Mean Lung Volume Research Articles

MRI and three dimensional ultrasonography in the assessment of pulmonary hypoplasia in fetuses with urinary tract anomalies

PurposeTo analyze the correlation and agreement between three dimensional (3D) US and MRI in the assessment of pulmonary volumes of fetuses with different types of urinary tract malformations (UTM) and high-risk of pulmonary hypoplasia (PH). Patients and methodsThirty-nine fetuses with various UTM, at risk for PH were involved in this cross-sectional study. 3D volume US data sets of the fetal lungs were acquired. The right, left and total lung volumes were calculated separately using the virtual organ computer-aided analysis (VOCAL) method with a 30° rotation. MRI of fetal lung was obtained with assessment of signal intensity and lung volumetry. Comparison between mean lung volumes was performed using unpaired t test. Agreement between the 3D-US and MRI methods was done using Cohen kappa test. ResultsGood agreement was detected between the two methods (Kappa=0.629, p=0.001). The measured lung volumes by 3D-US were smaller than those measured by MRI (p>0.05, non-significant). MRI showed greater specificity, PPV and diagnostic accuracy (100% each) than 3D-US (50%, 88.9% and 90% respectively). ConclusionThere is a good concordance between 3D-US and MRI in the evaluation of PH in fetuses with UTM. MRI could be reserved for borderline cases of pulmonary hypoplasia and the difficult diagnostic situations.

SU‐F‐J‐22: Lung VolumeVariability Assessed by Bh‐CBCT in 3D Surface Image Guided Deep InspirationBreath Hold (DIBH) Radiotherapy for Left‐Sided Breast Cancer

Purpose:With the increasing use of DIBH techniques for left‐sided breast cancer, 3D surface‐image guided DIBH techniques have improved patient setup and facilitated DIBH radiation delivery. However, quantification of the daily separation between the heart and left breast still presents a challenge. One method of assuring separation is to ensure consistent left lung filling. With this in mind, the aim of this study is to retrospectively quantify left lung volume from weekly breath hold‐CBCTs (bh‐CBCT) of left‐sided breast patients treated using a 3D surface imaging system.Methods:Ten patients (n=10) previously treated to the left breast using the C‐Rad CatalystHD system (C‐RAD AG, Uppsala Sweden) were evaluated. Patients were positioned with CatalystHD and with bh‐CBCT. bh‐CBCTs were acquired at the validation date, first day of treatment and at subsequent weekly intervals. Total treatment courses spanned from 3 to 5 weeks. bh‐CBCT images were exported to VelocityAI and the left lung volume was segmented. Volumes were recorded and analyzed.Results:A total of 41 bh‐CBCTs were contoured in VelocityAI for the 10 patients. The mean left lung volume for all patients was 1657±295cc based on validation bh‐CBCT. With the subsequent lung volumes normalized to the validation lung volume, the mean relative ratios for all patients were 1.02±0.11, 0.97±0.14, 0.98±0.11, 1.02±0.01, and 0.96±0.02 for week 1, 2, 3, 4, and 5, respectively. Overall, the mean left lung volume change was ≤4.0% over a 5‐week course; however left lung volume variations of up to 28% were noted in a select patient.Conclusion:With the use of the C‐RAD CatalystHD system, the mean lung volume variability over a 5‐week course of DIBH treatments was ≤4.0%. By minimizing left lung volume variability, heart to left breast separation maybe more consistently maintained.AN Gutierrez has a research grant from C‐RAD AG.

Benefits of adaptive radiation therapy in lung cancer as a function of replanning frequency.

To quantify the potential benefit associated with daily replanning in lung cancer in terms of normal tissue dose sparing and to characterize the tradeoff between adaptive benefit and replanning frequency. A set of synthetic images and contours, derived from weekly active breathing control images of 12 patients who underwent radiation therapy treatment for nonsmall cell lung cancer, is generated for each fraction of treatment using principal component analysis in a way that preserves temporal anatomical trends (e.g., tumor regression). Daily synthetic images and contours are used to simulate four different treatment scenarios: (1) a "no-adapt" scenario that simulates delivery of an initial plan throughout treatment, (2) a "midadapt" scenario that implements a single replan for fraction 18, (3) a "weekly adapt" scenario that simulates weekly adaptations, and (4) a "full-adapt" scenario that simulates daily replanning. An initial intensity modulated radiation therapy plan is created for each patient and replanning is carried out in an automated fashion by reoptimizing beam apertures and weights. Dose is calculated on each image and accumulated to the first in the series using deformable mappings utilized in synthetic image creation for comparison between simulated treatments. Target coverage was maintained and cord tolerance was not exceeded for any of the adaptive simulations. Average reductions in mean lung dose (MLD) and volume of lung receiving 20 Gy or more (V20lung) were 65 ± 49 cGy (p = 0.000 01) and 1.1% ± 1.2% (p = 0.0006), respectively, for all patients. The largest reduction in MLD for a single patient was 162 cGy, which allowed an isotoxic escalation of the target dose of 1668 cGy. Average reductions in cord max dose, mean esophageal dose (MED), dose received by 66% of the heart (D66heart), and dose received by 33% of the heart (D33heart), were 158 ± 280, 117 ± 121, 37 ± 77, and 99 ± 120 cGy, respectively. Average incremental reductions in MLD for the midadapt, weekly adapt, and full-adapt treatments were 38, 18, and 8 cGy, respectively. Incremental reductions in MED for the same treatments were 57, 37, and 23 cGy. Reductions in MLD and MED for the full-adapt treatment were correlated with the absolute decrease in the planning target volume (r = 0.34 and r = 0.26). Adaptive radiation therapy for lung cancer yields clinically relevant reductions in normal tissue doses for frequencies of adaptation ranging from a single replan up to daily replanning. Increased frequencies of adaptation result in additional benefit while magnitude of benefit decreases.

Immediate breast reconstruction with anatomical implants following mastectomy: The radiation perspective

Immediate implant-based breast reconstruction followed by postmastectomy radiation therapy (PMRT) is controversial because of the risk of compromised treatment plans and concerns regarding cosmetic outcomes. We evaluated the effects of immediate direct-to-implant breast reconstruction with anatomical implants on the quality of PMRT delivered by 3-dimensional conformal radiotherapy (3D-CRT). In this retrospective, single-institution study, patients who had undergone reconstruction with direct anatomic implant, performed by a single surgeon, received 3D-CRT between 2008 and 2013. For each patient, 2 plans (including or excluding internal mammary nodes [IMN]) were created and calculated. The primary end point was the dose distribution among reconstructed breasts, heart, lungs, and IMNs, and between right and left breasts. Of 29 consecutive patients, 11 received right-sided and 18 received left-sided PMRT to a total dose of 50Gy. For plans excluding IMN coverage, mean Dmean for right and left reconstructed breasts was 49.09Gy (98.2% of the prescribed dose) and 48.51Gy (97.0%), respectively. For plans including IMNs, mean Dmean was 49.15Gy (98.3%) for right and 48.46Gy (96.9%) for left reconstructed breasts; the mean IMN Dmean was 47.27Gy (right) and 47.89Gy (left). Heart Dmean was below 1.56Gy for all plans. Mean total lung volume receiving a dose of ≥ 20Gy was 13.80% to 19.47%. PMRT can be delivered effectively and safely by 3D-CRT after direct-to-implant breast reconstruction with anatomical implants, even if patients require IMN treatment.

Inclusion of functional information from perfusion SPECT improves predictive value of dose–volume parameters in lung toxicity outcome after radiotherapy for non-small cell lung cancer: A prospective study

Background and purposeTo compare functional and standard dose–volume parameters as predictors of postradiation pulmonary toxicity in lung cancer patients undergoing curative chemo-radiotherapy (RT) studied prospectively. Material and methodsA total of 58 patients treated with Intensity Modulated RT (60–66Gy) were analysed. Standard dose–volume parameters were extracted from treatment planning computed tomography (CT) scans. Corresponding functional dose–volume parameters were calculated from perfusion single-photon emission computed tomography (SPECT). Primary end-point was radiation pneumonitis (RP) grade 2–5. ResultsFunctional mean lung dose (MLD) and lung volumes receiving 5, 10, 20 and 30Gy (V5–V30, respectively) revealed high correlation with corresponding standard parameters (r>0.8). Standard MLD, V20 and V30 were significantly higher in patients with RP (p=0.01). All functional parameters were significantly higher in the RP patients (p<0.03). In multivariate analysis functional parameters produced superior risk estimates, while all standard parameters, except V30, were not related to the risk of RP. Area under the curve (AUC) for functional metrics generally exceeded the AUC for corresponding standard parameters, but they were not significantly different from each other. ConclusionSPECT-based functional parameters were better to predict the risk of RP compared to standard CT-based dose–volume parameters. Functional parameters may be useful to guide radiotherapy planning in order to reduce the risk of radiation-induced toxicity.

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen- and carbon dioxide-chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli. We hypothesized that simultaneous stimulation of O2 - and CO2 -sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16 and 21% O2 ) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2). Tidal volume, arterial pressure, heart rate and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. The MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (P < 0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction.

SU‐E‐T‐122: Anisotropic Analytical Algorithm (AAA) Vs. Acuros XB (AXB) in Stereotactic Treatment Planning

Purpose:To evaluate dosimetric differences between superposition beam model (AAA) and determinant photon transport solver (AXB) in lung SBRT and Cranial SRS dose computations.Methods:Ten Cranial SRS and ten Lung SBRT plans using Varian, AAA _11.0 were re‐planned using Acuros _XB_11.0 with fixed MU. 6MV photon Beam model with HD120_MLC used for dose calculations. Four non‐coplanar conformal arcs used to deliver 21Gy or 18Gy to SRS targets (0.4 to 6.2cc). 54Gy (3Fractions) or 50Gy (5Fractions) was planned for SBRT targets (7.3 to 13.9cc) using two VAMT non‐coplanar arcs. Plan comparison parameters were dose to 1% PTV volume (D1), dose to 99% PTV volume( D99), Target mean (Dmean), Conformity index (ratio of prescription isodose volume to PTV), Homogeneity Index [ (D2%‐D98%)/Dmean] and R50 (ratio of 50% of prescription isodose volume to PTV). OAR parameters were Brain volume receiving 12Gy dose (V12Gy) and maximum dose (D0.03) to Brainstem for SRS. For lung SBRT, maximum dose to Heart and Cord, Mean lung dose (MLD) and volume of lung receiving 20Gy (V20Gy) were computed. PTV parameters compared by percentage difference between AXB and AAA parameters. OAR parameters and HI compared by absolute difference between two calculations. For analysis, paired t‐test performed over the parameters.Results:Compared to AAA, AXB SRS plans have on average 3.2% lower D99, 6.5% lower CI and 3cc less Brain_V12. However, AXB SBRT plans have higher D1, R50 and Dmean by 3.15%, 1.63% and 2.5%. For SRS and SBRT, AXB plans have average HI 2 % and 4.4% higher than AAA plans. In both techniques, all other parameters vary within 1% or 1Gy. In both sets only two parameters have P&gt;0.05.Conclusion:Even though t‐test results signify difference between AXB and AAA plans, dose differences in dose estimations by both algorithms are clinically insignificant.

Pulmonary function tests – an easy selection method for respiratory-gated radiotherapy in patients with left-sided breast cancer

Purpose. The purpose of this study was to establish a feasible and convenient method for selection of the subset of patients with left-sided breast cancer for whom respiratory-gated radiotherapy (RT) would be necessary to meet the national recommendation regarding radiation dose to the heart.Material and methods. The volume of heart receiving a dose equal to or higher than 25 Gy (V25Gy), the mean heart dose (Dmean) and total lung volume (TLV-CT) were obtained from treatment plans based on computer tomography (CT) series recorded during free breathing (FB), and the correlation between dose to the heart and TLV-CT was studied. Second, the correlation between TLV-CT and TLV defined from three pulmonary function tests (PFTs); spirometry, gas diffusion and plethysmograhy, was evaluated.Results. Dose to the heart (V25Gy and Dmean) decreased with increasing TLV-CT. Pearson's correlation coefficient (r) for TLV-CT versus V25Gy and Dmean was equal (r = −0.809, p < 0.01) for patients planned for tangential breast RT only, and r = −0.853 and −0.861 (p < 0.01) for patients planned for loco-regional RT. Regression analysis showed good correlation between TLV-CT and TLV calculated from pulmonary function tests (R2 ≥ 0.717, p < 0.01).Conclusion. TLV defined by routine pulmonary function tests can be used to identify the subset of left-sided breast cancer patients who require respiratory-gated RT.

Alveolar type II epithelial cell dysfunction in rat experimental hepatopulmonary syndrome (HPS).

The hepatopulmonary syndrome (HPS) develops when pulmonary vasodilatation leads to abnormal gas exchange. However, in human HPS, restrictive ventilatory defects are also observed supporting that the alveolar epithelial compartment may also be affected. Alveolar type II epithelial cells (AT2) play a critical role in maintaining the alveolar compartment by producing four surfactant proteins (SPs, SP-A, SP-B, SP-C and SP-D) which also facilitate alveolar repair following injury. However, no studies have evaluated the alveolar epithelial compartment in experimental HPS. In this study, we evaluated the alveolar epithelial compartment and particularly AT2 cells in experimental HPS induced by common bile duct ligation (CBDL). We found a significant reduction in pulmonary SP production associated with increased apoptosis in AT2 cells after CBDL relative to controls. Lung morphology showed decreased mean alveolar chord length and lung volumes in CBDL animals that were not seen in control models supporting a selective reduction of alveolar airspace. Furthermore, we found that administration of TNF-α, the bile acid, chenodeoxycholic acid, and FXR nuclear receptor activation (GW4064) induced apoptosis and impaired SP-B and SP-C production in alveolar epithelial cells in vitro. These results imply that AT2 cell dysfunction occurs in experimental HPS and is associated with alterations in the alveolar epithelial compartment. Our findings support a novel contributing mechanism in experimental HPS that may be relevant to humans and a potential therapeutic target.

Cardiorespiratory interactions: the relationship between mechanical ventilation and hemodynamics.

The overall goal of the cardiorespiratory system is to provide the organs and tissues of the body with an adequate supply of oxygen in relation to oxygen consumption. An understanding of the complex physiologic interactions between the respiratory and cardiac systems is essential to optimal patient management. Alterations in intrathoracic pressure are transmitted to the heart and lungs and can dramatically alter cardiovascular performance, with significant differences existing between the physiologic response of the right and left ventricles to changes in intrathoracic pressure. In terms of cardiorespiratory interactions, the clinician should titrate the mean airway pressure to optimize the balance between mean lung volume (ie, arterial oxygenation) and ventricular function (ie, global cardiac output), minimize pulmonary vascular resistance, and routinely monitor cardiorespiratory parameters closely. Oxygen delivery to all organs and tissues of the body should be optimized, but not necessarily maximized. The heart and lungs are, obviously, connected anatomically but also physiologically in a complex relationship.

Automated Lung Volumetry from Routine Thoracic CT Scans: How Reliable is the Result?

Today, lung volumes can be easily calculated from chest computed tomography (CT) scans. Modern postprocessing workstations allow automated volume measurement of data sets acquired. However, there are challenges in the use of lung volume as an indicator of pulmonary disease when it is obtained from routine CT. Intra-individual variation and methodologic aspects have to be considered. Our goal was to assess the reliability of volumetric measurements in routine CT lung scans. Forty adult cancer patients whose lungs were unaffected by the disease underwent routine chest CT scans in 3-month intervals, resulting in a total number of 302 chest CT scans. Lung volume was calculated by automatic volumetry software. On average of 7.2 CT scans were successfully evaluable per patient (range 2-15). Intra-individual changes were assessed. In the set of patients investigated, lung volume was approximately normally distributed, with a mean of 5283 cm(3) (standard deviation = 947 cm(3), skewness = -0.34, and curtosis = 0.16). Between different scans in one and the same patient the median intra-individual standard deviation in lung volume was 853 cm(3) (16% of the mean lung volume). Automatic lung segmentation of routine chest CT scans allows a technically stable estimation of lung volume. However, substantial intra-individual variations have to be considered. A median intra-individual deviation of 16% in lung volume between different routine scans was found.

Analysis of predictive factors for lung injury after forward-planned intensity-modulated radiotherapy in whole breast irradiation.

PurposeThis study was performed to assess frequency, timings of occurrence, and predictors of radiologic lung damage (RLD) after forward-planned intensity-modulated radiotherapy (FIMRT) for whole breast irradiation.MethodsWe retrospectively reviewed medical records of 157 breast cancer patients and each of their serial chest computed tomography (CT) taken 4, 10, 16, and 22 months after completion of breast radiotherapy (RT). FIMRT was administered to whole breast only (n=152), or whole breast and supraclavicular regions (n=5). Dosimetric parameters, such as mean lung dose and lung volume receiving more than 10 to 50 Gy (V10-V50), and clinical parameters were analyzed in relation to radiologic lung damage.ResultsIn total, 104 patients (66.2%) developed RLD after whole breast FIMRT. Among the cases of RLD, 84.7% were detected at 4 months, and 15.3% at 10 months after completion of RT. More patients of 47 or younger were found to have RLD at 10 months after RT than patients older than the age (11.7% vs. 2.9%, p=0.01). In univariate and multivariate analyses, age >47 and V40 >7.2% were significant predictors for higher risk of RLD.ConclusionRLD were not infrequently detected in follow-up CT after whole breast FIMRT. More detected cases of RLD among younger patients are believed to have developed at later points after RT than those of older patients. Age and V40 were significant predictors for RLD after whole breast intensity-modulated radiotherapy.

Prospective Assessment of Optimal Individual Position (Prone Versus Supine) for Breast Radiotherapy: Volumetric and Dosimetric Correlations in 100 Patients

Damage to heart and lung from breast radiotherapy is associated with increased cardiovascular mortality and lung cancer development. We conducted a prospective study to evaluate which position is best to spare lung and heart from radiotherapy exposure. One hundred consecutive Stage 0-IIA breast cancer patients consented to participate in a research trial that required two computed tomography simulation scans for planning both supine and prone positions. The optimal position was defined as that which best covered the contoured breast and tumor bed while it minimized critical organ irradiation, as quantified by the in-field heart and lung volume. The trial was designed to plan the first 100 patients in each position to study correlations between in-field volumes of organs at risk and dose. Fifty-three left and 47 right breast cancer patients were consecutively accrued to the trial. In all patients, the prone position was optimal for sparing lung volume compared to the supine setup (mean lung volume reduction was 93.5 cc for right and 103.6 cc for left breast cancer patients). In 46/53 (87%) left breast cancer patients best treated prone, in-field heart volume was reduced by a mean of 12 cc and by 1.8 cc for the other 7/53 (13%) patients best treated supine. As predicted, supine-prone differences in in-field volume and mean dose of heart and lung were highly correlated (Spearman's correlation coefficient for left breast cancer patients was 0.90 for heart and 0.94 for lung and 0.92 for right breast cancer patients for lung). Prone setup reduced the amount of irradiated lung in all patients and reduced the amount of heart volume irradiated in 87% of left breast cancer patients. In-field organ volume is a valid surrogate for predicting dose; the trial continued to the planned target of400.

An evaluation of three dimensional conformal radiation therapy versus intensity modulated radiation therapy in radical chemoradiation of esophageal cancer: A dosimetric study

Aims: To evaluate the feasibility whether intensity-modulated radiotherapy (IMRT) can be used to reduce doses to normal thoracic structures than three-dimensional conformal radiotherapy (3DCRT) in treating esophageal cancer and to compare normal tissue complication probability (NTCP) for lung between two treatment plans. Materials and Methods: A prospective study was carried out from 2009 to 2011, in which 15 inoperable patients of esophageal cancer who were suitable for radical chemoradiation were enrolled. All patients were treated with 3DCRT. In first phase, patients were treated with external beam radiation therapy (EBRT) dose of 36Gy in 20 fractions in 4 weeks, along with concurrent weekly chemotherapy with cisplatinum and 5-fluorouracil (5 FU). In second phase, boost dose of 18Gy in 10 fractions in 2 weeks was given. An IMRT plan was generated for each patient. Plan sum of both the 3D CRT and IMRT plans were compared. Doses to critical structures and NTCP for lung were compared between 3DCRT and IMRT plans. Results: The mean lung dose and volumes of lung receiving 20 Gy, 10 Gy, and 5 Gy (V20, V10, and V5) were significantly lower with 3DCRT plans as compared to IMRT plans. The mean dose to heart and spinal cord was higher in 3DCRT arm. There was no difference in dose distribution to the liver between the 3D CRT and IMRT techniques. The NTCP for lung was lower with 3D CRT than IMRT. Conclusion: IMRT technique needs further dosimetric study as well as further clinical trials before implication of this technique replacing 3D CRT technique with escalated dose for the treatment of esophageal cancer in our setup. IMRT using seven fields provided no improvement over 3DCRT.

Effect of antenatal corticosteroid treatment on the fetal lung: a magnetic resonance imaging study

To investigate the effect of antenatal corticosteroid treatment on the fetal lung using magnetic resonance imaging. Prospective evaluation of 30 consecutive singleton pregnancies that received antenatal corticosteroid treatment (12 mg betamethasone i.m. on admission and 24 h later) because of threatened preterm birth. Fetal lungs were assessed using T2-weighted single-shot fast spin-echo images of a whole-body 1.5-T superconducting unit twice: less than 24 h and more than 48 h after the first course of betamethasone. Lung volumes and lung-liver signal-intensity ratios were compared between the two time points. Nine patients had to be excluded from the analysis because they did not complete the study protocol as required. Ten female and 11 male fetuses with a gestational age between 23.4 and 32.6 weeks were included in the final analysis. The mean gestational age of included fetuses was 27.5 ± 2.8 weeks. Using a linear regression model, a significant influence of gestational age on ln fetal lung volume (r(2)=0.414; P<0.0001) and lung-liver signal-intensity ratios (r(2)=0.271, P<0.0001) was found. Between the two evaluated time points, a significant increase in lung-liver signal-intensity ratios (2.34 ± 0.72 vs. 3.22 ± 1.12, P<0.0001), but not in mean lung volumes (46.6 ± 20.7 cm(3) vs. 48.8 ± 16.0 cm(3) , P=0.292), was observed. We demonstrate a significant increase in lung-liver signal-intensity ratios after antenatal corticosteroid treatment for induction of lung maturation which most likely reflects changing properties of the fetal lung parenchyma. This could potentially be useful in non-invasively assessing the effect of antenatal corticosteroid treatment on the lungs of fetuses at risk for preterm birth.

Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke–induced chronic obstructive pulmonary disease in adult mice

ABSTRACTThe impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes.

Insulin-like Growth Factor-binding Protein-3 (IGFBP-3) Blocks the Effects of Asthma by Negatively Regulating NF-κB Signaling through IGFBP-3R-mediated Activation of Caspases

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein known for modulating mitogenic and metabolic actions of IGFs as well as exerting a variety of biological actions not involving IGFs. Here, we show that IGFBP-3 blocks specific physiological consequences of asthma in an IGF-independent manner in vitro and in vivo. IGFBP-3 treatment effectively reduced all physiological manifestations of asthma examined in vivo (airway hyper-responsiveness, cellular and pathological changes in bronchoalveolar lavage fluid and lung tissue, and expression of numerous proinflammatory molecules). These unique IGFBP-3 effects were further confirmed in IGFBP-3-transgenic mice, thus strengthening the notion of IGFBP-3 actions within the respiratory system. Using human epithelial cells, we demonstrated the following: 1) IGFBP-3 blocks TNF-α-induced expression of proinflammatory molecules; 2) IGFBP-3 attenuates the TNF-α-induced migratory response of eosinophils; and 3) IGFBP-3 negatively regulates TNF-α-induced expression of the key NF-κB regulatory molecules IκBα and p65-NF-κB at the post-translational level. We identified that IGFBP-3 degrades IκBα and p65-NF-κB proteins through IGFBP-3 receptor (IGFBP-3R)-mediated activation of caspases thereby inhibiting TNF-α-induced activation of NF-κB signaling cascades. This unique IGFBP-3/IGFBP-3R action was further confirmed by demonstrating complete inhibition of IGFBP-3 action in the presence of caspase inhibitors as well as IGFBP-3R siRNAs. Non-IGF-binding IGFBP-3 mutants further proved the IGF-independent action of IGFBP-3. Our findings indicate that IGFBP-3 inhibits airway inflammation and hyper-responsiveness via an IGF-independent mechanism that involves activation of IGFBP-3R signaling and cross-talk with NF-κB signaling. The IGFBP-3/IGFBP-3R system therefore plays a pivotal role in the pathogenesis of asthma and can serve as a newly identified potential therapeutic target for this debilitating disease.

Prospective Respiratory Gated Carbon Nanotube Micro Computed Tomography

Challenges remain in the imaging of the lungs of free-breathing mice. Although computed tomographic (CT) imaging is near optimal from a contrast perspective, the rapid respiration rate, limited temporal resolution, and inflexible x-ray pulse control of most micro-CT scanners limit their utility in pulmonary imaging. Carbon nanotubes (CNTs) have permitted the development of field emission cathodes, with rapid switching and precise pulse control. The goal of this study was to explore the utility of a CNT-based micro-CT system for application in quantitative pulmonary imaging. Twelve CB57/B6 mice were imaged during peak inspiration and end-exhalation using the CNT micro-CT system. The respiratory trace was derived from a sensor placed underneath the abdomen of the animal. Animals were allowed to breathe freely during the imaging under isoflurane anesthesia. Images were reconstructed using isotropic voxels of 77-μm resolution (50 kVp, 400 projections, 30-ms x-ray pulse). Lung volumes were measured with region-growing techniques and thresholds derived from the surrounding air and soft tissues. Basic functional parameters, including tidal volume, functional reserve capacity and minute volume, were also calculated. The average scan time was 13.4 ± 1.8 minutes for each phase of the respiratory cycle. Mean lung volumes at peak inspiration and end-expiration were 0.23 ± 0.026 and 0.11 ± 0.024 mL, respectively. The average minute volume was 11.93 ± 2.64 mL/min. The results of this study demonstrate the utility of a CNT-based micro-CT system in acquiring prospectively gated images from free-breathing mice for obtaining physiologic data. This technique provides an alternative to breath-hold techniques requiring intubation and offers greater dose efficiency than retrospective gating techniques.

Longitudinal measures of lung function in infants with bronchopulmonary dysplasia

We previously demonstrated that infants with a history of bronchopulmonary dysplasia (BPD) exhibit airflow obstruction and air trapping. The purpose of this study was to assess longitudinal changes in pulmonary function in infants with a history of BPD over the first 3 years of life, and the relationship to somatic growth. Spirometry was measured using the raised volume rapid thoracoabdominal compression technique, and lung volumes measured by plethysmography. Eighteen infants (mean gestational age ± SD 27.3 ± 2.2 weeks, birthweight 971 ± 259 g) underwent two lung function studies. Average age at first test was 58.8 weeks. Spirometry demonstrated significant reductions in forced expiratory volume in 0.5 sec (FEV(0.5), 76.0 ± 15.9% predicted, Z-score -2.13 ± 1.69), forced expiratory flow at 75% of expired forced vital capacity (FEF(75), 54.8 ± 31.1%, -3.58 ± 2.73), and FEF(25-75) (67.8 ± 33.3%, -1.79 ± 1.76). Group mean total lung capacity (TLC) was in the low normal range (82.9 ± 13.5% predicted) and residual volume (RV)/TLC was mildly elevated (122.4 ± 38.2% predicted). Repeat testing was performed an average of 32.7 weeks after initial testing. At re-evaluation, group mean lung volumes and flows tracked at or near their previous values; thus, in general, there was a lack of catch-up growth. However, compared to infants with below average or average somatic growth (as represented by g/day), infants with above average growth showed significantly greater improvements in percent predicted FVC, FEV(0.5), TLC, and RV/TLC (all P < 0.05, ANOVA). We conclude that longitudinal measures of pulmonary function in infants and young children with BPD demonstrate significant airflow obstruction and modest restriction, which tends to persist with time. On the other hand, infants with above average somatic growth showed greater lung growth than their peers. Additional studies examining the effects of various nutritional regimens on lung function are warranted.

Assessment of air space size and surface area

LETTERS TO THE EDITORAssessment of air space size and surface areaB. Lande, and W. MitznerB. LandeDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and W. MitznerDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MarylandPublished Online:01 Mar 2010https://doi.org/10.1152/japplphysiol.00006.2010MoreSectionsPDF (26 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations to the editor: Dr. Knudsen and colleagues (1) are to be congratulated for a very important paper, comparing two different approaches for quantifying air space chord lengths in fixed lungs. The ability to make these measurements in an unbiased manner is very important in assessing pathological changes in emphysema models. The paper also highlights the relation between mean air space chord length (Lm; with either method) and lung volume, which is often overlooked by many investigators. However, with regard to this latter point, there is an issue in the data that is not entirely clear. In the rabbit model, the lung is inflated such that the lung air volume at 80% of total lung capacity (D80) is increased by a factor of 2 compared with that at 40% of total lung capacity (D40) (Table 1, 72 vs. 36 ml). Such a doubling of volume would be consistent with a ≈25% increase in any linear dimension of similar structures. However, the reported measurements of Lm show increases of 80% with the direct method and 64% with the indirect method. Thinking in the other direction, an 80% increase in linear dimension would be consistent with over a fivefold increase in air volume, but this is not even close to what was measured. It is not clear what accounts for this large discrepancy, but it clearly will also lead to a substantial underestimate of the calculated internal surface area. Since the surface area calculation assumes a similar shape, perhaps the shifting volume between alveoli and ducts observed contributes to an error of this magnitude. However, a similar error is present in the treated and untreated surfactant protein-D null mice, which show a smaller change in duct/alveoli partitioning. We hope that the authors may be able to clarify why there is such a discrepancy between the Lm and lung volume measurements, and when it is appropriate to use Eq. 1 [Lm = 4·(V/S), where V/S is volume-to-surface ratio] to calculate surface area in other experimental models with pathophysiological changes in the lung parenchyma. If the surface area calculation is so exquisitely sensitive to the duct/alveoli partitioning, then is it still useful to use it as a reliable index of pathological changes in structure?REFERENCE1. Knudsen L, Weibel ER, Gundersen HJ, Weinstein FV, Ochs M. Assessment of air space size characteristics by intercept (chord) measurement: an accurate and efficient stereological approach. J Appl Physiol (12 3, 2009). doi:10.1152/japplphysiol.01100.2009.ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: W. Mitzner, Dept. of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205 (e-mail: [email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Related ArticlesReply to Lande and Mitzner 01 Mar 2010Journal of Applied Physiology More from this issue > Volume 108Issue 3March 2010Pages 760-760 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00006.2010PubMed20233838History Published online 1 March 2010 Published in print 1 March 2010 Metrics