scholarly journals Extracellular histones in lung dysfunction: a new biomarker and therapeutic target?

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402096535
Author(s):  
Pratap Karki ◽  
Konstantin G. Birukov ◽  
Anna A. Birukova
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Therapeutic Effects ◽  
Lung Dysfunction ◽  
Extracellular Histones

Extracellular histones released from injured or dying cells following trauma and other severe insults can act as potent damage-associated molecular patterns. In fact, elevated levels of histones are present in human circulation in hyperinflammatory states such as acute respiratory distress syndrome and sepsis. The molecular mechanisms owing to histone-induced pathologies are at the very beginning of elucidating. However, neutralization of histones with antibodies, histone-binding or histone-degrading proteins, and heparan sulfates have shown promising therapeutic effects in pre-clinical acute respiratory distress syndrome and sepsis models. Various cell types undergoing necrosis and apoptosis or activated neutrophils forming neutrophil extracellular traps have been implicated in excessive release of histones which further augments tissue injury and may culminate in multiple organ failure. At the molecular level, an uncontrolled inflammatory cascade has been considered as the major event; however, histone-activated coagulation and thrombosis represent additional pathologic events reflecting coagulopathy. Furthermore, epigenetic regulation and chemical modifications of circulating histones appear to be critically important in their biological functions as evidenced by increased cytotoxicity associated with citrullinated histone. Herein, we will briefly review the current knowledge on the role of histones in acute respiratory distress syndrome and sepsis, and discuss the future potential of anti-histone therapy for treatment of these life-threatening disorders.

scholarly journals Exogenous Surfactant Therapy for Pediatric Patients with Acute Respiratory Distress Syndrome

1997 ◽  
Vol 4 (1) ◽  
pp. 21-26 ◽  
Author(s):  
James F Lewis ◽  
Jasvinder S Dhillon ◽  
Ram N Singh ◽  
Craig C Johnson ◽  
Timothy C Frewen
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Pilot Study ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Pediatric Patients ◽  
Distress Syndrome ◽  
Exogenous Surfactant ◽  
Lung Dysfunction ◽  
Surfactant Administration ◽  
Severe Lung

Exogenous surfactant administration is currently being tested in patients with the acute respiratory distress syndrome (ARDS). The results of the studies have varied because several factors may influence the host’s response to this therapy. This clinical pilot study was designed to evaluate the safety and efficacy of exogenous surfactant administration in pediatric patients with ARDS. Surfactant was administered to 13 patients with severe lung dysfunction, and eight of these patients experienced a significant improvement in oxygenation after the first dose of surfactant. In these patients the exogenous surfactant was administered within 48 h of the diagnosis of ARDS, whereas in the five patients who did not respond, surfactant was administered several days after the onset of ARDS. Responders also spent fewer days on a mechanical ventilator and less time in intensive care compared with nonresponders. Based on the results of this pilot study, a more appropriate multicentre clinical trial should be designed to evaluate this treatment strategy.

Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome

2020 ◽  
Author(s):  
Declan Byrnes ◽  
Claire H. Masterson ◽  
Antonio Artigas ◽  
John G. Laffey
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Stromal Cells ◽  
Distress Syndrome ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Phase Iii ◽  
High Morbidity ◽  
Lung Dysfunction

AbstractSepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The “proinflammatory” response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some—but not all—underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.

scholarly journals Basic and clinical research progress in acute lung injury/acute respiratory distress syndrome

2018 ◽  
Vol 7 (2) ◽  
pp. 38-43 ◽  
Author(s):  
Tong Wang
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Severe Infection ◽  
Research Progress ◽  
Severe Stage

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an acute progressive respiratory failure caused by severe infection, trauma, shock, poisoning, inhaled harmful gas, acute pancreatitis, and pathological obstetrics. ALI and ARDS demonstrate similar pathophysiological changes. The severe stage of ALI is defined as ARDS. At present, a significant progress has been achieved in the study of the pathogenesis and pathophysiology of ALI/ARDS. Whether or not ALI/ARDS patients can recover depends on the degree of lung injury, extra-pulmonary organ damage, original primary disease of a patient, and adequacy in supportive care. Conservative infusion strategies and protective lung ventilation reduce ARDS disability and mortality. In this study, the pathogenesis of ALI/ARDS, lung injury, molecular mechanisms of lung repair, and conservative infusion strategies and pulmonary protective ventilation are reviewed comprehensively.

scholarly journals Early Upregulation of Acute Respiratory Distress Syndrome-Associated Cytokines Promotes Lethal Disease in an Aged-Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Infection

2009 ◽  
Vol 83 (14) ◽  
pp. 7062-7074 ◽  
Author(s):  
Barry Rockx ◽  
Tracey Baas ◽  
Gregory A. Zornetzer ◽  
Bart Haagmans ◽  
Timothy Sheahan ◽  
...  
Keyword(s):  
Immune Response ◽  
Acute Respiratory Distress Syndrome ◽  
Severe Acute Respiratory Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Host Response ◽  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Aged Mice ◽  
Young Mice

ABSTRACT Several respiratory viruses, including influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV), produce more severe disease in the elderly, yet the molecular mechanisms governing age-related susceptibility remain poorly studied. Advanced age was significantly associated with increased SARS-related deaths, primarily due to the onset of early- and late-stage acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways by which SARS-CoV infection induces changes in the host response, leading to death.

Extracellular Histones Play an Inflammatory Role in Acid Aspiration-induced Acute Respiratory Distress Syndrome

2015 ◽  
Vol 122 (1) ◽  
pp. 127-139 ◽  
Author(s):  
Yanlin Zhang ◽  
Zongmei Wen ◽  
Li Guan ◽  
Ping Jiang ◽  
Tao Gu ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Systemic Inflammation ◽  
Distress Syndrome ◽  
Protective Effects ◽  
Acid Aspiration ◽  
Gastric Aspiration ◽  
Antihistone Antibody ◽  
Extracellular Histones

Abstract Background: Systemic inflammation is a key feature in acid aspiration-induced acute respiratory distress syndrome (ARDS), but the factors that trigger inflammation are unclear. The authors hypothesize that extracellular histones, a newly identified inflammatory mediator, play important roles in the pathogenesis of ARDS. Methods: The authors used a hydrochloric acid aspiration-induced ARDS model to investigate whether extracellular histones are pathogenic and whether targeting histones are protective. Exogenous histones and antihistone antibody were administered to mice. Heparin can bind to histones, so the authors studied whether heparin could protect from ARDS using cell and mouse models. Furthermore, the authors analyzed whether extracellular histones are clinically involved in ARDS patients caused by gastric aspiration. Results: Extracellular histones in bronchoalveolar lavage fluid of acid-treated mice were significantly higher (1.832 ± 0.698) at 3 h after injury than in sham-treated group (0.63 ± 0.153; P = 0.0252, n = 5 per group). Elevated histones may originate from damaged lung cells and neutrophil infiltration. Exogenous histones aggravated lung injury, whereas antihistone antibody markedly attenuated the intensity of ARDS. Notably, heparin provided a similar protective effect against ARDS. Analysis of plasma from ARDS patients (n = 21) showed elevated histones were significantly correlated with the degree of ARDS and were higher in nonsurvivors (2.723 ± 0.2933, n = 7) than in survivors (1.725 ± 0.1787, P = 0.006, n = 14). Conclusion: Extracellular histones may play a contributory role toward ARDS by promoting tissue damage and systemic inflammation and may become a novel marker reflecting disease activity. Targeting histones by neutralizing antibody or heparin shows potent protective effects, suggesting a potentially therapeutic strategy.

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