Plasma sCD146 is a potential biomarker for acute exacerbation of chronic obstructive pulmonary disease

Abstract

This study examined the levels of soluble CD146 (sCD146) in plasma samples from patients with chronic obstructive pulmonary disease (COPD) and assessed the relationship between sCD146 and the severity of COPD. A total of 97 COPD patients were recruited from 20 medical centers in Jiangsu, China, including 13 stable subjects and 84 exacerbated subjects. The plasma sCD146 level in exacerbated subjects (28.77 ± 10.80 ng/mL) was significantly lower than that in stable subjects (38.84 ± 15.00 ng/mL). In the high sCD146 group, the proportion of subjects with modified Medical Research Council (mMRC) scores of 0–1 was higher, the proportion of subjects with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 was lower, and the proportion of subjects with ≥1 hospitalizations in the past year was lower. The plasma sCD146 level was negatively correlated with the COPD Assessment Test (CAT) score (r = −0.2664, p = 0.0087). Logistic regression analysis showed that sCD146 was an independent risk factor for acute exacerbation of COPD (AECOPD). Receiver operating characteristic (ROC) analysis suggested that sCD146 combined with sex, age, pulmonary function, and acute exacerbations in the past year had clinical value for the accurate identification of AECOPD, with an area under the ROC curve (AUC) of 0.908 (95% CI: 0.810–1.000, p < 0.001). In addition, there was a significant negative correlation between plasma sCD146 and S100A9 (r = −0.3939, p < 0.001).

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

CD146, as a cell adhesion molecule, has been found to be involved in various diseases in recent years. CD146 also plays an important role in chronic obstructive pulmonary disease (COPD). When bacterial infections occur in the lungs, CD146 amplifies lung inflammation through proinflammatory effects. sCD146, as a soluble form of CD146, is easily detected in body fluids such as plasma. At present, the diagnosis of acute exacerbation of COPD (AECOPD) is still based on patient self‐reports, and the role of sCD146 in assessing COPD disease severity has not yet been reported.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The purpose of this study was to evaluate the clinical value of plasma sCD146 in assessing AECOPD.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The decrease in plasma sCD146 was associated with an increased risk of acute exacerbations in COPD, indicating that sCD146 is a potential biomarker for assessing the severity and prognosis of AECOPD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results suggest that plasma sCD146 may be valuable in assessing the severity of COPD and supplementing sCD146 might be a new treatment strategy for AECOPD.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that seriously affects the quality of life and health of patients. ¹ Acute exacerbation of COPD (AECOPD) refers to an acute worsening of respiratory symptoms that occurs within 14 days in COPD patients who require additional therapy. Exacerbations are an important factor leading to the early death of COPD patients. Accurate identification and early intervention are key to delaying disease progression. Currently, the identification of AECOPD mainly relies on the self‐reported symptoms of patients. There are no reliable, stable, or sensitive biomarkers to help clinicians make accurate judgments. Respiratory tract infections are common causes of AECOPD. In recent years, researchers on biomarkers for AECOPD have mainly focused on blood inflammatory markers. Blood biomarkers have the characteristics of easy acquisition, easy detection, and high sensitivity. Therefore, we collected plasma samples from COPD subjects in different regions of Jiangsu Province to find biomarkers that can effectively evaluate the exacerbation and severity of COPD.

CD146, also known as melanoma cell adhesion molecule (MCAM) or mucin 18 (MUC18), was discovered in 1987. ² CD146 is mainly located at endothelial cell junctions ³ and can act as a membrane receptor to receive extracellular signals and regulate various intracellular signaling pathways. It plays an important role in intercellular adhesion, the inflammatory response, and tumor cell migration. ⁴ In recent years, with increasing research efforts, CD146 has become an important indicator for the diagnosis and prognosis of multiple diseases. CD146 is involved in the pathophysiological process of COPD. ⁵ When bacterial infections occur in the lungs, CD146 plays a proinflammatory role, amplifying lung inflammation. ⁶ In contrast, CD146 deficiency can reduce epithelial mesenchymal transition and airway remodeling. ⁷ Recently, we have reported that CD146 deficiency may aggravate lung inflammation in a mouse model of COPD. ⁸

CD146 exists in body fluids (blood, urine) in a soluble form (sCD146). sCD146 shows chemotactic activity toward endothelial cells and has angiogenic effects. ⁹ Compared with healthy controls, sera sCD146 was increased in COPD patients. ³ However, there is currently a lack of sufficient evidence on the evaluation value of plasma sCD146 for COPD disease severity. As a result, we aimed to further explore the clinical value of sCD146 in the assessment of AECOPD.

METHODOLOGY

Study participants

A total of 97 participants with COPD were recruited from 20 medical centers, including 13 stable patients and 84 exacerbated patients. The enrollment period was from November 2019 to November 2021. The inclusion criteria were as follows: (1) aged between 40 and 80 years and (2) a diagnosis of COPD based on the pulmonary function criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), with the presence of a postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) < 0.70. The exclusion criteria were as follows: (1) any chronic respiratory diseases other than COPD and (2) unable to provide written informed consent or cooperate with the study researchers.

Data collection

At enrollment, demographic data, medical history, COPD Assessment Test (CAT) score, modified Medical Research Council (mMRC) score, disease control status, frequency of exacerbations in the past year, comorbidities, and medications were collected through the questionnaire. The severity of COPD was assessed through physical examination, peripheral blood evidence, and pulmonary function tests. Moderate‐to‐severe exacerbations were defined as requiring treatment with antibiotics and/or systemic corticosteroids or requiring emergency or hospital admission. Frequent exacerbations were defined as ≥2 acute exacerbations per year.

Plasma sample collection

The subjects provided 4 mL of fasting venous blood samples into vacuum tubes containing anticoagulant, which were then kept at room temperature for 60 min. The samples were then centrifuged at 500 g for 5 min. The upper layer of plasma was collected and stored in liquid nitrogen for future use.

Enzyme‐linked immunosorbent assay (ELISA)

sCD146 (DY932‐05; R&D), MMP‐9 (DY911‐05; R&D, Minneapolis, MN, USA), and S100A8/S100A9 (DY8226‐05; R&D) in human plasma were measured by each ELISA kit according to the manufacturer's instructions. The general process included coating the capture antibody overnight and then adding the blocking solution, diluted standard, plasma samples, detecting antibody, horseradish peroxidase, and stop solution in sequence. The concentration of each substance in the plasma was calculated based on the standard curve.

Statistical analysis

For baseline characteristics, continuous data that followed a normal distribution were represented as the mean ± standard deviation, while those that did not follow a normal distribution were represented as medians (first quartile, third quartile). Categorical data were represented using frequencies and percentages. Continuous variables were tested using a two‐tailed t‐test or Wilcoxon rank sum test, while categorical variables were tested using Pearson chi‐square test or Fisher exact test.

By determining the cutoff value of plasma sCD146 levels, patients were divided into high sCD146 and low sCD146 groups. We selected two methods to obtain the cutoff value. One was based on the data of the receiver operating characteristic (ROC) curve, and the cutoff value was determined according to the maximum Youden index. The other was based on the plasma data of 97 COPD subjects, and the cutoff value was determined according to the mean value. Considering the cutoff value based on the ROC curve was too large, there was a significant difference in the number of patients between the two groups. We ultimately chose to use the mean value of 97 COPD as the cutoff value. The distribution of patients with different mMRC scores, GOLD grades, and COPD‐related hospitalizations in the past year were compared between the two groups. Spearman correlation analysis was used to assess the correlation between sCD146 and different variables.

Logistic regression analysis was performed to determine the relationship between sCD146 and both acute exacerbation and frequent exacerbation of COPD. Considering that numerous variables could affect acute exacerbations, we adjusted for potential confounding factors. The adjustment factors for the acute exacerbation model included sex, age, exacerbations in the past year, FEV₁/FVC and FEV₁/predicted. The adjustment factors for the frequent exacerbation model included age, sex, body mass index (BMI), course of disease, smoking status, and concomitant asthma. The ROC analysis was established for sCD146, and the area under the ROC curve (AUC) was used to evaluate its predictive value for acute exacerbation patients.

A p value less than 0.05 was considered statistically significant. All statistical tests were performed using GraphPad Prism 8 (GraphPad) and IBM SPSS Statistics version 22 (SPSS Inc.).

Ethics statement

The study was approved by the Ethics Research Committee of the First Affiliated Hospital of Nanjing Medical University (Approval No.: 2019‐SR‐129). A written consent form was obtained from each participant.

RESULTS

Baseline characteristics

A total of 97 COPD subjects were included in the study (Table 1), including 13 stable subjects and 84 exacerbated subjects. The mean age of the subjects was 64.5 years, 89.7% were male, and the mean BMI was 22.7 kg/m². Some 74.2% of subjects had a smoking history, and 18.6% were current smokers.

TABLE 1.

Patient characteristics.

Parameter	Total (N = 97)	Stable (N = 13)	Exacerbated (N = 84)	P value
Baseline characteristics
Age at cohort entry, years	64.5 ± 10.6	62.1 ± 8.9	64.9 ± 10.8	0.3753
Male	87 (89.7)	10 (76.9)	77 (91.7)	0.1295
BMI, kg/m2	22.7 ± 4.3	22.4 ± 3.2	22.8 ± 4.5	0.7456
Current smoker	18 (18.6)	3 (23.1)	15 (17.9)	0.6943
COPD assessments
mMRC score	2.2 ± 0.9	1.6 ± 1.0	2.2 ± 0.8	0.0173*
CAT score	19.7 ± 7.0	12.1 ± 6.6	20.8 ± 6.4	<0.0001*
GOLD stage
1	2 (2.2)	1 (9.1)	1 (1.3)	0.108
2	25 (28.1)	5 (45.5)	20 (25.6)
3	36 (40.4)	4 (36.4)	32 (41.2)
4	26 (29.2)	1 (9.1)	25 (32.1)
Disease courses, years	11.5 ± 9.6	7.8 ± 7.0	12.1 ± 10.0	0.1467
Disease control situations
Good	15 (16.1)	5 (41.7)	10 (12.3)	0.006*
Moderate	38 (40.9)	6 (50.0)	32 (39.5)
Bad	40 (43.0)	1 (8.3)	39 (48.1)
Days of symptoms until cohort entry	9.0 (3.8, 20.0)	8.5 (4.5, 22.5)	8.0 (3.0, 20.0)	0.8153
Comorbidities
Asthma	12 (16.4)	2 (18.2)	10 (16.1)	>0.9999
Bronchiectasis	6 (7.2)	1 (9.1)	5 (8.1)	>0.9999
Allergic rhinitis	4 (5.5)	2 (18.2)	2 (3.2)	0.1053
Laboratory tests
FEV1/FVC, %	52.4 ± 13.9	61.0 ± 14.4	51.1 ± 13.4	0.0209*
FEV1/pre, %	42.1 ± 17.4	52.6 ± 19.4	40.5 ± 16.7	0.0245*
IgE, KU/L	71.3 (26.8146.3)	18.3 (5.7381.6)	76.1 (29.7150.7)	0.0769
FeNO, ppb	24.0 (17.0, 36.8)	24.5 (12.0, 43.5)	24.0 (17.0, 35.5)	0.9545
Blood neutrophil percentage, %	69.7 ± 13.5	69.0 ± 11.2	69.9 ± 14.2	0.8574
Blood eosinophil percentage, %	1.4 (0.2, 2.8)	1.2 (0.1, 2.7)	1.5 (0.2, 2.8)	0.4918
Medications
LABA	37 (38.1)	6 (46.2)	31 (36.9)	0.5512
LABA‐ICS	46 (47.4)	6 (46.2)	40 (47.6)	>0.9999
Home oxygen therapy	22 (23.2)	0 (0)	22 (26.8)	0.0346*
Regular medication rate, %
≥90	27 (34.6)	9 (81.8)	18 (26.9)	0.005*
70–89	13 (16.7)	0 (0)	13 (19.4)
50–69	23 (29.5)	2 (18.2)	21 (31.3)
<50	15 (19.2)	0 (0)	15 (22.4)

Note: Data are presented as the mean ± standard deviation (SD) or median (first quartile, third quartile), or n (%). Bold type denotes statistical significance (*p < 0.05).

Abbreviations: BMI, body mass index; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FeNO, exhaled nitric oxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long‐acting beta₂‐agonists; LABA‐ICS, LABA combination with inhaled corticosteroids; mMRC, modified Medical Research Council; ppb, parts‐per‐billion.

The subjects were assessed for the COPD condition at the time of enrollment. The mean duration of COPD was 11.5 years. The mMRC score at enrollment averaged 2.2 points, and the CAT score averaged 19.7 points. The mMRC and CAT scores were significantly higher in exacerbated subjects than in stable subjects. 69.6% of subjects had GOLD grades of 3 or 4. Among the self‐reported disease control of patients, 16.1% felt that their disease control was good, 40.9% moderate, and 43% poor. The proportion of exacerbated subjects who felt that their disease was poorly controlled was significantly higher than that of stable subjects. The median time from symptom onset to seeking medical attention was 9 days. There were no significant differences in the comorbidities between the two groups. In pulmonary function testing, the mean FEV₁/FVC was 52.4%, the mean FEV₁/predicted was 42.1%, and the lung function index of exacerbated subjects was significantly lower than stable subjects. The median serum IgE level was 71.3 KU/L. The median exhaled nitric oxide (FeNO) level was 24 parts‐per‐billion (ppb). The mean blood neutrophil percentage was 69.7%, and the median blood eosinophil percentage was 1.4%.

The medications currently used by COPD subjects were mainly long‐acting beta₂‐agonists in combination with inhaled corticosteroids (LABA+ICS). Some 23.2% of subjects underwent home oxygen therapy. The proportion of exacerbated subjects who underwent home oxygen therapy was significantly higher than that of stable subjects. Only 34.6% of subjects had a regular medication rate of 90% or more. Exacerbated subjects had a significantly lower regular medication rate than stable subjects.

The exacerbation events in the past year of the two groups were evaluated (Table 2). The incidence of moderate‐to‐severe exacerbation and hospitalization in exacerbated subjects was significantly higher than that in stable subjects; 61.3% of exacerbated subjects had ≥2 moderate‐to‐severe exacerbations in the past year, and 60.7% had ≥1 hospitalizations. There were no significant differences in the symptoms of exacerbations between the two groups.

TABLE 2.

Exacerbations for chronic obstructive pulmonary disease in the year prior to cohort entry.

Parameter	Total (N = 97)	Stable (N = 13)	Exacerbated (N = 84)	P value
Moderate/severe exacerbations
0	13 (14.8)	6 (46.2)	7 (9.3)	0.002*
1	26 (29.5)	4 (30.8)	22 (29.3)
≥2	49 (55.7)	3 (23.1)	46 (61.3)
Hospitalizations
0	43 (44.3)	10 (76.9)	33 (39.3)	0.0156*
≥1	54 (55.7)	3 (23.1)	51 (60.7)
Symptoms
Cough	61 (64.2)	6 (46.2)	55 (67.1)	0.212
Dyspnea	31 (32.6)	4 (30.8)	27 (32.9)	>0.9999
Wheeze	51 (53.7)	7 (53.9)	44 (53.7)	>0.9999
Chest tightness	47 (49.5)	4 (30.8)	43 (52.4)	0.2321

Note: Data are presented as n (%). Bold type denotes statistical significance (*p < 0.05).

Association of plasma sCD146 with COPD exacerbations

Compared with stable subjects (38.84 ± 15.00 ng/mL), the plasma sCD146 level was significantly reduced in exacerbated subjects (28.77 ± 10.80 ng/mL) (Figure 1a). As the number of moderate‐to‐severe exacerbations gradually increased in the past year, the level of sCD146 gradually decreased (Figure 1b). In addition, compared with subjects with good disease control (35.84 ± 12.52 ng/mL), subjects with poor disease control had significantly lower plasma sCD146 levels (27.05 ± 10.29 ng/mL) (Figure 1c). Based on the mean plasma sCD146 level of 30.14 ng/mL in the 97 COPD subjects, the subjects were divided into high and low sCD146 expression groups. The proportion of subjects with mMRC scores of 0 to 3 was increased in the high sCD146 group (Figure 1d). The proportion of subjects with GOLD grade 4 and ≥1 exacerbations in the past year was lower in the high sCD146 group (Figure 1e,f). These results suggested that plasma sCD146 was associated with COPD exacerbations, which may be a potential method for assessing COPD severity and control status.

FIGURE 1.

Relationship between sCD146 and disease severity. (a) sCD146 levels in plasma from stable chronic obstructive pulmonary disease (COPD) subjects and exacerbated COPD subjects. (b) sCD146 levels in plasma from different groups of moderate‐to‐severe exacerbation subjects. (c) sCD146 level in plasma from different groups of disease control situation subjects. (d–f) The distribution of patients with different modified Medical Research Council (mMRC) scores, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, and COPD‐related hospitalizations in the past year in the high sCD146 and low sCD146 groups. *p < 0.05; **p < 0.01. Bar graphs and data are presented as the mean ± standard deviation (SD).

A correlation analysis between the level of sCD146 and clinical assessment indicators related to COPD was performed. We found a significantly negative correlation between sCD146 and the CAT score (r = −0.2664, p = 0.0087) (Figure S1A). However, there were no significant correlations between sCD146 and FEV₁/FVC, FEV₁/predicted, FeNO, blood neutrophil percentage, or blood eosinophil percentage (Figure S1B–F).

Diagnostic value of plasma sCD146 in COPD exacerbations

Logistic regression analysis showed that after adjusting for age, sex, exacerbations, and hospitalizations in the past year, as well as FEV₁/FVC and FEV₁/predicted at enrollment, sCD146 was independently associated with AECOPD (odds ratio [OR]: 0.885, 95% confidence interval (95% CI): 0.81–0.967, p = 0.007) (Table 3).

TABLE 3.

Logistic regression analysis of sCD146 and acute exacerbation of chronic obstructive pulmonary disease.

Parameter	OR	95% CI	P value
sCD146 expression	0.885	0.81–0.967	0.007*
Sex	0.23	0.027–1.948	0.177
Age at cohort entry	1.077	0.974–1.191	0.146
Exacerbations ≥2 in the past year	1.703	0.212–13.701	0.617
Hospitalizations ≥1 in the past year	4.917	0.622–38.877	0.131
FEV1/FVC	0.936	0.847–1.034	0.194
FEV1/predicted	0.997	0.937–1.062	0.933

Note: Bold type denotes statistical significance (*p < 0.05).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; OR, odds ratio.

ROC curve analysis indicated the discriminatory capacity of plasma sCD146 for AECOPD (Figure 2a). The AUC was 0.712 (95% CI: 0.547–0.876, p = 0.0141). When the cutoff value of sCD146 was 36.99 ng/mL, the maximum Youden index was achieved. The discriminatory capacity of plasma sCD146 combined with sex, age, exacerbations in the past year, FEV₁/FVC, and FEV₁/predicted for AECOPD was significantly enhanced (Figure 2b), with an AUC of 0.908 (95% CI: 0.810–1.000, p < 0.001). These results indicated that plasma sCD146 was a good biomarker for diagnosing AECOPD, and that the diagnostic efficiency was higher when combined with other factors.

FIGURE 2.

Receiver operator curves for sCD146 and acute exacerbation of chronic obstructive pulmonary disease (AECOPD). (a) Area under the curve (AUC) for AECOPD using plasma sCD146 level, which was 0.712. (b) AUC for AECOPD using plasma sCD146 combined with sex, age, exacerbation in the past year, FEV₁, forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC), and FEV₁/predicted, which was 0.908.

Logistic regression analysis demonstrated that after adjusting for age, sex, BMI, duration of COPD, smoking status, and presence of asthma, sCD146 was independently associated with frequent exacerbations of COPD in the past year (OR: 0.957, 95% CI: 0.920–0.995, p = 0.027) (Table 4). This suggested that sCD146 also had potential evaluation value for frequent exacerbations of COPD.

TABLE 4.

Logistic regression analysis of sCD146 and frequent exacerbation of chronic obstructive pulmonary disease.

Parameter	OR	95% CI	P value
sCD146 expression	0.957	0.92–0.995	0.027*
Sex	2.839	0.431–18.704	0.278
Age at cohort entry	0.992	0.95–1.036	0.711
BMI	1.051	0.93–1.187	0.425
Disease courses, year	1.012	0.961–1.066	0.647
Smoking history	1.748	0.497–6.144	0.384
Asthma	0.083	0.012–0.58	0.012

Note: Bold type denotes statistical significance (*p < 0.05).

Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio.

Relationship between plasma sCD146, S100A9, and MMP‐9

S100A8 and S100A9 are members of the S100 protein family and usually exist in the form of dimers, which can be involved in the occurrence and development of COPD. ¹⁰ Previous studies have shown that serum levels of S100A8/S100A9 in AECOPD patients are elevated and negatively correlated with lung function. ¹¹ CD146 is a key receptor for S100A8/A9. ¹² After binding of S100A8/A9 to CD146, the expression of MMP‐9 is upregulated by activating mitogen‐activated protein kinase kinase 8 (MAP3K8), further promoting the inflammatory response. ¹³ sCD146 can act as a decoy to competitively bind to S100A8/A9 in the extracellular region, thereby blocking the binding of S100A8/A9 to CD146 and alleviating the inflammatory response (Figure 3a). Compared with stable subjects, there was a tendency for plasma levels of S100A9 and MMP‐9 to increase in exacerbated subjects (Figure 3b,c), but there was no significant difference between the two groups. Plasma S100A9 and MMP‐9 were significantly positively correlated (r = 0.2896, p = 0.004) (Figure 3d). Plasma sCD146 was significantly negatively correlated with S100A9 (r = −0.3939, p < 0.001) (Figure 3e), but there was no significant correlation with MMP‐9 (Figure 3f). Based on these results, we speculated that plasma sCD146 may alleviate COPD inflammation by blocking the binding of S100A9‐CD146.

FIGURE 3.

Relationship between plasma sCD146, S100A9, and MMP‐9. (a) Schematic diagram of sCD146 blocking S100A9‐CD146 binding. (b, c) Quantification of S100A9 and MMP‐9 in plasma from stable chronic obstructive pulmonary disease (COPD) subjects and exacerbated COPD subjects. (d) Correlation analysis of plasma S100A9 and MMP‐9. (e) Correlation analysis of plasma S100A9 and sCD146. (f) Correlation analysis of plasma MMP‐9 and sCD146. Bar graphs and data are presented as the mean ± standard deviation (SD).

DISCUSSION

In this study, we conducted a disease assessment on 97 COPD subjects and found that the plasma sCD146 level in exacerbated subjects was significantly lower than that in stable subjects. The combination of sCD146 with factors such as sex, age, pulmonary function, and exacerbations in the last year can be used to accurately identify AECOPD. In addition, plasma sCD146 was negatively correlated with S100A9, suggesting that sCD146 can inhibit inflammation by binding to S100A9.

Endothelial cells play a positive role in the development of both acute and chronic pulmonary diseases. ¹⁴ The proportion of circulating endothelial cells is significantly increased in patients with frequent exacerbations of COPD, indicating severe endothelial injury and dysfunction. ¹⁵ Endothelial injury leads to abnormal pulmonary microcirculatory blood flow and increased microvascular permeability, which worsens with the progression of the disease and the severity of airway obstruction. ¹⁶ , ¹⁷ CD146, an endothelial cell adhesion molecule, is involved in the pathogenesis of various inflammatory autoimmune diseases. ¹⁸ CD146 is released in soluble form (sCD146) through a metalloproteinase‐dependent mechanism. Both CD146 and sCD146 participate in the migration of monocytes across endothelial cells during inflammation, further regulating inflammatory responses. ¹⁹ The changes in CD146 level in COPD patients, however, are controversial. Some studies show that CD146 is significantly overexpressed in airway epithelial cells of COPD patients, ²⁰ , ²¹ but significantly reduced in circulating endothelial cells, ³ while other studies suggest that there is no change in the number of circulating CD146 endothelial microparticles in stable or exacerbated COPD patients. ²² Our study found a significant decrease in plasma sCD146 levels in AECOPD subjects. Endothelial injury in COPD may decrease expression of CD146 in endothelial cells and subsequently reduce the release of soluble forms. Conversely, sCD146 can inhibit its proinflammatory effect by silencing membrane‐bound CD146, ⁹ which may lead to the continuous consumption of sCD146 with disease progression. This also indicated that sCD146 had protective effects and can be used as a potential indicator for clinical intervention to control inflammation and alveolar damage. In addition, CD146 is also expressed in airway epithelial cells, smooth muscle cells, and pericytes. The main source of plasma sCD146 is still unclear. The CD146 expression may vary in different cell types. Dynamic monitoring should be adopted for changes in CD146 levels at different stages of COPD. Currently, the assessment of AECOPD mainly focuses on the severity of disease. The presence of comorbidities, medications, and the number of previous exacerbation events can increase the risk of acute exacerbations. ²³ Our study found that subjects with a higher frequency of exacerbations in the past year and subjects with poor self‐reported disease control had significantly lower plasma sCD146 levels. However, sCD146 was only significantly correlated with the CAT score, rather than indicators such as lung function, blood neutrophil counts, and blood eosinophil counts. This result suggested that sCD146 has good application value for symptom assessment. In clinical practice, sCD146 may be used to comprehensively assess the severity of AECOPD. However, the evaluation threshold of sCD146 needs to be further supported by large‐scale data. After adjusting for relevant confounding factors, we found that plasma sCD146 was an independent predictor of AECOPD. When combined with factors such as sex, age, pulmonary function, and exacerbations in the past year, the predictive value of AECOPD was greater than that of the sCD146 single prediction model. Accurately identifying high‐risk patients with acute exacerbation helps with early diagnosis and precise treatment. sCD146 undoubtedly provides us with a new diagnostic approach.

AECOPD is a common pulmonary disease with diverse etiologies, including respiratory tract infections, smoking, and air pollution. ²⁴ Among these, respiratory tract infections are the most common cause. ²⁵ The exacerbations induced by infection can increase airway inflammation and activation of inflammatory cells, leading to worsening of airway narrowing and airflow limitation. S100A9 is released in large amounts during infections and stress. It activates the proinflammatory transcription factor NF‐κB through TLR4 signaling and secretes proinflammatory cytokines, participating in the development of inflammatory diseases. ²⁶ Previous studies have shown that serum S100A9 levels are significantly elevated in patients with AECOPD. ¹⁰ In this study, we found that plasma S100A9 levels were higher in AECOPD subjects than in stable subjects, but the difference was not significant. CD146 is a key receptor for S100A9, and its binding promotes cell migration, invasion, and attachment to endothelial cells. ²⁷ It also participates in tumor cell metastasis and the inflammatory response by inducing matrix metalloproteinases. ¹³ However, the interaction between CD146 and S100A9 has only been studied in the field of oncology. ¹² , ¹³ Our study found that plasma sCD146 levels were negatively correlated with S100A9. We speculated that sCD146 can act as a decoy to block the binding of S100A8/A9 to CD146, thereby inhibiting the inflammatory response induced by protease activation. ²⁸ This indicates that sCD146 not only has clinical diagnostic value for AECOPD but also has potential therapeutic effects. MMP‐9 is a common matrix metalloproteinase expressed widely in endothelial cells, and its relationship with COPD has been extensively demonstrated. ²⁹ In this study, we found that plasma MMP‐9 levels were also elevated in AECOPD subjects compared with stable subjects and positively correlated with S100A9 levels. Therefore, we speculate that sCD146 may alleviate the progression of COPD by blocking S100A9‐CD146 binding. In COPD‐like mice, CD146 deficiency aggravated COPD via the increased production of S100A9 and MMP‐9 in macrophages, ⁸ which indicated that S100A9 and MMP‐9 might have potential associations with COPD inflammation and CD146. This also supports some of our results in this article. Due to the limited sample size in the present study, the therapeutic value of sCD146 remains to be further studied.

However, several potential limitations should also be addressed. First, our sample size is relatively small. Compared with the exacerbated group (n = 84), the population of the stable group is limited (n = 13). Furthermore, the level of sCD146 widely overlaps between the two groups. Combining the above two points, the cutoff value based on the existing data may result in more false‐negative results. In subsequent studies, we should increase the sample size to ensure a relative balance between the stable and exacerbated groups. At the same time, a more accurate cutoff value should be determined to distinguish stable and exacerbated disease status. Second, due to the limitation of the number of subjects, we only divided COPD patients into high sCD146 and low sCD146 groups. More classification results of COPD patients urgently need to be explored A dynamic monitoring method should be adopted to accurately record the changes in plasma CD146 levels in COPD patients.

CONCLUSIONS

In summary, we found that with the progressive worsening of COPD, plasma sCD146 showed a significant downward trend. This indicated that plasma sCD146 may be of clinical value in assessing disease severity. Plasma sCD146 serves as a potential biomarker for AECOPD and can guide clinicians in timely interventions to reduce the incidence of AECOPD and control disease progression. Supplementing sCD146 may be a new treatment strategy for AECOPD.

AUTHOR CONTRIBUTIONS

X.J., J.J., and M.Z. wrote the manuscript. M.Z., N.J., and M.H. designed the research. X.J., J.J., S.Z., J.W., Q.M., Z.W., and Z.C. performed the research and analyzed the data.

FUNDING INFORMATION

This research was supported by the Precision Medicine Research of The National Key Research and Development Plan of China (2016YFC0905800), the National Natural Science Foundation of China (81770031, 81970031), the Natural Science Foundation of Jiangsu Province (BK20171501, BK20181497), and the Key Research and Development Project of Jiangsu Province (BE2020616).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Supporting information

Figure S1:

Jia X, Jiang J, Yang C, et al. Plasma sCD146 is a potential biomarker for acute exacerbation of chronic obstructive pulmonary disease. Clin Transl Sci. 2024;17:e13754. doi: 10.1111/cts.13754

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available upon reasonable request from the corresponding author.