Chronic exposure to diesel exhaust may cause small airway wall thickening without lumen narrowing: a quantitative computerized tomography study in Chinese diesel engine testers

Abstract Background Diesel exhaust (DE) is a major source of ultrafine particulate matters (PM) in ambient air and contaminates many occupational settings. Airway remodeling assessed using computerized tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural changes of small airways caused by chronic DE exposure is unknown. Wall and lumen areas of 6th and 9th generations of four candidate airways were quantified using end-inhalation CT scans in 78 diesel engine testers (DET) and 76 non-DETs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response relationship. Results Environmental monitoring and CCAM showed a much higher PM exposure in DETs, which was associated with higher wall area and wall area percent for 6th generation of airways. However, no reduction in lumen area was identified. No study subjects met spirometry diagnosis of airway obstruction. This suggested that small airway wall thickening without lumen narrowing may be an early feature of airway remodeling in DETs. The effect of DE exposure status on wall area percent did not differ by lobes or smoking status. Although the trend test was of borderline significance between categorized CCAM and wall area percent, subjects in the highest CCAM category has a 14% increase in wall area percent for the 6th generation of airways compared to subjects in the lowest category. The impact of DE exposure on FEV1 can be partially explained by the wall area percent with mediation effect size equal to 20%, Pperm = 0.028). Conclusions Small airway wall thickening without lumen narrowing may be an early image feature detected by CT and underlie the pathology of lung injury in DETs. The pattern of changes in small airway dimensions, i.e., thicker airway wall without lumen narrowing caused by occupational DE exposure was different to that (i.e., thicker airway wall with lumen narrowing) seen in our previous study of workers exposed to nano-scale carbon black aerosol, suggesting constituents other than carbon cores may contribute to such differences. Our study provides some imaging indications of the understanding of the pulmonary toxicity of combustion derived airborne particulate matters in humans.

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Small Airway Wall Thickening Assessed by Computerized Tomography Is Associated With Low Lung Function in Chinese Carbon Black Packers

Toxicological Sciences ◽

10.1093/toxsci/kfaa134 ◽

2020 ◽

Vol 178 (1) ◽

pp. 26-35

Author(s):

Xue Cao ◽

Li Lin ◽

Akshay Sood ◽

Qianli Ma ◽

Xiangyun Zhang ◽

...

Keyword(s):

Lung Function ◽

Carbon Black ◽

Elemental Carbon ◽

Airway Remodeling ◽

Forced Expiratory Volume ◽

Small Airway ◽

Wall Thickening ◽

Dependent Manner ◽

Airway Wall ◽

Wall Area

Abstract Nanoscale carbon black as virtually pure elemental carbon can deposit deep in the lungs and cause pulmonary injury. Airway remodeling assessed using computed tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural airway changes caused by carbon black exposure remain unknown. Wall and lumen areas of sixth and ninth generations of airways in 4 lobes were quantified using end-inhalation CT scans in 58 current carbon black packers (CBPs) and 95 non-CBPs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response. Environmental monitoring and CCAM showed a much higher level of elemental carbon exposure in CBPs, which was associated with higher wall area and lower lumen area with no change in total airway area for either airway generation. This suggested small airway wall thickening is a major feature of airway remodeling in CBPs. When compared with wall or lumen areas, wall area percent (WA%) was not affected by subject characteristics or lobar location and had greater measurement reproducibility. The effect of carbon black exposure status on WA% did not differ by lobes. CCAM was associated with WA% in a dose-dependent manner. CBPs had lower FEV1 (forced expiratory volume in 1 s) than non-CBPs and mediation analysis identified that a large portion (41–72%) of the FEV1 reduction associated with carbon black exposure could be explained by WA%. Small airway wall thickening as a major imaging change detected by CT may underlie the pathology of lung function impairment caused by carbon black exposure.

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Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.2.366 ◽

1997 ◽

Vol 83 (2) ◽

pp. 366-370 ◽

Cited By ~ 26

Author(s):

Robert H. Brown ◽

Wayne Mitzner ◽

Elizabeth M. Wagner

Keyword(s):

Dose Response ◽

Lung Volume ◽

Bronchial Artery ◽

Wall Thickening ◽

Airway Wall ◽

Lung Inflation ◽

Wall Area ◽

Airway Edema ◽

Airway Constriction

Brown, Robert H., Wayne Mitzner, and Elizabeth M. Wagner.Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83(2): 366–370, 1997.—Inflammatory changes and airway wall thickening are suggested to cause increased airway responsiveness in patients with asthma. In five sheep, the dose-response relationships of individual airways were measured at different lung volumes to methacholine (MCh) before and after wall thickening caused by the inflammatory mediator bradykinin via the bronchial artery. At 4 cmH2O transpulmonary pressure (Ptp), 5 μg/ml MCh constricted the airways to a maximum of 18 ± 3%. At 30 cmH2O Ptp, MCh resulted in less constriction (to 31 ± 5%). Bradykinin increased airway wall area at 4 and 30 cmH2O Ptp (159 ± 6 and 152 ± 4%, respectively; P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased airway luminal area (13 ± 2%; P< 0.01), and the dose-response curve was significantly lower ( P = 0.02). At 30 cmH2O, postbradykinin, the maximal airway narrowing was not significantly different (26 ± 5%; P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect on the MCh-induced airway constriction. We conclude that inflammatory fluid leakage in the airways cannot be a primary cause of airway hyperresponsiveness.

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Effects of lung volume, bronchoconstriction, and cigarette smoke on morphometric airway dimensions

Journal of Applied Physiology ◽

10.1152/jappl.1988.64.3.913 ◽

1988 ◽

Vol 64 (3) ◽

pp. 913-919 ◽

Cited By ~ 26

Author(s):

A. L. James ◽

P. D. Pare ◽

J. C. Hogg

Keyword(s):

Smooth Muscle ◽

Cigarette Smoke ◽

Lung Volume ◽

Muscle Tone ◽

Cigarette Smoke Exposure ◽

Wall Thickening ◽

Airway Wall ◽

Lung Inflation ◽

Wall Area ◽

Airway Dimensions

To examine the role of airway wall thickening in the bronchial hyperresponsiveness observed after exposure to cigarette smoke, we compared the airway dimensions of guinea pigs exposed to smoke (n = 7) or air (n = 7). After exposure the animals were anesthetized with urethan, pulmonary resistance was measured, and the lungs were removed, distended with Formalin, and fixed near functional residual capacity. The effects of lung inflation and bronchoconstriction on airway dimensions were studied separately by distending and fixing lungs with Formalin at total lung capacity (TLC) (n = 3), 50% TLC (n = 3), and 25% TLC (n = 3) or near residual volume after bronchoconstriction (n = 3). On transverse sections of extraparenchymal and intraparenchymal airways the following dimensions were measured: the internal area (Ai) and internal perimeter (Pi), defined by the epithelium, and the external area (Ae) and external perimeter (Pe), defined by the outer border of smooth muscle. Airway wall area (WA) was then calculated, WA = Ae - Ai. Ai, Pe, and Ae decreased with decreasing lung volume and after bronchoconstriction. However, WA and Pi did not change significantly with lung volume or after bronchoconstriction. After cigarette smoke exposure airway resistance was increased (P less than 0.05); however, there was no difference in WA between the smoke- and air-exposed groups when the airways were matched by Pi. We conclude that Pi and WA are constant despite changes in lung volume and smooth muscle tone and that airway hyperresponsiveness induced by cigarette smoke is not mediated by increased airway wall thickness.

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A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00116.2014 ◽

2014 ◽

Vol 307 (7) ◽

pp. L557-L565 ◽

Cited By ~ 23

Author(s):

Irene M. J. Eurlings ◽

Mieke A. Dentener ◽

Evi M. Mercken ◽

Rafael de Cabo ◽

Ken R. Bracke ◽

...

Keyword(s):

Two Dimensions ◽

Small Airway ◽

Wall Thickening ◽

Suitable Model ◽

Matrix Remodeling ◽

Airway Wall ◽

Copd Patients ◽

Tnf Α ◽

Chronic Models ◽

Airway Walls

Remodeling in chronic obstructive pulmonary disease (COPD) has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recently we showed comparable alterations of the extracellular matrix (ECM) compounds collagen, hyaluoran, and elastin in alveolar and small airway walls of COPD patients. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal lipopolysaccharide instillation, or local tumor necrosis factor (TNF) expression [surfactant protein C (SPC)-TNFα mice], were stained for elastin, collagen, and hyaluronan. Furthermore TNF-α matrix metalloproteinase (MMP)-2, -9, and -12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFα mice. Furthermore TNF-α and MMP-2 and -9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFα mice. We show that only SPC-TNFα mice show changes in elastin remodeling that are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFα model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP-2 and MMP-9 in the breakdown of elastin in airways and alveoli of SPC-TNFα mice.

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Airway wall attenuation: a biomarker of airway disease in subjects with COPD

Journal of Applied Physiology ◽

10.1152/japplphysiol.00216.2009 ◽

2009 ◽

Vol 107 (1) ◽

pp. 185-191 ◽

Cited By ~ 44

Author(s):

George R. Washko ◽

Mark T. Dransfield ◽

Raúl San José Estépar ◽

Alejandro Diaz ◽

Shin Matsuoka ◽

...

Keyword(s):

Lung Function ◽

Wall Thickness ◽

Airway Disease ◽

Wall Thickening ◽

Chronic Obstructive ◽

Airway Wall ◽

Wall Area ◽

Computer Based ◽

Structure Density ◽

Contrast Reduction

The computed tomographic (CT) densities of imaged structures are a function of the CT scanning protocol, the structure size, and the structure density. For objects that are of a dimension similar to the scanner point spread function, CT will underestimate true structure density. Prior investigation suggests that this process, termed contrast reduction, could be used to estimate the strength of thin structures, such as cortical bone. In this investigation, we endeavored to exploit this process to provide a CT-based measure of airway disease that can assess changes in airway wall thickening and density that may be associated with the mural remodeling process in subjects with chronic obstructive pulmonary disease (COPD). An initial computer-based study using a range of simulated airway wall sizes and densities suggested that CT measures of airway wall attenuation could detect changes in both wall thickness and structure density. A second phantom-based study was performed using a series of polycarbonate tubes of known density. The results of this again demonstrated the process of contrast reduction and further validated the computer-based simulation. Finally, measures of airway wall attenuation, wall thickness, and wall area (WA) divided by total cross-sectional area, WA percent (WA%), were performed in a cohort of 224 subjects with COPD and correlated with spirometric measures of lung function. The results of this analysis demonstrated that wall attenuation is comparable to WA% in predicting lung function on univariate correlation and remain as a statistically significant correlate to the percent forced expiratory volume in 1 s predicted when adjusted for measures of both emphysema and WA%. These latter findings suggest that the quantitative assessment of airway wall attenuation may offer complementary information to WA% in characterizing airway disease in subjects with COPD.

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Vessel growth and collapsible pressure-area relationship

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.4.h2030 ◽

1997 ◽

Vol 273 (4) ◽

pp. H2030-H2043 ◽

Cited By ~ 20

Author(s):

Gary Drzewiecki ◽

Shawn Field ◽

Issam Moubarak ◽

John K.-J. Li

Keyword(s):

High Pressures ◽

Wall Thickening ◽

Lumen Area ◽

Jugular Veins ◽

Wall Area ◽

Wall Properties ◽

Vessel Growth ◽

Pressure Area ◽

Lumen Narrowing ◽

Wall Growth

The role that the pattern of vessel wall growth plays in determining pressure-lumen area (P-A) and pressure-compliance curves was examined. A P-A vessel model was developed that encompasses the complete range of pressure, including negative values, and accounts for size given the fixed length, nonlinear elastic wall properties, constant wall area, and collapse. Data were obtained from excised canine carotid and femoral arteries, jugular veins, and elastic tubing. The mean error of estimate was 8 mmHg for all vessels studied and 2 mmHg for blood vessels. The P-A model was employed to examine two patterns of arterial wall thickening, outward growth and remodeling (constant wall area), under the assumption of constant wall properties. The model predicted that only outward wall growth resets compliance such that it increases at a given arterial pressure, explaining previously contradictory data. In addition, it was found that outward wall growth increases the lumen area between normal and high pressures. Remodeling resulted in lumen narrowing and a decrease in compliance for positive pressures.

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Faculty Opinions recommendation of Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1067069.520052 ◽

2007 ◽

Author(s):

Caroline Owen

Keyword(s):

Growth Factors ◽

Cigarette Smoke ◽

Airway Remodeling ◽

Small Airway ◽

Airway Wall

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Heterogeneity of airway wall dimensions in humans: a critical determinant of lung function in asthmatics and nonasthmatics

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00421.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. L425-L431 ◽

Cited By ~ 13

Author(s):

Christopher D. Pascoe ◽

Chun Y. Seow ◽

Tillie L. Hackett ◽

Peter D. Paré ◽

Graham M. Donovan

Keyword(s):

Airway Remodeling ◽

Airflow Obstruction ◽

Small Airways ◽

Airway Wall ◽

Critical Determinant ◽

Mean Values ◽

Airway Narrowing ◽

Wall Area ◽

First Time ◽

Fixed Airflow Obstruction

Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the largest effect on increasing maximal airway narrowing. Simulated heterogeneity in the dimensions and properties of the airway wall can further amplify airway narrowing. Using measurements made on histological sections from donor lungs, we show for the first time that there is profound heterogeneity of ASM area and wall area in both nonasthmatics and asthmatics. Using a mathematical model, we found that this heterogeneity, together with changes in the mean values, contributes to an increased baseline resistance and elastance in asthmatics as well as a leftward shift in the responsiveness of the airways to a simulated agonist in both nonasthmatics and asthmatics. The ability of heterogeneous wall dimensions to shift the dose-response curve is largely due to an increased susceptibility for the small airways to close. This research confirms that heterogeneity of airway wall dimensions can contribute to exaggerated airway narrowing and provides an actual assessment of the magnitude of these effects.

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Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.1.140 ◽

1997 ◽

Vol 83 (1) ◽

pp. 140-147 ◽

Cited By ~ 54

Author(s):

Rodney K. Lambert ◽

Peter D. Paré

Keyword(s):

Smooth Muscle ◽

Shear Modulus ◽

Airway Remodeling ◽

Bronchial Hyperresponsiveness ◽

Lung Parenchyma ◽

Wall Thickening ◽

Forced Expiration ◽

Airway Wall ◽

Airway Narrowing ◽

Muscle Shortening

Lambert, Rodney K., and Peter D. Paré. Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J. Appl. Physiol.83(1): 140–147, 1997.—When airways narrow, either through the action of smooth muscle shortening or during forced expiration, the lung parenchyma is locally distorted and provides an increased peribronchial stress that resists the narrowing. Although this interdependence has been well studied, the quantitative significance of airway remodeling to interdependence has not been elucidated. We have used an improved computational model of the bronchial response to smooth muscle agonists to investigate the relationships between airway narrowing (as indicated by airway resistance), parenchymal shear modulus, adventitial thickening, and inner wall thickening at lung recoil pressures of 4, 5, and 8 cmH2O. We have found that, at low recoil pressures, decreases in parenchymal shear modulus have a significant effect that is comparable to that of moderate thickening of the airway wall. At higher lung recoil pressures, the effect is negligible.

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