scholarly journals A human disease model of SARS-CoV-2-induced lung injury and immune responses with a microengineered organ chip

2020 ◽  
Author(s):  
Min Zhang ◽  
Peng Wang ◽  
Ronghua Luo ◽  
Yaqing Wang ◽  
Zhongyu Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lung Injury ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Human Disease ◽  
Disease Model ◽  
Transcriptional Analysis ◽  
Type I ◽  
Organ Level

AbstractCoronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that seriously endangers human health. There is an urgent need to build physiological relevant human models for deep understanding the complex organ-level disease processes and facilitating effective therapeutics for COVID-19. Here, we first report the use of microengineered alveolus chip to create a human disease model of lung injury and immune responses induced by native SARS-CoV-2 at organ-level. This biomimetic system is able to reconstitute the key features of human alveolar-capillary barrier by co-culture of alveolar epithelial and microvascular endothelial cells under microfluidic flow. The epithelial cells on chip showed higher susceptibility to SARS-CoV-2 infection than endothelial cells identified by viral spike protein expression. Transcriptional analysis showed distinct responses of two cell types to SARS-CoV-2 infection, including activated type I interferon (IFN-I) signaling pathway in epithelium and activated JAK-STAT signaling pathway in endothelium. Notably, in the presence of circulating immune cells, a series of alveolar pathological changes were observed, including the detachment of endothelial cells, recruitment of immune cells, and increased production of inflammatory cytokines (IL-6, IL-8, IL-1β and TNF-α). These new findings revealed a crucial role of immune cells in mediating lung injury and exacerbated inflammation. Treatment with antiviral compound remdesivir could suppress viral copy and alleviate the disruption of alveolar barrier integrity induced by viral infection. This bioengineered human organ chip system can closely mirror human-relevant lung pathogenesis and immune responses to SARS-CoV-2 infection, not possible by other in vitro models, which provides a promising and alternative platform for COVID-19 research and preclinical trials.

scholarly journals Biomimetic Human Disease Model of SARS‐CoV‐2‐Induced Lung Injury and Immune Responses on Organ Chip System

2020 ◽  
pp. 2002928
Author(s):  
Min Zhang ◽  
Peng Wang ◽  
Ronghua Luo ◽  
Yaqing Wang ◽  
Zhongyu Li ◽  
...  
Keyword(s):  
Lung Injury ◽  
Immune Responses ◽  
Human Disease ◽  
Disease Model

Pathological Alternations of Mediastinal Fat-Associated Lymphoid Cluster and Lung in a Streptozotocin-Induced Diabetic Mouse Model

2020 ◽  
pp. 1-14
Author(s):  
Yaser H.A. Elewa ◽  
Osamu Ichii ◽  
Teppei Nakamura ◽  
Yasuhiro Kon
Keyword(s):  
Endothelial Cells ◽  
Lung Injury ◽  
Mouse Model ◽  
Immune Cells ◽  
Inflammatory Markers ◽  
Inflammatory Marker ◽  
Diabetic Mouse ◽  
Control Group ◽  
Injury Progression

Diabetes is a devastating global health problem and is considered a predisposing factor for lung injury progression. Furthermore, previous reports of the authors revealed the role of mediastinal fat-associated lymphoid clusters (MFALCs) in advancing respiratory diseases. However, no reports concerning the role of MFALCs on the development of lung injury in diabetes have been published. Therefore, this study aimed to examine the correlations between diabetes and the development of MFALCs and the progression of lung injury in a streptozotocin-induced diabetic mouse model. Furthermore, immunohistochemical analysis for immune cells (CD3+ T-lymphocytes, B220+ B-lymphocytes, Iba1+ macrophages, and Gr1+ granulocytes), vessels markers (CD31+ endothelial cells and LYVE-1+ lymphatic vessels “LVs”), and inflammatory markers (TNF-α and IL-5) was performed. In comparison to the control group, the diabetic group showed lung injury development with a significant increase in MFALC size, immune cells, LVs, and inflammatory marker, and a considerable decrease of CD31+ endothelial cells in both lung and MFALCs was observed. Furthermore, the blood glucose level showed significant positive correlations with MFALCs size, lung injury, immune cells, inflammatory markers, and LYVE-1+ LVs in lungs and MFALCs. Thus, we suggest that the development of MFALCs and LVs could contribute to lung injury progression in diabetic conditions.

Natural surfactant and hyperoxic lung injury in primates. II. Morphometric analyses

1994 ◽  
Vol 76 (3) ◽  
pp. 1002-1010 ◽  
Author(s):  
P. J. Fracica ◽  
S. P. Caminiti ◽  
C. A. Piantadosi ◽  
F. G. Duhaylongsod ◽  
J. D. Crapo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Type I ◽  
Fibroblast Proliferation ◽  
Surfactant Treatment ◽  
Natural Surfactant ◽  
Hyperoxic Lung Injury ◽  
Diffuse Lung

Diffuse lung injury is accompanied by low compliance and hypoxemia with histological evidence of endothelial and alveolar epithelial cell disruption. The histological effects of treatment of an acute diffuse lung injury with a natural surfactant product were evaluated in a primate model because surfactant function and content have been shown to be abnormal in diffuse lung injury in both animals and humans. Ten baboons were ventilated with 100% O2 for 96 h, and 5 were given an aerosol of natural porcine surfactant. Physiological and biochemical measurements of the effects of hyperoxia and surfactant treatment are presented in a companion paper. After O2 exposure, lungs were fixed and processed for quantitative electron microscopy. The responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. The hyperoxic animals treated with surfactant were compared with the untreated animals; the treatments altered neutrophil distribution, fibroblast proliferation, and changes in the volumes of type I epithelial cells and endothelial cells. Surfactant-treated animals also had decreased lamellar body volume density in type II epithelial cells and preservation of endothelial cell integrity. These changes suggest complex effects of natural surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction as well as significant interstitial inflammation and fibroblast proliferation. We conclude that natural surfactant treatment of hyperoxic lung injury in primates resulted in partial protection of epithelial and endothelial cells but also increased the accumulation of fibroblasts in the lung.

scholarly journals Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Ning Na ◽  
Daqiang Zhao ◽  
Jinhua Zhang ◽  
Jiaqing Wu ◽  
Bin Miao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Akt Signaling ◽  
Control Group ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Allograft Survival ◽  
Kidney Allograft

Abstract Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4+ T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

scholarly journals Signaling Pathways Implicated in Carbon Nanotube-Induced Lung Inflammation

2020 ◽  
Vol 11 ◽  
Author(s):  
Jie Dong
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Lung Inflammation ◽  
Lung Diseases ◽  
Human Lung ◽  
Disease Model ◽  
Tissue Response ◽  
Commercial Applications

Inflammation is a tissue response to a variety of harmful stimuli, such as pathogens, irritants, and injuries, and can eliminate insults and limit tissue damage. However, dysregulated inflammation is recognized as a cause of many human diseases, exemplified by organ fibrosis and cancer. In this regard, inflammation-promoted fibrosis is commonly observed in human lung diseases, such as idiopathic pulmonary fibrosis and pneumoconiosis. Carbon nanotubes (CNTs) are a type of nanomaterials with unique properties and various industrial and commercial applications. On the other hand, certain forms of CNTs are potent inducers of inflammation and fibrosis in animal lungs. Notably, acute inflammation is a remarkable phenotype elicited by CNTs in the lung during the early acute phase post-exposure; whereas a type 2 immune response is evidently activated and dominates during the late acute and chronic phases, leading to type 2 inflammation and lung fibrosis. Numerous studies demonstrate that these immune responses involve distinct immune cells, various pathologic factors, and specific functions and play crucial roles in the initiation and progression of inflammation and fibrosis in the lung exposed to CNTs. Thus, the mechanistic understanding of the immune responses activated by CNTs has drawn great attention in recent years. This article reviews the major findings on the cell signaling pathways that are activated in immune cells and exert functions in promoting immune responses in CNT-exposed lungs, which would provide new insights into the understanding of CNT-induced lung inflammation and inflammation-driven fibrosis, the application of CNT-induced lung inflammation and fibrosis as a new disease model, and the potential of targeting immune cells as a therapeutic strategy for relevant human lung diseases.

scholarly journals Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans

2011 ◽  
Vol 208 (12) ◽  
pp. 2357-2366 ◽  
Author(s):  
Marina Caskey ◽  
François Lefebvre ◽  
Abdelali Filali-Mouhim ◽  
Mark J. Cameron ◽  
Jean-Philippe Goulet ◽  
...  
Keyword(s):  
Immune Responses ◽  
Subcutaneous Administration ◽  
Innate Immune ◽  
Transcriptional Analysis ◽  
Yellow Fever Vaccine ◽  
Type I ◽  
Innate Immune Responses ◽  
Double Stranded Rna ◽  
Viral Vaccine ◽  
Immune Pathways

Adjuvants are critical for the success of vaccines. Agonists of microbial pattern recognition receptors (PRRs) are promising new adjuvant candidates. A mechanism through which adjuvants enhance immune responses is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double-stranded RNA (polyinosinic:polycytidylic acid [poly IC] stabilized with poly-l-lysine [poly ICLC]), an agonist for toll-like receptor (TLR) 3, and the cytosolic RNA helicase MDA-5. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC, showed up-regulation of genes involved in multiple innate immune pathways in all subjects, including interferon (IFN) and inflammasome signaling. Blocking type I IFN receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate immune pathways were similarly induced in volunteers immunized with the highly efficacious yellow fever vaccine. Therefore, a chemically defined PRR agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immune responses in humans.

scholarly journals Knockdown of TFPI-Anchored Endothelial Cells Exacerbates Lipopolysaccharide-Induced Acute Lung Injury Via NF-κB Signaling Pathway

Shock ◽  
2019 ◽  
Vol 51 (2) ◽  
pp. 235-246 ◽  
Author(s):  
Bao Q. Wang ◽  
Meng Shi ◽  
Jian P. Zhang ◽  
Xie Wu ◽  
Mei J. Chang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway

scholarly journals Endoglin: An ‘Accessory’ Receptor Regulating Blood Cell Development and Inflammation

2020 ◽  
Vol 21 (23) ◽  
pp. 9247
Author(s):  
Steffen K. Meurer ◽  
Ralf Weiskirchen
Keyword(s):  
Endothelial Cells ◽  
Immune System ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Vascular Lesions ◽  
Type I ◽  
And Function ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the ‘accessory’ receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages.

scholarly journals Mint3 potentiates TLR3/4- and RIG-I–induced IFN-β expression and antiviral immune responses

2016 ◽  
Vol 113 (42) ◽  
pp. 11925-11930 ◽  
Author(s):  
Wanwan Huai ◽  
Hui Song ◽  
Zhongxia Yu ◽  
Wenwen Wang ◽  
Lihui Han ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Infection ◽  
Immune Cells ◽  
Feedback Mechanism ◽  
Type I ◽  
Tnf Receptor ◽  
Interacting Protein ◽  
Type I Ifns ◽  
Irf3 Activation ◽  
Inducible Gene

Type I IFNs (IFN-α/β) play crucial roles in the elimination of invading viruses. Multiple immune cells including macrophages recognize viral infection through a variety of pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)–like receptors, and initiate type I IFN secretion and subsequent antiviral immune responses. However, the mechanisms by which host immune cells can produce adequate amounts of type I IFNs and then eliminate viruses effectively remain to be further elucidated. In the present study, we show that munc18-1–interacting protein 3 (Mint3) expression can be markedly induced during viral infection in macrophages. Mint3 enhances TLR3/4- and RIG-I–induced IRF3 activation and IFN-β production by promoting K63-linked polyubiquitination of TNF receptor-associated factor 3 (TRAF3). Consistently, Mint3 deficiency greatly attenuated antiviral immune responses and increased viral replication. Therefore, we have identified Mint3 as a physiological positive regulator of TLR3/4 and RIG-I–induced IFN-β production and have outlined a feedback mechanism for the control of antiviral immune responses.

Sign in / Sign up

Export Citation Format

Share Document