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1.1. The Challenges To understand normal lung function, the processes of growth and development, and the mechanisms and effects of diseases, we need information about the 3D structure of the lung. Quantification of organ structure is based upon 3D physical attributes of tissues, cells, organelles, alveoli, airways, and blood vessels. When structures of interest are inaccessible or too small to be seen macroscopically, we rely on physical or optical sections through a few representative samples taken from the large heterogeneous organ. The resulting 2D images confer incomplete information about the 3D structure, and may not accurately represent true 3D properties, leading to possible misinterpretation when measurements are made on 2D sections. Because structural quantification is often considered the “gold standard” in evaluating experimental intervention, disease severity, and treatment response, it is imperative that these quantitative methods are (1) accurate to allow meaningful interpretation of results, (2) efficient to yield adequate precision with reasonable effort, (3) of adequate statistical power to encompass inherent variability, and (4) adherent to uniform standards to facilitate comparisons among experimental groups and across different studies. The lung poses special challenges, some of which are outlined below and discussed in later sections:   (a) Heterogeneity of lung structure requires standardized preparation methods. The inflated lung consists of mostly air; only 10 to 15% of its volume consists of tissue (cells, fibers, and matrix) and blood. In vivo lung volume and relative volumes of air, tissue, and blood fluctuate widely, while gravitational and nongravitational gradients cause spatial heterogeneity in structure and function. Failure to standardize physiological variables or minimize tissue distortion introduces uncertainties or errors into subsequent measurements, to the point of their being meaningless (1). Careful selection of fixation and preparation methods that minimize shrinkage obviates this problem (Section 3).   (b) Selected microscopic sections should provide a fair sample of the whole organ. The practice of picking specific samples or sections often fails to account for regional heterogeneity, leading to biased conclusions with respect to the whole organ. Deliberately choosing sections that contain a particular compartment (e.g., profiles of alveolar type 2 epithelial cells) overestimates their abundance within the whole lung. Using a sampling scheme that covers all regions with equal probability alleviates this problem (Section 4).   (c) Measurements made on microscopic sections must be related to the whole organ or an appropriate reference volume. Studies continue to appear that report only relative measurements (i.e., volume and surface densities or ratios) without knowledge of the lung volume. These ratios are dependent on lung inflation, and must be multiplied by absolute lung volume to obtain accurate total quantities of the structures of interest. Uncertainties regarding lung volume can bias data interpretation. For example, enlarged mean airspace size need not signify emphysema or alveolar hypoplasia; the finding could also be caused by overinflation. Careful measurement of the lung volume eliminates this error (Section 5).   (d) Lung structures are irregular and their geometry easily altered by pathology and intervention. Measurements on 2D images that rely on assumed geometry may misrepresent the 3D structure. Examples include estimating alveolar size from cross-sectional areas of alveolar profiles, and reporting alveolar surface area by the length of alveolar profile boundary. These measures can severely misrepresent the 3D structure of interest. Airspace size is often inferred from the mean linear intercept (Lm), which in fact measures airspace volume-to-surface ratio and can be converted to diameter or volume only by assuming a shape factor. Airspace distortion, or selective distortion of alveolar ducts but not alveolar sacs, can invalidate shape assumptions (Section 6).   (e) The number of lung cells cannot be estimated by counting their profiles on random histologic sections because larger cells have a greater probability of being sampled. For example, if experimental intervention causes selective cell hypertrophy, the increased probability of counting cell profiles will lead to wrong conclusions. Again, using stereologic methods that are free of geometric assumptions eliminates this error (Sections 6–7).   (f) In contrast to acinar structures that exhibit nearly random orientation (isotropy) and homogeneous distribution, conducting airways and blood vessels exhibit preferred directions (anisotropy) and inhomogeneous distribution, which alter their sampling probability on random sections. Specific sampling procedures that account for their nonrandom nature should be employed to ensure unbiased representation on 2D sections (Section 8).   (g) Assessment of endobronchial or lung biopsy specimens is limited by their nonrandom nature and a lack of external reference parameter. Endobronchial biopsy specimens are also anisotropic with distinct luminal and basal sides and with respect to airway generations. To minimize potential errors in quantification, specimens should be processed with their orientation randomized and analyzed with respect to an internal reference parameter (Section 9).   (h) The new imaging techniques CT and MRI offer the possibility of obtaining high-fidelity images of lung structure in vivo that can be used for quantitative assessment of structural changes. Since their images are sections of the organ, stereology can ensure accurate measurements (Section 10).Definition of terms (section of text where term is defined) Accuracy (Sec. 1.2); ALP-sector (Sec. 2.1, item a); Anisotropy (Sec. 1.1, item f); Apparent diffusion coefficient (ADC) (Sec. 10.4.1); Arithmetic mean thickness of air-blood barrier (Sec. 6.7); Bias (Sec. 1.2); Buffon's needle (Sec. 1.3); Cavalieri Principle/Method (Sec. 1.3); Coarse nonparenchyma (Sec. 6.2); Coarse parenchyma (Sec. 6.2); Computer-aided stereology systems (Sec. 2.2, item c); Connectivity of airway branching systems (Sec. 8.1); Delesse principle (Sec. 1.3); “Design-based” (Sec. 1.2); Dichotomous branching of airways (Sec. 8.1, Fig. 9A); Disector principle: physical, optical (Sec. 2.1, items d and e); “Do more less well” (Sec. 2.2, item c); Sec. 4.4; Efficiency (Sec. 4.4); Euler characteristic (Sec. 6.4); Fine nonparenchyma (Sec. 6.2; Figure 5); Fine parenchyma (Sec. 6.2; Equation 12); Fractal tree (Sec. 8.1); Fractionator sampling (Sec. 4.2.5; Figure 4); Global estimators (Sec. 2.1); “Gold standard” in fixation (Sec. 3.1); Harmonic mean thickness of air–blood barrier (Sec. 6.7); Horsfield ordering system (Sec. 8.1; Figure 9b); Isector (isotropic orientation) (Figure 4); Isotropic uniform random (IUR) sampling (Sec. 4.2.3); Isotropy (Sec. 1.1, item f); Local estimators (Sec. 2.1, item e); Mean chord length or mean linear intercept (Sec. 6.6); Monopodial airway branching (Sec. 8.1); Morphometry (Sec. 2.1); Multistage stratified morphometric analysis (Sec. 6.1); Multistage stratified sampling (Sec. 4.2.6); Nucleator (Sec. 2.1, item e); Number-weighted mean particle volume (Sec. 2.1, items e and f); Orientator (Sec. 4.2.3); Point-sampled intercept (Sec. 2.1, item e); Precision (Sec. 1.2); Reference space (Sec. 5); Reference lung volume (Sec. 5.1); “Reference trap” (Sec. 5); Relative deposition index (RDI) (Sec. 7.2); Relative labeling index (RLI) (Sec. 7.2); Rotator (Sec. 2.1, item e); Sampling (Sec. 2.1, Sec. 4); Sampling fraction (Sec. 6.4; Figure 4); Sampling procedures (Sec. 4.2); Sampling rules (Sec. 4.1); “Silver standards” in fixation technique (Sec. 3.1; Sec. 3.3); Stereology (Sec. 2.1); Strahler ordering system (Sec. 8.1; Figure 9b); Stratified uniform random (StUR) sampling (Sec. 4.2.2); Surface density (Sec 2.1, item b; Sec. 6.3); Systematic uniform random sampling (SURS) (Sec. 4.2.1); Test probes, test systems (Sec. 2.1, item a; Sec. 6.9; Figure 6); Uniform random sections (Sec. 4.2.1; Sec. 4.2.2; Sec. 4.2.3); Vertical sections (Sec. 4.2.4; Figure 3); Volume density (Sec. 2.1, item b; Sec. 6.2); Volume-weighted mean particle volume (Sec. 2.1, items e and f).Open in a separate window   Figure 3.   Vertical sections. (A) An arbitrary horizontal reference plane, such as a cutting board, is considered fixed and the vertical section is perpendicular to this horizontal plane. Airways selected by microdissection can be sampled by this vertical section scheme, by bisecting the airway longitudinally and laying it flat with the luminal surface up. In this orientation, the arrow that runs from base to apex of the epithelium indicates the direction of the vertical axis, V. (B) Bisected airway can be cut into strips of tissue. (C) Each airway tissue strip is cut following a random rotation of the cutting angle to achieve uniform randomness. (D) The blocks are then selected by SURS procedures for embedding with the vertical direction maintained in the embedding mold. Reproduced by permission from Reference 208.

american journal of respiratory and critical care medicine

An Official Research Policy Statement of the American Thoracic Society/European Respiratory Society: Standards for Quantitative Assessment of Lung Structure