Developmental signals do not further accentuate nonuniform postpneumonectomy compensatory lung growth

2007 ◽  
Vol 102 (3) ◽  
pp. 1170-1177 ◽  
Author(s):  
Priya Ravikumar ◽  
Cuneyt Yilmaz ◽  
D. Merrill Dane ◽  
Robert L. Johnson ◽  
Aaron S. Estrera ◽  
...  
Keyword(s):  
Lower Lobe ◽  
Normal Lung ◽  
Lung Growth ◽  
Growth And Remodeling ◽  
High Resolution Computed Tomography ◽  
Tissue Volume ◽  
Small Vessels ◽  
Compensatory Lung Growth ◽  
Lung Expansion ◽  
Before And After

Mechanical forces imposed on lung tissue constitute major stimuli for normal lung development and postpneumonectomy (PNX) compensatory growth and remodeling. Superimposing developmental signals on PNX signals augments compensatory alveolar growth but exaggerates airway-parenchymal dissociation (i.e., dysanaptic lung growth); the latter tends to offset benefits derived from the former. In adult dogs after PNX, lobar expansion and growth of the remaining lobes were markedly non-uniform (Ravikumar et al. J Appl Physiol 97:1567–1574, 2004). We hypothesized that superimposing developmental and post-PNX signals further accentuates nonuniformity of lobar growth. We used high-resolution computed tomography (HRCT) to follow regional lung expansion and growth in foxhounds undergoing right PNX at 2.5 mo of age compared with litter-matched control (Sham) animals; scans were performed 4 and 10 mo following surgery, i.e., before and after somatic maturity. Air and tissue volumes were measured in each lobe; tissue volume estimated by HRCT includes air-free tissue and blood in small vessels <1 mm. Interlobar nonuniformity of tissue volume was absent at 4 mo but evident 10 mo after PNX; growth of the remaining left lower lobe gradually lagged behind other lobes. At maturity, nonuniformity of lobar growth in pneumonectomized puppies was similar to that previously reported in pneumonectomized adults. We conclude that superimposing developmental and post-PNX signals enhances some aspects of compensatory lung growth and remodeling without altering its nonuniform spatial distribution.

scholarly journals Noninvasive quantification of heterogeneous lung growth following extensive lung resection by high-resolution computed tomography

2009 ◽  
Vol 107 (5) ◽  
pp. 1569-1578 ◽  
Author(s):  
Cuneyt Yilmaz ◽  
Priya Ravikumar ◽  
D. Merrill Dane ◽  
Dennis J. Bellotto ◽  
Robert L. Johnson ◽  
...  
Keyword(s):  
Computed Tomography ◽  
High Resolution ◽  
Connective Tissue ◽  
Coefficient Of Variation ◽  
Lung Resection ◽  
Lung Growth ◽  
High Resolution Computed Tomography ◽  
Extensive Resection ◽  
Compensatory Lung Growth

To quantify the in vivo magnitude and distribution of regional compensatory lung growth following extensive lung resection, we performed high-resolution computed tomography at 15- and 30-cmH2O transpulmonary pressures and measured air and tissue (including microvascular blood) volumes within and among lobes in six adult male foxhounds, before and after balanced 65% lung resection (∼32% removed from each side). Each lobe was identified from lobar fissures. Intralobar gradients in air and tissue volumes were expressed along standardized x, y, z-coordinate axes. Fractional tissue volume (FTV) was calculated as the volume ratio of tissue/(tissue + air). Following resection compared with before, lobar air and tissue volumes increased 1.8- to 3.5-fold, and whole lung air and tissue volumes were 67 and 90% of normal, respectively. Lobar-specific compliance doubled post-resection, and whole lung-specific compliance normalized. These results are consistent with vigorous compensatory growth in all remaining lobes. Compared with pre-resection, post-resection interlobar heterogeneity of FTV, assessed from the coefficient of variation, decreased at submaximal inflation, but was unchanged at maximal inflation. The coefficient of variation of intralobar FTV gradients changed variably due to the patchy development of thickened pleura and alveolar septa, with elevated alveolar septal density and connective tissue content in posterior-caudal and peripheral regions of the remaining lobes; these areas likely experienced disproportional mechanical stress. We conclude that HRCT can noninvasively and quantitatively assess the magnitude and spatial distribution of compensatory lung growth. Following extensive resection, heterogeneous regional mechanical lung strain may exceed the level that could be sustained solely by existing connective tissue elements.

The oncogeneTrop2regulates fetal lung cell proliferation

2011 ◽  
Vol 301 (4) ◽  
pp. L478-L489 ◽  
Author(s):  
Annie R. A. McDougall ◽  
Stuart B. Hooper ◽  
Valerie A. Zahra ◽  
Foula Sozo ◽  
Camden Y. Lo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fetal Lung ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Lung Growth ◽  
Ki 67 ◽  
Alveolar Epithelial ◽  
Fetal Rat ◽  
Lung Expansion

The factors regulating growth of the developing lung are poorly understood, although the degree of fetal lung expansion is critical. The oncogene Trop2 (trophoblast antigen 2) is upregulated during accelerated fetal lung growth, and we hypothesized that it may regulate normal fetal lung growth. We investigated Trop2 expression in the fetal and neonatal sheep lung during accelerated and delayed lung growth induced by alterations in fetal lung expansion, as well as in response to glucocorticoids. Trop2 expression was measured using real-time PCR and localized spatially using in situ hybridization and immunofluorescence. During normal lung development, Trop2 expression was higher at 90 days gestational age (GA; 4.0 ± 0.8) than at 128 days GA (1.0 ± 0.1), decreased to 0.5 ± 0.1 at 142 days GA (full term ∼147 days GA), and was positively correlated to lung cell proliferation rates ( r = 0.953, P < 0.005). Trop2 expression was regulated by fetal lung expansion, but not by glucocorticoids. It was increased nearly threefold by 36 h of increased fetal lung expansion ( P < 0.05) and was reduced to ∼55% of control levels by reduced fetal lung expansion ( P < 0.05). Trop2 expression was associated with lung cell proliferation during normal and altered lung growth, and the TROP2 protein colocalized with Ki-67-positive cells in the fetal lung. TROP2 was predominantly localized to fibroblasts and type II alveolar epithelial cells. Trop2 small interfering RNA decreased Trop2 expression by ∼75% in cultured fetal rat lung fibroblasts and decreased their proliferation by ∼50%. Cell viability was not affected. This study demonstrates that TROP2 regulates lung cell proliferation during development.

Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia

2006 ◽  
Vol 291 (1) ◽  
pp. L119-L127 ◽  
Author(s):  
Vivek Balasubramaniam ◽  
Anne M. Maxey ◽  
Danielle B. Morgan ◽  
Neil E. Markham ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Nodal Point ◽  
Fold Increase ◽  
Normal Lung ◽  
Lung Growth ◽  
Vascular Growth ◽  
Neonatal Hypoxia ◽  
Compensatory Lung Growth ◽  
Lung Structure ◽  
Inhaled No

We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS−/−) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide (NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS−/− mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS−/− mice during recovery. Mice (1 day old) from heterozygous (eNOS+/−) parents were placed in hypobaric hypoxia (FiO2= 0.16). After 10 days, pups were to recovered in room air (HR group) or inhaled NO (10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS−/− mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient (eNOS+/+) mice (increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS+/− was not different from eNOS+/+. Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS−/− mice that completely restored normal lung structure. eNOS+/− mice (HR group) had a 2.5-fold increase in lung vascular endothelial growth factor (VEGFR)-2 protein compared with eNOS+/+ ( P < 0.05). eNOS−/− mice (HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS−/− (HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS−/− mice.

scholarly journals Separating in vivo mechanical stimuli for postpneumonectomy compensation: physiological assessment

2013 ◽  
Vol 114 (1) ◽  
pp. 99-106 ◽  
Author(s):  
D. Merrill Dane ◽  
Cuneyt Yilmaz ◽  
Aaron S. Estrera ◽  
Connie C. W. Hsia
Keyword(s):  
Wound Healing ◽  
Lung Volume ◽  
Mechanical Stimuli ◽  
Lung Growth ◽  
Growth And Remodeling ◽  
Lung Expansion ◽  
Physiological Assessment ◽  
The Right ◽  
Sustained Increase

Following right pneumonectomy (PNX), the remaining lung expands and its perfusion doubles. Tissue and microvascular mechanical stresses are putative stimuli for initiating compensatory lung growth and remodeling, but their relative contributions to overall compensation remain uncertain. To temporally isolate the stimuli related to post-PNX lung expansion (parenchyma deformation) from those related to the sustained increase in perfusion (microvascular distention and shear), we replaced the right lung of adult dogs with a custom-shaped inflated prosthesis. Following stabilization of perfusion and wound healing 4 mo later, the prosthesis was either acutely deflated (DEF group) or kept inflated (INF group). Physiological studies were performed pre-PNX, 4 mo post-PNX (inflated prosthesis, INF1), and again 4 mo postdeflation (DEF) compared with controls with simultaneous INF prosthesis (INF2). Perfusion to the remaining lung increased ∼76–113% post-PNX (INF1 and INF2) and did not change postdeflation. Post-PNX (INF prosthesis) end-expiratory lung volume (EELV) and lung and membrane diffusing capacities (DlCO and DmCO) at a given perfusion were 25–40% below pre-PNX baseline. In the INF group EELV, DlCO and DmCO remained stable or declined slightly with time. In contrast, all of these parameters increased significantly after deflation and were 157%, 26%, and 47%, respectively, above the corresponding control values (INF2). Following delayed deflation, lung expansion accounted for 44%-48% of total post-PNX compensatory increase in exercise DlCO and peak O2 uptake; the remainder fraction is likely attributable to the increase in perfusion. Results suggest that expansion-related parenchyma mechanical stress and perfusion-related microvascular stress contribute in equal proportions to post-PNX alveolar growth and remodeling.

VDUP1: a potential mediator of expansion-induced lung growth and epithelial cell differentiation in the ovine fetus

2006 ◽  
Vol 290 (2) ◽  
pp. L250-L258 ◽  
Author(s):  
C. E. Filby ◽  
S. B. Hooper ◽  
F. Sozo ◽  
V. A. Zahra ◽  
S. J. Flecknoe ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Differentiation ◽  
Epithelial Cell ◽  
Lung Development ◽  
Fetal Lung ◽  
Normal Lung ◽  
Mrna Levels ◽  
Lung Growth ◽  
Fetal Sheep ◽  
Lung Expansion

The degree of fetal lung expansion is a critical determinant of fetal lung growth and alveolar epithelial cell (AEC) differentiation, although the mechanisms involved are unknown. As VDUP1 (vitamin D3-upregulated protein 1) can modulate cell proliferation, can induce cell differentiation, and is highly expressed in the lung, we have investigated the effects of fetal lung expansion on VDUP1 expression and its relationship to expansion-induced fetal lung growth and AEC differentiation in fetal sheep. Alterations in fetal lung expansion caused profound changes in VDUP1 mRNA levels in lung tissue. Increased fetal lung expansion significantly reduced VDUP1 mRNA levels from 100 ± 8% in control fetuses to 37 ± 4, 46 ± 4, and 45 ± 9% of control values at 2, 4, and 10 days of increased fetal lung expansion, respectively. Reduced fetal lung expansion increased VDUP1 mRNA levels from 100 ± 16% in control fetuses to 162 ± 16% of control values after 7 days. VDUP1 was localized to airway epithelium in small bronchioles, AECs, and some mesenchymal cells. Its expression was inversely correlated with cell proliferation during normal lung development ( R2 = 0.972, P < 0.002) as well as in response to alterations in fetal lung expansion ( R2 = 0.956, P < 0.001) and was positively correlated with SP-B expression during normal lung development ( R2 = 0.803, P < 0.0001) and following altered lung expansion ( R2 = 0.817, P < 0.001). We suggest that VDUP1 may be an important mediator of expansion-induced lung cell proliferation and AEC differentiation in the developing lung.

scholarly journals Radiologic evaluation using computed tomography for compensatory lung growth; a prospective comparison with histological data from a large animal model

2021 ◽  
Author(s):  
Keiji Ohata ◽  
Toyofumi F. Chen-Yoshikawa ◽  
Masatsugu Hamaji ◽  
Takeshi Kubo ◽  
Tatsuo Nakamura ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Lung Resection ◽  
Large Animal Model ◽  
Large Animal ◽  
Lung Growth ◽  
Lung Weight ◽  
Tissue Volume ◽  
Compensatory Lung Growth ◽  
Post Surgery ◽  
Ct Data

Abstract Background Non-invasive analysis using computed tomography (CT) data may be a promising candidate to evaluate neo-alveolarization in adult lungs following lung resection. This study evaluates and compares the validity of CT analysis with histologic morphometry for compensatory lung growth in a large animal model.Methods We calculated the radiologic tissue volume and the radiologic lung weight from CT data taken at 1, 3, and 6 months post-surgery on 15 male beagle dogs that had a right thoractotomy, bilobectomy, or pneumonectomy (n = 5 in each group). Results were analyzed using one-way ANOVA and were subsequently compared to histologic findings of tissue samples at 6 months post-surgery using Pearson’s correlation.Results An increase in radiologic tissue volume and radiologic lung weight was identified, which was positively correlated with histologic lung parenchymal amounts (correlation coefficient = 0.955 and 0.934, respectively, p < 0.001). Histology of lung specimens at six months post-surgery revealed an increase in the tissue amount in both Bilobectomy and Peumonectomy groups, which was consistent with compensatory lung growth.Conclusion Radiologic tissue volume and radiologic lung weight reflected compensatory lung growth following lung resection. Radiologic assessment using CT data can be a promising clinical modality to evaluate postoperative lung growth.

scholarly journals Effect of unilateral diaphragmatic paralysis on postpneumonectomy lung growth

2013 ◽  
Vol 305 (6) ◽  
pp. L439-L445 ◽  
Author(s):  
Alexandra B. Ysasi ◽  
Janeil M. Belle ◽  
Barry C. Gibney ◽  
A. V. Fedulov ◽  
Willi Wagner ◽  
...  
Keyword(s):  
Minute Ventilation ◽  
Mechanical Stretch ◽  
Activity Level ◽  
Cyclic Stretch ◽  
Normal Lung ◽  
Costal Margin ◽  
Lung Growth ◽  
Lung Weight ◽  
Compensatory Lung Growth ◽  
Diaphragmatic Muscle

Respiratory muscle-associated stretch has been implicated in normal lung development (fetal breathing movements) and postpneumonectomy lung growth. To test the hypothesis that mechanical stretch from diaphragmatic contraction contributes to lung growth, we performed left phrenic nerve transections (PNT) in mice with and without ipsilateral pneumonectomy. PNT was demonstrated by asymmetric costal margin excursion and confirmed at autopsy. In mice with two lungs, PNT was associated with a decrease in ipsilateral lung volume ( P < 0.05) and lung weight ( P < 0.05). After pneumonectomy, PNT was not associated with a change in activity level, measureable hypoxemia, or altered minute ventilation; however, microCT scanning demonstrated altered displacement and underinflation of the cardiac lobe within the first week after pneumonectomy. Coincident with the altered structural realignment, lung impedance measurements, fitted to the constant-phase model, demonstrated elevated airway resistance ( P < 0.05), but normal peripheral tissue resistance ( P > 0.05). Most important, PNT appeared to abrogate compensatory lung growth after pneumonectomy; the weight of the lobes of the right lung was significantly less than pneumonectomy alone ( P < 0.001) and indistinguishable from nonsurgical controls ( P > 0.05). We conclude that the cyclic stretch associated with diaphragmatic muscle contraction is a controlling factor in postpneumonectomy compensatory lung growth.

scholarly journals Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment

2013 ◽  
Vol 114 (8) ◽  
pp. 961-970 ◽  
Author(s):  
Priya Ravikumar ◽  
Cuneyt Yilmaz ◽  
Dennis. J. Bellotto ◽  
D. Merrill Dane ◽  
Aaron S. Estrera ◽  
...  
Keyword(s):  
Lung Volume ◽  
Ex Vivo ◽  
Left Lung ◽  
Mechanical Stimuli ◽  
Growth And Remodeling ◽  
High Resolution Computed Tomography ◽  
Surface Areas ◽  
Lung Expansion ◽  
Alveolar Tissue

Following right pneumonectomy (PNX), the remaining lung expands and its perfusion more than doubles. Tissue and microvascular mechanical stresses are putative stimuli for compensatory lung growth and remodeling, but their relative contribution remains uncertain. To temporally separate expansion- and perfusion-related stimuli, we replaced the right lung of adult dogs with a customized inflated prosthesis. Four months later, the prosthesis was either acutely deflated (DEF) or kept inflated (INF). Thoracic high-resolution computed tomography (HRCT) was performed pre- and post-PNX before and after prosthesis deflation. Lungs were fixed for morphometric analysis ∼12 mo post-PNX. The INF prosthesis prevented mediastinal shift and lateral lung expansion while allowing the remaining lung to expand 27–38% via caudal elongation, associated with reversible capillary congestion in dependent regions at low inflation and 40–60% increases in the volumes of alveolar sepal cells, matrix, and fibers. Delayed prosthesis deflation led to further significant increases in lung volume, alveolar tissue volumes, and alveolar-capillary surface areas. At postmortem, alveolar tissue volumes were 33% higher in the DEF than the INF group. Lateral expansion explains ∼65% of the total post-PNX increase in left lung volume assessed in vivo or ex vivo, ∼36% of the increase in HRCT-derived (tissue + microvascular blood) volume, ∼45% of the increase in ex vivo septal extravascular tissue volume, and 60% of the increase in gas exchange surface areas. This partition agrees with independent physiological measurements obtained in these animals. We conclude that in vivo signals related to lung expansion and perfusion contribute separately and nearly equally to post-PNX growth and remodeling.

scholarly journals Functional effect of longitudinal heterogeneity in constricted airways before and after lung expansion

2012 ◽  
Vol 112 (1) ◽  
pp. 237-245 ◽  
Author(s):  
C. Wongviriyawong ◽  
R. S. Harris ◽  
H. Zheng ◽  
M. Kone ◽  
T. Winkler ◽  
...  
Keyword(s):  
Lung Volume ◽  
Total Lung Capacity ◽  
Cross Sectional Area ◽  
Cylindrical Shape ◽  
Sectional Area ◽  
High Resolution Computed Tomography ◽  
Cross Sectional ◽  
Lung Capacity ◽  
Lung Expansion ◽  
Before And After

Heterogeneity in narrowing among individual airways is an important contributor to airway hyperresponsiveness. This paper investigates the contribution of longitudinal heterogeneity (the variability along the airway in cross-sectional area and shape) to airway resistance ( Raw). We analyzed chest high-resolution computed tomography scans of 8 asthmatic (AS) and 9 nonasthmatic (NA) subjects before and after methacholine (MCh) challenge, and after lung expansion to total lung capacity. In each subject, Raw was calculated for 35 defined central airways with >2 mm diameter. Ignoring the area variability and noncircular shape results in an underestimation of Raw (%Utotal) that was substantial in some airways (∼50%) but generally small (median <6%). The average contribution of the underestimation of Raw caused by longitudinal heterogeneity in the area (%Uarea) to %Utotal was 36%, while the rest was due to the noncircularity of the shape (%Ushape). After MCh challenge, %Uarea increased in AS and NA ( P < 0.05). A lung volume increase to TLC reduced %Utotal and %Uarea in both AS and NA ( P < 0.0001, except for %Utotal in AS with P < 0.01). Only in NA, %Ushape had a significant reduction after increasing lung volume to TLC ( P < 0.005). %Uarea was highly correlated, but not identical to the mean-normalized longitudinal heterogeneity in the cross-sectional area [CV2( A)] and %Ushape to the average eccentricity of the elliptical shape. This study demonstrates that Raw calculated assuming a cylindrical shape and derived from an average area along its length may, in some airways, substantially underestimate Raw. The observed changes in underestimations of Raw with the increase in lung volume to total lung capacity may be consistent with, and contribute in part to, the differences in effects of deep inhalations in airway function between AS and NA subjects.

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