scholarly journals A Microfluidic System to Measure Neonatal Lung Compliance Over Late Stage Development as a Functional Measure of Lung Tissue Mechanics

2020 ◽  
Vol 142 (10) ◽  
Author(s):  
Laurel E. Schappell ◽  
Daniel J. Minahan ◽  
Jason P. Gleghorn
Keyword(s):  
Lung Development ◽  
Morphological Changes ◽  
Microfluidic System ◽  
Lung Compliance ◽  
Tissue Mechanics ◽  
Neonatal Mouse ◽  
Lung Mechanics ◽  
Mouse Lung ◽  
Neonatal Lung ◽  
Functional Measure

Abstract Premature birth interrupts the development of the lung, resulting in functional deficiencies and the onset of complex pathologies, like bronchopulmonary dysplasia (BPD), that further decrease the functional capabilities of the immature lung. The dysregulation of molecular targets has been implicated in the presentation of BPD, but there is currently no method to correlate resultant morphological changes observed in tissue histology with these perturbations to differences in function throughout saccular and alveolar lung development. Lung compliance is an aggregate measure of the lung's mechanical properties that is highly sensitive to a number of molecular, cellular, and architectural characteristics, but little is known about compliance in the neonatal mouse lung due to measurement challenges. We have developed a novel method to quantify changes in lung volume and pressure to determine inspiratory and expiratory compliance throughout neonatal mouse lung development. The compliance measurements obtained were validated against compliance values from published studies using mature lungs following enzymatic degradation of the extracellular matrix (ECM). The system was then used to quantify changes in compliance that occurred over the entire span of neonatal mouse lung development. These methods fill a critically important gap connecting powerful mouse models of development and disease to measures of functional lung mechanics critical to respiration and enable insights into the genetic, molecular, and cellular underpinnings of BPD pathology to improve lung function in premature infants.

scholarly journals Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

2009 ◽  
Vol 297 (4) ◽  
pp. L641-L649 ◽  
Author(s):  
Min Yee ◽  
Patricia R. Chess ◽  
Sharon A. McGrath-Morrow ◽  
Zhengdong Wang ◽  
Robert Gelein ◽  
...  
Keyword(s):  
Lung Function ◽  
Bronchoalveolar Lavage ◽  
Protein Content ◽  
Lung Development ◽  
Lung Compliance ◽  
Lung Mechanics ◽  
Type I ◽  
Adult Mice ◽  
Epithelial Development ◽  
Surfactant Composition

Despite its potentially adverse effects on lung development and function, supplemental oxygen is often used to treat premature infants in respiratory distress. To understand how neonatal hyperoxia can permanently disrupt lung development, we previously reported increased lung compliance, greater alveolar simplification, and disrupted epithelial development in adult mice exposed to 100% inspired oxygen fraction between postnatal days 1 and 4. Here, we investigate whether oxygen-induced changes in lung function are attributable to defects in surfactant composition and activity, structural changes in alveolar development, or both. Newborn mice were exposed to room air or 40%, 60%, 80%, or 100% oxygen between postnatal days 1 and 4 and allowed to recover in room air until 8 wk of age. Lung compliance and alveolar size increased, and airway resistance, airway elastance, tissue elastance, and tissue damping decreased, in mice exposed to 60–80% oxygen; changes were even greater in mice exposed to 100% oxygen. These alterations in lung function were not associated with changes in total protein content or surfactant phospholipid composition in bronchoalveolar lavage. Moreover, surface activity and total and hydrophobic protein content were unchanged in large surfactant aggregates centrifuged from bronchoalveolar lavage compared with control. Instead, the number of type II cells progressively declined in 60–100% oxygen, whereas levels of T1α, a protein expressed by type I cells, were comparably increased in mice exposed to 40–100% oxygen. Thickened bundles of elastin fibers were also detected in alveolar walls of mice exposed to ≥60% oxygen. These findings support the hypothesis that changes in lung development, rather than surfactant activity, are the primary causes of oxygen-altered lung function in children who were exposed to oxygen as neonates. Furthermore, the disruptive effects of oxygen on epithelial development and lung mechanics are not equivalently dose dependent.

scholarly journals Lymphatic function is required prenatally for lung inflation at birth

2014 ◽  
Vol 211 (5) ◽  
pp. 815-826 ◽  
Author(s):  
Zoltán Jakus ◽  
Jason P. Gleghorn ◽  
David R. Enis ◽  
Aslihan Sen ◽  
Stephanie Chia ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Vascular Function ◽  
Lymphatic Vessels ◽  
Lung Compliance ◽  
Late Gestation ◽  
Lung Mechanics ◽  
Lymphatic Function ◽  
Lung Inflation ◽  
Neonatal Lung ◽  
Lipoprotein Complex

Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.

scholarly journals Hyperoxia-induced changes in mouse lung mechanics: forced oscillations vs. barometric plethysmography

2001 ◽  
Vol 90 (6) ◽  
pp. 2221-2230 ◽  
Author(s):  
Ferenc Peták ◽  
Walid Habre ◽  
Yves R. Donati ◽  
Zoltán Hantos ◽  
Constance Barazzone-Argiroffo
Keyword(s):  
Respiratory System ◽  
Airway Resistance ◽  
Tissue Mechanics ◽  
Lung Damage ◽  
Lung Mechanics ◽  
Forced Oscillations ◽  
Whole Body ◽  
Mouse Lung ◽  
Diffuse Lung Disease ◽  
Respiratory System Resistance

Hyperoxia-induced lung damage was investigated via airway and respiratory tissue mechanics measurements with low-frequency forced oscillations (LFOT) and analysis of spontaneous breathing indexes by barometric whole body plethysmography (WBP). WBP was performed in the unrestrained awake mice kept in room air ( n = 12) or in 100% oxygen for 24 ( n = 9), 48 ( n = 8), or 60 ( n = 9) h, and the indexes, including enhanced pause (Penh) and peak inspiratory and expiratory flows, were determined. The mice were then anesthetized, paralyzed, and mechanically ventilated. Airway resistance, respiratory system resistance at breathing frequency, and tissue damping and elastance were identified from the LFOT impedance data by model fitting. The monotonous decrease in airway resistance during hyperoxia correlated best with the increasing peak expiratory flow. Respiratory system resistance and tissue damping and elastance were unchanged up to 48 h of exposure but were markedly elevated at 60 h, with associated decreases in peak inspiratory flow. Penh was increased at 24 h and sharply elevated at 60 h. These results indicate no adverse effect of hyperoxia on the airway mechanics in mice, whereas marked parenchymal damage develops by 60 h. The inconsistent relationships between LFOT parameters and WBP indexes suggest that the changes in the latter reflect alterations in the breathing pattern rather than in the mechanical properties. It is concluded that, in the presence of diffuse lung disease, Penh is inadequate for characterization of the mechanical status of the respiratory system.

scholarly journals Loss of Thy-1 inhibits alveolar development in the newborn mouse lung

2009 ◽  
Vol 296 (5) ◽  
pp. L738-L750 ◽  
Author(s):  
Teodora Nicola ◽  
James S. Hagood ◽  
Masheika L. James ◽  
Mark W. MacEwen ◽  
Timothy A. Williams ◽  
...  
Keyword(s):  
Lung Development ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Lung Compliance ◽  
Extracellular Matrix Protein ◽  
Endothelial Cell Proliferation ◽  
Mouse Lung ◽  
Newborn Mouse ◽  
Alveolar Development

Transforming growth factor (TGF)-β mediates hypoxia-induced inhibition of alveolar development in the newborn lung. TGF-β is regulated primarily at the level of activation of latent TGF-β. Fibroblasts expressing Thy-1 (CD90) inhibit TGF-β activation. We hypothesized that loss of Thy-1 due to hypoxia may be a mechanism by which hypoxia increases TGF-β activation and that animals deficient in Thy-1 will simulate the effects of hypoxia on lung development. To determine if loss of Thy-1 occurred during hypoxia, non-transgenic (C57BL/6) wild-type (WT) mice exposed to hypoxia were evaluated for Thy-1 mRNA and protein. To determine if Thy-1 deficiency simulated hypoxia, WT and Thy-1 null ( Thy-1 −/−) mice were exposed to air or hypoxia from birth to 2 wk, the critical period of lung development, and lung histology, function, parameters related to TGF-β signaling, and extracellular matrix protein content were measured. To test if the phenotype in Thy-1 −/− mice was due to excessive TGF-β signaling, measurements were also performed in Thy-1 −/− mice administered TGF-β neutralizing antibody (1D11). We observed that hypoxia reduced Thy-1 mRNA and Thy-1 staining in WT mice. Thy-1 −/− mice had impaired alveolarization, increased TGF-β signaling, reduced lung epithelial and endothelial cell proliferation but increased fibroblast proliferation, and increased collagen and elastin. Lung compliance was lower, and tissue but not airway resistance was higher in Thy-1 −/− mice at 2 wk. Thy-1 −/− mice given 1D11 had improved alveolar development and lung function. These data support the hypothesis that hypoxia, by reducing Thy-1, increases TGF-β activation, and thereby inhibits normal alveolar development.

Lung mechanics, cellularity, and surfactant after prenatal starvation in guinea pigs

1986 ◽  
Vol 60 (5) ◽  
pp. 1610-1614 ◽  
Author(s):  
A. J. Lechner ◽  
D. C. Winston ◽  
J. E. Bauman
Keyword(s):  
Guinea Pigs ◽  
Lung Compliance ◽  
Lung Mechanics ◽  
Diffusing Capacity ◽  
Elastic Recoil ◽  
Lung Weight ◽  
Neonatal Lung ◽  
Ad Libitum ◽  
Surfactant Phospholipids ◽  
The Impact

Prenatal starvation in the guinea pig causes reduced pulmonary diffusing capacity and retarded alveolarization among neonates. To study the impact of such starvation on biochemical and mechanical properties of the neonatal lung, pregnant guinea pigs were fed ad libitum throughout gestation or starved with 50% rations during their last trimester. Neonatal body weight was 35% less due to starvation, and dry lung weight, DNA, and protein contents were decreased 26, 36, and 31%, respectively (P less than 0.001 for all). Hematological data indicated no anemia, hypoproteinemia, or altered glucocorticoid levels due to starvation. Total surfactant phospholipids in these neonates were reduced 61% in lavage and 35% in the neonatal lung tissue, although surfactant compositions were similar to controls. Specific lung compliance in the air-filled lungs was not altered, but the saline-filled lungs were more distensible over deflation pressures of 9–18 cmH2O (transpulmonary). Although starvation retarded both lung cellularity and surfactant, only that portion of lung elastic recoil attributable to tissue forces was affected.

Androgen receptor and 17β-HSD type 2 regulation in neonatal mouse lung development

2009 ◽  
Vol 311 (1-2) ◽  
pp. 109-119 ◽  
Author(s):  
Eric Boucher ◽  
Pierre R. Provost ◽  
Julie Plante ◽  
Yves Tremblay
Keyword(s):  
Androgen Receptor ◽  
Lung Development ◽  
Neonatal Mouse ◽  
Mouse Lung

Prenatal iodine deficiency results in structurally and functionally immature lungs in neonatal rats

2012 ◽  
Vol 302 (10) ◽  
pp. L1037-L1043 ◽  
Author(s):  
Madan M. Godbole ◽  
Geeta Rao ◽  
B. N. Paul ◽  
Vishwa Mohan ◽  
Preeti Singh ◽  
...  
Keyword(s):  
Drinking Water ◽  
Thyroid Hormone ◽  
Respiratory Distress ◽  
Lung Development ◽  
Thyroid Hormone Receptor ◽  
Alveolar Epithelium ◽  
Lung Compliance ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Deficient Diet

Maternal hypothyroidism affects postnatal lung structure. High prevalence of hypothyroxinemia (low T4, normal T3) in iodine-deficient pregnant women and associated risk for neuropsychological development along with high infant/neonatal mortality ascribed to respiratory distress prompted us to study the effects of maternal hypothyroxinemia on postnatal lung development. Female Sprague Dawley rats were given a low-iodine diet (LID) with 1% KClO4in drinking water for 10 days, to minimize thyroid hormone differences. Half of these rats were continued on iodine-deficient diet; ID (LID with 0.005% KClO4) for 3 mo, whereas the rest were switched to an iodine-sufficient diet; IS [LID + potassium iodide (10 μg iodine/20 g of diet + normal drinking water)]. Pups born to ID mothers were compared with age-matched pups from IS mothers at postnatal days 8 (P8) and 16 (P16) ( n = 6–8/group). ID pups had normal circulating T3 but significantly low T4 levels ( P < 0.05) and concomitantly approximately sixfold higher thyroid hormone receptor-β mRNA in alveolar epithelium. Lung histology revealed larger and irregularly shaped alveoli in ID pups relative to controls. Lung function was assessed at P16 using a double-chambered plethysmograph and observed reduced tidal volume, peak inspiratory and expiratory flow, and dynamic lung compliance in ID pups compared with IS pups. Significant lowering of surfactant protein (SP)-B and SP-C mRNA and protein found in ID pups at P16. ID pups had 16-fold lower matrix metalloproteinase-9 mRNA levels in their alveolar epithelium. In addition, mRNA levels of thyroid transcription factor-1 and SP-D were significantly higher (3-fold) compared with IS pups. At P16, significantly lower levels of SP-B and SP-C found in ID pups may be responsible for immature lung development and reduced lung compliance. Our data suggest that maternal hypothyroxinemia may result in the development of immature lungs that, through respiratory distress, could contribute to the observed high infant mortality in ID neonates.

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