Normal structure and function of the lung parenchyma depend upon elastic fibers. Amorphous elastin is biochemically stable in vitro, and may provide a metabolically stable structural framework for the lung parenchyma. To test the metabolic stability of elastin in the normal human lung parenchyma, we have (a) estimated the time elapsed since the synthesis of the protein through measurement of aspartic acid racemization and (b) modeled the elastin turnover through'measurement ofthe prevalence of nuclear weapons-related "C. Elastin purified by a new technique from normal lung parenchyma was hydrolyzed; then the prevalences of D-aspartate and "4C were measured by gas chromatography and accelerator-mass spectrometry, respectively. D-aspartate increased linearly with age; K,,.,p (1.76x 10-3yr-') was similar to that previously found for extraordinarily stable human tissues, indicating that the age of lung parenchymal elastin corresponded with the age of the subject. Radiocarbon prevalence data also were consistent with extraordinary metabolic stability of elastin; the calculated mean carbon residence time in elastin was 74 yr (95% confidence limits, 40-174 yr). These results indicate that airspace enlargement characteristic of "aging lung" is not associated with appreciable new synthesis of lung parenchymal elastin. The present study provides the first tissue-specific evaluation of turnover of an extracellular matrix component in humans and underscores the potential importance of elastin for maintenance of normal lung structure. Most importantly, the present work provides a foundation for strategies to directly evaluate extracellular matrix injury and repair in diseases of lung (especially pulmonary emphysema), vascular tissue, and skin. (J. Clin. Invest. 1991.

Diffusion MRI of hyperpolarized 3He shows that the apparent diffusion coefficient (ADC) of 3 He gas is highly restricted in the normal lung and becomes nearly unrestricted in severe emphysema. The nature of this restricted diffusion provides information about lung structure; however, no direct comparison with histology in human lungs has been reported. The purpose of this study is to provide information about 3 He gas diffusivity in explanted human lungs, and describe the relationship between 3 He diffusivity and the surface area to lung volume ratio (SA/V) and mean linear intercept (L m ) measurements-the gold standard for diagnosis of emphysema. Explanted lungs from patients who were undergoing lung transplantation for advanced COPD, and donor lungs that were not used for transplantation were imaged via

Purified human leukocyte elastase was injected into the tracheas of 46 hamsters. Thirteen animals died spontaneously within 1 week, with extensive lung hemorrhage. The elastin content of the lungs was only slightly less than control values 3 hours after injection. At 2 months, the lungs of the remaining animals showed mild, patchy emphysema and morphometric changes consistent with emphysema. These results contrasted with the effects of a similar elastolytic dose of pancreatic elastase administered to 26 other hamsters in that only one animal died spontaneously, the lung elastin content 3 hours after injection was substantially decreased, and severe emphysema was present 2 months later. Leukocyte elastase appears to be capable of causing emphysema; but unlike pancreatic elastase, leukocyte elastase produces emphysema that is mild, even at a dose sufficient to produce intense lung hemorrhage and a high mortality.

Rationale: The airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction. Objectives: To examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair. Methods: The expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV 1 by linear regression analysis. Measurements and Main Results: After corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-a1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3a1) decreased in small airways in association with FEV 1 . In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1a1, and transforming growth factor-b3) decreased in the surrounding lung tissue in association with progression of COPD. Conclusions: The progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.

Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.

Ceria is a common component of engine aftertreatment catalysts due to its oxygen storage ability, its redox properties, and its role in stabilizing Pt against sintering. The interactions between ceria and NH3 or NO x were investigated to better understand the role of ceria in oxidation reactions occurring over a diesel oxidation catalyst, in the reduction of NO x on lean NO x traps, and in the selective catalytic oxidation (SCO) of NH3. Ceria proved active in NO oxidation, selective catalytic reduction of NO by NH3 (NH3–SCR), and NH3–SCO reactions. Between 100 and 450 °C, both NH3 and NO x adsorbed on ceria simultaneously. In the absence of NO x , NH3 was oxidized over CeO2 forming N2 via a two-step selective catalytic reduction mechanism at low temperature and NO x at high temperature. In the presence of NO x , NH3 reacted with adsorbed NO x species, again forming N2 at lower temperatures (250–450 °C), while at higher temperature, a significant portion of the NH3 was oxidized, with product NO formed.

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-Long-range diffusivity of hyperpolarized 3 He gas was measured from the decay rate of sinusoidally modulated longitudinal nuclear magnetization in three normal donor and nine severely emphysematous explanted human lungs. This (long-range) diffusivity, which we call D sec, is measured over seconds and centimeters and is ϳ10 times smaller in healthy lungs (0.022 cm 2 /s) than the more traditionally measured Dmsec, which is measured over milliseconds and submillimeters. The increased restriction of D sec reflects the complex, tortuous paths required to navigate long distances through the maze of branching peripheral airways. In emphysematous lungs, D sec is substantially increased, with some regions showing nearly the unrestricted value of the self-diffusion coefficient (0.88 cm 2 /s for dilute 3 He in air, a 40-fold increase). This suggests the presence of large collateral pathways opened by alveolar destruction that bypass the airways proper. This destruction was confirmed by comparison with histology in seven lungs and by removal of trapped gas via holes in the pleural surface in five lungs. emphysema; diffusivity; airways; transplant surgery; alveolar destruction IN RECENT YEARS,3 He magnetic resonance imaging has been shown to be an effective tool for characterizing lung ventilation and microstructure. Maps of 3 He spin density have been used to identify ventilation defects in a variety of lung diseases (11,15), and measurements of restricted diffusion over millisecond time scales have been a powerful probe of emphysema (3,4,20,21,29). Air space expansion and tissue destruction due to emphysema result in fewer and larger air spaces; alveolar walls, which normally restrict gas diffusion, are absent, giving rise to an increase in gas diffusivity (19,25). During a typical experimental diffusion time of 2 ms, most 3 He atoms cannot diffuse from one acinar airway (e.g., an alveolar duct) to its neighbor; thus the results are sensitive only to the size and geometry of alveoli and individual alveolar-lined airways within the acinus (8, 29).Measurements of 3 He diffusion over longer times and distances are possible with spatially modulated longitudinal magnetization, because the time constant for relaxation of longitudinal magnetization (T 1 ) is much longer than the time constant for transverse magnetization (T * 2 ): in humans at 1.5 T, T 1 of 3 He in lung is Ն20 s and T * 2 is 20 ms (11). Spatial modulation of longitudinal magnetization has been used to monitor cardiac or thoracic motion (1, 7, 17); in the air spaces of lungs as used here, the motion of 3 He is stochastic (diffusive) and results in attenuation of the spatial modulation (16). Diffusion averages across the spatially modulated magnetization, so the diffusivity may be determined from the decay rate of the amplitude of the modulation. Recently, experiments of 3 He diffusion over seconds and centimeters via magnetization tagging have shown that the long-range diffusivity (D sec ) is very restricted in healthy human and canine lungs: 0.015-0.02 cm 2 /s (...