The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing contact between the air in the ...alveoli and the blood in the alveolar capillaries, which can be entered into physiological equations for predicting oxygen uptake. This information is provided by morphometric studies involving stereological methods and allows estimates of the pulmonary diffusing capacity of the human lung that agree, in experimental studies, with the maximal oxygen consumption. The basis for this “machine lung” structure lies in the complex design of the cells building an extensive air-blood barrier with minimal cell mass.
With the new volume EM techniques, like serial block face scanning electron microscopy (SBF-SEM), new devices for three-dimensional (3D) reconstructions based on automated serial sectioning of tissue ...blocks and scanning their surfaces in between have become available (4). According to Crapo and colleagues (8) the mean AE1 cell volume in this lung was 1,996 mm3, and the mean basement membrane surface covered 4,053 mm2. Hannover Medical School Hannover, Germany Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research Hannover, Germany and REBIRTH Cluster of Excellence Hannover, Germany Ewald R. Weibel, Dr. med4 University of Bern Bern, Switzerland Christian Mühlfeld, Dr. med. Hannover Medical School Hannover, Germany Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research Hannover, Germany REBIRTH Cluster of Excellence Hannover, Germany and Charite - Universitaetsmedizin Berlin‡ Berlin, Germany *Corresponding author (e-mail: schneider.jan@mh-hannover.de). †Ewald R. Weibel passed away February 19, 2019, at the age of 89.
1 Institute of Anatomy, University of Bern, Bern, Switzerland; ;
2 Stereology and Electron Microscopy Research Laboratory, University of Aarhus, Aarhus, Denmark; and ;
3 Institute of Functional and ...Applied Anatomy, Hannover Medical School, Hannover, Germany
Submitted 28 September 2009
; accepted in final form 1 December 2009
The mean linear intercept (chord) length ( L m ) is a useful parameter of peripheral lung structure as it describes the mean free distance in the air spaces. It is often misinterpreted as a measure of "alveolar size," and its estimation is fraught with a number of pitfalls. We present two methods for the accurate estimation of L m : 1 ) the indirect method, which derives L m from the volume-to-surface ratio of air spaces estimated by point counting methods, and 2 ) the direct method, which uses a set of random intercepts and calculates L m from their frequency distribution, for which we introduce a new and accurate method. Both methods are efficient and, with proper precautions, unbiased. The meaning of L m is assessed in two different examples. In a physiological study, the effect of different inflation levels is studied, showing that L m critically depends on lung inflation. In an experimental study on emphysema-like changes in a genetic mouse model, the effect of heterogeneity of air space size is assessed; these results are obtained partly because of differences in lung volume due to altered recoil in the emphysematous lungs. In conclusion, although L m is not a robust parameter of internal lung structure because it crucially depends on lung volume, it is still a valid measure for which accurate and efficient methods are available that yield additional parameters such as size distribution or alveolar surface area.
lung; alveoli; morphometry; stereology; mean linear intercept; emphysema; lung mechanics
Address for reprint requests and other correspondence: E. R. Weibel, Institute of Anatomy, Univ. of Bern, Baltzerstr. 2, CH-3000 Bern, Switzerland (e-mail: weibel{at}ana.unibe.ch ).
Establishing the 3D architecture and morphometry of the intact pulmonary acinus is an essential step toward a more complete understanding of the relationship of lung structure and function. We ...combined a special fixation method with a unique volumetric nondestructive imaging technique and image processing tools to separate individual acini in the mouse lung. Interior scans of the parenchyma at a resolution of 2 µm enabled the reconstruction and quantitative study of whole acini by image analysis and stereologic methods, yielding data characterizing the 3D morphometry of the pulmonary acinus. The 3D reconstructions compared well with the architecture of silicon rubber casts of mouse acini. The image-based segmentation of individual acini allowed the computation of acinar volume and surface area, as well as estimation of the number of alveoli per acinus using stereologic methods. The acinar morphometry of male C57BL/6 mice age 12 wk and 91 wk was compared. Significant increases in all parameters as a function of age suggest a continuous change of the lung morphometry, with an increase in alveoli beyond what has been previously viewed as the maturation phase of the animals. Our image analysis methods open up opportunities for defining and quantitatively assessing the acinar structure in healthy and diseased lungs. The methods applied here to mice can be adjusted for the study of similarly prepared human lungs.
The logarithmic nature of the allometric equation suggests that metabolic rate scaling is related to some fractal properties of the organism. Two universal models have been proposed, based on (1) the ...fractal design of the vasculature and (2) the fractal nature of the 'total effective surface' of mitochondria and capillaries. According to these models, basal and maximal metabolic rates must scale as M3/4. This is not what we find. In 34 eutherian mammalian species (body mass Mb ranging from 7 g to 500 kg) we found VO2max to scale with the 0.872 (+/-0.029) power of body mass, which is significantly different from 3/4 power scaling. Integrated structure-function studies on a subset of eleven species (Mb 20 g to 450 kg) show that the variation of VO2max with body size is tightly associated with the total volume of mitochondria and of the locomotor musculature capillaries. In athletic species the higher VO2max is linked to proportionally larger mitochondrial and capillary volumes. As a result, VO2max is linearly related to both total mitochondrial and capillary erythrocyte volumes, as well as to their surface areas. Consequently, the allometric variation of maximal metabolic rate is directly related to the scaling of the total effective surfaces of mitochondria and capillaries, thus confirming the basic conjecture of the second fractal models but refuting the arguments for 3/4 power scaling. We conclude that the scaling of maximal metabolic rate is determined by the energy needs of the cells active during maximal work. The vascular supply network is adapted to the needs of the cells at their working limit. We conjecture that the optimization of the arterial tree by fractal design is the result rather than the cause of the evolution of metabolic rate scaling. The remaining question is why the energy needs of locomotion scale with the 0.872 or 7/8 power of body mass.
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