Exosomes derived from adipose-derived stem cells alleviate cigarette smoke-induced lung inflammation and injury by inhibiting alveolar macrophages pyroptosis

Abstract Background Chronic obstructive pulmonary disease (COPD) is a frequently encountered disease condition in clinical practice mainly caused by cigarette smoke (CS). The aim of this study was to investigate the protective roles of human adipose-derived stem cells-derived exosomes (ADSCs-Exo) in CS-induced lung inflammation and injury and explore the underlying mechanism by discovering the effects of ADSCs-Exo on alveolar macrophages (AMs) pyroptosis. Methods ADSCs were isolated from human adipose tissues harvested from three healthy donors, and then ADSCs-Exo were isolated. In vivo, 24 age-matched male C57BL/6 mice were exposed to CS for 4 weeks, followed by intratracheal administration of ADSCs-Exo or phosphate buffered saline. In vitro, MH-S cells, derived from mouse AMs, were stimulated by 2% CS extract (CSE) for 24 h, followed by the treatment of ADSCs-Exo or phosphate buffered saline. Pulmonary inflammation was analyzed by detecting pro-inflammatory cells and mediators in the bronchoalveolar lavage fluid. Lung histology was assessed by hematoxylin and eosin staining. Mucus production was determined by Alcian blue-periodic acid-Schiff staining. The profile of AMs pyroptosis was evaluated by detecting the levels of pyroptosis-indicated proteins. The inflammatory response in AMs and the phagocytic activity of AMs were also investigated. Results In mice exposed to CS, the levels of pro-inflammatory cells and mediators were significantly increased, mucus production was markedly increased and lung architecture was obviously disrupted. AMs pyroptosis was elevated and AMs phagocytosis was inhibited. However, the administration of ADSCs-Exo greatly reversed these alterations caused by CS exposure. Consistently, in MH-S cells with CSE-induced properties modelling those found in COPD, the cellular inflammatory response was elevated, the pyroptotic activity was upregulated while the phagocytosis was decreased. Nonetheless, these abnormalities were remarkably alleviated by the treatment of ADSCs-Exo. Conclusions ADSCs-Exo effectively attenuate CS-induced airway mucus overproduction, lung inflammation and injury by inhibiting AMs pyroptosis. Therefore, hADSCs-Exo may be a promising cell-free therapeutic candidate for CS-induced lung inflammation and injury.

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Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

10.20944/preprints202108.0220.v2 ◽

2021 ◽

Author(s):

Shikha Sharma ◽

Qixin Wang ◽

Thivanka Muthumalage ◽

Irfan Rahman

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Cigarette Smoke ◽

Calcium Binding ◽

Lung Inflammation ◽

Inflammatory Cells ◽

Mouse Lung ◽

Control Mechanisms ◽

Histopathological Changes ◽

Mitochondrial Quality Control

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

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Inflammatory cellular response to mechanical ventilation in elastase-induced experimental emphysema: role of pre-existing alveolar macrophages infiltration

10.1101/205989 ◽

2017 ◽

Author(s):

Anahita Rouze ◽

Guillaume Voiriot ◽

Elise Guivarch ◽

Françoise Roux ◽

Jeanne Tran Van Nhieu ◽

...

Keyword(s):

Mechanical Ventilation ◽

Alveolar Macrophages ◽

Pulmonary Emphysema ◽

Lung Inflammation ◽

Cellular Response ◽

Invasive Mechanical Ventilation ◽

Inflammatory Cells ◽

Chord Length ◽

Lung Mechanics ◽

Chronic Obstructive

ABSTRACTBackgroundAn excessive pulmonary inflammatory response could explain the poor prognosis of chronic obstructive pulmonary disease (COPD) patients submitted to invasive mechanical ventilation. The aim of this study was to evaluate the response to normal tidal volume (Vt) mechanical ventilation in a murine model of pulmonary emphysema, which represents the alveolar component of COPD. In this model, two time points associated with different levels of lung inflammation but similar lung destruction, were analyzed.MethodsC57BL/6 mice received a tracheal instillation of 5 IU of porcine pancreatic elastase (Elastase mice) or the same volume of saline (Saline mice). Fourteen (D14) and 21 (D21) days after instillation, mice were anesthetized, intubated, and either mechanically ventilated (MV) with a normal Vt (8 mL/kg) or maintained on spontaneous ventilation (SV) during two hours. We analyzed respiratory mechanics, emphysema degree (mean chord length by lung histological analysis), and lung inflammation (bronchoalveolar lavage (BAL) cellularity, proportion and activation of total lung inflammatory cells by flow cytometry).ResultsAs compared with Saline mice, Elastase mice showed a similarly increased mean chord length and pulmonary compliance at D14 and D21, while BAL cellularity was comparable between groups. Lung mechanics was similarly altered during mechanical ventilation in Elastase and Saline mice. Activated alveolar macrophages CD11bmid were present in lung parenchyma in both Elastase SV mice and Elastase MV mice at D14 but were absent at D21 and in Saline mice, indicating an inflammatory state with elastase at D14 only. At D14, Elastase MV mice showed a significant increase in percentage of neutrophils concomitant with a decrease in percentage of alveolar macrophages in total lung, as compared with Elastase SV mice. Furthermore, alveolar macrophages of Elastase MV mice at D14 overexpressed Gr1, and monocytes showed a trend to overexpression of CD62L, compared with Elastase SV mice.ConclusionsIn an elastase-induced model of pulmonary emphysema, normal Vt mechanical ventilation produced an increase in the proportion of pulmonary neutrophils, and an activation of alveolar macrophages and pulmonary monocytes. This response was observed only when the emphysema model showed an underlying inflammation (D14), reflected by the presence of activated alveolar macrophages CD11bmid.

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Bone Marrow Mesenchymal Stem Cells Inhibit Lipopolysaccharide-Induced Inflammatory Reactions in Macrophages and Endothelial Cells

Mediators of Inflammation ◽

10.1155/2016/2631439 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Dequan Li ◽

Cong Wang ◽

Chuang Chi ◽

Yuanyuan Wang ◽

Jing Zhao ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Inflammatory Response ◽

Alveolar Macrophages ◽

Inflammatory Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Human Umbilical Cord ◽

Marrow Mesenchymal Stem Cells

Background. Systemic inflammatory response syndrome (SIRS) accompanied by trauma can lead to multiple organ dysfunction syndrome (MODS) and even death. Early inhibition of the inflammation is necessary for damage control. Bone marrow mesenchymal stem cells (BMSCs), as a novel therapy modality, have been shown to reduce inflammatory responses in human and animal models.Methods. In this study, we used Western blot, quantitative PCR, and enzyme-linked immunosorbent assay (ELISA) to assess the activity of BMSCs to suppress the inflammation induced by lipopolysaccharide (LPS) in human umbilical cord endothelial cells (HUVECs) and alveolar macrophages.Results. Our results demonstrated that LPS caused an inflammatory response in alveolar macrophages and HUVECs, increased permeability of HUVEC, upregulated expression of toll-like receptor (TLR) 2, TLR4, phosphorylated p65, downregulated release of IL10, and promoted release of TNF-αin both cells. Coculture with BMSCs attenuated all of these activities induced by LPS in the two tested cell types.Conclusions. Together, our results demonstrate that BMSCs dosage dependently attenuates the inflammation damage of alveolar macrophages and HUVECs induced by LPS.

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Low-Power Laser Irradiation Suppresses Inflammatory Response of Human Adipose-Derived Stem Cells by Modulating Intracellular Cyclic AMP Level and NF-κB Activity

PLoS ONE ◽

10.1371/journal.pone.0054067 ◽

2013 ◽

Vol 8 (1) ◽

pp. e54067 ◽

Cited By ~ 55

Author(s):

Jyun-Yi Wu ◽

Chia-Hsin Chen ◽

Chau-Zen Wang ◽

Mei-Ling Ho ◽

Ming-Long Yeh ◽

...

Keyword(s):

Stem Cells ◽

Cyclic Amp ◽

Inflammatory Response ◽

Low Power ◽

Laser Irradiation ◽

Adipose Derived Stem Cells ◽

Power Laser

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Epithelial Ablation of Miro1/Rhot1 GTPase Augments Lung Inflammation by Cigarette Smoke

Pathophysiology ◽

10.3390/pathophysiology28040033 ◽

2021 ◽

Vol 28 (4) ◽

pp. 501-512

Author(s):

Shikha Sharma ◽

Qixin Wang ◽

Thivanka Muthumalage ◽

Irfan Rahman

Keyword(s):

Quality Control ◽

Cigarette Smoke ◽

Inflammatory Mediators ◽

Calcium Binding ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Mitochondrial Quality Control ◽

Lung Epithelial ◽

Notable Increase

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.

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Could Arachidonic Acid-Derived Pro-Resolving Mediators Be a New Therapeutic Strategy for Asthma Therapy?

Frontiers in Immunology ◽

10.3389/fimmu.2020.580598 ◽

2020 ◽

Vol 11 ◽

Author(s):

Daniella Bianchi Reis Insuela ◽

Maximiliano Ruben Ferrero ◽

Diego de Sá Coutinho ◽

Marco Aurélio Martins ◽

Vinicius Frias Carvalho

Keyword(s):

Arachidonic Acid ◽

Inflammatory Response ◽

Lung Inflammation ◽

Clinical Investigation ◽

Inflammatory Cells ◽

Airway Epithelial ◽

Asthmatic Patients ◽

Beneficial Effects

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE2 and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ2 (15d-PGJ2) while from LOXs are the LXA4 and LXB4. In different models of asthma, PGE2, 15d-PGJ2, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts in vitro. In addition, PGE2, 15d-PGJ2, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype in vitro and in vivo. Although PGE2 and LXA4 showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE2 caused side effects, while LXA4 presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.

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