Open Access

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

Contributed equally
Critical Care201418:508

https://doi.org/10.1186/s13054-014-0508-y

Received: 28 April 2014

Accepted: 26 August 2014

Published: 19 November 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.

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.
Figure 1

Details of the study design. Healthy volunteers and patients with stable chronic obstructive pulmonary disease (sCOPD) or acute exacerbation of COPD (AECOPD) at day 1 (D1), day 3 (D3) or day 10 (D10) of hospital admission of hospital were recruited into the present study according to the criteria stated in the text. All clinical information was collected and transferred into the clinical informatics database using the Digital Evaluation Score System. mRNAs of peripheral blood monocytes were harvested, and gene expression profiles were measured by human gene expression array and subjected to bioinformatics analysis. AECOPD-specific biomarkers were selected by integrating gene functional networks and profiles with clinical informatics data.

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.
Figure 2

Scatterplots showing variations in gene expression profiles. Scatterplots of peripheral blood monocytes between patients with stable chronic obstructive pulmonary disease (Stable COPD) (A), acute exacerbation of chronic obstructive pulmonary disease at day 1 of hospital admission (AECOPD-D1) (B), AECOPD at day 3 of hospital admission (AECOPD-D3) (C) or AECOPD at day 10 of hospital admission (AECOPD-D10) (D) compared with healthy controls. Scatterplots also illustrate variations between AECOPD-D1 (E), AECOPD-D3 (F) or AECOPD-D10 (G) and stable COPD; between AECOPD-D3 (H) or AECOPD-D10 (I) with AECOPD-D1; and between AECOPD-D3 and AECOPD-D10 (J).

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.

Figure 3

Dynamic patterns of changes of gene expression of peripheral blood monocytes. Consistent decrease (A) or consistent increase (B), followed by a decrease (C), or a decrease followed by a recovery (D), in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) at day 1 (AE-1), day 3 (AE-3) and day 10 (AE-10) of hospital admission as compared with changes seen in patients with stable COPD.

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).
Figure 4

Gene expression profile comparisons regarding the biological process. Graphs describe co–differentially upregulated genes (A) and downregulated genes (B) in the biological process of peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease (COPD), including those with stable COPD and acute exacerbation of COPD (AECOPD), as compared to healthy control subjects. Also shown are co–differentially expressed upregulated genes (C) and downregulated genes (D) from patients with AECOPD, as compared to patients with stable COPD and healthy control subjects.

Figure 5

Gene expression profile comparisons regarding the cellular component. Graphs describe co–differentially upregulated genes (A) or downregulated genes (B) in the cellular component of peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease (COPD), including stable COPD and acute exacerbation of COPD (AECOPD), as compared to healthy control subjects. Also shown are co–differentially expressed upregulated genes (C) or downregulated genes (D) from patients with AECOPD, as compared to both patients with stable COPD and healthy control subjects. MHC, Major histocompatibility complex.

Figure 6

Gene expression profile comparisons regarding molecular function. Graphs describe co–differentially upregulated genes (A) or downregulated genes (B) in the molecular function of peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease (COPD), including stable COPD and acute exacerbation of COPD (AECOPD), as compared to healthy control subjects. Also shown are co–differentially expressed upregulated genes (C) or downregulated genes (D) from patients with AECOPD, as compared to both patients with stable COPD and healthy control subjects. MHC, Major histocompatibility complex.

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).
Figure 7

Gene expression profile comparisons regarding signaling pathways. Graphs describe co–differentially upregulated genes (A) in different pathways of peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease (COPD), including patients with stable COPD and acute exacerbation of COPD (AECOPD), as compared to healthy control subjects. Also shown are co–differentially expressed upregulated genes (B) or downregulated genes (C) from patients with AECOPD, as compared to patients with stable COPD and healthy control subjects. ECM, Extracellular matrix; MHC, Major histocompatibility complex; Pi3K, Phosphatidylinositol 3-kinase.

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

Notes

Abbreviations

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

Declarations

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).

Authors’ Affiliations

(1)
Department of Respiratory Medicine, Zhongshan Hospital, Fudan University
(2)
Department of Respiratory Medicine, Wenzhou Medical University and The First Hospital
(3)
Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Shanghai Respiratory Research Medicine

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