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Therapeutic Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Recovering From Murine Pulmonary Emphysema Under Cigarette Smoke Exposure.

ABSTRACT: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 10⁶ (low dose), 1 × 10⁷ (medium dose), and 3 × 10⁷ cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.

SUBMITTER: Chen XY

PROVIDER: S-EPMC8502916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on the Acute Cigarette Smoke-Induced Pulmonary Inflammation Model.

Project description:Cigarette smoke (CS) has been reported to induce oxidative stress and inflammatory process in the lungs. However, the role of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the regulation of pulmonary inflammation remains unclear. The objective of this study is to investigate the effects of hUC-MSCs on lung inflammation in the acute CS-induced pulmonary inflammation animal model. Eight-week-old male C57BL/6 mice were intravenously administered 3 × 106, 1 × 107, and 3 × 107 cells/kg of hUC-MSCs as well as normal saline alone (control) after 3 days of CS exposure. Mice exposed to high-efficiency particulate air (HEPA)-filtered room air served as the CS control group. High-dose (3 × 107 cells/kg) hUC-MSC administration significantly decreased tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) of CS-exposed mice (p < 0.05). The chemokine (CXC motif) ligand 1/keratinocyte chemoattractant (CXCL1/KC) in BALF were significantly reduced by low-dose (3 × 106 cells/kg) and high-dose (3 × 107 cells/kg) hUC-MSC (p < 0.05). Medium-dose hUC-MSC administration decreased interleukin (IL)-1β in lung of mice, and TNF-α and caspase-3 were decreased in the lung of CS-exposed mice by medium- and high-dose MSC (p < 0.05). Low-dose hUC-MSCs significantly elevated serum CXCL1/KC and IL-1β in CS-exposed mice (p < 0.05). Our results suggest that high-dose hUC-MSCs reduced pulmonary inflammation and had antiapoptotic effects in acute pulmonary inflammation.

| S-EPMC7434987 | biostudies-literature

Secretoglobin 3A2 protects lung from developing cigarette smoke-induced pulmonary emphysema.

Project description:Secretoglobin (SCGB) 3A2 is a bioactive molecule exhibiting various functions such as improving allergic airway inflammation and pulmonary fibrosis and promoting bronchial branching and proliferation during lung development. To determine if and how SCGB3A2 is involved in chronic obstructive pulmonary disease (COPD), a multifactorial disease with both airway and emphysematous lesions, a COPD mouse model was created by exposing Scgb3a2-deficient (KO), Scgb3a2-lung-specific overexpressing (TG), and wild type (WT) mice to cigarette smoke (CS) for 6 months. The KO mice showed loss of lung structure under control condition, and CS exposure resulted in more expansion of airspace and destruction of alveolar wall than WT mouse lungs. In contrast, TG mouse lungs showed no significant changes after CS exposure. SCGB3A2 increased the expression and phosphorylation of signal transducers and activators of transcription (STAT)1 and STAT3, and the expression of α1-antitrypsin (A1AT) in mouse lung fibroblast-derived MLg cells and mouse lung epithelial-derived MLE-15 cells. In MLg cells, A1AT expression was decreased in Stat3-knockdown cells, and increased upon Stat3 overexpression. STAT3 formed a homodimer when cells were stimulated with SCGB3A2. Chromatin immunoprecipitation and reporter assays demonstrated that STAT3 binds to specific binding sites on the Serpina1a gene encoding A1AT and upregulates its transcription in lung tissues of mice. Furthermore, nuclear localization of phosphorylated STAT3 upon SCGB3A2 stimulation was detected by immunocytochemistry. These findings demonstrate that SCGB3A2 protects the lungs from the development of CS-induced emphysema by regulating A1AT expression through STAT3 signaling.

| S-EPMC10118454 | biostudies-literature

Pulmonary epithelial neuropilin-1 deletion enhances development of cigarette smoke-induced emphysema.

Project description:RationaleCigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development.ObjectivesWe sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS.MethodsTransgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1-deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides.Measurements and main resultsGenetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide.ConclusionsThese data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development.

| S-EPMC2742758 | biostudies-literature

Cigarette smoke-induced reduction of C1q promotes emphysema.

Project description:Alteration of innate immune cells in the lungs can promote loss of peripheral tolerance that leads to autoimmune responses in cigarette smokers. Development of autoimmunity in smokers with emphysema is also strongly linked to the expansion of autoreactive T helper (Th) cells expressing interferon gamma (Th1), and interleukin 17A (Th17). However, the mechanisms responsible for enhanced self-recognition and reduced immune tolerance in smoker with emphysema remain less clear. Here we show that C1q, a component of the complement protein 1 complex (C1), is downregulated in lung CD1a+ antigen presenting cells (APCs) isolated from emphysematous human, and mouse lung APCs after chronic cigarette smoke exposure. C1q potentiated the function of APCs to differentiate CD4+ T cells to Tregs, while it inhibited Th17 cell development and proliferation. Mice deficient in C1q that were exposed to chronic smoke exhibited exaggerated lung inflammation marked by increased Th17 cells, while reconstitution of C1q in the lungs enhanced Tregs abundance, dampened smoke-induced lung inflammation, and reversed established emphysema. Our findings demonstrate that cigarette smoke-mediated loss of C1q could play a key role in reduced peripheral tolerance, which could be explored to treat emphysema.

| S-EPMC6629245 | biostudies-other

Correlation of Cigarette Smoke-Induced Pulmonary Inflammation and Emphysema in C3H and C57Bl/6 Mice.

Project description:Cigarette smoke (CS)-exposed mice have been used to model airway inflammation and emphesema in humans; however, the impact of exposure duration, sex, and strain differences in susceptibility to progression of airway inflammation and to emphesema are poorly investigated. This study was designed to determine the association between inflammation and emphysema by exposing 2 strains of mice, C3H/HeN (C3H) and C57BL/6 (Bl/6), to filtered air (FA) or CS for 10, 16, or 22 weeks. Both genders and strains of CS-exposed mice developed pulmonary inflammation as characterized by cell counts in the bronchoalveolar lavage fluid (BALF) and the levels of matrix metalloproteinases (MMPs) in the BALF. CS exposure caused persistently higher number of BALF macrophages in C3H compared to BL/6 mice, while more BALF neutrophils and persistently higher MMP-2 and MMP-9 levels were observed in BL/6 mice. The mean linear intercept (Lm) increased progressively by 26%, 33%, and 55% at 10, 16, and 22 weeks, respectively, in CS-exposed C3H mice compared to the matched air controls. In BL/6 mice, although CS exposure also increased the Lm compared to FA controls, no further increase in Lm beyond the levels observed at 16 weeks of exposure was observed by 22 weeks. These findings suggest that extent of inflammation is not associated with severity of emphysema and underscores the importance of carefully selecting the mouse strains and endpoints when exploring effective treatments for emphesema.

| S-EPMC4830240 | biostudies-literature

Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways.

Project description:Although cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6 and NZW/LacJ) and two genetic models with mutations in COPD genome-wide association study genes (HHIP and FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene expression patterns that correlate with severity of emphysema in murine and human lungs. Xenobiotic metabolism and nuclear erythroid 2-related factor 2-mediated oxidative stress response were commonly regulated molecular response patterns in C57BL/6, Hhip+/-, and Fam13a-/- murine strains exposed chronically to CS. The CS-resistant Fam13a-/- mouse and NZW/LacJ strain revealed gene expression response pattern differences. The Fam13a-/- strain diverged in gene expression compared with C57BL/6 control only after CS exposure. However, the NZW/LacJ strain had a unique baseline expression pattern, enriched for nuclear erythroid 2-related factor 2-mediated oxidative stress response and xenobiotic metabolism, and converged to a gene expression pattern similar to the more susceptible wild-type C57BL/6 after CS exposure. These results suggest that distinct molecular pathways may account for resistance to emphysema. Surprisingly, there were few genes commonly modulated in mice and humans. Our study suggests that gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS.

| S-EPMC5516276 | biostudies-literature

Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema.

Project description:The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

| S-EPMC3934169 | biostudies-literature

The role of NOXO1 in the mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

Project description:NOXO1 KO mice seem to be protected from cigarette smoke-induced emphysema and pulmonary hypertension. Since the molecular mechanisms are not clear yet, this microarray experiment should help to identify the molecular differences in these KO mice compared to the wild-type (WT), figuring out how the protection occurs. Since we believe that vascular altertions could not only be responsible for vascular remodeling but also the trigger for emphysema development, we microdissected pre-capillary vessels from WT and KO mice, both controls and smoke-exposed. In addition, alveolar septa were microdissected to investigate the alveolar changes.

2020-03-01 | GSE112287 | GEO

Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema.

Project description:Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke-induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress-dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-kappaB (NF-kappaB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-kappaB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke-induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury.

| S-EPMC3956129 | biostudies-literature

Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice.

Project description:RationaleChronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both.MethodsC57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted.ResultsPreventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages.ConclusionCigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice.

| S-EPMC4461257 | biostudies-literature

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