scholarly journals Single Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis

2020 ◽  
Author(s):  
Jonas C. Schupp ◽  
Sara Khanal ◽  
Jose L. Gomez ◽  
Maor Sauler ◽  
Taylor S. Adams ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Single Cell ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Chloride Transport ◽  
Immune Dysfunction ◽  
Mononuclear Phagocytes ◽  
Activated Monocytes

AbstractCystic fibrosis (CF) is a life-shortening multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction that perpetuates inflammation. The airways provide a window into CF pathogenesis, as immune cells display exaggerated inflammatory responses and impaired phagocytic function, contributing to tissue injury. In order to define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum. We show that the airway immune cell repertoire shifted from alveolar macrophages in HC to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF, separated into three archetypes: activated monocytes, monocyte-derived macrophages, and heat-shock activated monocytes. Neutrophils were most prevalent in CF, with a dominant immature proinflammatory archetype. While CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs. Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress towards personalized applications of therapeutic and genomic developments, we hope this inflammation profiling approach will enable further discoveries that change the natural history of CF lung disease.

scholarly journals Single-Cell Protein and RNA Expression Analysis of Mononuclear Phagocytes in Intestinal Mucosa and Mesenteric Lymph Nodes of Ulcerative Colitis and Crohn’s Disease Patients

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 813
Author(s):  
Laurence Chapuy ◽  
Marika Sarfati
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Single Cell ◽  
Immune Cell ◽  
Mononuclear Phagocytes ◽  
Cell Protein ◽  
Lymphoid Tissues ◽  
Intermediate Cell ◽  
And Function

Inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are driven by an abnormal immune response to commensal microbiota in genetically susceptible hosts. In addition to epithelial and stromal cells, innate and adaptive immune systems are both involved in IBD immunopathogenesis. Given the advances driven by single-cell technologies, we here reviewed the immune landscape and function of mononuclear phagocytes in inflamed non-lymphoid and lymphoid tissues of CD and UC patients. Immune cell profiling of IBD tissues using scRNA sequencing combined with multi-color cytometry analysis identifies unique clusters of monocyte-like cells, macrophages, and dendritic cells. These clusters reflect either distinct cell lineages (nature), or distinct or intermediate cell types with identical ontogeny, adapting their phenotype and function to the surrounding milieu (nurture and tissue imprinting). These advanced technologies will provide an unprecedented view of immune cell networks in health and disease, and thus may offer a personalized medicine approach to patients with IBD.

ClC-5: ontogeny of an alternative chloride channel in respiratory epithelia

2002 ◽  
Vol 282 (3) ◽  
pp. L501-L507 ◽  
Author(s):  
Rebecca D. Edmonds ◽  
Ian V. Silva ◽  
William B. Guggino ◽  
Robert B. Butler ◽  
Pamela L. Zeitlin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Chloride Transport ◽  
Premature Death ◽  
Fetal Lung ◽  
Chloride Secretion ◽  
Normal Lung ◽  
Ribonuclease Protection Assay

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.

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 Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Benjamin Wilde ◽  
Antonios Katsounas
Keyword(s):  
Liver Cirrhosis ◽  
Systemic Inflammation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Significant Risk ◽  
Kidney Injury ◽  
Immune Dysfunction ◽  
Developed Countries ◽  
Bacterial Peritonitis ◽  
End Stage

Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world’s most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports—and is supported by—uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as “leaky gut.” Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.

scholarly journals Proteomic profile of cystic fibrosis sputum cells in adults chronically infected with Pseudomonas aeruginosa

2017 ◽  
Vol 50 (1) ◽  
pp. 1601569 ◽  
Author(s):  
Sally H. Pattison ◽  
David S. Gibson ◽  
Elinor Johnston ◽  
Samantha Peacock ◽  
Keith Rivera ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Cell Death ◽  
Lung Function ◽  
Lung Disease ◽  
Protein Identification ◽  
Immune Cell ◽  
Small Gtpase ◽  
Cellular Proteins ◽  
Extracellular Proteases

Lung disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and involves chronic infection and perturbed immune responses. Tissue damage is mediated mostly by extracellular proteases, but other cellular proteins may also contribute to damage through their effect on cell activities and/or release into sputum fluid by means of active secretion or cell death.We employed MudPIT (multidimensional protein identification technology) to identify sputum cellular proteins with consistently altered abundance in adults with CF, chronically infected with Pseudomonas aeruginosa, compared with healthy controls. Ingenuity Pathway Analysis, Gene Ontology, protein abundance and correlation with lung function were used to infer their potential clinical significance.Differentially abundant proteins relate to Rho family small GTPase activity, immune cell movement/activation, generation of reactive oxygen species, and dysregulation of cell death and proliferation. Compositional breakdown identified high abundance of proteins previously associated with neutrophil extracellular traps. Furthermore, negative correlations with lung function were detected for 17 proteins, many of which have previously been associated with lung injury.These findings expand our current understanding of the mechanisms driving CF lung disease and identify sputum cellular proteins with potential for use as indicators of disease status/prognosis, stratification determinants for treatment prescription or therapeutic targets.

scholarly journals The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease

2009 ◽  
Vol 297 (5) ◽  
pp. L828-L836 ◽  
Author(s):  
David P. Nichols ◽  
Assem G. Ziady ◽  
Samuel L. Shank ◽  
Jean F. Eastman ◽  
Pamela B. Davis
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Related Factor ◽  
Preclinical Models ◽  
Cytokines And Chemokines ◽  
Cystic Fibrosis Lung Disease ◽  
Culture Models ◽  
Multiple Cell ◽  
Anti Inflammatory

Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9( 11 )-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have significantly reduced airway inflammatory responses to both LPS and flagellin when treated with CDDO before inflammatory challenge. Anti-inflammatory effects observed include reduced airway neutrophilia, reduced concentrations of proinflammatory cytokines and chemokines, and reduced weight loss. Our findings with the synthetic triterpenoids in multiple cell culture models of CF human airway epithelia agree with effects previously described in other disease models (e.g., neoplastic cells). These include the ability to reduce NF-κB activation while increasing nuclear factor erythroid-related factor 2 (Nrf2) activity. As these two signaling pathways appear to be pivotal in regulating the net inflammatory response in the CF airway, these compounds are a promising potential anti-inflammatory therapy for CF lung disease.

scholarly journals Cystic fibrosis–adaptedPseudomonas aeruginosaquorum sensinglasRmutants cause hyperinflammatory responses

2015 ◽  
Vol 1 (6) ◽  
pp. e1500199 ◽  
Author(s):  
Shantelle L. LaFayette ◽  
Daniel Houle ◽  
Trevor Beaudoin ◽  
Gabriella Wojewodka ◽  
Danuta Radzioch ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Opportunistic Pathogen ◽  
Respiratory Epithelial Cells ◽  
Adaptive Mutations ◽  
Cystic Fibrosis Lung Disease ◽  
Airway Infections ◽  
Respiratory Epithelial

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogenPseudomonas aeruginosaand severe neutrophilic pulmonary inflammation.P. aeruginosaundergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator genelasRcommonly arise. We sought to define how mutations inlasRalter host-pathogen relationships. We demonstrate thatlasRmutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease–dependent cytokine degradation. In subacute pulmonary infections,lasRmutant–infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected withlasRmutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients.

scholarly journals Update on Respiratory Fungal Infections in Cystic Fibrosis Lung Disease and after Lung Transplantation

2020 ◽  
Vol 6 (4) ◽  
pp. 381
Author(s):  
Sabine Renner ◽  
Edith Nachbaur ◽  
Peter Jaksch ◽  
Eleonora Dehlink
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Chloride Transport ◽  
Lung Damage ◽  
Western World ◽  
Detection Rates ◽  
Airway Infections ◽  
The Impact

Cystic fibrosis is the most common autosomal-recessive metabolic disease in the Western world. Impaired trans-membrane chloride transport via the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes thickened body fluids. In the respiratory system, this leads to chronic suppurative cough and recurrent pulmonary infective exacerbations, resulting in progressive lung damage and respiratory failure. Whilst the impact of bacterial infections on CF lung disease has long been recognized, our understanding of pulmonary mycosis is less clear. The range and detection rates of fungal taxa isolated from CF airway samples are expanding, however, in the absence of consensus criteria and univocal treatment protocols for most respiratory fungal conditions, interpretation of laboratory reports and the decision to treat remain challenging. In this review, we give an overview on fungal airway infections in CF and CF-lung transplant recipients and focus on the most common fungal taxa detected in CF, Aspergillus fumigatus, Candida spp., Scedosporium apiospermum complex, Lomentospora species, and Exophiala dermatitidis, their clinical presentations, common treatments and prophylactic strategies, and clinical challenges from a physician’s point of view.

scholarly journals Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

2021 ◽  
Vol 8 ◽  
Author(s):  
Jordan R. Yaron ◽  
Liqiang Zhang ◽  
Qiuyun Guo ◽  
Shelley E. Haydel ◽  
Alexandra R. Lucas
Keyword(s):  
Immune Response ◽  
Serine Protease ◽  
Serine Proteases ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
The Body ◽  
Vascular Tree ◽  
Regulatory Pathways ◽  
Endothelial Cell Surface

The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, “off-the-shelf” system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are theserineproteaseinhibitors, termedserpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a “respiratory” coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

scholarly journals Extravascular CX3CR1+Cells Extend Intravascular Dendritic Processes into Intact Central Nervous System Vessel Lumen

2013 ◽  
Vol 19 (4) ◽  
pp. 778-790 ◽  
Author(s):  
Deborah S. Barkauskas ◽  
Teresa A. Evans ◽  
Jay Myers ◽  
Agne Petrosiute ◽  
Jerry Silver ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Laser Scanning ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Critical Role ◽  
Laser Scanning Microscopy ◽  
Direct Access

AbstractWithin the central nervous system (CNS), antigen-presenting cells (APCs) play a critical role in orchestrating inflammatory responses where they present CNS-derived antigens to immune cells that are recruited from the circulation to the cerebrospinal fluid, parenchyma, and perivascular space. Available data indicate that APCs do so indirectly from outside of CNS vessels without direct access to luminal contents. Here, we applied high-resolution, dynamic intravital two-photon laser scanning microscopy to directly visualize extravascular CX3CR1+APC behavior deep within undisrupted CNS tissues in two distinct anatomical sites under three different inflammatory stimuli. Surprisingly, we observed that CNS-resident APCs dynamically extend their cellular processes across an intact vessel wall into the vascular lumen with preservation of vessel integrity. While only a small number of APCs displayed intravascular extensions in intact, noninflamed vessels in the brain and the spinal cord, the frequency of projections increased over days in an experimental autoimmune encephalomyelitis model, whereas the number of projections remained stable compared to baseline days after tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma. Our observation of this unique behavior by parenchyma CX3CR1+cells in the CNS argues for further exploration into their functional role in antigen sampling and immune cell recruitment.

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