Barbara A. Lutey

The Role of Matrix Metalloproteinase-9 in Cigarette Smoke–induced Emphysema

RATIONALE Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. OBJECTIVES To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. METHODS Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. MEASUREMENTS AND MAIN RESULTS Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. CONCLUSIONS These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

Hyperpolarized 3He MR Imaging: Physiologic Monitoring Observations and Safety Considerations in 100 Consecutive Subjects

PURPOSE To evaluate the safety of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging. MATERIALS AND METHODS Local institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized (3)He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years +/- 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300-500 mL (3)He and 0-2700 mL N(2) and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (Spo(2)) were monitored continuously throughout each study. The effects of (3)He MR imaging on vital signs and Spo(2) and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed Spo(2) were assessed. Any subjective symptoms were noted. RESULTS Except for a small postimaging decrease in mean heart rate (from 78 beats per minute +/- 13 to 73 beats per minute +/- 11, P < .001), there was no effect on vital signs. A mean transient decrease in Spo(2) of 4% +/- 3 was observed during the first minute after gas inhalation (P < .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest Spo(2) and pulmonary function parameters other than baseline Spo(2) (r = 0.36, P = .001). The lowest mean Spo(2) varied by 1% between the first and second and second and third doses (P < .001) and was unrelated to clinical classification (P = .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred. CONCLUSION Hyperpolarized (3)He MR imaging can be safely performed in healthy subjects, heavy smokers, and those with severe obstructive airflow limitation, although unpredictable transient desaturation suggests that potential subjects should be carefully screened for comorbidities.

In Vivo Detection of Acinar Microstructural Changes in Early Emphysema with 3He Lung Morphometry

PURPOSE To quantitatively characterize early emphysematous changes in the lung microstructure of current and former smokers with noninvasive helium 3 ((3)He) lung morphometry and to compare these results with the clinical standards, pulmonary function testing (PFT) and low-dose computed tomography (CT). MATERIALS AND METHODS This study was approved by the local institutional review board, and all subjects provided informed consent. Thirty current and former smokers, each with a minimum 30-pack-year smoking history and mild or no abnormalities at PFT, underwent (3)He lung morphometry. This technique is based on diffusion MR imaging with hyperpolarized (3)He gas and yields quantitative localized in vivo measurements of acinar airway geometric parameters, such as airway radii, alveolar depth, and number of alveoli per unit lung volume. These measurements enable calculation of standard morphometric characteristics, such as mean linear intercept and surface-to-volume ratio. RESULTS Noninvasive (3)He lung morphometry was used to detect alterations in acinar structure in smokers with normal PFT findings. When compared with smokers with the largest forced expiratory volume in 1 second (FEV(1)) to forced vital capacity (FVC) ratio, those with chronic obstructive pulmonary disease had significantly reduced alveolar depth (0.07 mm vs 0.13 mm) and enlarged acinar ducts (0.36 mm vs 0.3 mm). The mean alveolar geometry measurements in the healthiest subjects were in excellent quantitative agreement with literature values obtained by using invasive techniques (acinar duct radius, 0.3 mm; alveolar depth, 0.14 mm at 1 L above functional residual capacity). (3)He lung morphometry depicted greater abnormalities than did PFT and CT. No adverse events were associated with inhalation of (3)He gas. CONCLUSION (3)He lung morphometry yields valuable noninvasive insight into early emphysematous changes in alveolar geometry with increased sensitivity compared with conventional techniques.

Effects of CT section thickness and reconstruction kernel on emphysema quantification relationship to the magnitude of the CT emphysema index.

RATIONALE AND OBJECTIVES Computed tomography (CT) section thickness and reconstruction kernel each influence CT measurements of emphysema. This study was performed to assess whether their effects are related to the magnitude of the measurement. MATERIALS AND METHODS Low-radiation-dose multidetector CT was performed in 21 subjects representing a wide range of emphysema severity. Images were reconstructed using 20 different combinations of section thickness and reconstruction kernel. Emphysema index values were determined as the percentage of lung pixels having attenuation lower than multiple thresholds ranging from -960 HU to -890 HU. The index values obtained from the different thickness-kernel combinations were compared by repeated measures analysis of variance and Bland-Altman plots of mean versus difference in all subjects, and correlated with quantitative histology (mean linear intercept, Lm) in a subset of resected lung specimens. RESULTS The effects of section thickness and reconstruction kernel on the emphysema index were significant (P < .001) and diminished as the index attenuation threshold was raised. The changes in index values from changing the thickness-kernel combination were largest for subjects with intermediate index values (10%-30%), and became progressively smaller for those with lower and higher index values. This pattern was consistent regardless of the thickness-kernel combinations compared and the HU threshold used. Correlations between the emphysema index values obtained with each thickness-kernel combination and Lm ranged from r = 0.55-0.68 (P = .007-.03). CONCLUSION The effects of CT section thickness and kernel on emphysema index values varied systematically with the magnitude of the emphysema index. All reconstruction techniques provided significant correlations with quantitative histology.

Original investigationEffects of CT Section Thickness and Reconstruction Kernel on Emphysema Quantification: Relationship to the Magnitude of the CT Emphysema Index

RATIONALE AND OBJECTIVES Computed tomography (CT) section thickness and reconstruction kernel each influence CT measurements of emphysema. This study was performed to assess whether their effects are related to the magnitude of the measurement. MATERIALS AND METHODS Low-radiation-dose multidetector CT was performed in 21 subjects representing a wide range of emphysema severity. Images were reconstructed using 20 different combinations of section thickness and reconstruction kernel. Emphysema index values were determined as the percentage of lung pixels having attenuation lower than multiple thresholds ranging from -960 HU to -890 HU. The index values obtained from the different thickness-kernel combinations were compared by repeated measures analysis of variance and Bland-Altman plots of mean versus difference in all subjects, and correlated with quantitative histology (mean linear intercept, Lm) in a subset of resected lung specimens. RESULTS The effects of section thickness and reconstruction kernel on the emphysema index were significant (P < .001) and diminished as the index attenuation threshold was raised. The changes in index values from changing the thickness-kernel combination were largest for subjects with intermediate index values (10%-30%), and became progressively smaller for those with lower and higher index values. This pattern was consistent regardless of the thickness-kernel combinations compared and the HU threshold used. Correlations between the emphysema index values obtained with each thickness-kernel combination and Lm ranged from r = 0.55-0.68 (P = .007-.03). CONCLUSION The effects of CT section thickness and kernel on emphysema index values varied systematically with the magnitude of the emphysema index. All reconstruction techniques provided significant correlations with quantitative histology.

Accurate Measurement of Small Airways on Low-Dose Thoracic CT Scans in Smokers

BACKGROUND Partial volume averaging and tilt relative to the scan plane on transverse images limit the accuracy of airway wall thickness measurements on CT scan, confounding assessment of the relationship between airway remodeling and clinical status in COPD. The purpose of this study was to assess the effect of partial volume averaging and tilt corrections on airway wall thickness measurement accuracy and on relationships between airway wall thickening and clinical status in COPD. METHODS Airway wall thickness measurements in 80 heavy smokers were obtained on transverse images from low-dose CT scan using the open-source program Airway Inspector. Measurements were corrected for partial volume averaging and tilt effects using an attenuation- and geometry-based algorithm and compared with functional status. RESULTS The algorithm reduced wall thickness measurements of smaller airways to a greater degree than larger airways, increasing the overall range. When restricted to analyses of airways with an inner diameter < 3.0 mm, for a theoretical airway of 2.0 mm inner diameter, the wall thickness decreased from 1.07 ± 0.07 to 0.29 ± 0.10 mm, and the square root of the wall area decreased from 3.34 ± 0.15 to 1.58 ± 0.29 mm, comparable to histologic measurement studies. Corrected measurements had higher correlation with FEV₁, differed more between BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index scores, and explained a greater proportion of FEV1 variability in multivariate models. CONCLUSIONS Correcting for partial volume averaging improves accuracy of airway wall thickness estimation, allowing direct measurement of the small airways to better define their role in COPD.

Emphysema quantification in inflation-fixed lungs using low-dose computed tomography and 3He magnetic resonance imaging.

Objective: To evaluate the use of inflation-fixed lung tissue for emphysema quantification with computed tomography (CT) and 3He magnetic resonance (MR) diffusion imaging. Methods: Fourteen subjects representing a range of chronic obstructive pulmonary disease severity who underwent complete or lobar lung resection were studied. Computed tomographic measurements of lung attenuation and MR measurements of the hyperpolarized 3He apparent diffusion coefficient (ADC) in resected specimens fixed in inflation with heated formalin vapor were compared with measurements obtained before fixation. Results: The mean (SD) CT emphysema indices were 56% (17%) before and 58% (19%) after fixation (P = 0.77; R = 0.76). Index differences correlated with differences in lung volume (R2 = 0.47). The mean (SD) 3He ADCs were 0.40 (0.15) cm2/s before and 0.39 (0.14) cm2/s after fixation (P = 0.03, R = 0.98). The CT emphysema index and the 3He ADC were correlated before (R = 0.89) and after fixation (R = 0.79). Conclusions: Concordance of CT and 3He MR imaging measurements in unfixed and inflation-fixed lungs supports the use of inflation-fixed lungs for quantitative imaging studies in emphysema.

Experimental evidence of age-related adaptive changes in human acinar airways

The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized (3)He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized (3)He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger.

Measuring small airways in transverse CT images correction for partial volume averaging and airway tilt.

RATIONALE AND OBJECTIVES Airway wall dimensions can be determined in vivo using transverse computed tomographic (CT) images, but the measurement of airway phantoms shows that the wall thickness is consistently overestimated for small airways. This phantom study was performed to derive and test corrections to the measurements on the basis of consideration of partial volume averaging and tilt effects. MATERIALS AND METHODS A lung phantom with six polycarbonate tubes embedded in foam was scanned, and the cross-sectional dimensions of the tubes were determined using the full width at half maximum, zero crossing, and phase congruency edge detection methods. Equations were derived using the reported wall intensity to correct for partial volume averaging. Corrections for the overestimation of the wall thickness due to the tilt of the tube with respect to the CT z-axis were also derived. RESULTS All three methods (full width at half maximum, zero crossing, and phase congruency) overestimated the wall thickness of the small polycarbonate tubes. It was verified that two sources of error were partial volume averaging and tilt that was introduced when the phantom was positioned with tube axes at an angle to the CT z-axis. The corrections were applied to the measured tube wall dimensions and substantially reduced the deviation of the CT measurements from the true values. CONCLUSIONS Correcting for partial volume effects and airway tilt greatly increases the accuracy of simulated airway wall measurements in transverse CT images.

Original investigationMeasuring Small Airways in Transverse CT Images: Correction for Partial Volume Averaging and Airway Tilt

RATIONALE AND OBJECTIVES Airway wall dimensions can be determined in vivo using transverse computed tomographic (CT) images, but the measurement of airway phantoms shows that the wall thickness is consistently overestimated for small airways. This phantom study was performed to derive and test corrections to the measurements on the basis of consideration of partial volume averaging and tilt effects. MATERIALS AND METHODS A lung phantom with six polycarbonate tubes embedded in foam was scanned, and the cross-sectional dimensions of the tubes were determined using the full width at half maximum, zero crossing, and phase congruency edge detection methods. Equations were derived using the reported wall intensity to correct for partial volume averaging. Corrections for the overestimation of the wall thickness due to the tilt of the tube with respect to the CT z-axis were also derived. RESULTS All three methods (full width at half maximum, zero crossing, and phase congruency) overestimated the wall thickness of the small polycarbonate tubes. It was verified that two sources of error were partial volume averaging and tilt that was introduced when the phantom was positioned with tube axes at an angle to the CT z-axis. The corrections were applied to the measured tube wall dimensions and substantially reduced the deviation of the CT measurements from the true values. CONCLUSIONS Correcting for partial volume effects and airway tilt greatly increases the accuracy of simulated airway wall measurements in transverse CT images.