Similar Datasets
Project description:Lung genes modification in elastase-induced emphysema following in utero nicotine exposure
| PRJNA704966 | ENA
Project description:Purpose: The goal of this study is to address if in utero and early life nicotine exposure can prime the offspring to be more succetible to develop emphysema in adulthood Methods: A mouse model of two hits: a prenatal hit and a later insult delivered in adulthood was used in this study. In brief, Nicotine (200 mg/L) was supplied immediately after mating and administered to the females in drinking water supplemented with 2% saccharin for the whole period of gestation and until the post-natal day 16 (nicotine group). As a control, we used drinking water with 2% saccharin (control group). Pups born from nicotine-exposed or control mothers were intranasally instilled with elastase or saline at the age of 11 weeks and sacrificed at post-elastase day (ped) 21. Lungs were collected at ped21 and laser dissected to separate the emphysematous and normal-looking tissue from elastase-instilled lungs. The RNA was then extracted and submited to RNAseq analysis. We had 6 different groups: two for saline instilled animals (normal_control_saline (C-S), normal_nicotine-saline (N-S)), and for elastase-instilled animals we had 4 groups: 2 for emphysematous regions (emphysema_ControlElastase (eC-E) and emphysema_NicotineElastase(eN-E)) and 2 for normal regions (normal_ControlElastase(nC-E) and normal_NicotineElastase(nN-E)). Results: Nicotine upregulated zero and 46 genes and downregulated 2 and 29 in saline and elastase instilled respectivelly. Elastase upregulated zero and 3 and downregulated 1 and 1 genes in controls and nicotine-pretreated samples respectively. Pathway analysis performed with differentially expressed genes due to nicotine-pretreatment in elastase instilled animals with MetaCore software (https://portal.genego.com/) (fold change of 2 or more and p<0.05) revealed downregulation of the several immune system related pathways, gamma-secretase proteolitic pathway, ubiquitin-proteasomal pathway, notch signaling pathway and others. Conclusions: Our results identify the the early nicotine exposure as an important insult that affects the proteomic signature at ped21
2022-03-09 | GSE167568 | GEO
Project description:Purpose: The goal of this study is to address if in utero and early life nicotine exposure can affect genetic profile in early ephysema Methods: A mouse model of two hits: a prenatal hit and a later insult delivered in adulthood was used in this study. In brief, Nicotine (200 mg/L) was supplied immediately after mating and administered to the females in drinking water supplemented with 2% saccharin for the whole period of gestation and until the post-natal day 16 (nicotine group). As a control, we used drinking water with 2% saccharin (control group). Pups born from nicotine-exposed or control mothers were intranasally instilled with elastase or saline at the age of 11 weeks and sacrificed at post-elastase day (ped) 3. Whole lung were collected at ped3 and total RNA was sequenced. We had 4 different groups: control_saline (C-S), control_elastase (C-E), nicotine_saline (N-S) and nicotine_elastase (N-E). ALl the groups had 3 replicas, except N-E group that had 5 different replicas. Results: At ped3 nicotine upregulated 219 and 2 and downregulated 2 and 109 genes in saline and elastase-instilled samples respectively. Elastase upregulated 723 and 439 and downregulated 116 and 77 genes in controls and nicotine-pretreated samples respectively. Pathway analysis performed with MetaCore software (https://portal.genego.com/) (fold change of 2 or more and p<0.05) revealed many identical pathway activated by elastase instillation in both controls and nicotine-pretreated samples such as the cell cycle, DNA damage and cell adhesion, but also revieled the main difference in activation of the immune system between the controls and nicotine-pretreated samples. Conclusions: Our results identify the the early nicotine exposure as an important insult that affects the proteomic signature at ped3
2022-03-09 | GSE167567 | GEO
Project description:Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease-antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.
| S-EPMC3789187 | biostudies-literature
Project description:In utero smoke exposure has been shown to have detrimental effects on lung function and to be associated with persistent wheezing and asthma in children. One potential mechanism of IUS effects could be alterations in DNA methylation, which may have life-long implications. The goal of this study was to examine the association between DNA methylation and nicotine exposure in fetal lung and placental tissue in early development; nicotine exposure in this analysis represents a likely surrogate for in-utero smoke. We performed an epigenome-wide analysis of DNA methylation in fetal lung tissue (n = 85, 41 smoke exposed (48%), 44 controls) and the corresponding placental tissue samples (n = 80, 39 smoke exposed (49%), 41 controls) using the Illumina HumanMethylation450 BeadChip array. Differential methylation analyses were conducted to evaluate the variation associated with nicotine exposure. The most significant CpG sites in the fetal lung analysis mapped to the PKP3 (P = 2.94 × 10(-03)), ANKRD33B (P = 3.12 × 10(-03)), CNTD2 (P = 4.9 × 10(-03)) and DPP10 (P = 5.43 × 10(-03)) genes. In the placental methylome, the most significant CpG sites mapped to the GTF2H2C and GTF2H2D genes (P = 2.87 × 10(-06) - 3.48 × 10(-05)). One hundred and one unique CpG sites with P-values < 0.05 were concordant between lung and placental tissue analyses. Gene Set Enrichment Analysis demonstrated enrichment of specific disorders, such as asthma and immune disorders. Our findings demonstrate an association between in utero nicotine exposure and variable DNA methylation in fetal lung and placental tissues, suggesting a role for DNA methylation variation in the fetal origins of chronic diseases.
| S-EPMC4623268 | biostudies-literature
Project description:IntroductionPulmonary emphysema is a major component of chronic obstructive pulmonary disease (COPD). Emphysema progression attributed not only to alveolar structure loss and pulmonary regeneration impairment, but also to excessive inflammatory response, proteolytic and anti-proteolytic activity imbalance, lung epithelial cells apoptosis, and abnormal lung remodeling. To ameliorate lung damage with higher efficiency in lung tissue engineering and cell therapy, pre-differentiating graft cells into more restricted cell types before transplantation could enhance their ability to anatomically and functionally integrate into damaged lung. In this study, we aimed to evaluate the regenerative and repair ability of lung alveolar epithelium in emphysema model by using lung epithelial progenitors which pre-differentiated from amniotic fluid mesenchymal stem cells (AFMSCs).MethodsPre-differentiation of eGFP-expressing AFMSCs to lung epithelial progenitor-like cells (LEPLCs) was established under a modified small airway growth media (mSAGM) for 7-day induction. Pre-differentiated AFMSCs were intratracheally injected into porcine pancreatic elastase (PPE)-induced emphysema mice at day 14, and then inflammatory-, fibrotic-, and emphysema-related indices and pathological changes were assessed at 6 weeks after PPE administration.ResultsAn optimal LEPLCs pre-differentiation condition has been achieved, which resulted in a yield of approximately 20% lung epithelial progenitors-like cells from AFMSCs in a 7-day period. In PPE-induced emphysema mice, transplantation of LEPLCs significantly improved regeneration of lung tissues through integrating into the lung alveolar structure, relieved airway inflammation, increased expression of growth factors such as vascular endothelial growth factor (VEGF), and reduced matrix metalloproteinases and lung remodeling factors when compared with mice injected with AFMSCs. Histopathologic examination observed a significant amelioration in DNA damage in alveolar cells, detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), the mean linear intercept, and the collagen deposition in the LEPLC-transplanted groups.ConclusionTransplantation of predifferentiated AFMSCs through intratracheal injection showed better alveolar regeneration and reverse elastase-induced pulmonary emphysema in PPE-induced pulmonary emphysema mice.
| S-EPMC6567664 | biostudies-literature
Project description:In a mouse model of elastase-induced emphysema, the effect of tetomilast against the emphysema development observed in C57BL/6J (C57) could be also detected in phosphodiesterase (PDE) 4D(+/+) but not in PDE4B(+/+), PDE4B(-/-), and PDE4D(-/-) mice. Based on this result, we hypothesized that the difference in the efficacy of tetomilast among these strains of mice might result from the differences in the levels of the target molecules of tetomilast other than PDE4 in each mouse strain. To test this hypothesis, we used microarrays to compare the expression levels of genes in the lungs of each mouse strain. The expression profiling by array demonstrated that the levels of cyclin-dependent kinase inhibitor 1 (CDKN1a) in PDE4B(+/+), PDE4B(-/-), and PDE4D(-/-) were higher than those in C57 and PDE4D(+/+).
2016-08-24 | GSE85962 | GEO
Project description:Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.
| S-EPMC3017437 | biostudies-other
Project description:In a mouse model of elastase-induced emphysema, the effect of tetomilast against the emphysema development observed in C57BL/6J (C57) could be also detected in phosphodiesterase (PDE) 4D(+/+) but not in PDE4B(+/+), PDE4B(-/-), and PDE4D(-/-) mice. Based on this result, we hypothesized that the difference in the efficacy of tetomilast among these strains of mice might result from the differences in the levels of the target molecules of tetomilast other than PDE4 in each mouse strain. To test this hypothesis, we used microarrays to compare the expression levels of genes in the lungs of each mouse strain. The expression profiling by array demonstrated that the levels of cyclin-dependent kinase inhibitor 1 (CDKN1a) in PDE4B(+/+), PDE4B(-/-), and PDE4D(-/-) were higher than those in C57 and PDE4D(+/+). Total RNAs were extracted from the lungs from naïve mice in each strain [C57, PDE4B(+/+), PDE4B(-/-), PDE4D(+/+), and PDE4D(-/)], and were used for microarray. In comparison with the expression levels of genes in C57, we retrieved the genes which expressed at the same levels in PDE4D(+/+), and at the different levels in PDE4B(+/+), PDE4B(-/-), and PDE4D(-/-).
2016-08-24 | E-GEOD-85962 | biostudies-arrayexpress
Project description:Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3-/- mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease.
| S-EPMC8760276 | biostudies-literature