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1.  Growth of the Lung Parenchyma Early in Life 
Rationale: Early in life, lung growth can occur by alveolarization, an increase in the number of alveoli, as well as expansion. We hypothesized that if lung growth early in life occurred primarily by alveolarization, then the ratio of pulmonary diffusion capacity of carbon monoxide (DlCO) to alveolar volume (VA) would remain constant; however, if lung growth occurred primarily by alveolar expansion, then DlCO/VA would decline with increasing age, as observed in older children and adolescents.
Objectives: To evaluate the relationship between alveolar volume and pulmonary diffusion capacity early in life.
Methods: In 50 sleeping infants and toddlers, with equal number of males and females between the ages of 3 and 23 months, we measured DlCO and VA using single breath-hold maneuvers at elevated lung volumes.
Measurements and Main Results: DlCO and VA increased with increasing age and body length. Males had higher DlCO and VA when adjusted for age, but not when adjusted for length. DlCO increased with VA; there was no gender difference when DlCO was adjusted for VA. The ratio of DlCO/VA remained constant with age and body length.
Conclusions: Our results suggest that surface area for diffusion increases proportionally with alveolar volume in the first 2 years of life. Larger DlCO and VA for males than females when adjusted for age, but not when adjusted for length, is primarily related to greater body length in boys. The constant ratio for DlCO/VA in infants and toddlers is consistent with lung growth in this age occurring primarily by the addition of alveoli rather than the expansion of alveoli.
PMCID: PMC2633059  PMID: 18996997
pulmonary diffusion capacity; alveolar volume; lung development
2.  Imaging the Interaction of Atelectasis and Overdistention in Surfactant Depleted Lungs 
Critical care medicine  2013;41(2):527-535.
Atelectasis and surfactant depletion may contribute to greater distension – and thereby injury – of aerated lung regions; recruitment of atelectatic lung may protect these regions by attenuating such overdistension. However, the effects of atelectasis (and recruitment) on aerated airspaces remain elusive. We tested the hypothesis that during mechanical ventilation, surfactant depletion increases the dimensions of aerated airspaces and that lung recruitment reverses these changes.
Prospective imaging study in an animal model.
Research imaging facility
27 healthy Sprague Dawley rats
Surfactant depletion was obtained by saline lavage in anesthetized, ventilated rats. Alveolar recruitment was accomplished using positive end-expiratory pressure (PEEP) and exogenous surfactant administration.
Measurements and Main Results
Airspace dimensions were estimated by measuring the apparent diffusion coefficient (ADC) of 3He, using diffusion-weighted hyperpolarized gas magnetic resonance imaging (MRI). Atelectasis was demonstrated using computerized tomography (CT) and by measuring oxygenation. Saline lavage increased atelectasis (increase in non-aerated tissue from 1.2 to 13.8% of imaged area, P<0.001), and produced a concomitant increase in mean ADC (~33%, P<0.001) vs. baseline; the heterogeneity of the CT signal and the variance of ADC were also increased. Application of PEEP and surfactant reduced the mean ADC (~23%, P<0.001), and its variance, in parallel to alveolar recruitment (i.e. less CT densities and heterogeneity, increased oxygenation).
Overdistension of aerated lung occurs during atelectasis, is detectable using clinically relevant MRI technology, and could be a key factor in the generation of lung injury during mechanical ventilation. Lung recruitment by higher PEEP and surfactant administration reduces airspace distension.
PMCID: PMC3557664  PMID: 23263577
Imaging/MRI; ARDS; Ventilator-Induced Lung Injury; Alveolar Recruitment; Artificial Respiration; Hyperpolarized Gas
3.  Flow-Volume Parameters in COPD Related to Extended Measurements of Lung Volume, Diffusion, and Resistance 
Pulmonary Medicine  2013;2013:782052.
Classification of COPD into different GOLD stages is based on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) but has shown to be of limited value. The aim of the study was to relate spirometry values to more advanced measures of lung function in COPD patients compared to healthy smokers. The lung function of 65 COPD patients and 34 healthy smokers was investigated using flow-volume spirometry, body plethysmography, single breath helium dilution with CO-diffusion, and impulse oscillometry. All lung function parameters, measured by body plethysmography, CO-diffusion, and impulse oscillometry, were increasingly affected through increasing GOLD stage but did not correlate with FEV1 within any GOLD stage. In contrast, they correlated fairly well with FVC%p, FEV1/FVC, and inspiratory capacity. Residual volume (RV) measured by body plethysmography increased through GOLD stages, while RV measured by helium dilution decreased. The difference between these RV provided valuable additional information and correlated with most other lung function parameters measured by body plethysmography and CO-diffusion. Airway resistance measured by body plethysmography and impulse oscillometry correlated within COPD stages. Different lung function parameters are of importance in COPD, and a thorough patient characterization is important to understand the disease.
PMCID: PMC3697409  PMID: 23844288
4.  3He Lung Morphometry Technique: Accuracy Analysis and Pulse Sequence Optimization 
The 3He lung morphometry technique (Yablonskiy et al, JAP, 2009), based on MRI measurements of hyperpolarized gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. 3D tomographic images of standard morphological parameters (mean airspace chord length, lung parenchyma surface-to-volume ratio, and the number of alveoli per unit lung volume) can be created from a rather short (several seconds) MRI scan. These parameters are most commonly used to characterize lung morphometry but were not previously available from in vivo studies. A background of the 3He lung morphometry technique is based on a previously proposed model of lung acinar airways, treated as cylindrical passages of external radius R covered by alveolar sleeves of depth h, and on a theory of gas diffusion in these airways. The initial works approximated the acinar airways as very long cylinders, all with the same R and h. The present work aims at analyzing effects of realistic acinar airway structures, incorporating airway branching, physiological airway lengths, a physiological ratio of airway ducts and sacs, and distributions of R and h. By means of Monte Carlo computer simulations, we demonstrate that our technique allows rather accurate measurements of geometrical and morphological parameters of acinar airways. In particular, the accuracy of determining one of the most important physiological parameter of acinar airways – surface-to-volume ratio – does not exceed several percent. Second, we analyze the effect of the susceptibility induced inhomogeneous magnetic field on the parameter estimate and demonstrate that this effect is rather negligible at B0 ≤ 3T and becomes substantial only at higher B0 Third, we theoretically derive an optimal choice of MR pulse sequence parameters, which should be used to acquire a series of diffusion attenuated MR signals, allowing a substantial decrease in the acquisition time and improvement in accuracy of the results. It is demonstrated that the optimal choice represents three not equidistant b-values: b1 = 0, b2 ~ 2 s/cm2, b3 ~ 8 s/cm2.
PMCID: PMC2993856  PMID: 20937564
lung morphometry; hyperpolarized gas; diffusion MRI
5.  PPARγ deficiency results in reduced lung elastic recoil and abnormalities in airspace distribution 
Respiratory Research  2010;11(1):69.
Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear hormone receptor that regulates gene expression, cell proliferation and differentiation. We previously described airway epithelial cell PPARγ deficient mice that develop airspace enlargement with decreased tissue resistance and increased lung volumes. We sought to understand the impact of airspace enlargement in conditionally targeted mice upon the physio-mechanical properties of the lung.
We measured elastic recoil and its determinants, including tissue structure and surface forces. We measured alveolar number using radial alveolar counts, and airspace sizes and their distribution using computer-assisted morphometry.
Air vs. saline-filled pressure volume profiles demonstrated loss of lung elastic recoil in targeted mice that was contributed by both tissue components and surface tension, but was proportional to lung volume. There were no significant differences in surfactant quantity/function nor in elastin and collagen content between targeted animals and littermate controls. Importantly, radial alveolar counts were significantly reduced in the targeted animals and at 8 weeks of age there were 18% fewer alveoli with 32% more alveolar ducts. Additionally, the alveolar ducts were 19% larger in the targeted animals.
Our data suggest that the functional abnormalities, including loss of recoil are secondary to altered force transmission due to differences in the structure of alveolar ducts, rather than changes in surfactant function or elastin or collagen content. These data further define the nature of abnormal lung maturation in the absence of airway epithelial cell PPARγ and identify a putative genetic determinant of dysanapsis, which may serve as a precursor to chronic lung disease.
PMCID: PMC2889874  PMID: 20525205
6.  Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. 
Thorax  1994;49(4):319-326.
BACKGROUND--Emphysema is currently defined as "a condition of the lung characterised by abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis." The functional and morphological changes that occur in emphysema have largely been attributed to changes in alveolar elastin rather than in collagen. A study was performed to determine whether the amount of collagen in the alveolar wall changes with age in the lungs of non-smokers and of smokers with different types of macroscopically defined emphysema in relation to a microscopic measurement of lung structure. METHODS--Total alveolar wall collagen was measured (as hydroxyproline) in known volumes of distended lung tissue (by reverse phase high pressure liquid chromatography) in the lungs of non-smokers (n = 23) and in regions sampled away from emphysematous lesions in the lungs of 36 smokers (four with no emphysema, 13 with centriacinar emphysema (CAE), nine with panacinar emphysema (PAE), and 10 with a mixture (MIX) of both PAE and CAE). Mean lung airspace wall surface area per unit volume (AWUV) was calculated from at least six random blocks per lung and on histological sections immediately adjacent to those prepared for collagen measurement with a rapid scanning device (fast interval processor). RESULTS--In non-smokers there was no significant correlation between the amount of collagen in the alveolar wall tissue and either mean lung AWUV or increasing patient age when amounts of collagen were expressed either per unit volume of distended lung (40 mm3 sample) or per unit surface area of airspace wall tissue. Smokers without emphysema had similar amounts of collagen to non-smokers. Lungs with PAE and MIX, but not CAE alone, contained significantly more collagen than normal when expressed per unit volume of airspace wall tissue whereas all groups, including CAE, contained significantly raised amounts of collagen when expressed per unit surface area. CONCLUSIONS--There is no significant age related change in the collagen content of the lungs of non-smokers which suggests that, as AWUV is lost with age, the main collagenous framework is maintained. However, in smokers with emphysema there is a loss of airspace wall tissue in regions remote from the macroscopic lesions that is accompanied by a net increase in collagen mass. The greater accumulation of collagen in MIX lungs than in CAE lungs suggests a greater degree of structural damage, indicative of an alternative pathogenetic mechanism operating between the different types of emphysema. Our results suggest an active alveolar wall fibrosis in emphysema as a consequence of cigarette smoking. It is suggested that the definition of emphysema may require further revision to include such change.
PMCID: PMC475363  PMID: 8202900
7.  “Small airways disease” in children: no test is best 
Thorax  1979;34(2):217-223.
Tests claimed to detect small airway disease were evaluated in children. Fifty-two subjects who were normal, 30 with cystic fibrosis (CF), and 35 with asthma were selected on the basis of normal spirometry, informed consent being obtained from them and their parents. Tests undertaken were measurement of maximum expiratory flow volume curves breathing air and a helium-oxygen gas mixture, single breath nitrogen washout curves, lung volumes, and, except in the normal subjects, measurement of arterial oxygen tension. Closing volumes were normal in most children with CF and asthma, whereas the slope of the alveolar plateau was abnormal in 83%. Maximum expiratory flow rate at 50% of total lung capacity was reduced in 65% and maximum mid-expiratory flow rate in 57%; residual volume increased in 51%, and results of other tests were abnormal in less than 50% of children.
There was evidence suggesting that lung disease was more patchy in children with mild CF than in those with interval phase asthma. These tests do not detect specific pathological processes in small airways but reflect the consequences of small airway abnormalities, which may vary in the same disease as well as in different diseases. No one test alone appears most useful. Together they contribute to understanding the functional abnormalities present in each individual.
PMCID: PMC471040  PMID: 483188
8.  Growth of Lung Parenchyma in Infants and Toddlers with Chronic Lung Disease of Infancy 
Rationale: The clinical pathology describing infants with chronic lung disease of infancy (CLDI) has been limited and obtained primarily from infants with severe lung disease, who either died or required lung biopsy. As lung tissue from clinically stable outpatients is not available, physiological measurements offer the potential to increase our understanding of the pulmonary pathophysiology of this disease.
Objectives: We hypothesized that if premature birth and the development of CLDI result in disruption of alveolar development, then infants and toddlers with CLDI would have a lower pulmonary diffusing capacity relative to their alveolar volume compared with full-term control subjects.
Methods: We measured pulmonary diffusing capacity and alveolar volume, using a single breath-hold maneuver at elevated lung volume. Subjects with chronic lung disease of infancy (23–29 wk of gestation; n = 39) were compared with full-term control subjects (n = 61) at corrected ages of 11.6 (4.8–17.0) and 13.6 (3.2–33) months, respectively.
Measurements and Main Results: Alveolar volume and pulmonary diffusing capacity increased with increasing body length for both groups. After adjusting for body length, subjects with CLDI had significantly lower pulmonary diffusing capacity (2.88 vs. 3.23 ml/min/mm Hg; P = 0.0004), but no difference in volume (545 vs. 555 ml; P = 0.58).
Conclusions: Infants and toddlers with CLDI have decreased pulmonary diffusing capacity, but normal alveolar volume. These physiological findings are consistent with the morphometric data obtained from subjects with severe lung disease, which suggests an impairment of alveolar development after very premature birth.
PMCID: PMC2874450  PMID: 20133928
pulmonary diffusing capacity; alveolar volume; lung parenchyma; bronchopulmonary dysplasia
9.  Chemical modulation of alveolar epithelial permeability. 
The volume and composition of fluid on the surface of the alveoli can affect alveolar ventilation, gas diffusion, and macrophage function. The passive permeability and active processes of the alveolar epithelial lining play a role in regulating surface fluid and are a potential site of damage by airborne chemicals. Like other epithelial barriers, the alveolar lining is permeable to lipophilic substances but restricts the transmural flow of small ions and hydrophilic nonelectrolytes (equivalent pore radius ca. 0.5-1.5 nm). The mammalian fetal lung and alveolar sacs of the adult bullfrog secrete Cl- and K+ into the airspace. Secretion by the fetal lung ceases at birth. Many environmental agents increase the permeability of the capillary endothelium and/or respiratory epithelium and induce pulmonary edema. Studies with bullfrog alveolar sacs have demonstrated that selective effects may or may not be followed by general derangement of the epithelial barrier. Exposure of the luminal surface to HgCl2 (10(-6) to 10(-4) M) induces a selective increase in Cl- secretion that is followed by a fall in transport and a general increase in ion permeation. CdCl2 (10(-5) to 10(-3) M) depresses ciliomotion on cells on the trabecula of the alveolus but does not affect Cl- secretion or transepithelial conductance. HNO3, like other mineral acids, increases conductance and the radii or pores in the barrier, whereas NaNO3 selectively inhibits Cl- secretion. Amphotericin B(10(7) to 10(-5) MJ) induces K+ secretion into the lumen of both bullfrog and rat lung. We conclude that environmental agents induce changes in epithelial function that may compromise the lung's ability to regulate respiratory fluid without destroying the characteristic permeability of the epithelial lining.
PMCID: PMC1568474  PMID: 6250808
10.  New automated technique for assessing emphysema on histological sections. 
Journal of Clinical Pathology  1991;44(12):1007-1011.
The assessment of emphysema in human lungs has traditionally been based on observations made on whole lung slices. These methods are inappropriate for the study of early emphysema, because as much as 75% of the alveolar wall surface area may have been lost by the time airspaces are visible to the naked eye. A new, automated image analysis system, the Fast Interval Processor (FIP), was used to measure airspace wall surface area per unit volume of lung tissue (AWUV). AWUV was measured on histological sections of lung tissue and expressed in mm2/mm3. The study sample consisted of resection specimens from 40 patients (32 men and 8 women whose ages ranged from 23-74 years). Histological sections from the inflated specimens were scanned using the FIP, and a mean AWUV value was calculated for each. The intra- and interobserver reproducibility of this method of measuring AWUV were examined. The results obtained using the FIP were also compared with those from an established image analysis system. The FIP is a fast, efficient technique which gave highly reproducible results comparable with those obtained with an established and much more time consuming measuring technique.
PMCID: PMC494969  PMID: 1791200
11.  Lung Morphometry with Hyperpolarized 129Xe: Theoretical Background 
Magnetic Resonance in Medicine  2011;67(3):856-866.
The 3He lung morphometry technique, based on MRI measurements of hyperpolarized 3He gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. In vivo 3D tomographic images of standard morphological parameters (airspace chord length, lung parenchyma surface-to-volume ratio, number of alveoli per unit volume) can be generated from a rather short (several seconds) MRI scan. The technique is based on a theory of gas diffusion in lung acinar airways and experimental measurements of diffusion attenuated MRI signal. The present work aims at developing the theoretical background of a similar technique based on hyperpolarized 129Xe gas. As the diffusion coefficient and gyromagnetic ratio of 129Xe gas are substantially different from those of 3He gas, the specific details of the theory and experimental measurements with 129Xe should be amended. We establish phenomenological relationships between acinar airway geometrical parameters and the diffusion attenuated MR signal for human and small animal lungs, both normal lungs and lungs with mild emphysema. Optimal diffusion times are shown to be about 5 ms for human and 1.3 ms for small animals. The expected uncertainties in measuring main morphometrical parameters of the lungs are estimated in the framework of Bayesian probability theory.
PMCID: PMC3184317  PMID: 21713985
lung morphometry; hyperpolarized gas; diffusion MRI; emphysema
12.  Respiratory function changes after asbestos pleurisy. 
Thorax  1980;35(1):31-36.
Six patients with radiographic evidence of diffuse pleural thickening after industrial asbestos exposure are described. Five had computed tomography of the thorax. All the scans showed marked circumferential pleural thickening often with calcification, and four showed no significant evidence of intrapulmonary fibrosis (asbestosis). Lung function testing showed reduction of the inspiratory capacity and the single-breath carbon monoxide transfer factor (TLCO). The transfer coefficient, calculated as the TLCO divided by the alveolar volume determined by helium dilution during the measurement of TLCO, was increased. Pseudo-static compliance curves showed markedly more negative intrapleural pressures at all lung volumes than found in normal people. These results suggest that the circumferential pleural thickening was preventing normal lung expansion despite abnormally great distending pressures. The pattern of lung function tests is sufficiently distinctive for it to be recognised in clinical practice, and suggests that the lungs are held rigidly within an abnormal pleura. The pleural thickening in our patients may have been related to the condition described as "benign asbestos pleurisy" rather than the interstitial fibrosis of asbestosis.
PMCID: PMC471216  PMID: 7361282
13.  Validation and Clinical Application of a First Order Step Response Equation for Nitrogen Clearance During FRC Measurement 
To derive a difference equation based on mass conservation and on alveolar tidal volumes for the calculation of Functional Residual Capacity. Derive an equation for the FRC from the difference equation. Furthermore, to derive and validate a step response equation as a solution of the difference equation within the framework of digital signal processing where the FRC is known a priori.
A difference equation for the calculation of Functional Residual Capacity is derived and solved as step response of a first order system. The step response equation calculates endtidal fractions of nitrogen during multiple breath nitrogen clearance. The step response equation contains the eigenvalue defined as the ratio of FRC to the sum of FRC and alveolar tidal ventilation. Agreement of calculated nitrogen fractions with measured fractions is demonstrated with data from a metabolic lung model, measurements from patients in positive pressure ventilation and volunteers breathing spontaneously. Examples of eigenvalue are given and compared between diseased and healthy lungs and between ventilatory settings.
Comparison of calculated and measured fractions of endtidal nitrogen demonstrates a high degree of agreement in terms of regression and bias and limits of agreement (precision) in Bland & Altman analysis. Examples illustrate the use of the eigenvalue as a possible discriminator between disease states.
The first order step response equation reliably calculates endtidal fractions of nitrogen during washout based on a Functional Residual Capacity. The eigenvalue may be a clinically valuable index alone or in conjunction with other indices in the analysis of respiratory states and may aid in the setting of the ventilator.
PMCID: PMC2798958  PMID: 18004668
physiologic monitoring; respiration disorder; functional residual capacity; nitrogen washout; digital signal processing; mechanical ventilators
14.  Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema 
Rationale: Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development.
Objectives: We sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS.
Methods: Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1–deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides.
Measurements and Main Results: Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide.
Conclusions: These data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development.
PMCID: PMC2742758  PMID: 19520907
chronic obstructive pulmonary disease; genetically modified mice; apoptosis
15.  Alveolar Dynamics during Respiration 
The change in alveolar size and number during the full breathing cycle in mammals remains unanswered, yet these descriptors are fundamental for understanding alveolar-based diseases and for improving ventilator management. Genetic and environmental mouse models are used increasingly to evaluate the evolution of disease in the peripheral lung; however, little is known regarding alveolar structure and function in the fresh, intact lung. Therefore, we have developed an optical confocal process to evaluate alveolar dynamics in the fresh intact mouse lung and as an initial experiment, have evaluated mouse alveolar dynamics during a single respiratory cycle immediately after passive lung deflation. We observe that alveoli become smaller and more numerous at the end of inspiration, and propose that this is direct evidence for alveolar recruitment in the mouse lung. The findings reported support a new hypothesis that requires recruitable secondary (daughter) alveoli to inflate via primary (mother) alveoli rather than from a conducting airway.
PMCID: PMC2335337  PMID: 18096874
alveolar recruitment; mechanics; mouse lung; confocal microscopy; collateral ventilation
16.  Critical evaluation of computerised x ray planimetry for the measurement of lung volumes. 
Thorax  1995;50(4):383-386.
BACKGROUND--Computerised x-ray planimetry has been advocated as an alternative to body plethysmography and helium dilution for measuring static lung volumes. The accuracy and reproducibility of this method has been assessed in comparison with these standard methods. METHODS--Plethysmographic and planimetric measurements of total lung capacity (TLC) and functional residual capacity (FRC) were made in 10 normal subjects and in 12 patients with chronic obstructive pulmonary disease (COPD), with additional helium dilution measurements in the latter 12 patients. RESULTS--Mean lung volumes (TLC and FRC) for groups of subjects measured by planimetry and by plethysmography were similar in both groups and larger than the helium dilution measurement in patients with COPD. Intraindividual agreement between planimetry and plethysmography was poor, however, with a wide confidence interval (-2.2 to +2.31). The planimeter did not measure reliably changes in volume from TLC to FRC in individuals. CONCLUSIONS--Mean lung volumes measured by planimetry in a group of patients probably reflect a regression to the mean of the computer algorithm rather than accurate TLC estimation. The technique is not yet robust enough to replace the established techniques of helium dilution or plethysmography.
PMCID: PMC474286  PMID: 7785011
17.  Fibroblast Growth Factor Receptors Control Epithelial–Mesenchymal Interactions Necessary for Alveolar Elastogenesis 
Rationale: The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation.
Objectives: To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation.
Methods: Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes.
Measurements and Main Results: Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor−1, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology.
Conclusions: Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.
PMCID: PMC2854333  PMID: 20093646
lung development; fibroblast growth factor receptor; alveogenesis; insulin-like growth factor−1; microarray
18.  Alveolar fractal box dimension inversely correlates with mean linear intercept in mice with elastase-induced emphysema 
A widely applicable model of emphysema that allows efficient and sensitive quantification of injury is needed to compare potential therapies.
To establish such a model, we studied the relationship between elastase dose and the severity of emphysema in female C57BL/6J mice. We compared alveolar fractal box dimension (DB), a new measure which is an assessment of the complexity of the tissue, with mean linear intercept (Lm), which is commonly used to estimate airspace size, for sensitivity and efficiency of measurement.
Emphysema was induced in female C57BL/6J mice by administering increasing intratracheal doses of porcine pancreatic elastase (PPE). Changes in morphology and static lung compliance (CL) were examined 21 days later. Correlation of DB with Lm was determined in histological sections of lungs exposed to PPE. The inverse relationship between DB and Lm was supported by examining similar morphological sections from another experiment where the development of emphysema was studied 1 to 3 weeks after instillation of human neutrophil elastase (HNE).
Lm increased with PPE dose in a sigmoidal curve. CL increased after 80 or 120 U/kg body weight (P < 0.05), but not after 40 U/kg, compared with the control. DB progressively declined from 1.66 ± 0.002 (standard error of the mean) in controls, to 1.47 ± 0.006 after 120 U PPE/kg (P < 0.0001). After PPE or HNE instillation, DB was inversely related to Lm (R = −0.95, P < 0.0001 and R = −0.84, P = 0.01, respectively), with a more negative slope of the relationship using HNE (P < 0.0001).
Intratracheal instillation of increasing doses of PPE yields a scale of progression from mild to severe emphysema. DB correlates inversely with Lm after instillation of either PPE or HNE and yields a rapid, sensitive measure of emphysema after elastase instillation.
PMCID: PMC3324997  PMID: 22500123
chronic obstructive pulmonary disease; pulmonary emphysema; lung morphometry; lung compliance
19.  Alveolar liquid pressure measured by micropuncture in isolated lungs of mature and immature fetal rabbits. 
Journal of Clinical Investigation  1987;79(6):1579-1588.
Increased alveolar surface tension due to surfactant deficiency is thought to result in a negative pressure surrounding pulmonary capillaries and to promote fluid filtration. To test this hypothesis, alveolar liquid pressure (Pliquid) was measured by micropuncture in isolated lungs of mature and immature fetal rabbits (with and without surfactant replacement) at different air inflation pressures (Pairway). Lung maturity was assessed by air pressure-volume (P-V) curves. Pliquid was correlated with surfactant content in the lungs and with alveolar size. Pliquid was lower in immature (2.3 +/- 0.7 cmH2O) than in mature (8.4 +/- 1.0 cmH2O) lungs at comparable Pairway (25 cmH2O) (P less than 0.01). The mean linear intercept, a measure of airspace dimensions was similar in all lungs (42.1 +/- 2.0 micron), but alveolar wash phospholipid/g wet lung was lower in immature than in mature lungs (0.05 +/- 0.01 vs. 0.49 +/- 0.30 mg) (P less than 0.01). Surfactant replacement in immature lungs resulted in P-V curves and Pliquid similar to those of mature lungs. If pericapillary interstitial liquid pressure approximates Pliquid, surfactant deficiency will predispose preterm infants to pulmonary edema.
PMCID: PMC424472  PMID: 3584460
20.  Comparison of two new methods for the measurement of lung volumes with two standard methods 
Thorax  1999;54(4):329-333.
BACKGROUND—The two most commonly used methods for the measurement of lung volumes are helium dilution and body plethysmography. Two methods have been developed which are both easier and less time consuming to perform. Mathematical modelling uses complex calculations from the flow-volume loop to derive total lung capacity (TLC), and the nitrogen balance technique uses nitrogen from the atmosphere to calculate lung volume in a similar way to helium dilution. This study was designed to compare the two new methods with the two standard methods.
METHODS—Sixty one subjects were studied, 23 with normal lung function, 17 with restrictive airway disease, and 21 with obstructive ventilatory defects. Each subject underwent repeated measurements of TLC by each of the four methods in random order. Reproducible values were obtained for each method according to BTS/ARTP guidelines. Bland-Altman plots were constructed for comparisons between the methods and paired t tests were used to assess differences in means.
RESULTS—Bland-Altman plots showed that the differences between body plethysmography and helium dilution fell into clinically acceptable ranges (agreement limits ±0.9 l). The agreement between mathematical modelling or the nitrogen balance technique and helium dilution or body plethysmography was poor (±1.8-3.4 l), especially for subjects with airflow obstruction.
CONCLUSIONS—Neither of the new methods agrees sufficiently with standard methods to be useful in a clinical setting.

PMCID: PMC1745479  PMID: 10092694
21.  Four-dimensional visualization of subpleural alveolar dynamics in vivo during uninterrupted mechanical ventilation of living swine 
Biomedical Optics Express  2013;4(11):2492-2506.
Pulmonary alveoli have been studied for many years, yet no unifying hypothesis exists for their dynamic mechanics during respiration due to their miniature size (100-300 μm dimater in humans) and constant motion, which prevent standard imaging techniques from visualizing four-dimensional dynamics of individual alveoli in vivo. Here we report a new platform to image the first layer of air-filled subpleural alveoli through the use of a lightweight optical frequency domain imaging (OFDI) probe that can be placed upon the pleura to move with the lung over the complete range of respiratory motion. This device enables in-vivo acquisition of four-dimensional microscopic images of alveolar airspaces (alveoli and ducts), within the same field of view, during continuous ventilation without restricting the motion or modifying the structure of the alveoli. Results from an exploratory study including three live swine suggest that subpleural alveolar air spaces are best fit with a uniform expansion (r 2 = 0.98) over a recruitment model (r 2 = 0.72). Simultaneously, however, the percentage change in volume shows heterogeneous alveolar expansion within just a 1 mm x 1 mm field of view. These results signify the importance of four-dimensional imaging tools, such as the device presented here. Quantification of the dynamic response of the lung during ventilation may help create more accurate modeling techniques and move toward a more complete understanding of alveolar mechanics.
PMCID: PMC3829543  PMID: 24298409
(110.4500) Optical coherence tomography; (170.2655) Functional monitoring and imaging
22.  An assessment of lung volumes and gas transfer in sickle-cell anaemia 
Thorax  1971;26(3):309-315.
Lung volumes, gas transfer, and anthropometry were assessed in sickle-cell anaemia in 13 patients with previous pulmonary episodes and 12 without this history. Respiratory symptoms were assessed with a standard questionnaire, total lung capacity and its subdivisions, the carbon monoxide transfer factor (TF), diffusion capacity of the alveolar capillary membrane (Dm), and the alveolar capillary blood volume (Vc) were measured, and stature, sitting height and chest diameters were recorded. Total lung capacity and vital capacity were reduced because the thorax was small relative to body size in these patients.
TF was reduced by anaemia, small lungs, and a low Dm which was not simply a consequence of small lungs. This reduction tended to be offset by an increase in Vc. The cause of the reduction in Dm above that due to small lungs was probably located in the pulmonary circulation. Anaemia was considered unlikely to be responsible, and although a difference between the reactivity of carbon monoxide with Hb A and Hb S may have contributed to the reduction in Dm and the increase in Vc, it was thought unlikely to be the only cause: Dm was significantly lower in patients with a history of pulmonary complications and in non-smokers than in those without this history and in smokers. Alveolar capillary collapse or occlusion may also have reduced Dm in sickle-cell anaemia and accounted for the greater reductions in those with previous pulmonary episodes and in non-smokers.
PMCID: PMC1019088  PMID: 5089498
23.  New pathological findings in emphysema of childhood: 1. Polyalveolar lobe with emphysema 
Thorax  1970;25(6):682-690.
A new pathological entity is here described—a polyalveolar lobe with or without emphysema—giving rise to the clinical features of childhood lobar emphysema.
A detailed and quantitative study of the airways, alveoli and arteries was carried out on the left upper lobe removed because of shortness of breath, thought to be due to `childhood lobar emphysema'. The child was 17 days old and the radiograph showed hypertransradiancy of the left lung. The alveolar number was increased five-fold. Alveolar size was normal, so it was found that emphysema, accepted today as a structural diagnosis, was not present. The increase in alveolar number seemed confined to the apical, posterior, and anterior segments, the lingula being unaffected. By contrast, the airways and arteries were normal for age in number, size and structure, suggesting that the condition was a `giantism' of the alveolar region. The blood flow was probably too low for the lobar volume; certainly the excessive alveolar number could not be due to increase in blood flow.
In two further specimens, previously dissected, a similar polyalveolar condition was found, associated with emphysema. The patients were older at the time of surgical resection and the emphysema may have developed post-natally. In all three cases the radiographic features had suggested emphysema. It is suggested that the condition be called `polyalveolar lobe', `with emphysema' or `without emphysema' being added as a separate item to the description.
PMCID: PMC472210  PMID: 5494677
24.  Nasal Ventilation Alters Mesenchymal Cell Turnover and Improves Alveolarization in Preterm Lambs 
Rationale: Bronchopulmonary dysplasia (BPD) is a frequent cause of morbidity in preterm infants that is characterized by prolonged need for ventilatory support in an intensive care environment. BPD is characterized histopathologically by persistently thick, cellular distal airspace walls. In normally developing lungs, by comparison, remodeling of the immature parenchymal architecture is characterized by thinning of the future alveolar walls, a process predicated on cell loss through apoptosis.
Objectives: We hypothesized that minimizing lung injury, using high-frequency nasal ventilation to provide positive distending pressure with minimal assisted tidal volume displacement, would increase apoptosis and decrease proliferation among mesenchymal cells in the distal airspace walls compared with a conventional mode of support (intermittent mandatory ventilation).
Methods: Accordingly, we compared two groups of preterm lambs: one group managed by high-frequency nasal ventilation and a second group managed by intermittent mandatory ventilation. Each group was maintained for 3 days.
Measurements and Main Results: Oxygenation and ventilation targets were sustained with lower airway pressures and less supplemental oxygen in the high-frequency nasal ventilation group, in which alveolarization progressed. Thinning of the distal airspace walls was accompanied by more apoptosis, and less proliferation, among mesenchymal cells of the high-frequency nasal ventilation group, based on morphometric, protein abundance, and mRNA expression indices of apoptosis and proliferation.
Conclusions: Our study shows that high-frequency nasal ventilation preserves the balance between mesenchymal cell apoptosis and proliferation in the distal airspace walls, such that alveolarization progresses.
PMCID: PMC2542442  PMID: 18556628
alveolar formation; bronchopulmonary dysplasia; chronic lung disease of prematurity; morphometry; stereology
25.  Refractive errors and corrections for OCT images in an inflated lung phantom 
Biomedical Optics Express  2012;3(5):1101-1109.
Visualization and correct assessment of alveolar volume via intact lung imaging is important to study and assess respiratory mechanics. Optical Coherence Tomography (OCT), a real-time imaging technique based on near-infrared interferometry, can image several layers of distal alveoli in intact, ex vivo lung tissue. However optical effects associated with heterogeneity of lung tissue, including the refraction caused by air-tissue interfaces along alveoli and duct walls, and changes in speed of light as it travels through the tissue, result in inaccurate measurement of alveolar volume. Experimentally such errors have been difficult to analyze because of lack of ’ground truth,’ as the lung has a unique microstructure of liquid-coated thin walls surrounding relatively large airspaces, which is difficult to model with cellular foams. In addition, both lung and foams contain airspaces of highly irregular shape, further complicating quantitative measurement of optical artifacts and correction. To address this we have adapted the Bragg-Nye bubble raft, a crystalline two-dimensional arrangement of elements similar in geometry to alveoli (up to several hundred μm in diameter with thin walls) as an inflated lung phantom in order to understand, analyze and correct these errors. By applying exact optical ray tracing on OCT images of the bubble raft, the errors are predicted and corrected. The results are validated by imaging the bubble raft with OCT from one edge and with a charged coupled device (CCD) camera in transillumination from top, providing ground truth for the OCT.
PMCID: PMC3342185  PMID: 22567599
(080.0080) Geometric optics; (080.2710) Inhomogeneous optical media; (100.2960) Image analysis; (170.5380) Physiology

Results 1-25 (626405)