scholarly journals Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune pathways related to tissue injury

2021 ◽  
Author(s):  
Amy R Cross ◽  
Carlos de Andrea ◽  
Manuel Landecho Acha ◽  
Lucia Cerundolo ◽  
Rachel Etherington ◽  
...  
Keyword(s):  
Immune Cell ◽  
Tissue Injury ◽  
Diffuse Alveolar Damage ◽  
Lung Damage ◽  
Deconvolution Analysis ◽  
Complex Interactions ◽  
Targeted Sampling ◽  
Gene Correlation ◽  
Differential Gene ◽  
Interferon Signalling

Severe lung damage in COVID-19 is known to involve complex interactions between diverse populations of immune and stromal cells. In this study, we applied a spatial transcriptomics approach to better delineate the cells, pathways and genes responsible for promoting and perpetuating severe tissue pathology in COVID-19 pneumonitis. Guided by tissue histology and immunohistochemistry we performed a targeted sampling of dozens of regions representing a spectrum of diffuse alveolar damage from the post-mortem lung of three COVID-19 patients. Application of a combination of differential gene expression, weighted gene correlation network, pathway and spatial deconvolution analysis stratified the sampled regions into five distinct groups according to degree of alveolar damage, levels of cytotoxic inflammation and innate activation, epithelial reorganization, and fibrosis. Integrative network analysis of the identified groups revealed the presence of proliferating CD8 T and NK cells in severely damaged areas along with signatures of cytotoxicity, interferon signalling and high expression of immune cell chemoattractants (including CXCL9/10/11 and CCL2). Areas of milder damage were marked by innate immune signalling (including TLR response, IL-1, IL-6) together with signatures of antigen presentation, and fibrosis. Based on these data we present a cellular model of tissue damage in terminal COVID-19 that confirms previous observations and highlights novel opportunities for therapeutic intervention.

scholarly journals Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation

2019 ◽  
Author(s):  
Benjamin Ng ◽  
Jinrui Dong ◽  
Sivakumar Viswanathan ◽  
Anissa A. Widjaja ◽  
Bhairav S. Paleja ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Immune Cell ◽  
Tissue Injury ◽  
Inflammatory Cells ◽  
Organ Damage ◽  
Lung Damage ◽  
Lung Fibroblasts ◽  
Stromal Compartment ◽  
Erk Activation

ABSTRACTTissue injury leads to activation of resident stromal, parenchymal and immune cells to initiate reparative processes that, if unresolved, can lead to fibrosis and organ damage. The directionality of effect between fibrosis and inflammation in the lung has been a point of debate for many years. Here, we tested the hypothesis that Interleukin 11 (IL11) signaling in fibroblasts is of primary importance for pulmonary fibrosis and that this event is upstream of lung inflammation. We generated mice with loxP-flanked Il11ra1 alleles and crossed them to a Col1a2-CreERT strain to enable Il11ra1 deletion in adult fibroblasts (Il11ra1-CKO mice). Lung fibroblasts from Il11ra1-CKO mice were selectively deleted for Il11ra1 and refractory to TGFβ1 stimulation. In the mouse model of bleomycin-induced lung fibrosis, Il11ra1-CKO mice had markedly reduced pulmonary fibrosis and lesser lung damage, which was accompanied by diminished ERK activation in the stromal compartment. Bleomycin lung injury in Il11ra1-CKO mice was also associated with diminished STAT3 activation in inflammatory cells, fewer pulmonary immune cell infiltrates and almost complete inhibition of NF-kB activation. These data reveal an essential role for IL11 signaling in fibroblasts for lung fibrosis and show that inflammation in the lung can be secondary to stromal activation.

scholarly journals Staphylococcal Enterotoxin B-Induced MicroRNA-155 Targets SOCS1 To Promote Acute Inflammatory Lung Injury

2014 ◽  
Vol 82 (7) ◽  
pp. 2971-2979 ◽  
Author(s):  
Roshni Rao ◽  
Prakash Nagarkatti ◽  
Mitzi Nagarkatti
Keyword(s):  
Lung Injury ◽  
Immune Cell ◽  
Tissue Injury ◽  
Staphylococcal Enterotoxin ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Staphylococcal Enterotoxin B ◽  
Functional Link ◽  
Ifn Γ ◽  
Enterotoxin B

ABSTRACTStaphylococcal enterotoxin B (SEB) causes food poisoning in humans. It is considered a biological weapon, and inhalation can trigger lung injury and sometimes respiratory failure. Being a superantigen, SEB initiates an exaggerated inflammatory response. While the role of microRNAs (miRNAs) in immune cell activation is getting increasing recognition, their role in the regulation of inflammatory disease induced by SEB has not been studied. In this investigation, we demonstrate that exposure to SEB by inhalation results in acute inflammatory lung injury accompanied by an altered miRNA expression profile in lung-infiltrating cells. Among the miRNAs that were significantly elevated, miR-155 was the most overexpressed. Interestingly, miR-155−/−mice were protected from SEB-mediated inflammation and lung injury. Further studies revealed a functional link between SEB-induced miR-155 and proinflammatory cytokine gamma interferon (IFN-γ). Through the use of bioinformatics tools, suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ, was identified as a potential target of miR-155. While miR-155−/−mice displayed increased expression ofSocs1, the overexpression of miR-155 led to its suppression, thereby enhancing IFN-γ levels. Additionally, the inhibition of miR-155 resulted in restoredSocs1expression. Together, our data demonstrate an important role for miR-155 in promoting SEB-mediated inflammation in the lungs throughSocs1suppression and suggest that miR-155 may be an important target in preventing SEB-mediated inflammation and tissue injury.

Molecular Bases for Pharmacotherapy of COVID -19

2021 ◽  
Vol 6 (5) ◽  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Mortality Rate ◽  
Large Scale ◽  
Tissue Injury ◽  
Diffuse Alveolar Damage ◽  
New Drugs ◽  
Patient Death ◽  
Double Positive ◽  
Host Cell Membrane

The most large-scale challenge aroused at the beginning of Y2020 was the global spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus. One year after we have nearly 270 thousand confirmed cases with mortality rate 1.3% in Georgia, and almost 120 billion confirmed cases with mortality rate 2.2% worldwide. As it is known, COVID-19 is triggered by coronavirus species 2 or SARS-CoV-2, which inters in the human body by binding to the angiotensin-converting enzyme 2 (ACE2) molecule on the host cell membrane via the viral spike protein and expresses complex pathological changes in many organs linked with vascular injuries. The most severe expression of this disease exposed by microscopic examination is bilateral diffuse alveolar damage with fibroblasts exudates, indicating Acute Respiratory Distress Syndrome (ARDS). Immune system plays crucial role in tissue damage. As clinical researches showed, the number of peripheral CD4+ and CD8 + T cells were significantly reduced, while their activity was hyper-expressed as evidenced by the high proportions of HLADR (CD4 3•47%) and CD38 (CD8 39•4%) double-positive fractions. Moreover, there was identified an amplified concentration of highly pro inflammatory CCR6+ Th17 in CD4 T cells. This date explains that severe tissue injury in later stages of COVID-19 is depend on the immune system abnormalities, but not on SARS-CoV-2 direct cell destruction. In the same time the scientists and doctors found out abnormalities in coagulation function in most of the severe COVID-19 patients, which were expressed in elevation of D-Dimer level and prolongation of prothrombin time, some of whom terminated in disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT) or fatal pulmonary thromboembolism (PTE). At the later stage in some severe patients it was identified thrombocytopenia as a result of excessive platelets consuming, which significantly affected on treatment and prognosis. More than 300 drugs are used for the treatment of COVID-19 worldwide. Now, the most popular treatments include Remdesivir, Hydroxychloroquine, Betamethasone, Tocilizumab, anti HIV drugs, and convalescent plasma. In the same time, WHO supports vaccines distribution for immunization. Currently, almost 8 vaccines are approved by different countries and more than 180 vaccines are under the clinical trails. Conclusion & Significance: Up till now it is challenging problem to combat SARS-CoV-2 with not well-defined origin and inexplicable biological characteristics as well as to control a pandemic of COVID-19 with such a high R0, a long incubation period and different disease outcomes. Unfortunately, we have limited understandings of particular mechanisms running to abnormal expression of immune system and coagulation processes. In the same time, we don’t have complete picture of vasculopathy leading to the tissue injury and patient death. Therefore, it is problematic to manage SARS-CoV-2 induced processes successfully using available drugs with no significant restoring effect on the organ damages in severe COVID-19 patients. So, we need new targets and new drugs for the prophylaxes and treatment of COVID-19 even we have vaccines available.

scholarly journals Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

2020 ◽  
Author(s):  
Vikramjeet Singh ◽  
Alexander Beer ◽  
Andreas Kraus ◽  
Xiaoni Zhang ◽  
Jinhua Xue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Systemic Inflammation ◽  
Immune Cell ◽  
Risk Group ◽  
Tissue Injury ◽  
Lung Epithelial Cells ◽  
Experimental Stroke ◽  
Virus Surface ◽  
Protein Levels

AbstractBackgroundThe newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.MethodsMice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.ResultsStrikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1β in the lungs. Higher gene expression of cytokines IL-6 and IL-1β was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression.ConclusionsWe demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.HighlightsBrain tissue injury increases ACE2 levels in the lungsBrain injury induces pro-inflammatory cytokine expression in the lungsBrain injury causes parenchymal inflammation and systemic lymphopenia

scholarly journals Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

2019 ◽  
Author(s):  
Audrey Bernut ◽  
Catherine A. Loynes ◽  
R. Andres Floto ◽  
Stephen A. Renshaw
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Innate Immune ◽  
Lung Damage ◽  
Tanshinone Iia ◽  
Sterile Inflammation ◽  
Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

scholarly journals A lepidic gene signature predicts patient prognosis and sensitivity to immunotherapy in lung adenocarcinoma

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Thinh T. Nguyen ◽  
Hyun-Sung Lee ◽  
Bryan M. Burt ◽  
Jia Wu ◽  
Jianjun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Gene Expression Analysis ◽  
Immune Cell ◽  
Expression Patterns ◽  
Immune Cell Infiltration ◽  
Histological Subtypes ◽  
Genomic Features ◽  
Differential Gene

Abstract Background Lung adenocarcinoma, the most common type of lung cancer, has a high level of morphologic heterogeneity and is composed of tumor cells of multiple histological subtypes. It has been reported that immune cell infiltration significantly impacts clinical outcomes of patients with lung adenocarcinoma. However, it is unclear whether histologic subtyping can reflect the tumor immune microenvironment, and whether histologic subtyping can be applied for therapeutic stratification of the current standard of care. Methods We inferred immune cell infiltration levels using a histological subtype-specific gene expression dataset. From differential gene expression analysis between different histological subtypes, we developed two gene signatures to computationally determine the relative abundance of lepidic and solid components (denoted as the L-score and S-score, respectively) in lung adenocarcinoma samples. These signatures enabled us to investigate the relationship between histological composition and clinical outcomes in lung adenocarcinoma using previously published datasets. Results We found dramatic immunological differences among histological subtypes. Differential gene expression analysis showed that the lepidic and solid subtypes could be differentiated based on their gene expression patterns while the other subtypes shared similar gene expression patterns. Our results indicated that higher L-scores were associated with prolonged survival, and higher S-scores were associated with shortened survival. L-scores and S-scores were also correlated with global genomic features such as tumor mutation burdens and driver genomic events. Interestingly, we observed significantly decreased L-scores and increased S-scores in lung adenocarcinoma samples with EGFR gene amplification but not in samples with EGFR gene mutations. In lung cancer cell lines, we observed significant correlations between L-scores and cell sensitivity to a number of targeted drugs including EGFR inhibitors. Moreover, lung cancer patients with higher L-scores were more likely to benefit from immune checkpoint blockade therapy. Conclusions Our findings provided further insights into evaluating histology composition in lung adenocarcinoma. The established signatures reflected that lepidic and solid subtypes in lung adenocarcinoma would be associated with prognosis, genomic features, and responses to targeted therapy and immunotherapy. The signatures therefore suggested potential clinical translation in predicting patient survival and treatment responses. In addition, our framework can be applied to other types of cancer with heterogeneous histological subtypes.

scholarly journals Immunohistochemical phenotyping of T cells, granulocytes, and phagocytes in the muscle of cancer patients: association with radiologically defined muscle mass and gene expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ana Anoveros-Barrera ◽  
Amritpal S. Bhullar ◽  
Cynthia Stretch ◽  
Abha R. Dunichand-Hoedl ◽  
Karen J. B. Martins ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Muscle Fiber ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cell Populations ◽  
Cd4 Cells ◽  
Gene Correlation

Abstract Background Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients. Methods Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; μm2) and radiologically (lumbar skeletal muscle index, SMI; cm2/m2 by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort. Results T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3−CD4+ cells were identified. Muscle fiber CSA (μm2) was positively correlated (Spearman’s r = > 0.45; p = < 0.05) with the total number of T cells, CD4, and CD8 T cells and granulocytes/phagocytes. In addition, patients with the smallest SMI exhibited fewer CD8 T cells within their muscle. Consistent with this, further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively associated (Pearson’s r = ≥ 0.5; p = <0.0001) with key genes within muscle catabolic pathways for signaling (ACVR2B), ubiquitin proteasome (FOXO4, TRIM63, FBXO32, MUL1, UBC, UBB, UBE2L3), and apoptosis/autophagy (CASP8, BECN1, ATG13, SIVA1). Conclusion The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3−CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 853 ◽  
Author(s):  
Wenguang Chang ◽  
Jianxun Wang
Keyword(s):  
Noncoding Rna ◽  
Immune Cell ◽  
Tissue Injury ◽  
Recipient Cell ◽  
Poor Response ◽  
Research Area ◽  
Pancreatic Tissue ◽  
Basic Knowledge ◽  
High Blood Glucose ◽  
Glucose Levels

Diabetes belongs to a group of metabolic disorders characterized by long term high blood glucose levels due to either inadequate production of insulin (Type 1 diabetes, T1DM) or poor response of the recipient cell to insulin (Type 2 diabetes, T2DM). Organ dysfunctions are the main causes of morbidity and mortality due to high glucose levels. Understanding the mechanisms of organ crosstalk may help us improve our basic knowledge and find novel strategies to better treat the disease. Exosomes are part of a newly emerged research area and have attracted a great deal of attention for their capacity to regulate communications between cells. In conditions of diabetes, exosomes play important roles in the pathological processes in both T1DM and T2DM, such as connecting the immune cell response to pancreatic tissue injury, as well as adipocyte stimulation to insulin resistance of skeletal muscle or liver. Furthermore, in recent years, nucleic acids containing exosomes—especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)—have been shown to mainly regulate communications between organs in pathological processes of diabetes, including influencing metabolic signals and insulin signals in target tissues, affecting cell viability, and modulating inflammatory pancreatic cells. Moreover, exosome miRNAs show promise in their use as biomarkers or in treatments for diabetes and diabetic complications. Thus, this paper summarizes the recent work on exosomes related to diabetes as well as the roles of exosomal miRNAs and lncRNAs in diabetic pathology and diagnosis in order to help us better understand the exact roles of exosomes in diabetes development.

Sign in / Sign up

Export Citation Format

Share Document