Relationship between plasma matrix metalloproteinase levels, pulmonary function, bronchodilator response, and emphysema severity

Figures & data

Table 1 Baseline characteristics of patients with and without chronic obstructive pulmonary disease

	Non-COPD	COPD				P-value
		Total	COPD 1	COPD 2	COPD 3–4	Between COPD	Non-COPD versus COPD
Number	36	57	19	33	5
Age, median (Q1, Q3)	73 (66, 77)	74 (71.5, 77)	74 (72, 78)	74 (71, 76)	75 (67, 78)	0.31a	0.31c
Male sex (%)	21 (58.3%)	40 (70.2%)	10 (52.6%)	26 (78.8%)	4 (80.0%)	0.12b	0.27b
Height (cm)	157.9±9.2	157.2±10.2	151.5±10.2	159.6±8.5	163.2±12.7	0.01a	0.73c
Body weight (kg)	59.4±8.8	55.3±9.2	54.3±9.1	55.2±8.9	59.0±12.0	0.61a	0.04c
BMI (kg/m^2)	23.8±2.9	22.3±2.6	23.6±2.2	21.6±2.7	21.9±2.0	0.03a	0.01c
Smoking						0.10b	0.12 b
Current smoker	9 (25%)	19 (33.3%)	2 (10.5%)	14 (42.4%)	3 (60%)
Ex-smoker	8 (22.2%)	20 (35.1%)	8 (42.1%)	11 (33.3%)	1 (20%)
Never smoker	19 (52.8%)	18 (31.6%)	9 (47.4%)	8 (24.2%)	1 (20.0%)
Pack-year	30 (18, 45)	30 (18.9, 40)	25.5 (15, 30)	30 (19, 42)	25 (19, 45)	0.43a	0.45c
Post BDR PFT
FVC (L)	2.79±0.70	2.79±0.73	2.86±0.72	2.86±0.73	2.09±0.55	0.08a	0.99c
FVC (% predicted)	94.9±19.7	94.8±17.3	112.5±9.9	89.5±9.0	62.2±7.8	<0.001a	0.98c
FEV1 (L)	2.11±0.53	1.63±0.48	1.78±0.47	1.65±0.43	1.00±0.33	0.004a	<0.001c
FEV1 (% predicted)	97.7±21.7	76.4±18.2	95.9±9.9	70.6±7.2	40.4±7.57	<0.001a	<0.001c
FEV1/FVC (%)	75.5±3.9	58.2±6.2	62.0±4.4	57.7±5.0	47.4±6.4	<0.001a	<0.001c
Reversibility FVC (L)	3.25±20.8	24.3±31.2	29.3±30.6	19.8±32.0	35.2±28.7	0.42a	0.001c
Reversibility FVC (%)	0.78±6.90	8.35±10.97	11.47±12.13	6.33±10.57	9.80±6.76	0.26a	<0.001c
Reversibility FEV1 (L)	5.42±9.47	8.82±14.7	8.63±12.89	9.36±16.62	8.19±3.66	0.89a	0.22c
Reversibility FEV1 (%)	2.50±4.39	3.96±6.28	4.74±6.18	3.82±6.73	2.00±3.08	0.68a	0.23c
Symptom score
mMRC	1 (0, 1.75)	1 (1, 2.75)	1 (1, 1.25)	1 (0, 3)	1 (0.5, 2)	0.39a	0.38c
CAT	16 (10.3, 22)	18 (9.5, 24.5)	18 (13, 21)	20 (8.5, 27.5)	14 (9, 22.5)	0.77a	0.81c
MMP level
MMP-1 (ng/mL)	3.89±2.53	5.31±3.98	4.96±3.81	5.75±4.36	3.90±1.23	0.20a	0.07c
MMP-8 (ng/mL)	9.15±3.79	8.48±4.73	7.89±4.69	8.54±4.67	10.37±5.78	0.69a	0.53c
MMP-9 (ng/mL)	112.7±72.3	116.6±71.2	106.5±61.1	115.5±73.9	161.4±87.5	0.50a	0.81c
MMP-12 (pg/mL)	51.2±12.0	51.0±12.5	52.3±14.0	48.9±11.7	55.2±11.9	0.73a	0.96c

Notes:

Data are expressed as mean ± SD. Non-COPD, FEV₁/FVC ≥0.7; COPD 1, FEV₁ >80% with FEV₁/FVC <0.7; COPD 2, 50% <FEV₁ ≤80% with FEV₁/FVC <0.7; COPD 3–4, FEV₁ ≤50% with FEV₁/FVC <0.7;

a Analyses of variance,

b Chi-square tests,

c Student’s t-tests.

Abbreviations: BMI, body mass index; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; MMP, matrix metalloproteinase; mMRC, modified Medical Research Council dyspnea scale; Post BDR PFT, post-bronchodilator pulmonary function test.

Table 2 Clinical characteristics of patients striated by chronic obstructive pulmonary disease and smoking status

	Non-COPD			P-value	COPD			P-value
	Current	Ex	Never		Current	Ex	Never
Number	9	8	19		19	20	18
Age, median (Q1, Q3)	73 (70.5, 77.5)	75 (66.5, 80.8)	72 (63, 76)	0.79a	73 (70, 75)	76 (71.3, 79)	74 (71.8, 77.3)	0.35a
Male sex	9 (100%)	8 (100%)	4 (21.1%)	<0.001b	19 (100%)	20 (100%)	1 (5.6%)	<0.001b
BMI	23.3±2.9	24.2±2.5	23.8±3.2	0.82a	21.8±2.4	22.9±2.7	22.2±2.6	0.39a
Symptom score
mMRC	1 (0.5, 2)	1 (0, 1)	1 (1, 2)	0.21a	1 (0, 2)	1 (1, 2)	1 (0.8, 3.0)	0.57a
CAT	13.0±8.6	12.6±5.6	20.4±9.9	0.051a	17.0±9.2	18.7±10.2	16.1±8.0	0.69a
Radiologic
EI	3.7±4.6	4.3±5.8	2.5±2.5	0.54a	10.5±8.2	12.1±9.3	4.7±3.9	0.01a
MWA	71.4±4.8	69.1±4.9	69.3±5.3	0.53a	71.3±3.4	68.9±5.3	71.5±3.5	0.06a
PA/A ratio	0.82 ±0.08	0.77±0.07	0.79±0.11	0.58a	0.78±0.07	0.79±0.12	0.81±0.14	0.77a
MMP level
MMP-1	3.4±2.1	2.1±0.9	4.7±2.8	0.07a	6.3±5.3	5.2±3.6	4.4±2.5	0.35a
MMP-8	12.0±5.5	9.7±3.7	7.4±4.2	0.06a	6.9±3.7	10.8±5.6	7.6±3.9	0.03a
MMP-9	137.4±77.6	126.0±67.8	95.0±70.1	0.33a	95.4±75.6	155.5±76.3	96.7±40.4	0.01a
MMP-12	61.0±5.9	56.3±6.7	45.5±12.0	0.01a	48.4±11.4	55.7±14.6	48.4±10.5	0.22a

Notes:

Data are expressed as mean ± SD;

a Analyses of variance,

b Chi-square tests.

Abbreviations: BMI, body mass index; CAT, COPD assessment test; EI, emphysema index; MMP, matrix metalloproteinase; mMRC, modified Medical Research Council dyspnea scale; MWA, mean wall area percentage; PA/A, pulmonary artery/ascending aorta.

Figure 1 Correlation between MMP levels and WBC count as determined by linear regression analyses.

Abbreviations: MMP, matrix metalloproteinase; WBC, white blood cell.

Figure 2 Correlation between MMP-1 levels and airway reversibility as determined by linear regression analyses.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; MMP, matrix metalloproteinase.

Table 3 Multivariable analysis examining the relationship between matrix metalloproteinase levels and lung function

	MMP-1		MMP-8		MMP-9		MMP-12
	β	P-value	β	P-value	β	P-value	β	P-value
*FVC (%)	−0.04	0.36	−0.28	0.01	−0.24	0.01	−0.19	0.07
*FEV1 (%)	−0.14	0.09	−0.20	0.03	−0.23	0.02	−0.15	0.12
*FEV1/FVC (%)	−0.20	0.03	−0.01	0.46	−0.14	0.11	−0.06	0.31
**Reversibility FVC (L)	0.25	0.01	0.09	0.20	0.14	0.09	0.10	0.22
**Reversibility FEV1 (L)	0.22	0.02	0.02	0.43	0.002	0.49	0.03	0.42

Notes:

* Adjusted by age, sex, height, body mass index, and smoking status;

** Adjusted by age, sex, height, body mass index, smoking status, and post-bronchodilator FVC (% predicted) or FEV₁ (% predicted).

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; MMP, matrix metalloproteinase.

Table 4 Multivariate analysis examining the relationship between MMP levels and computed tomography findings

	Model 1		Model 2
	β	P-value	β	P-value
Emphysema index
MMP-1	0.18	0.04	0.18	0.048
MMP-8	0.16	0.07	0.19	0.045
MMP-9	0.15	0.10	0.21	0.03
MMP-12	−0.08	0.42	−0.09	0.39
MWA
MMP-1	0.04	0.69	−0.04	0.74
MMP-8	0.003	0.98	0.01	0.91
MMP-9	0.008	0.94	0.03	0.80
MMP-12	−0.02	0.89	0.01	0.93
PA/A ratio
MMP-1	−0.08	0.46	−0.09	0.39
MMP-8	−0.18	0.10	−0.16	0.16
MMP-9	−0.13	0.25	−0.08	0.51
MMP-12	−0.02	0.88	0.04	0.78

Notes: Model 1: adjusted by age, sex, height, body mass index, smoking status, FVC (% predicted), and FEV₁ (% predicted); model 2: adjusted by age, sex, height, body mass index, smoking status, FVC (% predicted), FEV₁ (% predicted), and WBC count.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; MMP, matrix metalloproteinase; MWA, percentage of mean wall area; PA/A ratio, pulmonary artery/ascending aorta ratio; WBC, white blood cell.

Figure 3 Correlation between MMP levels and emphysema index in patients with chronic obstructive pulmonary disease as determined by linear regression analyses.

Abbreviations: %LAA-_950HU, low attenuation area ≤950 Hounsfield units; MMP, matrix metalloproteinase.

Table 5 Clinical characteristics of patients with and without airflow limitation and emphysema

	O−E−	O+E−	O−E+	O+E+	P-value
Number	11	11	7	26
Age, median (Q1, Q3)	74 (71, 80)	73 (67, 76)	72 (69, 77)	74 (69, 76.5)	0.48
Male sex, n (%)	15 (42.9%)	13 (81.2%)	9 (69.2%)	24 (82.8%)	0.003
Height (cm)	154.1±9.6	158.1±10.1	157.6±11.9	161.2±7.7	0.04
BMI (kg/m^2)	23.8±2.7	23.4±2.4	23.2±3.1	21.3±2.5	0.003
Smoking, n (%)					<0.001
Current	4 (11.4%)	10 (62.5%)	2 (15.4%)	12 (41.4%)
Ex	9 (25.7%)	2 (12.5%)	5 (38.5%)	12 (41.4%)
Never	22 (62.9%)	4 (25.0%)	6 (46.2%)	5 (17.2%)
Symptom score
mMRC	1 (0, 1.25)	1 (1, 3)	1 (1, 1.5)	1 (0, 3)	0.30
CAT	16.7±7.8	16.6±9.0	17.8±10.2	17.6±10.6	0.97
Radiologic
MWA (%)	71.0±2.9	71.2±4.7	66.1±4.9	70.9±4.2	0.047
EI (%)	2.0±1.0	3.0±1.4	10.9±8.4	14.1±7.5	<0.001
PA/A ratio	0.81±0.08	0.79±0.10	0.74±0.10	0.80±0.13	0.55
MMP level
MMP-1 (ng/mL)	4.08±2.88	5.02±3.42	5.37±4.50	5.93±4.50	0.64
MMP-8 (ng/mL)	7.78±5.93	7.72±4.73	8.13±2.71	9.20±4.75	0.77
MMP-9 (ng/mL)	93.1±53.7	118.5±78.9	123.1±74.7	124.0±75.2	0.68
MMP-12 (pg/mL)	52.1±13.5	55.1±9.6	52.0±16.4	49.3±11.9	0.81

Notes: Absence of airflow limitation and emphysema (O−E−); absence of airflow limitation and presence of emphysema (O−E+); presence of airflow limitation and absence of emphysema (O+E−); and presence of both airflow limitation and emphysema (O+E+). Data are expressed as mean ± SD unless otherwise stated.

Abbreviations: BMI, body mass index; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; EI, emphysema index; mMRC, modified Medical Research Council dyspnea scale; MWA, percentage mean wall area; MMP, matrix metalloproteinase; PA/A ratio, pulmonary artery/ascending aorta diameter ratio; SD, standard deviation.

Figure S1 Correlations between the various MMP levels examined as determined by linear regression analyses.

Abbreviation: MMP, matrix metalloproteinase.