scholarly journals DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Guo Li ◽  
Li Yuzhen ◽  
Chen Yi ◽  
Chen Xiaoxiang ◽  
Zhou Wei ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Alveolar Epithelial Cell ◽  
Disease Model ◽  
Lavage Fluid ◽  
Alveolar Epithelial ◽  
Fast Tracking ◽  
Lung Injury Model

Background. Paraquat (PQ) poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered.Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF) were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated.Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

scholarly journals IL-17 mediated macrophage polarization increased inflammatory damage in SWI-ALI models

2020 ◽  
Author(s):  
Jiayi Zhao ◽  
Jin Pu ◽  
Rong Zhang ◽  
Jian Fan ◽  
Yiping Han ◽  
...  
Keyword(s):  
Wound Healing ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Epithelial Cell ◽  
Macrophage Polarization ◽  
Alveolar Epithelial Cells ◽  
In Vitro Test ◽  
Alveolar Epithelial ◽  
Inflammatory Damage

Abstract BackgroundSeawater inhalation induced acute lung injury (SWI-ALI) is the common accident in daily naval training. To investigate the mechanism of SWI-ALI will help to improve the treatment effect. Alveolar macrophages (AM) is the majority of alveolar, also paly the key role in SWI-ALI repair. IL-17 also paly the key role in the innate immunity process.MethodIn this study, we used seawater induced the ALI in mouse model. And the lungs and serum were exacted at D1, D3, D7 and D14. The AM polarization were tested by flow cytometry. The IL-17 concentration were tested by ELISA. Then the IL-17 function were confirmed by in vitro test. The mouse alveolar epithelial cell and mouse AM were co-cultured. The test compared the wound healing effect of MAE with and without IL-17.ResultThe AM switch into M1 and IL-17A increased were found after seawater dosing. And the IL-17a supplement attenuated wound healing of alveolar epithelial cells through improve the polarization of AM were confirmed in vitro model.ConclusionThe high IL-I7 micro-environment will increased the inflammatory damage through induced macrophage polarization in acute lung injury. The IL-17 antagonists have the potential to increase clinical effect in SWI-ALI treatment.

H2O2 inhibits alveolar epithelial wound repair in vitro by induction of apoptosis

2004 ◽  
Vol 287 (2) ◽  
pp. L448-L453 ◽  
Author(s):  
Thomas Geiser ◽  
Masanobu Ishigaki ◽  
Coretta van Leer ◽  
Michael A. Matthay ◽  
V. Courtney Broaddus
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Cell Viability ◽  
Wound Repair ◽  
Wound Edge ◽  
Alveolar Epithelial ◽  
Induction Of Apoptosis

Reactive oxygen species (ROS) are released into the alveolar space and contribute to alveolar epithelial damage in patients with acute lung injury. However, the role of ROS in alveolar repair is not known. We studied the effect of ROS in our in vitro wound healing model using either human A549 alveolar epithelial cells or primary distal lung epithelial cells. We found that H2O2 inhibited alveolar epithelial repair in a concentration-dependent manner. At similar concentrations, H2O2 also induced apoptosis, an effect seen particularly at the edge of the wound, leading us to hypothesize that apoptosis contributes to H2O2-induced inhibition of wound repair. To learn the role of apoptosis, we blocked caspases with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). In the presence of H2O2, zVAD inhibited apoptosis, particularly at the wound edge and, most importantly, maintained alveolar epithelial wound repair. In H2O2-exposed cells, zVAD also maintained cell viability as judged by improved cell spreading and/or migration at the wound edge and by a more normal mitochondrial potential difference compared with cells not treated with zVAD. In conclusion, H2O2 inhibits alveolar epithelial wound repair in large part by induction of apoptosis. Inhibition of apoptosis can maintain wound repair and cell viability in the face of ROS. Inhibiting apoptosis may be a promising new approach to improve repair of the alveolar epithelium in patients with acute lung injury.

scholarly journals GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257281
Author(s):  
Silvia Speca ◽  
Caroline Dubuquoy ◽  
Christel Rousseaux ◽  
Philippe Chavatte ◽  
Pierre Desreumaux ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Lung Fibroblasts ◽  
Epithelial Cell Line ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Ppar Γ

The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.

M2 macrophages have unique transcriptomes but conditioned media does not promote profibrotic responses in lung fibroblasts or alveolar epithelial cells in vitro

2021 ◽  
Author(s):  
Elissa M Hult ◽  
Stephen James Gurczynski ◽  
Bethany B Moore
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Conditioned Media ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Alveolar Epithelial ◽  
Fibroblast Migration

Macrophages are critical regulators of pulmonary fibrosis. Their plasticity, proximity, and ability to crosstalk with structural cells of the lung make them a key cell type of interest in the regulation of lung fibrosis. Macrophages can express a variety of phenotypes which have been historically represented through an "M1-like" to "M2-like" delineation. In this classification, M1-like macrophages are proinflammatory and have increased phagocytic capacity compared to alternatively activated M2-like macrophages that are profibrotic and are associated with wound healing. Extensive evidence in the field in both patients and animal models align pulmonary fibrosis with M2 macrophages. In this paper, we performed RNAseq to fully characterize M1 vs. M2-skewed bone marrow-derived macrophages (BMDMs) and investigated the profibrotic abilities of M2 BMDM conditioned media (CM) to promote fibroblast migration, proliferation, alveolar epithelial cell (AEC) apoptosis, and mRNA expression of key fibrotic genes in both fibroblasts and in AECs. Although M2 CM-treated fibroblasts had increased migration and M2 CM-treated fibroblasts and AECs had increased expression of profibrotic proteins over M1 CM-treated cells, all differences can be attributed to M2 polarization reagents IL-4 and IL-13 also present in the CM. Collectively, these data suggest that the profibrotic effects associated with M2 macrophage CM in vitro are attributable to effects of polarization cytokines rather than additional factors secreted in response to those polarizing cytokines.

scholarly journals Blockade of endothelial, but not epithelial, cell expression of PD-L1 following severe shock attenuates the development of indirect acute lung injury in mice

2020 ◽  
Vol 318 (4) ◽  
pp. L801-L812 ◽  
Author(s):  
Shumin Xu ◽  
Qian Yang ◽  
Jianwen Bai ◽  
Tianzhu Tao ◽  
Lunxian Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Critical Role ◽  
Lavage Fluid ◽  
Protein Levels ◽  
Pulmonary Endothelial Cells ◽  
Junction Protein ◽  
Cell Expression ◽  
Intratracheal Delivery

This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post–septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1–driven pathological changes resulting from systemic stimuli such as Hem-CLP.

Sign in / Sign up

Export Citation Format

Share Document