Rationale and Objectives 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 ANOVA and Bland-Altman plots of mean vs. difference, 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<0.001) and diminished as the index threshold was raised. The changes in index values due to 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=0.007–0.03). 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.

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-packyear smoking history and mild or no abnormalities at PFT, underwent 3He 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 fi ndings. 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 signifi cantly 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.

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).Keywords: pulmonary disease, chronic obstructive; laser capture microdissection; mice, knockout Several studies have implicated matrix metalloproteinase-9 (MMP-9, gelatinase B, type IV collagenase B), in emphysema and chronic obstructive pulmonary disease (COPD) pathogenesis (1-5). MMP-9 can be accurately measured and is an elastolytic protease that is produced in large quantities by inflammatory cells, thus making it suitable for investigation in emphysema (5-7). However, because the pathophysiology of emphysema follows such an indolent course, developing over decades in response to cigarette smoke, a link between MMP-9 activity and alveolar destruction is lacking.Mouse models have identified several MMPs that cause airspace enlargement by overexpression (8, 9), or that prevent airspace enlargement by gene deletion in smoking models (10). The recent discovery that mice transgenically altered to overexpress human MMP-9 in alveolar macrophages develop progressive airspace enlargement (8) adds importance to the e...

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.

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 Ϯ 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 Ϯ 13 to 73 beats per minute Ϯ 11, P Ͻ .001), there was no effect on vital signs. A mean transient decrease in SpO 2 of 4% Ϯ 3 was observed during the first minute after gas inhalation (P Ͻ .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 ϭ 0.36, P ϭ .001). The lowest mean SpO 2 varied by 1% between the first and second and second and third doses (P Ͻ .001) and was unrelated to clinical classification (P ϭ .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred.

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.

Rationale: By creating artificial communications through bronchial walls into the parenchyma of explanted lungs (airway bypass), we expect to decrease the amount of gas trapped and to increase the rate and volume of air expelled during forced expirations. Objectives: To describe the mechanism by which airway bypass improves the mechanical properties of the emphysematous lung. Methods: Lung compartments and mechanics were measured before and after airway bypass, which was created by placement of three or four stent-suppported fenestrations in 10 emphysematous lungs removed at transplantation surgery. Measurements and Main Results: Minimal volume after passive deflation decreased by a mean of 1.54 L (range, 0.7-2.5 L) or 60% (range, 37-86%). Explanted VC increased by 1.30 L or 132% (range, 78-318%). Maximal expiratory flows and volumes increased. Flow resistance decreased. Conclusions: Because these data show that airway bypass improves the mechanics of breathing in severely emphysematous lungs in vitro, there is now strong empirical support that this procedure can improve ventilatory function in patients by reducing gas trapping and flow resistance.Keywords: transbronchial fenestrations; airway bypass; collateral ventilation Airway bypass is a therapy proposed for the treatment of emphysema (1, 2). The physiologic rationale is to tap into a region of trapped gas that cannot be expelled via the native bronchial tree and allow gas to escape. The procedure entails constructing artificial pathways or fenestrations through the wall of a bronchus into the surrounding parenchyma. Once the fenestration is made, drug-eluting stents are placed to maintain patency (3, 4). We report the mechanical properties of explanted emphysematous lungs before and shortly after the creation of three or four stent-supported fenestrations.Lung volumes and capacities are defined by the structure of the lungs in concert with the function of the thorax; therefore, standard physiologic terms are not appropriate for use with explanted emphysematous lungs. This situation is acknowledged by the modified designation of E (for explant) to all the standard terms. We hypothesize that airway bypass should decrease the minimal lung volume, theoretically at zero transpulmonary pressure, which we call explanted residual volume (ERV), increase the explanted vital capacity (EVC), and thereby improve the mechanics of breathing. Measurements in the present study include explanted total lung capacity (ETLC), its components (EVC and ERV), explanted maximal expiratory flow volume (EMEFV) curves, static pressure-volume diagrams, and measurements of flow resistance. The purposes of this study were to determine how and why airway bypass improves mechanical function and whether the result might have potential therapeutic benefit for patients with advanced emphysema. Some of the results of these studies have been previously reported in the form of an abstract (5). METHODSWe studied 10 severely emphysematous lungs explanted at lung transplantation. The Washington Uni...

No abstract