John A. Pierce

Hyperpolarized 3He diffusion MRI and histology in pulmonary emphysema.

Diffusion MRI of hyperpolarized 3He shows that the apparent diffusion coefficient (ADC) of 3He 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 3He gas diffusivity in explanted human lungs, and describe the relationship between 3He diffusivity and the surface area to lung volume ratio (SA/V) and mean linear intercept (Lm) 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 3He diffusion MRI. Histological measurements were made on the same specimens after they were frozen in the position of study. There is an inverse correlation between diffusivity and SA/V (and a positive correlation between diffusivity and Lm). An important result is that restricted 3He diffusivity separated normal from emphysematous lung tissue more clearly than the morphometric analyses. This effect may be due to the smaller histologic sampling size compared to the MRI voxel sizes. Magn Reson Med, 2006.

Variability of Pulmonary Function in Alpha-1-Antitrypsin Deficiency: Clinical Correlates

STUDY OBJECTIVE To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS AND MAIN RESULTS Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS 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.

Differential Expression of Tissue Repair Genes in the Pathogenesis of Chronic Obstructive Pulmonary Disease

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-alpha1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3alpha1) 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 1alpha1, and transforming growth factor-beta3) 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.

The Collagen and Elastin Content of the Lung in Emphysema

Excerpt Connective tissue fibers maintain the normal arrangement of lung structure. These are scleroprotein fibers: collagen, elastin, and reticulin. They are characterized by their insolubility, t...

Fibrous Network of the Lung and its Change with Age

The remarkable elastic behaviour of the lung entails both continuous tissue stress and a cyclic stress produced by the fluctuating difference between intrathoracic and intra-alveolar pressures throughout the entire span of life. In spite of these potentially disruptive forces, lung structure is preserved by the fibrous connective-tissue proteinscollagen, elastin, and reticulin. These extracellular proteins are characterized by their insolubility, resistance to destruction, and high tensile strength. Collagen and elastin both exhibit elastic behaviour, but great extensibility is a property only of elastin. The most reasonable assumption is that the elastic fibres, therefore, are principally responsible for the elastic behaviour of the lung tissue, but sure proof is lacking. Recently, Carton, Dainauskas, Tews, and Hass (1960) and Wright (1961) have described the nature of the network of elastic tissue in the lung. We sought to describe more fully the roles of collagenous and elastic fibres in the terminal air spaces of the lung, and thus their respective contributions to tissue elasticity and the general elastic performance of the lung. As the study developed, it seemed important to measure the amounts of collagen and elastin in the lung parenchyma and pleura. These findings have been correlated with the age of the subjects and interpreted according to knowledge about tissue elasticity.

Variability of Pulmonary Function in Alpha-1-Antitrypsin Deficiency: Residual Family Resemblance beyond the Effect of the Pi Locus

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin deficiency, two pulmonary function tests, FEV1 and FEF25-75, were examined in alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated highly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV1 but was shown for FEF25-75. For FEV1, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV1; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial traits.

Rheumatoid Lung Disease

Excerpt Rheumatoid arthritis is a systemic disease characterized by pain and disability in peripheral joints. The disease may affect any organ but exhibits a strong preference for tissues abundant ...

ELASTIC PROPERTIES AND THE GEOMETRY OF THE LUNGS

The elastic properties of the lung are of primary importance to normal function. A definitive study of these properties entails the simultaneous measurement of pressure and volume under static conditions. A plot of the relationship between pressure and volume in the lungs results in a curve which is approximately linear in the middle part of the vital capacity. The retractive force in this limited part of the curve is a direct function of volume. Although elastic performance is a complex phenomenon, the balance of lung elastic behavior occurs without a delay in time and the majority of the elastic work done on the lung during inspiration can be recovered on expiration. Maj or contributions are made to the over-all elastic behavior of the lungs by surface phenomena and tissue factors. Factors of minor importance include the bronchial and bronchiolar smooth muscle and the amount of blood in the pulmonary vascular bed. For many years the elastic properties of the lungs were attributed to elastic tissue fibers. Surface phenomena were not considered important until 1929 when von Neergaard (1) pointed out that the forces arising from the air liquid interfaces throughout the lung parenchyma could be eliminated by the complete replacement of the gas in the lungs with liquid. He demonstrated that pressure was less in the liquid-filled lung than in the air-filled lung at comparable volumes. He assumed an identical operation of tissue elastic factors in airand liquid-filled lungs. Radford (2) estimated the surface area of excised lungs, using the principles established by von Neergaard. The difference between air and saline pressure-volume curves during emptying was taken as a measure of the recoverable surface en-

Transpleural ventilation of explanted human lungs

Background: The hypothesis that ventilation of emphysematous lungs would be enhanced by communication with the parenchyma through holes in the pleural surface was tested. Methods: Fresh human lungs were obtained from patients with emphysema undergoing lung transplantation. Control human lungs were obtained from organ donors whose lungs, for technical reasons, were not considered suitable for implantation. Lungs were ventilated through the bronchial tree or transpleurally via a small hole communicating with the underlying parenchyma over which a flanged silicone tube had been cemented to the surface of the lung (spiracle). Measurements included flow-volume-time curves during passive deflation via each pathway; volume of trapped gas recovered from lungs via spiracles when no additional gas was obtainable passively from the airways; and magnetic resonance imaging assessment of spatial distribution of hyperpolarised helium (3He) administered through either the airways or spiracles. Results: In emphysematous lungs, passively expelled volumes at 20 s were 94% greater through spiracles than via the airways. Following passive deflation from the airways, an average of 1.07 litres of trapped gas volume was recoverable via spiracles. Regions were ventilated by spiracles that were less well ventilated via bronchi. Conclusions: Because of the extensive collateral ventilation present in emphysematous lungs, direct communication with the lung parenchyma through non-anatomical pathways has the potential to improve the mechanics of breathing and hence ventilation.

A CANINE MODEL FOR PRODUCTION OF SEVERE UNILATERAL PANACINAR EMPHYSEMA

The authors created a canine model of severe emphysema using whole lung lavage to deliver repeated porcine pancreatic elastase solution to the terminal airways and alveoli of the right lung. This model produces extreme unilateral panacinar emphysema closely resembling that encountered in patients with α1-antitrypsin deficiency. Because the contralateral lung remains functional, the animals can be maintained indefinitely. The model will be of value in developing imaging techniques capable of safely evaluating the effect of treatment on panacinar emphysema in α1-antitrypsin–deficient patients.