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Rationale: The chronic rejection of lung allografts is attributable to progressive small airway obstruction., Objectives: To determine precisely the site and nature of this type of airway obstruction., Methods: Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro-computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction., Measurements and Main Results: The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 μm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others., Conclusions: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

Rationale: The serial computed tomography findings and prognosis of the acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not yet well defined in a larger number of cases., Objectives: To evaluate the parenchymal abnormalities and prognosis using high-resolution computed tomography (HRCT) in acute exacerbation of IPF., Methods: The study consisted of clinical, laboratory, and HRCT data before and at the time of acute exacerbation in 64 episodes of 58 patients with IPF. A semiquantitative analysis of overall extent of parenchymal abnormalities, extent of alveolar opacity (ground-glass attenuation and consolidation), and extent of fibrotic opacity (reticulation and honeycombing) on CT was performed by two chest radiologists. The newly appeared parenchymal abnormalities were also classified into three patterns: peripheral, multifocal, and diffuse., Measurements and Main Results: In all patients, HRCT scans taken at the exacerbation showed typical signs of IPF and newly developing alveolar opacity. They included 34 patients of peripheral pattern, 8 of multifocal pattern, and 16 of diffuse pattern. Twenty-five patients died and 33 survived after the initial exacerbation. Worse survival was associated with patients with diffuse type compared with patients with multifocal and peripheral type. The CT patterns and overall CT extent were associated with an increased hazard of death after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, baseline FVC, and disease extent on CT. On multivariate analysis, the strongest correlations were observed between CT patterns (combined diffuse and multifocal versus peripheral) and survival (odds ratio, 4.629; 95% confidence interval, 1.900-11.278; P = 0.001)., Conclusions: HRCT extent and patterns are predictive of survival in acute exacerbation of IPF.

Rationale: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space., Objectives: To identify the responsible gene that causes pulmonary alveolar microlithiasis., Methods: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis., Measurements and Main Results: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function., Conclusion: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

A novel 85 kD glycoprotein (gp85) is a marker of the avesicular zone, a thin part of pulmonary endothelial cells separating alveolar and vascular compartments and lacking vesicles. This report presents the first evaluation whether mAb 30B3, a monoclonal antibody to gp85, can be used for targeting of drugs to the surface of lung endothelium. 125I-mAb 30B3 accumulated in isolated perfused lungs (IPL) (22.8 +/- 1.1 versus 0.5 +/- 0.1 %ID/g for 125I-IgG) and accumulated preferentially in the lungs after intravenous or intraarterial injection (10.9 +/- 0.7 and 11.0 +/- 1.5 versus 0.9 +/- 0.2 %ID/g for 125I-IgG). 125I-mAb 30B3 uptake in IPL was rapid (T1/2 15 min), saturable (Bmax appr. 10(5) molecules/cell), specific (inhibited by nonlabeled mAb 30B3) and temperature independent (26.3 +/- 2.1 versus 22.8 +/- 1.1 %ID/g at 6 degrees C versus 37 degrees C). Biotinylated mAb 30B3 permitted subsequent accumulation of perfused avidin derivative in IPL. Because these data indicated that mAb 30B3 binds to an accessible, poorly internalizable antigen in the lung, we conjugated mAb 30B3 with a plasminogen activator, 125I-tPA. After intravenous injection in rats, lung-to-blood ratio was 8.4 +/- 0.9 for mAb 30B3/125I-tPA versus 0.4 +/- 0.1 for IgG/125I-tPA, indicating that mAb 30B3 may deliver drugs, which was supposed to exert therapeutic action in the vascular lumen (e.g., antithrombotic proteins), to the surface of pulmonary endothelium.

The effects of a deep inspiration (DI) in individuals with asthma differ from those observed in healthy subjects. It has been postulated that the beneficial effect of lung inflation is mediated by airway stretch. One hypothesis to explain the defects in the function of lung inflation in asthma is that a DI may be unable to stretch the airways. This may result from attenuation of the tethering forces between the airways and the surrounding parenchyma. In the current study, we used high-resolution computed tomography (HRCT) to examine the ability of a DI to distend the airways of subjects with asthma (n = 10) compared with healthy subjects (n = 9) at baseline and after increasing airway tone with methacholine (MCh). We found that both at baseline and after the induction of smooth muscle tone with MCh, a DI distended the airways of healthy and asthmatic subjects to a similar extent, indicating that abnormal interdependence between the lung parenchyma and the airways is unlikely to play a major role in the loss or attenuation of the beneficial effect of lung inflation that characterizes asthma. Furthermore, we observed that after constriction had already been induced by MCh, following a DI, bronchodilation occurred in the healthy subjects but further bronchoconstriction occurred in the subjects with asthma. Our findings suggest that an abnormal excitation contraction mechanism in the airway smooth muscle of subjects with mild asthma counteracts the bronchodilatory effect of a DI. Therefore, the mechanism for reduced bronchodilation after DIs in subjects with mild asthma could be intrinsic to the airway smooth muscle.

Reports of bronchiolitis obliterans organizing pneumonia (BOOP) occurring in women after radiation therapy for breast cancer have suggested that radiation to the lung could participate in the development of BOOP. We now describe the clinical, radiographic, functional, and bronchoalveolar lavage characteristics of this syndrome in a series of 15 patients reported to the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P) in France. All 15 women (60 +/- 6 yr of age) fulfilled the following inclusion criteria: (1) radiation therapy to the breast within 12 mo, (2) general and/or respiratory symptoms lasting for at least 2 wk, (3) lung infiltrates outside the radiation port, and (4) no specific cause. The patients presented with fever, nonproductive cough, mild dyspnea, and peripheral alveolar opacities on chest radiograph with a characteristic migratory pattern. In five patients, BOOP was found at lung pathologic analysis. In all the patients dramatic improvement was obtained with corticosteroids, but relapses occurred in 12 patients while tapering or after stopping corticosteroids. This report demonstrates that a characteristic BOOP syndrome may occur after radiation therapy to the breast, including tangential radiation to the lung, thus suggesting that radiation therapy may prime the development of BOOP.

The lobar and cephalocaudal distribution of aerated and nonaerated lung and of PEEP-induced alveolar recruitment is unknown in acute lung injury (ALI). Dimensions of the lungs and volumes of aerated and nonaerated parts of each pulmonary lobe were measured using a computerized tomographic quantitative analysis and compared between 21 patients with ALI and 10 healthy volunteers. Distribution of PEEP-induced alveolar recruitment along the anteroposterior and cephalocaudal axis and influence of the resting volume of nonaerated lower lobes were also assessed. Anteroposterior and transverse dimensions of the lungs of the patients were similar to those of healthy volunteers, whereas cephalocaudal dimensions were reduced by more than 15%. Total lung volume (aerated plus nonaerated lung) was reduced by 27%. Volumes of upper and lower lobes were 99 and 48% of normal values. In addition to an anteroposterior gradient in the distribution of aerated and nonaerated areas, a cephalocaudal gradient was also observed. Nonaerated areas were predominantly found in juxtadiaphragmatic regions. PEEP-induced alveolar recruitment was more pronounced in nondependent than in dependent regions and in cephalad than in caudal regions. A significant correlation between resting volume of nonaerated lower lobes and regional PEEP-induced alveolar recruitment was observed. In ALI, loss of lung volume involves predominantly lower lobes. The thorax shortens along its cephalocaudal axis. PEEP-induced alveolar recruitment predominates in nondependent and cephalad lung regions and is inversely correlated with the resting volume of nonaerated lung.

The aim of this study was to assess positive end-expiratory pressure (PEEP)-induced lung overdistension and alveolar recruitment in six patients with acute lung injury (ALI) using a computed tomographic (CT) scan method. Lung overdistension was first determined in six healthy volunteers in whom CT sections were obtained at FRC and at TLC with a positive airway pressure of 30 cm H2O. In patients, lung volumes were quantified by the analysis of the frequency distribution of CT numbers on the entire lung at zero end-expiratory pressure (ZEEP) and PEEP. In healthy volunteers at FRC, the distribution of the density histograms was monophasic with a peak at -791 +/- 12 Hounsfield units (HU). The lowest CT number observed was -912 HU. At TLC, lung volume increased by 79 +/- 35% and the peak CT number decreased to -886 +/- 26 HU. More than 70% of the increase in lung volume was located below -900 HU, suggesting that this value can be considered as the threshold separating normal aeration from overdistension. In patients with ALI, at ZEEP the distribution of density histograms was either monophasic (n = 3) or biphasic (n = 3). The mean CT number was -319 +/- 34 HU. At PEEP 13 +/- 3 cm H2O, lung volume increased by 47 +/- 19% whereas mean CT number decreased to -538 +/- 171 HU. PEEP induced a mean alveolar recruitment of 320 +/- 160 ml and a mean lung overdistension of 238 +/- 320 ml. In conclusion, overdistended lung parenchyma of healthy volunteers is characterized by a CT number below -900 HU. This threshold can be used in patients with ALI for differentiating PEEP-induced alveolar recruitment from lung overdistension.

Nonspecific interstitial pneumonia/fibrosis (NSIP) has recently been individualized within the group of idiopathic interstitial pneumonias mainly based on a pathologic pattern of temporally uniform lesions distinct from usual, desquamative, and acute interstitial pneumonia. We studied 12 consecutive patients with NSIP at lung biopsy done as a diagnostic procedure for idiopathic interstitial lung disease. The patients were six males and six females, aged 52.5 +/- 11.8 yr. In 8 of 12 cases the pathologic lesions consisted of both cellular interstitial inflammation and fibrosis, whereas only cellular inflammation was present in three cases, and fibrosis in one. Dyspnea, cough, inspiratory crackles, and squeaks were the most common symptoms and signs. Six cases were cryptogenic. An associated disorder or a presumed cause was present in the other six patients, including underlying connective tissue disease (n = 3), organic dust exposure (n = 2), and prior acute lung injury (n = 1). Lung function tests found a restrictive ventilatory defect (11/12), impairment of TLCO (11/11), and hypoxemia at rest (7/12). Chest X-ray showed infiltrative opacities in all cases. Computed tomography of the chest in 11 cases mainly showed ground glass opacities (9/11), patchy areas of alveolar consolidation (6/ 11), and thickening of interlobular septas (5/11). All patients were treated with corticosteroids, and seven with immunosuppressive agents. All patients were alive at last follow-up, 50 +/- 40 mo after diagnosis. Ten patients (83%) were clinically improved or stabilized. Thus, despite its heterogeneity, NSIP deserves to be individualized as an original clinicopathologic entity and should be clearly distinguished from usual interstitial pneumonia, especially because of a better prognosis.