New insights on COPD imaging via CT and MRI

Multidetector-row computed tomography (MDCT) can be used to quantify morphological features and investigate structure/function relationship in COPD. This approach allows a phenotypical definition of COPD patients, and might improve our understanding of disease pathogenesis and suggest new therapeutical options. In recent years, magnetic resonance imaging (MRI) has also become potentially suitable for the assessment of ventilation, perfusion and respiratory mechanics. This review focuses on the established clinical applications of CT, and novel CT and MRI techniques, which may prove valuable in evaluating the structural and functional damage in COPD.     

Demonstration of dilatation of peripheral airways

Summary. To investigate the ability of various lung-function tests to demonstrate dilatation of peripheral airways, ten asthmatics inhaled increasing doses of a f2-agonist by two different and controlled techniques. Low inspiratory flow with a long post-inspi-ratory pause favoured peripheral deposition, and a high inspiratory flow with a short post-inspiratory pause favoured central deposition of drug in the airways. Ordinary spirometry, maximum expiratory flow rates after breathing air as well as a helium-oxygen mixture, a single breath N₂-test and resistance of the respiratory system were obtained before and after each of five terbutaline doses with both inhalation techniques. By using a double-dummy technique, the study could be performed double blinded. Effects were compared at doses giving equal effects on PEF, assumed to represent equal deposition of bronchodilator and effects on central airways. At such ‘iso A PEF doses’, particularly FVC and the slope of phase III of the N₂-test improved more following the slow inhalation technique. It is concluded that changes in those tests reflect dilatation in peripheral airways in asthmatics.,     

Analysis of the conducting airway system in the lung: A new method combining morphometry with mathematical modeling for airway classification

Although the lung is structurally complex, it is suitable for morphometric analysis of the structural determinants of lung function in health and disease. Analysis of the organized branching airways has been problematic because of the need to identify and classify airways before structural characteristics of different‐order branches can be determined. Airway casts have been used to identify relationships between branches, measure some structural features, and develop mathematical models that describe simply the relationships between generations. However, cast preparation destroys surrounding tissue, including the airway wall, thus precluding analysis of these structural elements. We describe a new approach using tissue sections which combines the classification of airways into Strahler order (SO) with tissue structural analysis. Lung‐tissue sections are prepared, and outer (OD) and inner (ID) diameters are determined over a wide range of airways. The line equation relating log OD vs. SO is determined using measured values for SO1 (terminal bronchioles) and SO8 (first branch bronchi). Mean ODs can then be calculated for each of the other SO groups, and measurements can be classified. Calculations can be made for the mean number of branches and airway lengths (given the log linear relationship of these factors with SO and morphometrically determined volume densities for airway lumen), and for individual airway resistance and total resistances for each SO. For an example, mean data are presented for airways in the adult sheep (n = 13). The methodology presented allows identification of subtle alterations in airway structures which may be affecting selected orders of airways, with specific implications for changes in lung function. Anat Rec 266:51–57, 2002. © 2002 Wiley‐Liss, Inc.     

RESPONSIVENESS AND SENSITIVITY TO CHOLINERGIC AGONISTS AND ANTAGONISTS IN BOVINE ISOLATED BRONCHIAL MUSCLE

1. Airways derived from different levels of the lung exhibit a difference in the reactivity and sensitivity to agonists. We have evaluated the effect of acetylcholine and cholinergic selective (pirenzepine, gallamine and 4-dipherylacetoxymethyl piperidine [4-DAMP]) and non-selective (atropine) antagonists on bovine proximal and distal smooth muscle preparations. 2. The distal preparations are more sensitive to acetylcholine than proximal bronchi. The relaxant effect of three selective antagonists on the distal and proximal tissues was the same when the results for each drug were compared. 3. Atropine and 4-DAMP were more potent than pirenzepine and gallamine in relaxing both proximal and distal bovine smooth muscle preparations. 4. These data suggest that the muscarinic sites on the smooth muscle of bovine airways are of the M3 subtype.     

Comparison of airway diameter measurements from an anthropomorphic airway tree phantom using hyperpolarized 3He MRI and high-resolution computed tomography.

An anthropomorphic airway tree phantom was imaged with both hyperpolarized (HP) 3He MRI using a dynamic projection scan and computed tomography (CT). Airway diameter measurements from the HP 3He MR images obtained using a newly developed model-based algorithm were compared against their corresponding CT values quantified with a well-established method. Of the 45 airway segments that could be evaluated with CT, only 14 airway segments (31%) could be evaluated using HP 3He MRI. No airway segments smaller than approximately 4 mm in diameter and distal to the fourth generation were adequate for analysis in MRI. For the 14 airway segments measured, only two airway segments yielded a non-equivalent comparison between the two imaging modalities, while eight more had inconclusive comparison results, leaving only four airway segments (29%) that satisfied the designed equivalence criteria. Some of the potential problems in airway diameter quantification described in the formulation of the model-based algorithm were observed in this study. These results suggest that dynamic projection HP 3He MRI may have limited utility for measuring airway segment diameters, particularly those of the central airways.     

3He MRI in mouse models of asthma.

In the study of asthma, a vital role is played by mouse models, because knockout or transgenic methods can be used to alter disease pathways and identify therapeutic targets that affect lung function. Assessment of lung function in rodents by available methods is insensitive because these techniques lack regional specificity. A more sensitive method for evaluating lung function in human asthma patients uses hyperpolarized (HP) (3)He MRI before and after bronchoconstriction induced by methacholine (MCh). We now report the ability to perform such (3)He imaging of MCh response in mice, where voxels must be approximately 3000 times smaller than in humans and (3)He diffusion becomes an impediment to resolving the airways. We show three-dimensional (3D) images that reveal airway structure down to the fifth branching and visualize ventilation at a resolution of 125 x 125 x 1000 microm(3). Images of ovalbumin (OVA)-sensitized mice acquired after MCh show both airway closure and ventilation loss. To also observe the MCh response in naive mice, we developed a non-slice-selective 2D protocol with 187 x 187 microm(2) resolution that was fast enough to record the MCh response and recovery with 12-s temporal resolution. The extension of (3)He MRI to mouse models should make it a valuable translational tool in asthma research.     

Association between inflammation and epithelial damage-restitution processes in allergic airways in vivo

Background Associations between allergen challenge-induced sites of epithelial damage and the distribution of leucocytes and extravasated plasma remain unexplored. Objective To study neutrophils, eosinophils, and fibrinogen at allergen challenge-induced patchy epithelial damage-restitution sites in guinea-pig trachea. Methods After local challenge tracheal tissue (cryo sections and whole-mounts) and lumen (selective tracheal lavage) were examined at 1, 5, and 24 h. Eosinophils, neutrophils and fibrinogen were identified by histochemistry. Results Neutrophils increased markedly in tracheal lavage fluids and in tissue and were strongly associated with the challenge-induced epithelial craters of damage-restitution. At 1 and 24 h eosinophils were increased in the tracheal lumen whereas the surrounding tissue displayed a reversed pattern. Gels rich in fibrinogen, neutrophils, and eosinophils were present in epithelial crater areas, protruding into the lumen. Clusters of free eosinophil granules, Cfegs, released through lysis of eosinophils, and neutrophils with long cytoplasmatic protrusions abounded in these crater areas. Conclusions The present findings provide important new insights into allergic airways where sites of epithelial damage-restitution processes emerge as the major loci for eosinophil, neutrophil, and plasma protein activities, the latter likely causing leukocyte adhesion and activation in vivo. The disttibution of eosinophils in this study suggests roles of these cells both in airway mucosa and in regional lymph nodes. Based on the present study we also propose that lysis of eosinophils and Cfegs generation are a major paradigm for activation of these cells in vivo.     

Compartmentalized transgene expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse lung enhances allergic airways inflammation

To investigate the role of GM-CSF in asthmatic airways inflammation, we have targeted GM-CSF transgene to the airway cells in a mouse model of ovalbumin (OVA)-induced allergic airways inflammation, a model in which there is marked induction of endogenous IL-5 and IL-4 but not GM-CSF. Following intranasal delivery of a replication-deficient adenoviral gene transfer vector (Ad), transgene expression was found localized primarily to the respiratory epithelial cells. Intranasal delivery of 0.03 × 10⁹ plaque-forming units (PFU) of AdGM-CSF into naive BALB/c mice resulted in prolonged and compartmentalized release of GM-CSF transgene protein with a peak concentration of ≈ 80 pg/ml detected in bronchoalveolar lavage fluid (BALF) at day 7, but little in serum. These levels of local GM-CSF expression per se resulted in no eosinophilia and only a minimum of tissue inflammatory responses in the lung of naive mice, similar to those induced by the control vector. However, such GM-CSF expression in the airways of OVA-sensitized mice resulted in a much greater and sustained accumulation of various inflammatory cell types, most noticeably eosinophils, both in BALF and airway tissues for 15–21 days post-OVA aerosol challenge, at which times airways inflammation had largely resolved in control mice. While the levels of IL-5 and IL-4 in BALF and the rate of eosinophil apoptosis were found similar between different treatments, there was an increased number of proliferative leucocytes in the lung receiving GM-CSF gene transfer. Our results thus provide direct experimental evidence that GM-CSF can significantly contribute to the development of allergic airways inflammation through potentiating and prolonging inflammatory infiltration induced by cytokines such as IL-5 and IL-4.     

Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease

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