Compensatory lung growth after bilobectomy in emphysematous rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Almeida FM
PROVIDER: S-EPMC5531597 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
Compensatory lung growth after bilobectomy in emphysematous rats.
Almeida Francine Maria FM Saraiva-Romanholo Beatriz Mangueira BM Vieira Rodolfo Paula RP Moriya Henrique Takachi HT Ligeiro-de-Oliveira Ana Paula AP Lopes Fernanda Dtqs FD Castro-Faria-Neto Hugo C HC Mauad Thais T Martins Milton Arruda MA Pazetti Rogerio R
PloS one 20170727 7
Lung volume reduction surgery (LVRS) is an option for emphysematous patients who are awaiting lung transplantation. LVRS reduces nonfunctional portions of lung tissues and favors the compensatory lung growth (CLG) of the remaining lobes. This phenomenon diminishes dyspnea and improves both the respiratory mechanics and quality of life for the patients. An animal model of elastase-induced pulmonary emphysema was used to investigate the structural and functional lung response after LVRS. Bilobecto ...[more]
Similar Datasets
Project description:In many mammals, including humans, removal of one lung (pneumonectomy) results in the compensatory growth of the remaining lung. Compensatory growth involves not only an increase in lung size, but also an increase in the number of alveoli in the peripheral lung; however, the process of compensatory neoalveolarization remains poorly understood. Here, we show that the expression of α-smooth muscle actin (SMA)-a cytoplasmic protein characteristic of myofibroblasts-is induced in the pleura following pneumonectomy. SMA induction appears to be dependent on pleural deformation (stretch) as induction is prevented by plombage or phrenic nerve transection (P < 0.001). Within 3 days of pneumonectomy, the frequency of SMA+ cells in subpleural alveolar ducts was significantly increased (P < 0.01). To determine the functional activity of these SMA+ cells, we isolated regenerating alveolar ducts by laser microdissection and analyzed individual cells using microfluidic single-cell quantitative PCR. Single cells expressing the SMA (Acta2) gene demonstrated significantly greater transcriptional activity than endothelial cells or other discrete cell populations in the alveolar duct (P < 0.05). The transcriptional activity of the Acta2+ cells, including expression of TGF signaling as well as repair-related genes, suggests that these myofibroblast-like cells contribute to compensatory lung growth.
| S-EPMC5283924 | biostudies-literature
Project description:Compensatory growth is a physiological phenomenon found in both humans and animals. However, the underlying mechanisms are unclear. In this study, for the first time, we investigated the role of microbiota in compensatory growth induced by protein restriction using a rat model. Weaned Sprague-Dawley rats were fed a low protein diet (L group), a normal protein diet (N group) and a low protein diet for 2 weeks followed by a normal protein diet (LN group). The results showed that in contrast with the inhibited growth of rats in the L group, compensatory growth was observed in the LN group. Meanwhile, rats in the LN group had increased concentrations of total short chain fatty acids, particularly butyrate, and an altered bacterial composition with modified abundances of Peptostreptococcaceae, Bifidobacteriaceae, Porphyromonadaceae and Prevotellaceae in the colonic content. Furthermore, gene expression analysis indicated that the rats that experienced compensatory growth had improved barrier function and innate immune function in the colon. Our data revealed the importance of colonic microbiota in achieving compensatory growth.
| S-EPMC5328828 | biostudies-literature
Project description:Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5-50 ?g/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 ?g/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen.
| S-EPMC5991715 | biostudies-literature
Project description:Target lung tissue selection remains a challenging task to perform for treating severe emphysema with lung volume reduction (LVR). In order to target the treatment candidate, the percentage of low attenuation volume (LAV%) representing the proportion of emphysema volume to whole lung volume is measured using computed tomography (CT) images. Although LAV% have shown to have a correlation with lung function in patients with chronic obstructive pulmonary disease (COPD), similar measurements of LAV% in whole lung or lobes may have large variations in lung function due to emphysema heterogeneity. The functional information of regional emphysema destruction is required for supporting the choice of optimal target. The purpose of this study is to develop an emphysema heterogeneity descriptor for the three-dimensional emphysematous bullae according to the size variations of emphysematous density (ED) and their spatial distribution. The second purpose is to derive a predictive model of airflow limitation based on the regional emphysema heterogeneity. Deriving the bullous representation and grouping them into four scales in the upper and lower lobes, a predictive model is computed using the linear model fitting to estimate the severity of lung function. A total of 99 subjects, 87 patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I~IV) and 12 control participants with normal lung functions (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 0.7) were evaluated. The final model was trained with stratified cross-validation on randomly selected 75% of the dataset (n = 76) and tested on the remaining dataset (n = 23). The dispersed cases of LAV% inconsistent with their lung function outcome were evaluated, and the correlation study suggests that comparing to LAV of larger bullae, the widely spread smaller bullae with equivalent LAV has a larger impact on lung function. The testing dataset has the correlation of r = -0.76 (p < 0.01) between the whole lung LAV% and FEV1/FVC, whereas using two ED % of scales and location-dependent variables to predict the emphysema-associated FEV1/FVC, the results shows their correlation of 0.82 (p < 0.001) with clinical FEV1/FVC.
| S-EPMC6930211 | biostudies-literature
Project description:Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 ?g/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2?, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.
| S-EPMC6300284 | biostudies-literature
Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how microRNA expression is altered with regional emphysema severity within the lung and how these microRNAs regulate disease-associated gene-expression networks. Results: We profiled microRNAs in different regions in the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions x 8 lungs = 64 samples). 63 microRNAs (p<0.05) were altered with regional emphysema severity as quantified by mean linear intercept (Lm). MicroRNA and gene expression data were then integrated in the same samples. A subset of microRNAs, including miR-638, miR-30c, and miR-181d, correlated with many of their predicted gene targets, suggesting a role in regulating the gene networks that underlie emphysematous lung destruction. Modulating miR-638 expression in primary human lung fibroblasts recapitulated the alterations in its targeted gene-expression network associated with emphysema progression. Pathway analysis revealed that genes involved in oxidative stress and accelerated aging were affected by miR-638 knock-down in fibroblasts. Many miR-638 gene targets in these pathways were amongst those negatively correlated with miR-638 expression in emphysematous lung tissue. Conclusions: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression associated with the oxidative stress response and aging in emphysematous lung tissue and fibroblasts.
2013-12-31 | GSE49881 | GEO
Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how microRNA expression is altered with regional emphysema severity within the lung and how these microRNAs regulate disease-associated gene-expression networks. Results: We profiled microRNAs in different regions in the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions x 8 lungs = 64 samples). 63 microRNAs (p<0.05) were altered with regional emphysema severity as quantified by mean linear intercept (Lm). MicroRNA and gene expression data were then integrated in the same samples. A subset of microRNAs, including miR-638, miR-30c, and miR-181d, correlated with many of their predicted gene targets, suggesting a role in regulating the gene networks that underlie emphysematous lung destruction. Modulating miR-638 expression in primary human lung fibroblasts recapitulated the alterations in its targeted gene-expression network associated with emphysema progression. Pathway analysis revealed that genes involved in oxidative stress and accelerated aging were affected by miR-638 knock-down in fibroblasts. Many miR-638 gene targets in these pathways were amongst those negatively correlated with miR-638 expression in emphysematous lung tissue. Conclusions: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression associated with the oxidative stress response and aging in emphysematous lung tissue and fibroblasts. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while microRNA expression was profiled in the adjacent sample from the same region using the NCode Version 3 microRNA microarrays (Invitrogen, Carlsbad, CA). After quality control 60 samples were used for the analysis.
2013-12-31 | E-GEOD-49881 | biostudies-arrayexpress
Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks. METHODS: We profiled microRNAs in different regions of the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions?×?8 lungs?=?64 samples). Regional emphysema severity was quantified by mean linear intercept. Whole genome microRNA and gene expression data were integrated in the same samples to build co-expression networks. Candidate microRNAs were perturbed in human lung fibroblasts in order to validate these networks. RESULTS: The expression levels of 63 microRNAs (P?<?0.05) were altered with regional emphysema. A subset, including miR-638, miR-30c, and miR-181d, had expression levels that were associated with those of their predicted mRNA targets. Genes correlated with these microRNAs were enriched in pathways associated with emphysema pathophysiology (for example, oxidative stress and accelerated aging). Inhibition of miR-638 expression in lung fibroblasts led to modulation of these same emphysema-related pathways. Gene targets of miR-638 in these pathways were amongst those negatively correlated with miR-638 expression in emphysema. CONCLUSIONS: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression pathways related to the oxidative stress response and aging in emphysematous lung tissue and lung fibroblasts.
| S-EPMC3971345 | biostudies-literature
Project description:To develop an "overlap syndrome (OS)" rat model by intermittent hypoxia (IH) exposure on the base of pre-existing emphysema, and to explore whether "OS" exposure results in more severe systemic inflammation, and whether the inflammation changes levels of coagulant/anticoagulant factors and oxidative stress status.Sixty Wistar rats were put into 4 groups: Control group; IH group, IH exposure; Emphysema group, smoke exposure; Overlap group, smoke exposure and IH exposure. We obtained peripheral blood for apoptosis of CD3(+)CD4(+), CD3(+)CD8(+) T lymphocytes and neutrophils, and for endothelial progenitor cell (EPC) counts. Tumor necrosis factor (TNF)-?, interleukin (IL)-6 and coagulant/anticoagulant factors [antithrombin (AT), fibrinogen (FIB), Factor VIII (FVIII) and von Willebrand factor (vWF)] were evaluated. We also obtained tissue blocks of lung, liver, pancreas, and right carotid artery for pathologic scoring and measurements of liver oxidative stress [superoxide dismutase (SOD) activity, catalase (CAT) activity and malondialdehyde (MDA) concentration].The levels of TNF-? and IL-6, CD3(+)CD4(+) T lymphocyte apoptosis, EPC counts, coagulant factors and MDA are the highest in Overlap group, the lowest in Control group, when the levels of neutrophil apoptosis, CD3(+)CD8(+) T lymphocyte apoptosis, AT, SOD and CAT are the lowest in Overlap group, the highest in Control group (all P values < 0.05).In model animals, when IH is combined with emphysema, there will be a more severe or an "overlapped" systemic/multiple organic inflammation, oxidative stress and hyper-coagulability. And the pro-inflammatory and pro-thrombotic status resulted from "OS" exposure may elicit a robust EPC mobilization, which needs further investigation.
| S-EPMC4348870 | biostudies-other
Project description:The purpose of this study was to determine how the initial distribution of elastase in mouse lungs determines the time course of tissue destruction and how structural heterogeneity at different spatial scales influences lung function. We evaluated lung function and alveolar structure in normal and emphysematous C57BL/6 mice at 2 and 21 days following orotracheal treatment with porcine pancreatic elastase (PPE). Initial distribution of elastase 1 h after treatment was assessed using red fluorescently labeled PPE (f-PPE) by laser scanning confocal microscopy. From measured input impedance of the respiratory system, the global lung compliance, and the variability of regional compliance were obtained. Lungs were fixed and equivalent airspace diameters were measured in four lobes of the right lung and three regions of the left lung. At day 2 and day 21, the mean airspace diameter of each region was significantly enlarged which was accompanied by an increased inter-regional heterogeneity. The deposition of f-PPE on day 0 was much more heterogeneous than the inter-regional diameters at both day 2 and day 21 and, at day 21, this reached statistical significance (p < 0.05). Microscale heterogeneity characterized by the overall variability of airspace diameters correlated significantly better with compliance than macroscale or inter-regional heterogeneity. Furthermore, while the spatial distribution of the inflammatory response does not seem to follow that of the elastase deposition, it correlates with the strongest regional determinant of lung function. These results may help interpret lung function decline in terms of structural deterioration in human patients with emphysema.
| S-EPMC4428081 | biostudies-other