Vascular remodeling and endothelial dysfunction in patients with occupational chronic obstructive pulmonary disease caused by exposure to industrial aerosol nanoparticles

全文:

BACKGROUND

The significance of chronic obstructive pulmonary disease (COPD) is determined by its high prevalence (ranking second among chronic non-communicable respiratory diseases [1]), associated disability, and premature mortality (ranking third among chronic non-communicable diseases).¹ The projected economic burden of COPD in Russia is 378.9 billion rubles (as of 2022) [2]. The disease significantly reduces the workforce, directly impacting the country’s economic security. Mortality among the working-age population (18–65 years) is 22.5 per 100,000 people or 4% [3].

Occupational chronic obstructive pulmonary disease (O-COPD) is a progressively worsening severe disease caused by exposure to harmful particles and gases in the workplace environment. In the structure of occupational diseases caused by chemical exposure, O-COPD ranks second, accounting for 19.2%.²

The burden of COPD is associated not only with progressive respiratory failure. Cardiovascular comorbidities are the cause of at least 50% of deaths in patients with COPD [4]. COPD increases the risk of heart failure [5], ischemic heart disease [6], hypertension [7], and atrial fibrillation [8]. Within 6 months after a moderate COPD exacerbation, the risk of acute myocardial infarction increases by 50%, while after a severe exacerbation, it is 6.4 times higher [9]. Cardiovascular diseases and COPD have a mutually aggravating effect, increasing the risk of death and reducing disease control effectiveness [7, 10]. The high comorbidity rate of COPD and cardiac pathology is associated with the impact of pro-inflammatory regulatory molecules on the vascular wall and myocardium, which enter the bloodstream from the lungs and bronchi.

In the case of O-COPD, the development of comorbidities is likely influenced by both the specific pattern of systemic inflammation and the direct impact of industrial aerosol components [11–13]. For example, the prevalence of atherosclerosis is higher in patients with occupational dust-related pathology than in non-exposed individuals [12]. Additionally, clinical and functional differences in heart failure have been observed [13]. Exposure to metals, silica dust, and toxic gases increases the risk of hypertension, atherosclerosis, and atherosclerosis-associated diseases [13].

Many industrial aerosols contain nanoparticles—particles measuring less than 100 nm in at least one dimension. The unique physical properties determined by their size contribute to the high biological activity of these particles and their potential health risks [14]. Nanoparticles can induce damage and inflammation in the bronchopulmonary system and modify the phenotype of O-COPD. Additionally, nanoparticles penetrate the bloodstream through the alveoli and directly interact with the vascular wall [15]. The mechanisms of this interaction remain understudied. At the same time, the known properties of nanoparticles suggest their independent role in the development of vascular pathology in O-COPD, highlighting the relevance of research in this field.

AIM

To determine the characteristics of arterial remodeling and endothelial function in patients with O-COPD resulting from exposure to nanoparticle-containing aerosols.

MATERIALS AND METHODS

Study Design

It was a single-center, observational, cross-sectional cohort study. Patients with O-COPD were examined as the main groups, while patients with COPD due to tobacco smoking constituted the reference group. COPD was diagnosed based on the spirometric criterion: a post-bronchodilator forced expiratory volume in 1th s to forced vital capacity ratio of less than 70% [16].

Eligibility Criteria

The patients included in the study met the following criteria: age 40 to 65 years, both men and women, and signed informed consent to participate.

Inclusion criteria for the main groups (O-COPD): workers from a mechanical engineering enterprise (the All-Russian Classifier of Types of Economic Activity (OKVED) code 30.30.32) exposed to industrial aerosols containing incidental nanoparticles; workers from other enterprises engaged in similar production processes and materials; a minimum work experience of 10 years under these conditions; and chronic respiratory symptoms for at least 5 years while working under these conditions.

Inclusion criteria for the reference group (COPD in tobacco smokers): no exposure to industrial aerosols throughout the entire work history; a minimum of 10 years of tobacco smoking (traditional cigarettes); and a pack-year index of at least 10.

Exclusion criteria: individuals with other chronic bronchopulmonary diseases (simple bronchitis and bronchial asthma were allowed); inflammatory diseases other than COPD; malignant neoplasms regardless of localization; vibration disease; stages IIA–III left ventricular heart failure; stage C5 chronic kidney disease; Child–Pugh class B–C liver cirrhosis; individuals unable to understand and comply with the study protocol; and contraindications to the study diagnostic procedures.

Study Conditions and Investigation of External (Occupational) Environmental Factors

Initially, an air quality study was conducted in the working area of a mechanical engineering enterprise (OKVED code 30.30.32). Air sampling with a volume of 200–600 L was performed using the PU-4E electric aspirator (NIKI MLT, Russia). The sample was passed through a Drechsel bottle filled with an absorbent solution (50 mL of deionized water). The nanoscale particle fraction was isolated by centrifuging the solution in a planetary centrifuge for 10 min at 1500 rpm. The particle sizes in the upper fraction of the solution were determined using scanning electron microscopy combined with an energy-dispersive analyzer (scanning electron microscope Zeiss EVO MA 15; Carl Zeiss, Germany) at magnifications ranging from 2000× to 8000×. The overall chemical (elemental) composition was determined using inductively coupled plasma atomic emission spectrometry on a high-resolution iCAP-6500 spectrometer (Thermo Scientific, USA).

The concentration of nanoparticles ranged from 5 to 625 ng/L. At the workstations of smelters and welders, metal nanoparticles predominated, with the highest mass concentrations recorded for aluminum (0.0031 µg/mL), iron (0.0042 µg/mL), and chromium (0.00021 µg/mL), while the concentration of silicon nanoparticles was minimal. Subsequently, the total concentration of metal nanoparticles was used for calculations. At the workstations of charge workers, molders, chippers, and grinders, the highest mass concentration was observed for silicon nanoparticles (0.035 µg/mL), whereas the concentration of metal nanoparticles was minimal. Based on these results, two study groups of patients with O-COPD were formed, depending on the predominant content of metal or silicon nanoparticles in the aerosols.

Data on gas and dust concentrations in the occupational environment, excluding particle size fractions, were obtained from hygienic assessments of working conditions conducted by experts from the Department of Occupational Hygiene and Community Hygiene of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor) in the Novosibirsk Region. These assessments were carried out as part of an occupational disease investigation at the Center for Occupational Pathology, State Budgetary Healthcare Institution of the Novosibirsk Region, City Clinical Hospital No. 2. At the workstations of the examined individuals, the maximum allowable concentrations were exceeded for copper (maximum single exposure by 1.5 times, time-weighted average by 2.9 times); manganese (maximum single exposure by 5.5 times, time-weighted average by 2.7 times); and silicon dioxide-containing dust (maximum single exposures by 1.5–10.2 times, time-weighted average by 6.5–16.1 times).

All subjects worked under conditions of physical overexertion, exposure to noise exceeding maximum permissible levels by 1.1–1.3 times. A total of 90.9% of patients with COPD developed from aerosols with silicon nanoparticles were exposed to local and/or general vibration exceeding maximum permissible levels by 10%–15%. A total of 60.4% of patients with O-COPD developed from aerosols with metal nanoparticles were exposed to a heating microclimate.

Study Duration

The study of patients was conducted from 2019 to 2023.

Main Study Outcome

Differences in parameters characterizing vascular wall morphology, blood flow, and vascular tone were evaluated between etiologically distinct O-COPD groups.

Methods for Registration of Outcomes

All diagnostic procedures were performed during the stable phase of O-COPD, in the absence of any acute or emergency conditions or acute infections.

To assess the structural characteristics of arterial vessels, duplex scanning of the brachiocephalic and brachial arteries, as well as the aorta, was performed with color Doppler flow mapping using the Vivid S70N system (GE Healthcare, USA). The system included an electrocardiogram recording module and a linear transducer with a frequency range of 3–9 MHz, applied in longitudinal anterior, longitudinal lateral, and transverse sections. An atherosclerotic plaque was detected by visualizing a structure protruding into the arterial lumen by 0.5 mm or 50% of the intima-media thickness (IMT) or a structure extending into the vessel lumen by 1.5 mm or more. IMT was measured in the distal part of the common carotid artery. Measurements were taken at end-diastole. In Doppler mode, arterial stiffness of the neck was assessed by evaluating the pulsatility and resistive indices of the common carotid artery. Pulse wave velocity was analyzed using Doppler ultrasonography with color Doppler flow mapping from the descending aortic arch to the aortic bifurcation [17].

Endothelial function was assessed by measuring flow-mediated dilation of the brachial artery. Baseline duplex scanning of the brachial artery was performed, followed by inflation of a cuff placed on the distal third of the upper arm to 50 mmHg above the systolic arterial pressure for 3 min. The cuff was then slowly decompressed, and after 1 min, the brachial artery diameter and its percentage increase were assessed [18]. Molecular markers of endothelial function were evaluated, including soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor, as well as fibrosis markers: transforming growth factor beta 1 (TGF-β1), procollagen type III N-terminal propeptide (PIIINP), and fibroblast growth factor 2 (FGF-2). For marker analysis, a solid-phase “sandwich” enzyme-linked immunosorbent assay (ELISA) was used on an ExpertPlus 8-channel microplate photometer (ASYS HITECH, Austria). The serum concentration of low-density lipoproteins was determined using a standard colorimetric method.

Additionally, a comprehensive lung function assessment was performed, including spirometry with a bronchodilator test using a MAS2-C spirometer (Belintelmed, Belarus), body plethysmography, and measurement of lung diffusion capacity for carbon monoxide using the single-breath method (PowerCube Body plethysmograph; Schiller, Germany).

Statistical Analysis

Sample size calculation principles: The required number of patients for inclusion in the study was estimated using Altman’s nomogram, based on a study power of 0.75.

Methods of statistical data analysis: The statistical analysis was performed using SPSS Statistics 29 (IBM, USA). The level of statistical significance for rejecting the null hypothesis was set at p = 0.017, accounting for the Bonferroni correction.

Standard descriptive statistical methods were applied. Results are presented as the median and interquartile range (Me [Q1; Q3]) for continuous variables and as percentages/proportions for ordinal variables. Independent sample comparisons for continuous variables were performed using the Kruskal–Wallis test, while ordinal variables were analyzed using Pearson’s χ² test, provided that the total number of observations was at least 50 and each category contained at least 5 observations. Associations were determined within each study group using linear regression analysis. IMT and flow-mediated dilation of the brachial artery were used as dependent variables. To control for confounding factors, the regression models included the following parameters: forced expiratory volume in 1th s, smoking status, hypertension, and vibration exposure. Continuous variables were dichotomized.

RESULTS

Participant Characteristics

The O-COPD group exposed to aerosols containing metal nanoparticles included 48 patients, comprising foundry workers (n = 29) and welders (n = 19). The O-COPD group exposed to aerosols containing silicon nanoparticles included 55 patients, consisting of charge workers (n = 5), molders (n = 22), chippers (n = 10), and grinders (n = 18). The reference group consisted of 50 tobacco-smoking patients. The main characteristics of the study participants are presented in Table 1. The groups were comparable in terms of sex, age, and COPD duration, while the occupational disease groups were also matched for work experience. The proportion of patients with comorbid hypertension (both controlled and uncontrolled), obesity, and diabetes mellitus—potential causes of vascular remodeling—was similar across the groups. However, ischemic heart disease, atrial fibrillation, and chronic kidney disease—potential consequences of vascular remodeling—were more prevalent in the O-COPD groups.

 

Table 1. Patients’ characteristics

Parameter	O-COPD (n = 103)		Smoking-related COPD (n = 50)	р
	Metal nanoparticles (n = 48)	Silicon nanoparticles (n = 55)
Work experience, years, Me [Q1; Q3]	23 [19; 26]	22 [20; 25]	N/A	0.316
Men, n (%)	45/93.8	52/94.5	46/92.0	0.442
Women, n (%)	3/6.2	3/5.5	4/8.0	0.439
Age, years, Me [Q1; Q3]	57 [55; 63]	59 [54; 64]	60 [55; 63]	0.318
Percentage of smokers, n (%)	15/31.23	18/32.73	50/1001, 2	0.001
Pack-year index, Me [Q1; Q3]	13 [11; 17]	14 [12; 16]	17 [13; 19]	0.142
Smoking duration, years, Me [Q1; Q3]	25 [20; 27]	24 [21; 26]	25 [21; 26]	0.225
COPD duration, years, Me [Q1; Q3]	12 [7; 15]	13 [9; 16]	14 [10; 16]	0.496
Work experience at the onset of O-COPD symptoms, years, Me [Q1; Q3]	11.0 [9.0; 14.5]	10 [8; 13]	N/A	0.233
FEV1/FVC, %, Me [Q1; Q3]	65 [63; 67]2, 3	69 [66; 68]1, 3	62 [58; 68]1, 2	0.011
FRC, %, Me [Q1; Q3]	195 [180; 210]2, 3	164 [155; 173]1, 3	172 [166; 182]1, 2	0.001
DLCO/Va, %, Me [Q1; Q3]	33 [30; 37]2, 3	46 [42; 55]1, 3	57 [52; 66]1, 2	0.001
LDL-C, mmol/L, Me [Q1; Q3]	2.5 [2.1; 2.9]	2.3 [2.0; 2.8]	2.6 [2.0; 2.9]	0.437
Comorbidity, n (%):
·         Controlled hypertension	12/25.0	16/29.1	15/30.0	0.260
·         Uncontrolled hypertension	9/18.8	9/16.4	8/16.0	0.312
·         Ischemic heart disease	5/10.43	9/16.43	3/6.01, 2	0.015
·         Heart failure	25/52.13	30/54.53	17/34.01, 2	0.009
·         Atrial fibrillation	7/14.63	7/12.73	3/6.01, 2	0.010
·         Stages II–IV chronic kidney disease	31/64.62, 3	29/52.713	19/38.01, 2	0.009
·         Lower extremity atherosclerosis	2/4.2	4/7.2	2/4.0	N/A
·         Obesity	5/10.4	6/10.9	6/12.0	0.142
·         Diabetes mellitus	3/6.3	3/5.5	4/8.0	0.155
Note: COPD, chronic obstructive pulmonary disease. Statistical significance of differences in values relative to the groups: 1, O-COPD due to exposure to aerosols primarily containing metal nanoparticles, 2, O-COPD due to exposure to aerosols primarily containing silicon nanoparticles, 3, Smoking-related COPD; N/A, not applicable. FEV1, forced expiratory volume in one second, FVC, forced vital capacity, FRC, functional residual capacity, DLCO/Va, diffusing capacity of the lungs adjusted for alveolar volume, LDL-C, low-density lipoprotein cholesterol in blood serum.

 

Primary Findings

Ultrasound evaluation of the vascular wall revealed the greatest increase in IMT, as well as a higher prevalence of carotid artery atherosclerosis and a greater percentage of arterial lumen narrowing due to atherosclerotic plaque, in the O-COPD group exposed to aerosols containing silicon nanoparticles (Table 2). This group also demonstrated higher systolic and lower mean linear blood flow velocities. The increase in the pulsatility index, resistive index of the brachiocephalic arteries, and pulse wave velocity in the aorta in patients with O-COPD due to nanoparticle aerosol exposure indicates increased arterial stiffness.

 

Table 2. Vascular remodeling and endothelial function parameters depending on the etiology of chronic obstructive pulmonary disease

Parameter	O-COPD (n = 103)		Smoking-related COPD (n = 50)	р
	Metal nanoparticles (n = 48)	Silicon nanoparticles (n = 55)
CIMT of the CCA, mm, Me [Q1; Q3]	0.9 [0.7; 1.0]2	1.2 [0.9; 1.5]1, 3	0.8 [0.7; 0.9]2	0.009
Percentage of patients with CIMT of the CCA > 0.9 mm, n (%)	21/43.92	39/70.91, 3	19/38.02	0.005
Atherosclerotic plaque in the brachiocephalic arteries, n (%)	11/22.92	23/41.81, 3	9/18.02	0.003
Hemodynamically significant atherosclerotic plaque in the brachiocephalic arteries, n (%)	3/6.3	5/9.0	2/4.0	н/п
Degree of stenosis in the brachiocephalic arteries at the site of the atherosclerotic plaque, %, Me [Q1; Q3]	35 [29; 41]2	55 [49; 61]1, 3	30 [25; 42]2	0.001
Systolic linear blood flow velocity in the CCA, cm/s, Me [Q1; Q3]	67.7 [52.6; 69.4]2	72.1 [70.3; 79.1]1, 3	68.9 [55.3; 70.6]2	0.001
Mean linear blood flow velocity in the CCA, cm/s, Me [Q1; Q3]	38.5 [35.8; 41.2]2, 3	31.1 [27.4; 36.2]1, 3	42.6 [39.2; 47.5]1, 2	0.005
PI CCA, Me [Q1; Q3]	1.2 [1.1; 1.4]2	1.5 [1.3; 1.7]1, 3	1.1 [1.1; 1.3]2	0.001
RI CCA, Me [Q1; Q3]	0.64 [0.60; 0.66]2, 3	0.69 [0.65; 0.70]1, 3	0.61 [0.56; 0.64]2, 3	0.010
Systolic linear blood flow velocity in the ECA, cm/s, Me [Q1; Q3]	66.2 [63.8; 68.1]2	70.3 [68.6; 74.9]1, 3	65.4 [62.7; 67.9]2	0.001
Mean linear blood flow velocity in the ECA, cm/s, Me [Q1; Q3]	28 [24.6; 31.5]2, 3	24 [20.3; 27.1]1, 3	30.4 [27.9; 35.3]1, 2	0.009
PI ECA, Me [Q1; Q3]	1.3 [1.2; 1.4]2, 3	1.6 [1.4; 1.8]1, 3	1.2 [1.1; 1.2]1, 2	0.002
RI ECA, Me [Q1; Q3]	0.69 [0.64; 0.74]2, 3	0.73 [0.70; 0.79]1, 3	0.66 [0.60; 0.69]2, 3	0.009
Systolic linear blood flow velocity in the ICA, cm/s, Me [Q1; Q3]	65.2 [60.7; 68.1]2	68.4 [65.0; 74.1]1, 3	65.9 [62.4; 67.7]2	0.010
Mean linear blood flow velocity in the ICA, cm/s, Me [Q1; Q3]	30.6 [27.4; 36.2]2	25.1 [21.7; 29.3]1, 3	31.2 [26.8; 35.5]2	0.009
PI ICA, Me [Q1; Q3]	1.3 [1.2; 1.4]2	1.7 [1.5; 1.8]1, 3	1.3 [1.2; 1.3]2	0.001
RI ICA, Me [Q1; Q3]	0.69 [0.65; 0.71]2	0.72 [0.70; 0.78]1, 3	0.68 [0.66; 0.70]2	0.009
Systolic linear blood flow velocity in the vertebral artery, cm/s, Me [Q1; Q3]	42.1 [40.5; 43.9]2	45.4 [42.6; 47.1]1, 3	41.0 [39.3; 43.2]2	0.003
Mean linear blood flow velocity in the vertebral artery, Me [Q1; Q3]	19.3 [18.1; 21.4]2	17.7 [16.4; 18.5]1, 3	21.7 [19.6; 23.3]2	0.001
PI of the vertebral artery, Me [Q1; Q3]	1.2 [1.1; 1.3]2	1.5 [1.3; 1.6]1, 3	1.2 [1.1; 1.2]2	0.001
RI of the vertebral artery, Me [Q1; Q3]	0.72 [0.68; 0.76]2, 3	0.78 [0.74; 0.81]1, 3	0.75 [0.70; 0.77]1, 2	0.009
Pulse wave velocity in the aorta, m/s, Me [Q1; Q3]	9.3 [8.9; 10.7]2, 3	12.6 [11.2; 14.1]1, 3	7.2 [6.9; 8.4]1, 2	0.001
Flow-mediated dilation of the brachial artery, %, Me [Q1; Q3]	3.8 [3.3; 4.6]2, 3	2.5 [2.1; 3.4]1, 3	4.7 [4.5; 5.3]1, 2	0.001
Soluble vascular cell adhesion molecule-1, pg/mL, Me [Q1; Q3]	18.5 [13.3; 23.1]2, 3	46.1 [37.8; 55.2]1, 3	12.9 [6.28; 17.6]1, 2	0.001
Von Willebrand factor, IU/L, Me [Q1; Q3]	4.9 [3.7; 6.2]2, 3	7.5 [6.0; 7.3]1, 3	3.1 [2.3; 3.8]1, 2	0.001
Note. Statistical significance of differences in values relative to the groups: 1, O-COPD due to exposure to aerosols primarily containing metal nanoparticles, 2, O-COPD due to exposure to aerosols primarily containing silicon nanoparticles, 3, smoking-related COPD. O-COPD, occupational chronic obstructive pulmonary disease, CIMT, carotid intima-media thickness, CCA, common carotid artery, ICA, internal carotid artery, ECA, external carotid artery, PI, pulsatility index, RI, resistive index.

 

 

In the O-COPD group exposed to aerosols containing metal nanoparticles, compared with the smoking-related COPD group, there was a decrease in the mean linear blood flow velocity in the common and external carotid arteries, an increase in the resistive index in the common, external carotid, and vertebral arteries, and an increase in the pulsatility index in the external carotid arteries. These findings also indicate a greater degree of vascular remodeling and increased arterial stiffness.

Statistically significant differences in pulse wave velocity in the aorta were identified between the study groups. The highest values were observed in the O-COPD group exposed to aerosols containing silicon nanoparticles, intermediate values were observed in the group exposed to metal nanoparticles, and the lowest values were observed in the tobacco-smoking COPD group.

Thus, ultrasound characteristics reflecting vascular remodeling (fibrosis and atherosclerosis) were more pronounced in O-COPD compared to smoking-related COPD, particularly in O-COPD caused by exposure to aerosols containing silicon nanoparticles.

The analysis of molecular factors revealed a profibrotic cytokine profile in the blood of patients with O-COPD exposed to silicon nanoparticle aerosols, along with the highest levels of active fibroproliferation markers. Specifically, TGF-β1 concentration was 944.6 [864.5; 966.7] pg/mL, FGF-2 was 16.3 [13.0; 19.6] pg/mL, and PIIINP was 92.1 [82.8; 101.4] ng/mL. For comparison, in O-COPD due to exposure to aerosols containing metal nanoparticles, the concentrations of these molecules were 713.0 [688.2; 736.6] pg/mL, 1.5 [1.41; 1.62] pg/mL, and 156.7 [141.5; 171.9] ng/mL, respectively. In the reference group, the values were 732.8 [654.4; 811.6] pg/mL, 8.3 [5.7; 11.3] pg/mL, and 28.5 [16.6; 42.3] ng/mL, respectively (p < 0.017); differences were statistically significant among all groups.

Flow-mediated dilation of the brachial artery was lowest in patients with O-COPD caused by exposure to silicon nanoparticle aerosols, indicating the highest degree of endothelial dysfunction. Intermediate values were recorded in the second O-COPD group (exposed to metal nanoparticles), while the highest values were observed in the reference group. Molecular factor analysis also revealed the highest concentrations of endothelial dysfunction and injury markers, including sVCAM-1 and von Willebrand factor, in O-COPD due to exposure to silicon nanoparticle aerosols.

According to regression analysis, the mass concentrations of nanoparticles in industrial aerosols and work experience were associated with vascular remodeling characteristics and endothelial function. With increasing nanoparticle concentrations, IMT increased, while the flow-mediated dilation of the brachial artery decreased. The strongest associations were observed for silicon nanoparticles (Tables 3 and 4).

 

Table 3. Relationships between environmental factors and carotid intima-media thickness

Independent variable (environmental factor)	В	Standard error of B	R	R2	Adjusted R2	р
O-COPD due to exposure to aerosols containing metal nanoparticles
Concentration of metal nanoparticles, mg/mL	0.008	0.001	0.61	0.37	0.36	0.001
Maximum one-time copper concentration, mg/m³	0.002	0.001	0.16	0.03	0.03	0.327
Time-weighted average copper concentration, mg/m³	0.001	0.001	0.18	0.03	0.03	0.322
Maximum one-time manganese concentration, mg/m³	0.003	0.002	0.15	0.02	0.02	0.406
Time-weighted average manganese concentration, mg/m³	0.002	0.001	0.19	0.04	0.03	0.185
Work experience, years	0.009	0.002	0.53	0.28	0.27	0.002
Pack-year index	0.008	0.001	0.20	0.04	0.03	0.192
O-COPD due to exposure to aerosols containing silicon nanoparticles
Concentration of silicon nanoparticles, mg/mL	0.005	0.001	0.70	0.49	0.47	0.001
Maximum one-time silica dust concentration, mg/m³	0.003	0.002	0.18	0.032	0.031	0.207
Time-weighted average silica dust concentration, mg/m³	0.004	0.002	0.21	0.044	0.043	0.170
Work experience, years	0.025	0.008	0.40	0.16	0.14	0.002
Pack-year index	0.003	0.001	0.23	0.06	0.04	0.296
Note: O-COPD, occupational chronic obstructive pulmonary disease. B, regression coefficient, R, coefficient of determination, R2, coefficient of determination squared, adjusted R2, adjusted coefficient of determination squared.

 

Table 4. Relationships between environmental factors and brachial artery flow-mediated dilation

Independent variable (environmental factor)	В	Standard error of B	R	R2	Adjusted R2	р
O-COPD due to exposure to aerosols containing metal nanoparticles
Concentration of metal nanoparticles, mg/mL	−0.010	0.003	0.72	0.52	0.51	0.001
Maximum one-time copper concentration, mg/m³	−0.001	0.001	0.09	0.008	0.007	0.762
Time-weighted average copper concentration, mg/m³	−0.002	0.001	0.15	0.023	0.022	0.412
Maximum one-time manganese concentration, mg/m³	−0.003	0.002	0.14	0.020	0.019	0.395
Time-weighted average manganese concentration, mg/m³	−0.001	0.001	0.11	0.012	0.011	0.429
Work experience, years	−0.012	0.002	0.75	0.56	0.55	0.001
Pack-year index	−0.025	0.004	0.70	0.49	0.48	0.001
O-COPD due to exposure to aerosols containing silicon nanoparticles
Concentration of silicon nanoparticles, mg/mL	−0.029	0.003	0.85	0.72	0.71	0.001
Maximum one-time silica dust concentration, mg/m³	−0.015	0.002	0.54	0.29	0.28	0.001
Time-weighted average silica dust concentration, mg/m³	−0.021	0.001	0.75	0.56	0.55	0.001
Work experience, years	−0.015	0.005	0.83	0.69	0.68	0.001
Pack-year index	−0.023	0.003	0.71	0.50	0.50	0.001
Note: O-COPD, occupational chronic obstructive pulmonary disease. B, regression coefficient, R, coefficient of determination, R2, coefficient of determination squared, adjusted R2, adjusted coefficient of determination squared.

 

Silicon-containing dust concentrations in workplace air, measured without consideration of particle size fractions, were associated with signs of endothelial dysfunction but did not affect vascular structural remodeling parameters. Metal concentrations in workplace air were not associated with the vascular parameters studied.

Additionally, a significant association was found between silicon nanoparticle concentrations and the molecular marker of fibrosis, PIIINP [regression coefficient (B) 2.1; coefficient of determination (R²) 0.92; p < 0.001], as well as markers of endothelial inflammation, sVCAM-1 (B = 1.6, R² = 0.85, p = 0.001). When dust concentrations were analyzed without considering particle size fractions, these patterns were not observed (p > 0.05).

DISCUSSION

Summary of the Primary Study Results

Differences in vascular remodeling and endothelial dysfunction were identified among the etiologically distinct COPD groups, as well as between occupational COPD and smoking-related COPD. Regression analysis revealed associations between vascular syndrome and occupational exposure characteristics, including mass concentrations of nanoparticles.

Discussion of the Primary Study Results

The clinical significance of endothelial dysfunction and arterial remodeling (IMT, vascular stiffness, etc.) is determined by their association with adverse cardiovascular events and hypertension [19, 20]. Studies of the general COPD population (regardless of phenotype) have demonstrated the presence of vascular remodeling, which is statistically significantly dependent on lung function [21, 22]. The most compelling evidence supports increased vascular stiffness and IMT [21–23]. Additionally, endothelial dysfunction is recognized as a key factor in the pathogenesis of COPD [18, 24]. For instance, reduced FMD of the brachial artery is associated with pulmonary hypertension and impaired lung function [16, 25].

This study further established that etiologically distinct O-COPD phenotypes caused by exposure to aerosols containing metal or silicon nanoparticles exhibit varying degrees of vascular remodeling and endothelial dysfunction, differing from smoking-related COPD. A correlation was identified with the intensity and duration of exposure to incidental nanoparticles. The associations observed for nanoparticles differed from those for the total aerosol mass. Thus, vascular remodeling and endothelial dysfunction in patients with O-COPD due to occupational aerosol exposure are likely associated, at least in part, with the impact of nanoparticles. For effective occupational health risk management, it is advisable to monitor not only the total concentrations of hazardous substances but also nanoparticle concentrations, particularly for assessing cardiovascular risk. Further development of respiratory protective equipment capable of reducing nanoparticle exposure intensity is necessary.

The most pronounced structural vascular changes (IMT, pulsatility index, and resistive index, indirectly reflecting arterial stiffness) and endothelial dysfunction were observed in cases of O-COPD caused by exposure to silicon nanoparticle aerosols. Given the elevated serum concentrations of TGF-β1, FGF-2, and PIIINP in this group, it can be hypothesized that fibroproliferation plays a significant role in the vascular remodeling process associated with exposure to silicon nanoparticles. The maximum increase in von Willebrand factor and sVCAM-1 blood concentrations further confirms endothelial cell activation [26]. The identified differences and associations may be explained by either the direct impact of nanoparticles on the vascular wall or an indirect effect mediated by the specific endotype of O-COPD, which is also influenced by aerosol properties [15].

The observed severity of vascular involvement underscores the need to consider patients with O-COPD due to exposure to silicon-containing dust as a high cardiovascular risk group. Regular ultrasound monitoring of the carotid arteries is essential for the early diagnosis and management of vascular damage. The established correlation with the intensity and duration of nanoparticle exposure raises the question of incorporating duplex vascular scanning into routine occupational health assessments for workers exposed to nanoparticles during industrial processes.

Study Limitations

The main limitations of this study include its single-center design and the use of a limited number of hygienic characteristics of nanoparticles. Further multicenter studies across various industries with unintended nanoparticle emissions in workplace air are advisable.

CONCLUSION

In the development of O-COPD due to exposure to nanoparticle-containing aerosols, the severity of vascular remodeling and endothelial dysfunction increases, with more pronounced effects observed with silicon nanoparticle exposure. This should be considered in occupational health surveillance programs.

ADDITIONAL INFORMATION

Author contributions. L.A. Shpagina, M.A. Zenkova, A.I. Saprykin, I.S. Shpagin, E.B. Logashenko, O.S. Kotova, E.V. Anikina — concept and design; L.A. Shpagina, M.A. Zenkova, A.I. Saprykin, E.B. Logashenko, I.S. Shpagin, O.S. Kotova, A.R. Tsygankova, G.V. Kuznetsova, E.G. Kondyurina, V.V. Zelenskaia, E.V. Anikina, N.V. Kamneva, V.A. Sergeev, T.N. Surovenko — data collection analysis and interpretation; L.A. Shpagina, E.B. Logashenko, I.S. Shpagin, O.S. Kotova, V.A. Sergeev — preparation of manuscript. All authors have approved the manuscript (version for publication) and have also agreed to be responsible for all aspects of the work, ensuring that issues related to the accuracy and integrity of any part of it are properly addressed and resolved.

Ethics approval. The present study was approved by the local Ethics Committee of the Novosibirsk State Medical University (protocol No. 121 by 21.11.2019).

Funding sources. The study was founded by Russian Science Foundation, grant No. 19-74-30011.

Disclosure of interests. The authors have no relationships, activities or interests for the last three years related with for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality. The authors did not use previously published information (text, illustrations, data) to create this paper.

Data availability statement. All data obtained in the present study are available in the article.

Generative AI. Generative AI technologies were not used for this article creation.

Provenance and peer-review. This paper was submitted to the journal on an initiative basis and reviewed according to the usual procedure. The review process involved an external reviewer, a member of the editorial board and the scientific editor of the publication.

¹ Global burden of disease study 2021. Available from: https://vizhub.healthdata.org/gbd-compare/ Accessed on July 27, 2024.

² On the State of Sanitary and Epidemiological Well-Being of the Population in the Russian Federation in 2023: State Report. Moscow: Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 2024. Available from: https://rospotrebnadzor.ru/documents/details.php?ELEMENT_ID=27779 Accessed on July 27, 2024.

作者简介

Lyubov Shpagina

Novosibirsk State Medical University

编辑信件的主要联系方式.
Email: lashpagina@gmail.com
ORCID iD: 0000-0003-0871-7551
SPIN 代码: 5773-6649

MD, Dr. Sci. (Medicine), Professor

俄罗斯联邦, Novosibirsk

Marina Zenkova

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences

Email: marzen@niboch.nsc.ru
ORCID iD: 0000-0003-4044-1049
SPIN 代码: 2284-2692

Dr. Sci. (Biology), Professor, Corresponding Member of the Russian Academy of Sciences

俄罗斯联邦, Novosibirsk

Anatoly Saprykin

Nikolaev Institute of Inorganic Chemistry of the Siberian Branch of the Russian Academy of Sciences

Email: saprykin@niic.nsc.ru
ORCID iD: 0000-0002-8999-8457
SPIN 代码: 4688-9801

Dr. Sci. (Engineering)

俄罗斯联邦, Novosibirsk

Evgenia Logashenko

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences

Email: evg.log@gmail.com
ORCID iD: 0000-0001-8977-5395
SPIN 代码: 7408-9400

Cand. Sci. (Biology)

俄罗斯联邦, Novosibirsk

Ilya Shpagin

Novosibirsk State Medical University

Email: doctor_ilya@mail.ru
ORCID iD: 0000-0002-3109-9811
SPIN 代码: 2892-6184

MD, Dr. Sci. (Medicine), Associate Professor

俄罗斯联邦, Novosibirsk

Olga Kotova

Novosibirsk State Medical University

Email: ok526@yandex.ru
ORCID iD: 0000-0003-0724-1539
SPIN 代码: 2488-0659

MD, Dr. Sci. (Medicine), Associate Professor

俄罗斯联邦, Novosibirsk

Alfia Tsygankova

Nikolaev Institute of Inorganic Chemistry of the Siberian Branch of the Russian Academy of Sciences

Email: mkb-2@yandex.ru
ORCID iD: 0000-0001-7126-276X
SPIN 代码: 6619-9694

Cand. Sci. (Chemistry)

俄罗斯联邦, Novosibirsk

Elena Kondyurina

Novosibirsk State Medical University

Email: econdur@yandex.ru
ORCID iD: 0000-0003-3250-3107
SPIN 代码: 8665-9138

MD, Dr. Sci. (Medicine), Professor

俄罗斯联邦, Novosibirsk

Vera Zelenskaya

Novosibirsk State Medical University

Email: v.zelenskaya@mail.ru
ORCID iD: 0000-0003-0344-9412
SPIN 代码: 9151-5099

MD, Dr. Sci. (Medicine), Associate Professor

俄罗斯联邦, Novosibirsk

Galina Kuznetsova

Novosibirsk State Medical University

Email: doktor67@list.ru
ORCID iD: 0000-0001-7428-9159

MD, Cand. Sci. (Medicine)

俄罗斯联邦, Novosibirsk

Ekaterina Anikina

Novosibirsk State Medical University

Email: mkb-2@yandex.ru
ORCID iD: 0000-0002-6047-1707
SPIN 代码: 3847-0025
俄罗斯联邦, Novosibirsk

Natalya Kamneva

Novosibirsk State Medical University

Email: natali.spor@yandex.ru
ORCID iD: 0000-0003-3251-0315
SPIN 代码: 8868-3043

MD, Cand. Sci. (Medicine)

俄罗斯联邦, Novosibirsk

Valery Sergeev

Novosibirsk State Medical University

Email: valerasergeev030197@yandex.ru
ORCID iD: 0009-0007-6984-4294
俄罗斯联邦, Novosibirsk

Tatyana Surovenko

Pacific State Medical University

Email: mkb-2@yandex.ru
ORCID iD: 0000-0001-7676-3213
SPIN 代码: 6169-4476

MD, Dr. Sci. (Medicine)

俄罗斯联邦, Vladivostok

参考

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