3
P8
21.5
SELENBP1
23.0
CLDN4
22.0
ARG1
21.8
PBEF1
21.6
ANXA3
24.7
LOC349196
22.0
SPDEF
21.9
S100P
21.6
IFI27
25.3
STAC2
22.2
LTF
21.9
MS4A3
21.8
C1QC
25.8
REXO1L3P
22.3
FOS
22.4
COL6A3
21.9
SEPP1
26.3
SCGB3A1
22.6
FAM46C
23.1
MANSC1
22.0
KLK11
26.9
RNASE1
22.6
ISLR
23.2
COL1A2
22.1
P8
27.0
AZGP1
22.6
COL1A2
23.2
GCA
22.1
LOC653723
29.5
H19
22.8
ATP1B1
23.3
LTBP2
22.5
LOC391359
  
23.8
SCNN1A
23.9
CHI3L1
22.7
LAMB2
  
23.8
SERPINE1
24.0
TMC5
22.8
AQP1
  
23.8
EPB42
24.2
CD24
24.0
C9orf61
  
23.8
C1QC
24.2
HP
24.1
C4BPA
  
23.9
RGS1
24.3
ISLR
24.2
LTBP2
  
23.9
ORM2
24.3
SIX1
24.3
UNQ473
  
24.1
COL5A1
24.5
APOE
24.5
TMEM139
  
24.5
MS4A3
24.6
COL3A1
24.6
N/A
  
25.6
CD177
24.6
LOC646309
25.7
OLFML3
  
25.6
APOE
24.7
CEACAM3
25.9
SNF1LK
  
26.4
C20orf114
24.9
AATK
25.9
A2M
  
26.6
BPIL1
25.3
LTF
26.4
FXYD3
  
27.1
CTSG
25.4
ALPL
27.0
HP
  
27.4
FOS
25.6
ACSL1
27.1
N/A
  
27.6
ALAS2
26.2
CEACAM6
27.4
LOC653509
  
28.0
INHBA
26.3
COL5A1
28.0
LDB2
  
28.0
TIMP3
26.4
KLK11
28.0
OLFML3
  
28.1
COL3A1
26.7
PRTN3
28.5
SFTPA1
  
28.1
SLC4A1
26.9
RGS1
28.6
MUC1
  
28.2
KLK11
27.3
KCNJ15
29.6
HSPA12B
  
28.2
LOC653492
27.4
CAMP
29.8
MFAP4
  
28.5
LOC203510
27.6
PLAU
  
  
28.7
CEACAM3
27.8
LTF
  
  
28.8
DCN
27.9
ANXA3
  
  
28.9
CEACAM1
28.0
H19
  
  
29.0
CEACAM6
28.0
SERPINE1
  
  
29.3
SELENBP1
28.1
LTF
  
  
29.7
KRT19
28.3
INHBA
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to healthy controls.
Table 6
Genes upregulated between 15- and 20-fold in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared with healthy control subjects a
Stable vs control
AE-1 vs control
AE-3 vs control
AE-10 vs control
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
15.2
LOC645558
15.0
CNN3
15.0
GPR109B
15.0
USP54
15.7
N/A
15.0
GPT2
15.0
LOC653492
15.0
MGC45438
15.9
LOC653455
15.1
ORM1
15.2
RNASE1
15.2
SLCO2A1
15.9
DUX4
15.1
LOC402110
15.3
FN1
15.3
AGER
16.1
LOC653768
15.1
MDK
15.5
ACSL1
15.3
FLJ11259
16.5
RAB17
15.2
ELF3
15.5
CDH5
15.5
CLEC3B
16.6
LOC653541
15.2
PSG8
15.6
FOLR3
15.8
ADCY4
16.6
LOC391763
15.3
SLC25A37
15.8
PVRL2
16.0
FN1
16.7
LOC642286
15.4
FKBP9
15.9
KRT19
16.1
HP
16.7
S100A14
15.5
C1QB
15.9
MDK
16.1
CKB
16.7
NBPF9
15.6
BPGM
16.0
APOC1
16.1
CYP4B1
16.9
PSG8
15.7
AQP9
16.3
NOL3
16.2
RARRES2
17.0
REXO1L6P
15.7
LOC402207
16.3
ATP1B1
16.3
TSPAN1
17.0
MLPH
15.7
PSG11
16.4
TMC4
16.6
SDC4
17.1
FAM90A7
16.0
KLK11
16.4
VEGF
16.7
ERG
17.4
LOC401650
16.2
KIAA0703
16.6
SPAG4
16.8
LOC653107
17.8
DUB3
16.2
IGFBP5
16.8
LIF
17.2
RAB25
17.9
MGC45438
16.2
IGFBP3
16.8
CCDC80
17.2
COL1A2
18.9
COL3A1
16.2
N/A
16.9
CEACAM3
17.3
DCN
19.1
LOC645732
16.2
SLC25A37
16.9
IGFBP3
17.5
TSPAN13
19.8
LOC392188
16.3
SIX1
17.1
CXCL2
17.6
HSD17B6
20.0
MUC1
16.3
LOC645009
17.2
FKBP9
17.8
RHOB
  
16.4
C1QA
17.2
CEACAM1
17.9
KRT19
  
16.5
UBD
17.7
ELF3
18.0
AQP9
  
16.6
LOC653342
17.7
CNN3
18.2
FOLR1
  
17.0
GPR97
17.8
PGLYRP1
18.2
IL1RL1
  
17.1
COL1A1
17.9
KRT23
18.2
SERPING1
  
17.3
ALPL
18.1
SLC44A4
18.3
MGC35295
  
17.4
FBLN1
18.1
SCNN1A
18.4
FLJ43663
  
17.5
HIG2
18.4
FBLN1
18.6
TGM2
  
17.7
COL8A1
18.5
HPR
18.6
ADH1C
  
17.9
TMC5
18.6
SYT7
18.7
KIAA1026
  
18.1
LTBP2
18.6
CEACAM8
19.1
DKFZP686A01247
  
18.4
SLC25A37
18.8
C1R
19.2
CCDC48
  
18.7
CEACAM3
18.8
COL1A1
19.2
ANKRD25
  
18.9
MPO
18.9
COL8A1
19.3
DMBT1
  
19.0
CD24
18.9
C1QC
19.4
MALL
  
19.0
CHI3L1
18.9
SFRP2
19.5
ANXA8
  
19.0
DCN
19.0
HIG2
19.5
SPRY4
  
19.1
P8
19.2
C1QB
19.7
ELF3
  
19.1
CEACAM6
19.2
GPRC5A
19.9
EHD2
  
19.1
ACSL1
19.3
MMP25
20.0
DCN
  
19.5
PRTN3
19.3
UBD
  
  
19.5
LIF
19.3
GADD45A
  
  
19.6
LTF
19.4
ISLR
  
  
19.7
ANXA3
19.5
ORM1
  
  
19.7
C1R
19.5
C20orf114
  
  
19.7
MUC1
19.5
LOC203510
  
  
19.8
PSG4
19.6
DCN
  
  
19.9
HP
19.7
FN1
  
    
19.8
DAAM2
  
    
19.9
FOLR3
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to healthy controls.
Table 7
Genes upregulated >30-fold in peripheral blood mononuclear cells of patients with AECOPD compared to patients with stable COPD a
AE-1 vs stable
AE-3 vs stable
AE-10 vs stable
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
37.3
MMP8
33.2
LOC646309
30.0
CCDC48
37.6
CEACAM5
34.7
SERPINE1
31.9
LOC653509
38.6
PLUNC
34.9
FOS
32.0
EPAS1
39.4
BPIL1
37.6
CYR61
32.2
CDH5
40.3
CYR61
39.5
CEACAM5
34.4
CLDN5
45.4
CEACAM5
39.6
PLUNC
36.3
SEPP1
55.2
CALCA
40.1
ARG1
38.7
CAV1
56.0
VSIG4
43.5
BPIL1
39.2
CYR61
103.9
CA1
46.0
CEACAM5
42.1
ADH1B
  
85.9
CALCA
44.2
CTGF
    
44.9
CAV1
    
45.1
GPRC5A
    
49.8
SEPP1
    
81.4
GPX3
aData are from patients with patients with acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to patients with stable chronic obstructive pulmonary disease (Stable).
Table 8
Genes upregulated between 20- and 30-fold in peripheral blood mononuclear cells of patients with AECOPD compared to patients with stable COPD a
AE-1 vs stable
AE-3 vs stable
AE-10 vs stable
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
20.1
MS4A3
20.5
GPR97
20.3
TIMP3
21.0
CEACAM6
20.6
ALPL
20.3
SLC6A4
21.1
SLC25A37
20.7
MTHFS
20.4
SFTPA2
21.2
DCN
21.0
FLJ32028
20.6
AKAP2
22.4
SPP1
21.4
ADM
20.7
DST
24.0
TCN1
23.3
ACSL1
21.2
TCF21
24.7
BPIL1
23.3
DCN
21.5
ADH1C
26.4
SLC25A37
24.3
MMP8
21.6
SLIT3
26.6
CTGF
24.5
TCN1
21.7
C9orf61
28.5
ARG1
25.3
FOS
22.5
FOSB
28.6
FOS
25.3
FOSB
25.5
MFAP4
29.5
SERPINE1
27.5
CTGF
26.0
GPX3
  
28.3
BPIL1
26.5
DCN
  
28.4
VSIG4
26.9
SFTPB
    
27.6
FBLN5
    
28.1
LOC653509
    
28.5
ADH1C
    
28.7
SFTPA1
    
28.7
TIMP3
aData are from patients with patients with acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to patients with stable chronic obstructive pulmonary disease (Stable).
Table 9
Genes upregulated between 15- and 20-fold in peripheral blood mononuclear cells of patients with AECOPD compared to patients with stable COPD a
AE-1 vs stable
AE-3 vs stable
AE-10 vs stable
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
15.6
ADM
15.2
LOC387763
15.0
VSIG4
15.8
DEFA4
15.2
MMP25
15.6
IL1RL1
16.2
DEFA4
15.3
USP15
15.8
PZP
16.2
C1R
15.5
C1R
16.0
LDB2
16.9
GPNMB
15.8
KCNJ15
16.2
FLJ43663
17.2
DCN
15.9
GADD45A
16.5
N/A
17.3
FAM46C
15.9
LRRC4
16.6
CD55
17.6
ALAS2
16.3
GLT1D1
16.8
CXCL2
17.6
CALCA
16.4
CD55
16.9
IL1RL1
17.9
GPNMB
16.5
CEACAM6
17.0
RHOB
18.2
DUSP1
16.6
SPP1
17.1
DLC1
18.2
CEACAM6
16.7
SLC25A37
17.2
VIPR1
18.2
SLC25A37
17.1
ORM1
17.2
CRYAB
18.7
FOS
17.2
CALCA
17.8
CNN3
18.9
SLC25A37
17.3
DUSP1
18.1
DCN
  
17.5
CD177
18.1
IFI27
  
17.6
GPNMB
18.2
SLIT2
  
17.7
MS4A3
18.3
RASIP1
  
17.8
DCN
18.8
MFAP4
  
17.8
GPR109A
19.0
CAMK2N1
  
17.9
BASP1
19.0
CD55
  
17.9
IL8RB
19.5
AGER
  
18.4
AQP9
19.9
DKFZP686A01247
  
18.7
DEFA4
  
  
18.8
QPCT
  
  
19.0
PBEF1
  
  
19.0
BASP1
  
  
19.0
CEACAM6
  
  
19.2
GNG10
  
  
19.7
GPNMB
  
  
19.7
GCA
  
  
20.0
RNASE3
  
aData are from patients with patients with acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission, as compared to patients with stable chronic obstructive pulmonary disease (Stable).
Table 10
Genes upregulated more than fivefold in peripheral blood mononuclear cells of patients with AECOPD a
AE-3 vs AE-1
AE-10 vs AE-1
AE-10 vs AE-3
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
5.1
TMEM50A
10.3
SUSD2
10.1
SLCO2A1
5.2
BCL2A1
10.6
TCF21
10.1
OAS3
5.3
C6orf32
10.6
FOLR1
10.1
C4BPA
6.0
PI3
10.7
C9orf61
10.2
DMBT1
7.0
KCNJ15
10.9
LOC653107
10.4
VSIG2
7.6
CISH
11.3
AGER
10.4
LOC653107
10.4
CISH
12.0
SLIT2
10.5
ITLN2
10.7
CISH
12.7
ITLN2
10.7
CX3CR1
  
12.9
FLRT3
10.7
MSLN
  
13.1
VIPR1
10.8
SOCS2
  
13.2
SOCS2
10.9
LOC653107
  
13.3
IL1RL1
11.7
FOLR1
  
13.4
LOC653107
11.7
GPX3
  
13.8
C4BPA
11.8
CLIC5
  
14.4
CYP4B1
11.8
SLIT2
  
14.4
LAMA3
11.9
LOC653107
  
15.1
CYP4B1
12.1
AQP1
  
15.2
ADH1C
12.6
LOC653509
  
15.7
MGC35295
12.6
ADH1C
  
15.8
GPX3
12.7
ADH1C
  
17.0
IL1RL1
12.8
ADH1B
  
17.9
MSLN
12.9
LAMA3
  
20.0
ADH1C
13.6
IL1RL1
  
22.4
ADH1B
13.6
CYP4B1
  
24.5
SLC6A4
13.9
FAM107A
  
35.3
FOLR1
14.2
LOC653107
    
14.9
CYP4B1
    
22.0
MGC35295
    
31.2
SLC6A4
aData are from day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission.
Table 11 lists the number of genes downregulated more than twofold, including 4,516, 2,975, 3,426 and 2,798 genes of PBMCs from patients with stable COPD on AE-1, AE-3 and AE-10, respectively, below controls; 3,207, 4,510 and 5288 genes on AE-1, AE-3 and AE-10, respectively, below stable COPD; 598 genes from AE-3 below AE-1; and 2,162 and 1,918 genes from AE-10 below those from AE-1 and AE-3, respectively. Downregulated genes of PBMCs from patients with stable COPD, AE-1, AE-3 or AE-10 greater than tenfold, between 10- and 8-fold or between 8- and 6-fold below healthy control subjects are listed in Tables 12, 13 and 14, respectively. Downregulated genes of PBMCs from patients at AE-1, AE-3 or AE-10 compared to stable COPD, or among patients with AECOPD, are shown in Tables 15 and 16.
Table 11
Number of downregulated genes in peripheral blood mononuclear cells of healthy control subjects, patients with stable COPD and patients with AECOPD a
 
Fold changes in upregulated genes ( n )
Compared pairs
>2
>5
>6
>8
>10
>15
>20
>30
>50
>100
Stable vs Con
4,516
135
55
9
4
2
1
0
0
0
AE-1 vs Con
2,975
182
107
47
22
7
4
1
0
0
AE-3 vs Con
3,426
225
149
65
35
11
5
2
0
0
AE-10 vs Con
2,798
124
73
31
16
2
1
1
0
0
AE-1 vs Stable
3,207
33
16
4
4
2
0
0
0
0
AE-3 vs Stable
4,510
125
71
21
8
3
1
0
0
0
AE-10 vs Stable
5,288
445
236
97
49
20
8
3
0
0
AE-3 vs AE-1
598
32
23
17
5
3
2
0
0
0
AE-10 vs AE-1
2,162
261
168
82
43
21
14
10
5
1
AE-10 vs AE-3
1,918
192
130
66
36
15
9
6
4
0
aData are from controls (Con) or patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of the hospital admission.
Table 12
Genes downregulated more than tenfold in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared to healthy control subjects a
Stable vs Con
AE-1 vs Con
AE-3 vs Con
AE-10 vs Con
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
10.7
EIF3S6
10.3
HAND1
10.2
GZMK
10.0
C21orf7
10.7
YLPM1
10.3
CD8B
10.5
CXCR3
10.0
NELL2
16.1
TFCP2L1
10.4
UBASH3A
10.6
AK5
10.4
C21orf7
21.0
SCP2
10.8
TRA@
10.7
TRA@
10.4
GFI1B
  
10.9
TRBV3-1
10.7
IL24
10.5
LOC129293
  
11.2
CD8B
10.9
CD6
10.5
LOC123876
  
11.4
MAL
10.9
N/A
10.7
HIST1H3H
  
11.4
LOC643514
11.2
KIAA0748
11.1
IL24
  
11.5
NELL2
11.4
LCK
11.4
GFI1B
  
11.7
TTC24
11.5
CD8B
11.9
CRTAC1
  
12.7
CD8B
12.3
APBB1
11.9
OR10A4
  
13.1
LEF1
12.3
IL12RB1
11.9
SAA3P
  
13.8
TCF7
12.5
TTC24
12.7
TTC24
  
14.2
LOC129293
12.5
GFI1B
14.9
TFCP2L1
  
14.5
LOC129293
12.5
CRTAC1
18.6
SCP2
  
15.6
TCF7
12.6
TRBV3-1
32.3
UNQ470
  
16.1
TCF7
12.6
ATG9B
  
  
16.8
CD8B
12.9
ABLIM1
  
  
21.8
TFCP2L1
12.9
LOC129293
  
  
25.4
CRTAC1
13.0
CD8B
  
  
27.9
SCP2
13.1
CD28
  
  
44.1
UNQ470
13.1
GRAP2
  
    
14.3
UBASH3A
  
    
14.4
CCR7
  
    
15.0
LOC129293
  
    
16.0
CD8B
  
    
18.1
UNQ470
  
    
18.7
SCP2
  
    
18.8
LEF1
  
    
19.3
LEF1
  
    
23.5
CD8B
  
    
24.3
TCF7
  
    
25.1
TCF7
  
    
30.4
TCF7
  
    
32.0
TFCP2L1
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of the hospital admission, as compared to healthy controls (Con).
Table 13
Genes downregulated between eight- and tenfold in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared to healthy control subjects a
Stable vs Con
AE-1 vs Con
AE-3 vs Con
AE-10 vs Con
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
8.2
AK5
8.1
CD3G
8.0
TRBV19
8.1
HFE2
8.6
TRA@
8.2
LY9
8.0
OTOA
8.2
TRA@
9.1
ZC3HAV1
8.2
AK5
8.1
CD7
8.6
UNQ470
9.3
MAL
8.2
C21orf7
8.1
GRAP2
8.6
CD248
9.7
TMEM50B
8.2
TRBC1
8.1
TNFRSF25
8.6
XG
  
8.3
ANKDD1A
8.2
C21orf7
8.7
ATG9B
  
8.4
CD6
8.2
EPHA6
8.8
LOC339778
  
8.4
RPS6KB1
8.2
GIMAP5
8.9
TCF7
  
8.5
TMEM50B
8.3
1-Sep
8.9
CCR7
  
8.7
YLPM1
8.3
UBASH3A
9.2
LOC644663
  
8.7
TRBV19
8.4
GIMAP7
9.4
LOC129293
  
8.8
FLT3LG
8.5
MGC23244
9.5
MGC39606
  
8.9
N/A
8.6
LOC645852
9.7
GZMK
  
9.1
LEF1
8.7
SCAP1
9.9
AK5
  
9.1
GZMK
9.0
HIST1H3H
9.9
TCF7
  
9.1
KIAA0748
9.0
HFE2
  
  
9.2
ABLIM1
9.2
GFI1B
  
  
9.5
C21orf7
9.2
TMEM50B
  
  
9.5
ATG9B
9.5
N/A
  
  
9.6
LCK
9.5
C21orf7
  
  
9.6
LOC647353
9.6
GATA3
  
  
9.8
CCR7
9.7
C21orf7
  
  
9.8
UNQ470
9.7
CD247
  
  
9.9
OR10A4
9.8
LCK
  
  
9.9
IL12RB1
9.8
KSP37
  
    
9.9
FAIM3
  
    
9.9
SPOCK2
  
    
9.9
TRA@
  
    
9.9
SH2D1B
  
    
10.0
GRAP2
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of the hospital admission, as compared to healthy controls (Con).
Table 14
Genes downregulated between six- and eightfold in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared to healthy control subjects a
Stable vs Con
AE-1 vs Con
AE-3 vs Con
AE-10 vs Con
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
6.0
NDUFV3
6.0
MAL
6.0
IL7R
6.0
HKDC1
6.0
C17orf45
6.0
ARHGAP12
6.0
CD28
6.1
TANC2
6.1
MAL
6.0
TRAPPC4
6.0
KIR2DS1
6.1
FAM5B
6.1
CXCR6
6.0
GNLY
6.0
FLJ20647
6.2
KIAA0748
6.1
SUCLA2
6.0
N/A
6.1
N/A
6.3
CD40LG
6.1
C21orf7
6.0
LOC642376
6.1
CLDN1
6.3
PCDH10
6.2
TNPO1
6.0
MYOZ3
6.1
TRBV5-4
6.3
LOC644273
6.2
LOC643514
6.1
FLJ20647
6.1
CARD11
6.3
CD96
6.2
ALS2CR13
6.1
CD96
6.1
LOC441320
6.3
TRA@
6.2
CREB1
6.2
MAL
6.1
ACADSB
6.3
TRBV3-1
6.2
C17orf45
6.2
GIMAP5
6.1
NXPH4
6.4
TRA@
6.3
NELL2
6.2
CLDN1
6.2
SCNN1D
6.4
LOC642483
6.3
C6orf32
6.2
CD3D
6.2
MTMR1
6.5
ANKDD1A
6.3
LOC642455
6.2
LY9
6.2
MAL
6.5
N/A
6.4
GMDS
6.3
LOC123876
6.2
ZAP70
6.5
N/A
6.4
ABHD6
6.3
TNFRSF25
6.3
MAL
6.5
LY9
6.4
DAPP1
6.3
C21orf7
6.3
IL2RB
6.6
CD8B
6.4
SH3BGRL
6.3
LOC645885
6.3
EDG8
6.6
MGC26597
6.5
IL7R
6.3
BLOC1S3
6.3
HKDC1
6.7
TRBV19
6.6
LOC441601
6.3
LOC644727
6.3
SCAP1
6.7
LOC145783
6.6
GPR18
6.4
CCDC45
6.3
LOC440455
6.8
CD8B
6.7
P2RX5
6.4
C21orf7
6.3
CD300E
6.9
C21orf7
6.7
LY9
6.5
CD28
6.4
LY9
6.9
UBASH3A
6.8
GGPS1
6.5
LOC440455
6.4
KIR2DS2
7.0
LOC400768
6.8
EIF3S6
6.5
IL24
6.4
SLAMF6
7.1
CD8B
6.8
ARHGAP15
6.5
GHRL
6.4
SAA3P
7.1
HAND1
6.8
SF3B1
6.5
FAM113B
6.4
SF3A2
7.2
LOC126075
6.8
GPR89A
6.5
LOC644663
6.5
UNQ470
7.2
TNFRSF7
6.9
LOC129293
6.5
C15orf37
6.5
C6orf21
7.3
LEF1
6.9
CPNE3
6.5
MAL
6.6
CD96
7.3
HLA-DOA
6.9
LY9
6.5
LOC644445
6.6
CD244
7.4
LOC646279
7.0
PIP3-E
6.6
LOC126075
6.6
N/A
7.4
YLPM1
7.0
TAF9
6.6
1-Sep
6.6
KLRK1
7.4
LOC643514
7.0
N/A
6.6
UBASH3A
6.6
C16orf5
7.5
MTMR1
7.0
KIAA0748
6.7
SAA3P
6.6
TRBC1
7.6
NOG
7.1
CD55
6.8
CD6
6.6
LOC339778
7.7
TCF7
7.2
EIF3S6
6.8
TRBV5-4
6.7
GNLY
7.7
KIAA0748
7.2
PGRMC2
6.9
1-Sep
6.7
LDLRAP1
7.7
C21orf7
7.3
C21orf7
6.9
LOC129293
6.8
HAND1
7.7
PRDM9
7.4
PSMD6
7.0
SCNN1D
6.8
CD3D
7.7
FCER2
7.5
ABLIM1
7.0
SIT1
6.8
FLJ45825
7.9
CD8B
7.6
STAG2
7.1
GATA3
6.8
SF3A2
8.0
LEF1
7.8
CCDC45
7.1
CD7
6.8
CXCR3
  
7.8
UNQ470
7.1
CDKN3
6.8
KIR3DL3
  
7.9
LY9
7.2
SCAP1
6.8
LAT
  
8.0
CD40LG
7.3
TRA@
6.9
CD52
  
  
7.3
LY9
6.9
TNFRSF7
  
  
7.3
DDAH1
6.9
LOC442726
  
  
7.3
TRA@
6.9
3-Sep
  
  
7.5
TNFRSF7
6.9
KIAA0748
  
  
7.5
KIAA0748
6.9
XG
  
  
7.6
ITM2A
6.9
KIAA1549
  
  
7.6
CD5
7.0
RNF157
  
  
7.6
D4S234E
7.0
SIT1
  
  
7.6
CD300E
7.0
CD1C
  
  
7.7
APBB1
7.0
SLC16A10
  
  
7.8
CD3D
7.0
CD3G
  
  
7.8
LCK
7.1
CD6
  
  
7.8
UBASH3A
7.1
LY9
  
  
7.9
XG
7.1
FLT3LG
  
    
7.1
LOC647353
  
    
7.2
LOC123876
  
    
7.2
CX3CR1
  
    
7.2
LOC126075
  
    
7.3
NELL2
  
    
7.4
LY9
  
    
7.4
MAL
  
    
7.4
KIR2DS2
  
    
7.4
CHIA
  
    
7.4
BIN1
  
    
7.5
CCDC78
  
    
7.5
MAL
  
    
7.5
C21orf7
  
    
7.5
KIR2DL4
  
    
7.6
CD6
  
    
7.6
CD3D
  
    
7.7
1-Sep
  
    
7.7
LCK
  
    
7.8
ITM2A
  
    
7.8
TRA@
  
    
7.9
SIT1
  
    
7.9
CD5
  
    
8.0
CD8A
  
    
8.0
LOC129293
  
aData are from patients with stable chronic obstructive pulmonary disease (Stable) or acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) after the hospital admission, as compared to healthy controls (Con).
Table 15
Genes downregulated more than fivefold in peripheral blood mononuclear cells of patients with AECOPD compared to patients with stable COPD a
AE-1 vs Stable
AE-3 vs Stable
AE-10 vs Stable
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
5.0
PRODH
10.2
KSP37
10.1
LOC646781
5.1
MT1F
10.3
DUB3
10.1
LOC389634
5.1
OR2A7
10.6
DUB3
10.1
LOC441056
5.3
CD8B
10.8
TCF7
10.1
LOC340243
5.4
CGI-38
11.2
CX3CR1
10.2
C1QL2
5.4
DMBT1
17.6
MGC35295
10.2
LOC653541
5.4
N/A
19.9
STAC2
10.2
LOC158318
5.4
GNLY
25.0
AZGP1
10.3
N/A
5.5
LCK
  
10.4
LOC644373
5.5
DZIP1
  
10.6
SPDEF
5.6
TCF7
  
10.7
DUX1
5.6
MGC45438
  
10.9
LOC643001
5.6
UNQ470
  
11.1
LOC391767
5.8
MGLL
  
11.2
LOC645509
5.8
B4GALNT3
  
11.7
FLJ36131
5.9
CGI-38
  
11.8
LOC441323
5.9
CGI-38
  
11.9
LOC440015
6.1
LOC388886
  
11.9
LOC441812
6.1
GNLY
  
12.0
TCEB3C
6.2
N/A
  
12.1
SPDEF
6.4
CD8B
  
12.3
DUX4
6.4
AEBP2
  
12.5
LOC285697
6.4
EDG8
  
12.9
LOC646066
6.5
PRDM16
  
13.3
LOC441873
6.8
CX3CR1
  
13.6
LOC645402
7.0
MGC45438
  
13.7
LOC285563
7.3
MST1
  
13.9
LOC391763
7.4
LOC644088
  
14.4
DUB3
7.5
EDG8
  
14.7
LOC391766
10.1
MGC45438
  
15.0
LOC392197
12.6
MGC35295
  
15.0
REXO1L2P
15.5
STAC2
  
15.2
DUB3
19.1
AZGP1
  
15.2
LOC402199
    
15.7
LOC653442
    
15.8
LOC653455
    
16.0
LOC402207
    
16.5
LOC391745
    
16.7
LOC392188
    
18.1
REXO1L6P
    
19.1
LOC391764
    
19.4
DUB3
    
20.6
LOC645836
    
21.0
LOC391749
    
23.8
LOC402110
    
24.2
REXO1L7P
    
29.6
REXO1L1
    
30.0
STAC2
    
33.5
REXO1L3P
    
39.7
REXO1L5P
aData are from patients acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) after the hospital admission, as compared to patients with stable chronic obstructive pulmonary disease (Stable).
Table 16
Genes downregulated more than fivefold in peripheral blood mononuclear cells of patients with AECOPD a
AE-3 vs AE-1
AE-10 vs AE-1
AE-10 vs AE-3
Fold changes
Genes
Fold changes
Genes
Fold changes
Genes
5.0
ITGB3
10.2
MPO
10.3
MOXD1
5.1
CGI-69
10.4
LOC653492
10.3
LOC152573
5.2
SPTB
10.5
SPP1
10.7
SPDEF
5.2
BCL2L1
10.6
ANK1
10.8
CCDC80
5.2
GATA1
11.0
DEFA4
11.0
CTSG
5.3
FBXO7
11.0
MOXD1
11.0
CAMP
5.6
SELENBP1
11.0
HIG2
11.3
PLA2G2D
5.8
OSBP2
11.1
OSBP2
11.4
SPP1
5.9
LOC643855
11.2
REXO1L3P
11.6
S100P
6.1
ERAF
11.6
SPDEF
11.7
SLC4A11
6.2
EPB49
12.0
COL1A1
11.8
COL3A1
6.2
MYH9
12.2
BPI
11.8
SPAG4
6.4
ALAS2
12.3
SNCA
12.5
THBS2
7.4
LOC644462
12.3
SLC4A11
12.7
MPO
7.8
GMPR
12.5
COL1A1
13.0
PRTN3
8.1
ANK1
12.6
AZU1
13.2
COL1A1
8.9
BPGM
12.6
ARG1
13.3
ELA2
9.1
FAM46C
13.2
GREM1
14.3
LIF
9.2
LOC643497
13.5
DEFA4
14.4
CEACAM5
9.4
TRIM58
13.5
ELA2
14.6
RNF183
9.4
MBNL3
14.2
CEACAM5
14.9
B3Gn-T6
9.5
EPB49
14.5
ITGA11
15.1
AZU1
9.6
EPB49
15.0
CEACAM8
15.4
ITGA11
9.6
EPB42
15.3
SPTB
15.9
DEFA4
9.7
EPB41
15.6
CEACAM5
16.4
CEACAM5
9.7
SLC14A1
16.6
LIF
17.5
MS4A3
9.9
EPB42
17.1
TRIM58
17.8
ARG1
10.1
SNCA
19.2
THY1
20.4
THY1
13.5
TRIM58
19.5
MS4A3
21.1
MS4A3
19.7
SLC4A1
23.1
TRIM58
22.5
SPP1
20.7
EPB41
24.1
MS4A3
34.4
SFRP2
21.6
CA1
27.1
SFRP2
49.9
PLUNC
  
29.9
EPB42
57.1
CALCA
  
30.4
SPP1
68.9
CALCA
  
41.9
ALAS2
80.4
BPIL1
  
43.8
EPB42
93.1
BPIL1
  
44.2
CALCA
  
  
48.5
PLUNC
  
  
55.5
SLC4A1
  
  
58.6
CALCA
  
  
70.0
BPIL1
  
  
84.3
BPIL1
  
  
109.9
CA1
  
aData are from patients with acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) after the hospital admission.

COPD-specific genes

To search for COPD-specific genes, co–differentially expressed genes of PBMCs from patients with stable COPD or AECOPD were compared with those from control subjects (listed in Additional file 4). There were five groups and four comparison pairs with information regarding fold changes and regulation (that is, SEQ-ID, fold change, log or absolute fold change, or regulation), normalized intensities or annotations (that is, GENE_NAME, synonyms, description, NCBI_GENE_ID, chromosome, GO, UniGene ID, TIGRID or Ensembl ID). Seventy-nine genes were upregulated and 23 genes downregulated in PBMCs from patients with COPD, including both stable COPD and AECOPD, as compared to the healthy control subjects, as shown in Table 17. Of them, 14 genes were upregulated and 2 were downregulated more than tenfold, as compared to control subjects, including carcinoembryonic antigen–related cell adhesion molecule 1, collagen type VIα3(VI), collagen type I(α)2(I), nucleolar protein 3 (apoptosis repressor with CARD domain), melanophilin, cell surface–associated mucin 1, nuclear protein 1, chemokine (C-X-C motif) ligand 17, claudin 4, ribonuclease 1, imprinted maternally expressed transcript, defensin α1, transcription factor CP2-like 1 and sterol carrier protein 2 (SCP2).
Table 17
Number and details of co–differentially up- or downregulated genes in peripheral blood mononuclear cells of patients with stable COPD or AECOPD compared to healthy control subjects a
Fold change
>5
>10
Upregulated
79
14
Downregulated
23
2
Unexpressed genes (>10)
SEQ-ID
Gene name
Full name of gene
Stable vs Con
AE-1 vs Con
AE-3 vs Con
AE-10 vs Con
D12502
CEACAM1
Carcinoembryonic antigen-related cell adhesion molecule 1
10.1
83.0
66.5
10.5
NM_004369
COL6A3
Collagen, type VI, α3
10.4
21.0
22.4
10.8
AF064599
NOL3
Nucleolar protein 3 (apoptosis repressor with CARD domain)
12.1
13.6
16.3
11.5
BC042586
COL1A2
Collagen, type I, α2
13.1
72.3
92.9
17.2
BC014473
CEACAM1
Carcinoembryonic antigen-related cell adhesion molecule 1
14.7
101.2
61.0
11.8
AY358857
MLPH
Melanophilin
17.0
10.3
12.8
12.2
AF348143
MUC1
Mucin 1, cell surface-associated
20.0
19.7
20.1
28.6
NM_012385
P8
p8 protein (candidate of metastasis 1)
20.1
19.1
21.3
22.1
BC093946
UNQ473
DMC
20.2
45.9
53.1
24.3
NM_001305
CLDN4
Claudin 4
23.0
34.4
39.1
20.7
NM_002933
RNASE1
Ribonuclease, RNase A family, 1 (pancreatic)
26.9
12.5
15.2
37.2
BC053636
H19
H19, imprinted maternally expressed untranslated mRNA
29.5
37.2
28.0
11.8
BC069423
DEFA1
Defensin, α1
33.0
96.1
86.7
10.2
XM_928349
LOC653600
Similar to neutrophil defensin 1 precursor (HNP-1) (HP-1) (HP1) (defensin, α1)
43.1
115.8
109.4
12.8
Downregulated genes (>5)
SEQ-ID
Gene name
Full name of genes
Stable vs Con
AE-1 vs Con
AE-3 vs Con
AE-10 vs Con
M38056
HLA-DOA
Major histocompatibility complex, class II, DOα
5.3
5.9
5.6
7.3
AY209188
SAA3P
Serum amyloid A3 pseudogene
5.3
6.7
6.4
11.9
BC069511
UBASH3A
Ubiquitin-associated and SH3 domain-containing, A
5.5
10.4
14.3
6.9
AJ421515
CRTAC1
Cartilage acidic protein 1
5.6
25.4
12.5
11.9
AL133666
EPHA6
EPH receptor A6
5.6
5.8
8.2
5.3
NM_020152
C21orf7
Chromosome 21 open reading frame 7
5.7
8.2
9.7
10.4
XM_089384
TTC24
Tetratricopeptide repeat domain 24
5.8
11.7
12.5
12.7
NM_006850
IL24
Interleukin 24
6.0
6.5
10.7
11.1
AL713701
C21orf7
Chromosome 21 open reading frame 7
6.1
9.5
9.5
10.0
XM_931594
LOC643514
Hypothetical protein LOC643514
6.2
11.4
5.7
7.4
NM_006159
NELL2
NEL-like 2 (chicken)
6.3
11.5
7.3
10.0
NM_002348
LY9
Lymphocyte antigen 9
6.7
8.2
7.4
6.5
XM_934852
LOC129293
Hypothetical protein LOC129293
6.9
14.5
12.9
9.4
BC062589
LY9
Lymphocyte antigen 9
6.9
7.3
7.1
5.5
XM_934149
KIAA0748
KIAA0748
7.0
7.5
11.2
6.2
BC008567
C21orf7
Chromosome 21 open reading frame 7
7.3
6.3
7.5
7.7
NM_138363
CCDC45
Coiled-coil domain containing 45
7.8
6.4
5.9
5.2
BC022101
UNQ470
GAAI470
7.8
44.1
18.1
32.3
BC027920
LY9
Lymphocyte antigen 9
7.9
6.2
5.8
5.3
BC033896
AK5
Adenylate kinase 5
8.2
8.2
10.6
9.9
XM_085151
YLPM1
YLP motif containing 1
10.7
8.7
5.1
7.4
NM_014553
TFCP2L1
Transcription factor CP2-like 1
16.1
21.8
32.0
14.9
NM_001007098
SCP2
Sterol carrier protein 2
21.0
27.9
18.7
18.6

AECOPD-specific genes

To search for AECOPD-specific genes, co–differentially expressed genes of PBMCs from patients with AECOPD on days 1, 3 and 10 were compared to those from either patients with stable COPD or healthy control subjects (listed in Additional file 4). There were five groups and six comparison pairs with information regarding fold changes and regulation (that is, SEQ-ID, fold change, log or absolute fold change, or regulation), normalized intensities or annotations (that is, GENE_NAME, synonyms, description, NCBI_GENE_ID, chromosome, GO, UniGene ID, TIGRID or Ensembl ID). As compared with both patients with stable COPD and healthy control subjects, 58 genes were upregulated more than fivefold and 238 downregulated more than twofold in patients with AECOPD. Of them, eight upregulated (more than tenfold) and eight downregulated (more than threefold) genes are listed in Table 18. These genes include FBJ murine osteosarcoma viral oncogene homologue (FOS); interferon α-inducible protein 27 (IFI27); cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF); G protein–coupled receptor family C group 5 member A (GPRC5A); FBJ murine osteosarcoma viral oncogene homologue B (FOSB); decorin (DCN); hypothetical LOC387763 (LOC387763); killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 2 (KIR2DS2); SH2 domain containing 1B (SH2D1B); CD8b molecule (CD8B); olfactory receptor family 2, subfamily W, member 5 (OR2W5); fibroblast growth factor binding protein 2 (FGF2); and transcription factor 7 (TCF7).
Table 18
Number of co–differentially up- or downregulated genes in peripheral blood mononuclear cells of patients with AECOPD compared to patients with stable COPD and healthy control subjects a
Fold change
>5
>10
Upregulated
58
8
Fold change
>2
>3
Downregulated
238
8
Selected co–differentially upregulated genes (>10-fold)
SEQ_ID
Gene name
AE-1
AE-3
AE-10
AE-1 vs Con
AE-1 vs Stable
AE-3 vs Con
AE-3 vs Stable
AE-10 vs Con
AE-10 vs Stable
BC004490
FOS
27.4
28.6
33.5
34.9
13.2
13.7
BC015492
IFI27
12.3
10.3
13.1
11.0
21.6
18.1
NM_001554
CYR61
12.0
40.3
11.2
37.6
11.7
39.2
NM_001901
CTGF
35.7
26.6
36.9
27.5
59.3
44.2
NM_003979
GPRC5A
21.2
12.6
19.2
11.4
75.8
45.1
NM_006732
FOSB
21.7
13.7
40.1
25.3
35.6
22.5
NM_133504
DCN
19.0
17.2
19.6
17.8
20.0
18.1
XM_373497
LOC387763
41.4
13.5
46.4
15.2
41.3
13.5
Selected co–differentially downregulated genes (>3-fold)
SEQ_ID
Gene names
AE-1
AE-3
AE-10
AE-1 vs Con
AE-1 vs Stable
AE-3 vs Con
AE-3 vs Stable
AE-10 vs Con
AE-10 vs Stable
AJ002102
KIR2DS2
3.7
3.8
7.4
7.6
4.2
4.4
BC022407
SH2D1B
3.0
3.7
4.8
5.9
3.1
3.8
BC066595
SH2D1B
3.6
3.2
9.9
8.9
3.6
3.2
BC100911
CD8B
11.2
4.4
16.0
6.3
7.9
3.1
NM_001004698
OR2W5
3.7
3.1
4.7
4.0
3.7
3.1
NM_004931
CD8B
10.3
5.3
11.5
5.9
6.6
3.4
NM_031950
KSP37
4.8
5.0
9.8
10.2
3.0
3.1
NM_201633
TCF7
15.6
5.6
30.4
10.8
8.9
3.2

Dynamic change in gene expression in patients with AECOPD

Dynamic changes (down–down, down–up, up–down and up–up) of co–differentially expressed genes of PBMCs from patients with AECOPD are listed in Additional file 4, including fold changes and regulation (that is, SEQ-ID, fold change, log or absolute fold change, or regulation), normalized intensities or annotations (that is, GENE_NAME, synonyms, description, NCBI_GENE_ID, chromosome, GO, UniGene ID, TIGRID or Ensembl ID). Table 19 shows the dynamic changes in the patterns of down–down (52 genes), down–up (131 genes), up–down (238 genes) and up–up (8 genes) more than twofold, as compared with the gene expression on the previous day. The major genes of PBMCs from patients with AECOPD were aminolevulinate, delta-, synthase 2 (ALAS2), erythrocyte membrane protein band 4.2 (EPB42) and carbonic anhydrase I (CA1) in a down–down pattern; selenium-binding protein 1 (SELENBP1) and myosin heavy chain 9, non-muscle (MYH9), in a down–up pattern; HLA complex group 27 (HCG27), BCL2-related protein A1 (BCL2A1), G protein–coupled receptors 109A and 109B (GPR109A and GPR109B) in an up–down pattern; and zeta protein kinase C (PRKCZ), ATP-binding cassette, subfamily A, member 8 (ABCA8), and folate receptor 1 (adult) (FOLR1) in an up–up pattern (Table 19). Levels of genes from patients with AECOPD were also compared with those from patients with stable COPD, as shown in Figure 3, where positive or negative values indicate up- or downregulation as compared with those from patients with stable COPD. When correlated with DESS, ALAS2 and CA1 had similar patterns of change with DESS.
Table 19
Number of genes in peripheral blood mononuclear cells of patients with AECOPD a
 
Down–down
Down–up
Up–down
Up–up
Total
353
784
1,005
127
>2-fold
52
131
238
8
>4-fold
3
3
7
0
>5-fold
2
0
0
0
Selected co–differentially expressed genes at the down–down pattern (>4-fold)
SEQ-ID
Gene name
Full name of gene
AE-3 vs AE-1
AE-10 vs AE-3
NM_000032
ALAS2
Aminolevulinate, delta-, synthase 2
6.4
6.5
BC099627
EPB42
Erythrocyte membrane protein band 4.2
9.9
4.4
BC027890
CA1
Carbonic anhydrase I
21.6
5.1
Selected co–differentially expressed genes at the down–up pattern (>4-fold)
SEQ-ID
Gene name
Full name of gene
AE-3 vs AE-1
AE-10 vs AE-3
AK127453
N/A
Homo sapiens cDNA FLJ45545 fis, clone BRTHA2034281.
4.7
5.7
NM_003944
SELENBP1
Selenium-binding protein 1
5.6
4.1
BC090921
MYH9
Myosin, heavy chain 9, non-muscle
6.2
4.1
Selected co–differentially expressed genes at the up–down pattern (>4-fold)
SEQ-ID
Gene name
Full name of gene
AE-3 vs AE-1
AE-10 vs AE-3
NM_181717
HCG27
HLA complex group 27
4.1
7.3
NM_177551
GPR109A
G protein-coupled receptor 109A
4.3
7.5
NM_006018
GPR109B
G protein-coupled receptor 109B
4.4
5.1
AF249277
MTHFS
5,10-methenyltetrahydrofolate synthetase (5-formyltetrahydrofolate cyclo-ligase)
4.6
5.3
AY234180
BCL2A1
BCL2-related protein A1
5.2
4.0
BC010952
PI3
Peptidase inhibitor 3, skin-derived (SKALP)
6.0
4.4
NM_002243
KCNJ15
Potassium inwardly rectifying channel, subfamily J, member 15
7.0
4.8
Selected co–differentially expressed genes at the up–up pattern (>2-fold)
SEQ-ID
Gene name
Full name of gene
AE-3 vs AE-1
AE-10 vs AE-3
Z15108
PRKCZ
Protein kinase C, zeta
2.0
2.8
BC037798
CGI-38
Brain-specific protein
2.0
2.4
NM_001033581
PRKCZ
Protein kinase C, zeta
2.1
2.8
NM_007168
ABCA8
ATP-binding cassette, subfamily A, member 8
2.1
4.0
AK022468
SORBS1
Sorbin and SH3 domain containing 1
2.3
3.5
NM_006403
NEDD9
Neural precursor cell expressed, developmentally downregulated 9
2.3
2.2
NM_023037
FRY
Furry homologue (Drosophila)
2.3
2.1
NM_016730
FOLR1
Folate receptor 1 (adult)
3.0
11.7
Down–down
GENE_NAME
SEQ_ID
AE-1 vs Stable
AE-3 vs Stable
AE-10 vs Stable
 
ALAS2
NM_000032
17.64
2.76
−2.37
 
EPB42
BC099627
10.02
1.01
−4.37
 
CA1
BC027890
103.93
4.81
−1.06
Down–up
GENE_NAME
SEQ_ID
AE-1 vs Stable
AE-3 vs Stable
AE-10 vs Stable
 
N/A
AK127453
−1.69
−7.90
−1.38
 
SELENBP1
NM_003944
3.97
−1.41
2.92
 
MYH9
BC090921
−1.36
−8.40
−2.04
Up–down
GENE_NAME
SEQ_ID
AE-1 vs Stable
AE-3 vs Stable
AE-10 vs Stable
 
HCG27
NM_181717
1.09
4.47
−1.63
 
GPR109A
NM_177551
4.12
17.79
2.36
 
GPR109B
NM_006018
2.64
11.64
2.28
 
MTHFS
AF249277
4.51
20.75
3.95
 
BCL2A1
AY234180
2.38
12.45
3.11
 
PI3
BC010952
1.03
6.20
1.42
 
KCNJ15
NM_002243
2.25
15.78
3.26
Up–up
GENE_NAME
SEQ_ID
AE-1 vs Stable
AE-3 vs Stable
AE-10 vs Stable
 
PRKCZ
Z15108
−1.25
1.61
4.46
 
CGI-38
BC037798
−5.87
−2.86
−1.18
 
PRKCZ
NM_001033581
−1.61
1.30
3.64
 
ABCA8
NM_007168
−1.27
1.68
6.69
 
SORBS1
AK022468
1.28
2.92
10.30
 
NEDD9
NM_006403
2.43
5.57
12.15
 
FRY
NM_023037
−1.11
2.08
4.34
 
FOLR1
NM_016730
−4.20
−1.39
8.39
aData are from acute exacerbation of chronic obstructive pulmonary disease on day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of the hospital admission. Comparisons are between AE-1 and AE-3 or between AE-3 and AE-10.

Gene ontology analysis and pathway analysis

Within ten comparison pairs, up- or downregulated genes mainly involved in the biological process are shown in Figures S3 and S4 of Additional file 2, those in cellular components are shown in Figures S5 and S6 of Additional file 2 and those in molecular functions are shown in Figures S7 and S8 of Additional file 2. Additional file 5 lists gene numbers for ten comparison pairs with certain GO terms and different ranges of enrichment scores.
In the biological process, COPD-specific upregulated genes were involved mainly in peptide cross-linking, blood vessel development, biological adhesion or cell adhesion (Figure 4A). COPD-specific downregulated genes were involved mainly in T cell receptor signaling pathways, antigen receptor–mediated signaling pathways, immune response–activating cell surface receptor signaling pathways or steroid biosynthetic process (Figure 4B). AECOPD-specific genes upregulated in response to organic substance, response to wounding, multicellular organismal process or response to chemical stimulus are shown in Figure 4C. AECOPD-specific downregulated genes were involved mainly in the regulation of immune response and the immune system process or in the immune response and immune system process themselves (Figure 4D). In the cellular component, COPD-specific upregulated genes were involved mainly in the extracellular region, the extracellular matrix part, the proteinaceous extracellular matrix or the extracellular matrix (Figure 5A). COPD-specific downregulated genes were involved mainly in the major histocompatibility complex class II (MHC II) protein complex, microbody lumen, peroxisomal matrix or MHC II protein complex (Figure 5B). AECOPD-specific upregulated genes were involved mainly in the extracellular region part, the extracellular matrix, the extracellular space or the extracellular region (Figure 5C). AECOPD-specific downregulated genes were involved mainly in the cell periphery and the plasma membrane and were integral to the plasma membrane and intrinsic to the plasma membrane (Figure 5D). In molecular function, COPD-specific upregulated genes participated mainly in extracellular matrix structural constituent, platelet-derived growth factor binding, serine-type endopeptidase activity and protein binding (Figure 6A). COPD-specific downregulated genes were involved mainly in nucleoside kinase activity, MHC class II receptor activity, C-acyltransferase activity and ephrin receptor activity (Figure 6B). AECOPD-specific upregulated genes were involved mainly in protein binding, growth factor binding, calcium ion binding and polysaccharide binding (Figure 6C). AECOPD-specific downregulated genes were involved mainly in receptor activity, signaling receptor activity, molecular transducer activity and signal transducer activity (Figure 6D).
COPD-specific upregulated genes also participated in extracellular matrix receptor interaction, protein digestion and absorption, focal adhesion and the phosphatidylinositol 3-kinase-Akt signaling pathway (Figure 7A). AECOPD-specific upregulated genes participated in Chagas disease, complement and coagulation cascades, pertussis and Staphylococcus aureus infection (Figure 7B). AECOPD-specific downregulated genes participated in antigen processing and presentation, natural killer cell–mediated cytotoxicity, graft-versus-host disease and thyroid cancer (Figure 7C).

Discussion

PBMCs play a critical and important role in the occurrence of AECOPD, owing to less capacity for balancing the proinflammatory immune response caused by infection and for secreting adequate amounts of anti-inflammatory cytokines [22]. The fact that patients with COPD are more susceptible to acute exacerbation has been suggested to be associated with PBMC dysfunction and failure of adaptation to infection, stimuli or hypoxia, although there have been not yet studies on the phenotypes of PBMCs in AECOPD. For example, PBMCs from patients with COPD could not induce hypoxia-inducible factor 1 and vascular endothelial growth factor, owing to a reduction in histone deacetylase 7 under hypoxic condition [23]. It was suggested that overproduction of proinflammatory cytokines (CXCL6 and interleukin 6 (IL-6)) from human PBMCs could be stimulated by the infection through activation of Toll-like receptor 4, nicotinamide adenine dinucleotide phosphate oxidase phosphatidylinositol 3-kinase and nuclear factor κB [24], at least as partial mechanisms by which PBMCs may be involved in the occurrence of AECOPD. The present study provides initial evidence that dynamic alterations of PBMC genetic phenotypes occurred in patients with AECOPD after their hospital admission and during their hospital stay.
Gene expression profiles of PBMCs were investigated in patients with COPD, compared with healthy controls and correlated with lung function measurement [12]. Differential expression of 45 known genes was identified, of which 16 markers had significant correlation with quantitative traits and differential expression between cases and controls and 2 genes, RP9 and NAPE-PLD, were identified as decreased in patients with COPD, as compared to controls, in both lung tissue and blood. Gene expression profiles of PBMCs were recently identified and validated in smokers with and without COPD and corrected with clinical phenotypes such as sex, age, body mass index, family history, smoking status and pack-years of smoking [25]. Of them, 16 candidate genes were found to be associated with airflow obstruction and secondary clinical phenotypes, 12 with emphysema, 13 with gas trapping and 8 with distance walked. Both previous studies demonstrated the gene expression profiles of PBMCs from patients with stable COPD and addressed the potential significance of smoking. In the present study, we selected healthy control subjects and patients who were not current smokers and demonstrated gene expression profiles of PBMCs from patients with COPD, including stable COPD and AECOPD. We addressed COPD-specific gene expression profiles that should appear in both stable COPD and COPD exacerbation conditions and found COPD-specific 79 genes were upregulated and 23 genes down-regulated more than fivefold as compared with gene expression in controls. In the present study, we selected consistent up- or downregulated gene expression on days 1, 3 and 10 of AECOPD-specific as compared with gene expression in both healthy controls and patients with stable COPD, as AECOPD-specific gene expression profiles. We found that 58 AECOPD-specific genes were upregulated more than fivefold and 238 genes were downregulated more than twofold, as compared to both control subjects and patients with stable COPD.
Variation of gene expression profiles is dependent upon multiple uncontrollable factors, such as study population, age, history, genetic background and treatment. In addition, gene expression profiles vary between harvested sample types, such as sputum, bronchoalveolar lavage fluid, blood or lung tissues. For example, 102 genes were identified to distinguish between non- or mild emphysema and severe emphysema in lung tissue [15] and to distinguish 70 microRNAs and 2,667 mRNAs between smoking patients with or without COPD [26]. In the present study, we investigated gene expression profiles of PBMCs from control subjects, patients with stable COPD, and patients with AECOPD on day 1, day 3 and day 10 of hospital admission, and we found about 3,000 overexpressed genes and 2,000 downregulated genes in patients with stable COPD or AECOPD, as compared with control subjects. These findings indicate that those COPD-specific genes exist in the stable COPD condition and during acute exacerbations of COPD.
Of the COPD-specific genes we studied, CEACAM1, COL6A3, NOL3, COL1A2, MLPH, MUC1, P8, UNQ473, CLDN4, RNASE1, H19, DEFA1 and LOC653600 were upregulated more than tenfold, mainly related to nuclear proteins, collagens or molecular structure. We noted that transcription factor CP2 (TFCP2L1) and SCP2 were downregulated more than tenfold. In previous studies, these genes, including CEACAM1, TFCP2L1 and SCP2, were not found to be associated with COPD. The SCP2 gene is located within chromosome 1 and encodes the nonspecific lipid transfer protein SCP2, which is involved in organellar fatty acid metabolism [27],[28] and the translocation of cytoplasmic free cholesterol to the mitochondria [29]. Our results indicate that PBMCs from patients with stable COPD or AECOPD had downregulated SCP2, which might point to severe metabolic disorder and thus that SCP2 downregulation might contribute to one of the common comorbidities of COPD [30]. TFCP2 is a member of a family of transcription factors that regulate genes involved in events from early development to terminal differentiation [31]. PBMCs with downregulated TFCP2 of patients with COPD might have less capacity of the transcriptional switch of globin gene promoters, many other cellular and viral gene promoters, or interaction with certain inflammatory response factors, although the exact mechanism and pathological role remain unclear.
AECOPD-specific gene expression profiles were selected by comparing them with both healthy control subjects and patients with stable COPD, including 647 upregulated genes and 238 downregulated genes (greater than twofold upregulation). Of them, FOS, IFI27, CYR61, CTGF, GPRC5A, FOSB, DCN and LOC387763 were upregulated more than tenfold and KIR2DS2, SH2D1B, CD8B, OR2W5, KSP37 and TCF7 were downregulated more than threefold.
We noticed that some genes, such as FOS, CYR61 and CTGF, were upregulated in PBMCs from patients with either stable COPD or AECOPD, consistent with the lung tissue gene expression profiles of patients with COPD or smokers, in whom the genes were expressed mainly in alveolar epithelial cells, airway epithelial cells and stromal and inflammatory cells [14]. Other genes, including GPRC5A, LOC387763 and KIR2DS2, were not found to be associated with AECOPD in previous publications. CTGF is a cysteine-rich peptide implicated in several biological processes, such as cell proliferation, survival and migration, and involved in pulmonary vascular remodeling and hypertension in COPD. It was evidenced by the experimental finding that CTGF short-hairpin RNA could significantly prevent CTGF and cyclin D1 expression, arrest cell cycle at the G0/G1 phase, suppress cell proliferation in smoking-exposed pulmonary smooth muscle cells and ameliorate pulmonary vascular remodeling [32]. Another study demonstrated that some inflammatory genes (IL-1β, IL-6, IL-8, CCL2 and CCL8) were upregulated, whereas some growth factor receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) were downregulated in lung tissue samples from patients who were current smokers or had moderate COPD [33].
Downregulation of TCF7 was found in PBMCs of patients with COPD and current smoking and was correlated with some clinical phenotypes, such as emphysema, gas trapping and distance walked [25]. In the present study, we also found that TCF7 was downregulated in ex-smokers with COPD by about an absolute threefold compared with control subjects, and, in patients with AECOPD, TCF7 was downregulated by about an absolute tenfold compared with both control subjects and patients with stable COPD. These findings indicate that TCF7 not only is a COPD-specific gene but also is associated with the severity of the disease. TCF7 is a member of a family of HMG box containing factors associated with β-catenin to mediate Wnt signaling, controls the switch between cell self-renewal and differentiation and plays a role in B cell and T cell development. TCF7 was found to be the most downregulated transcription factor when CD34+ cells switched into CD34− cells through a coordinated regulation of the binding between TCF7 and the short isoforms of RUNX1 [34]. It is possible the downregulation of TCF7 and associated regulation may be one part of molecular mechanism of PBMC incapacity during AECOPD.
Dynamic alterations of gene expression profiles in patients with AECOPD were evaluated with dynamic DESS scores. ALAS2, EPB42 and CA1 were co–differentially expressed with a down–down type in patients with AECOPD. Among these three genes, the CA1 gene encodes a protein which is important in respiratory function, fluid secretion and maintenance of cellular acid–base homeostasis [35]. The genes with a down–up type included SELENBP1, MYH9 and an unnamed gene in chromosome 19, both of which are associated with psychotic disorders [36],[37]. One limitation of the present study is the small sample size, which detracts from the generalizability of the results presented.

Conclusions

Dynamic alterations of PBMC gene expression profiles were initially investigated in patients with AECOPD, as compared with healthy control subjects or patients with stable COPD. A panel of genes, including eight that were upregulated and eight that were downregulated, were recommended as AECOPD-specific dynamic biomarkers. AECOPD-specific up- or downregulated genes in the biological process, cellular components or molecular function were defined and participated in complement and coagulation cascades, infection, antigen processing and presentation, natural killer cell–mediated cytotoxicity, and/or cancer-causing potential. The integration of dynamic bioinformatics with clinical phenotypes helped us to identify and validate AECOPD-specific biomarkers to help define the severity, duration and response of the disease to therapies.

Key messages

  • Circulating dynamic biomarkers were identified for the specificity and severity of AECOPD.
  • A panel of 16 genes were selected as AECOPD-specific biomarkers.
  • This is an initial study designed to examine gene expression profiles of peripheral blood mononuclear cells and identify dynamic changes of AECOPD-specific biomarkers.

Additional files

Acknowledgements

The work was supported by Shanghai Leading Academic Discipline Project (project B115), Zhongshan Distinguished Professor Grant (to XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600), the Zhejiang Provincial Natural Science Foundation (Z2080988), the Zhejiang Provincial Science Technology Department Foundation (2010C14011) and the Ministry of Education, Academic Special Science and Research Foundation for PhD Education (20130071110043).

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

XW carried out the study, participated in the data analysis and drafted the manuscript. XRS participated in the data mining and analysis. CSC and CXB participated in the study design and data analysis and helped to revise the manuscript. XDW conceived of the study, participated in its design and coordination and finalized the manuscript. All authors read and approved the final manuscript.
Anhänge

Electronic supplementary material

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Metadaten
Titel
Dynamic gene expressions of peripheral blood mononuclear cells in patients with acute exacerbation of chronic obstructive pulmonary disease: a preliminary study
verfasst von
Xiaodan Wu
Xiaoru Sun
Chengshui Chen
Chunxue Bai
Xiangdong Wang
Publikationsdatum
01.12.2014
Verlag
BioMed Central
Erschienen in
Critical Care / Ausgabe 6/2014
Elektronische ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-014-0508-y

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