scholarly journals Reevaluation of Lung Injury in TNF-Induced Shock: The Role of the Acid Sphingomyelinase

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Lucy K. Reiss ◽  
Ute Raffetseder ◽  
Lydia Gibbert ◽  
Hannah K. Drescher ◽  
Konrad L. Streetz ◽  
...  
Keyword(s):  
Blood Gases ◽  
Multiple Organ ◽  
Acid Sphingomyelinase ◽  
Lung Mechanics ◽  
Organ Injury ◽  
Cardiovascular Failure ◽  
Proinflammatory Mediators ◽  
Reflex Tachycardia ◽  
Lung Histopathology ◽  
Lethal Shock

Tumor necrosis factor (TNF) is a well-known mediator of sepsis. In many cases, sepsis results in multiple organ injury including the lung with acute respiratory distress syndrome (ARDS). More than 20-year-old studies have suggested that TNF may be directly responsible for organ injury during sepsis. However, these old studies are inconclusive, because they relied on human rather than conspecific TNF, which was contaminated with endotoxin in most studies. In this study, we characterized the direct effects of intravenous murine endotoxin-free TNF on cardiovascular functions and organ injury in mice with a particular focus on the lungs. Because of the relevance of the acid sphingomyelinase in sepsis, ARDS, and caspase-independent cell death, we also included acid sphingomyelinase-deficient (ASM-/-) mice. ASM-/- and wild-type (WT) mice received 50 μg endotoxin-free murine TNF intravenously alone or in combination with the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD) and were ventilated at low tidal volume while lung mechanics were followed. Blood pressure was stabilized by intra-arterial fluid support, and body temperature was kept at 37°C to delay lethal shock and to allow investigation of blood gases, lung histopathology, proinflammatory mediators, and microvascular permeability 6 hours after TNF application. Besides the lungs, also the kidneys and liver were examined. TNF elicited the release of inflammatory mediators and a high mortality rate, but failed to injure the lungs, kidneys, or liver of healthy mice significantly within 6 hours. Mortality in WT mice was most likely due to sepsis-like shock, as indicated by metabolic acidosis, high procalcitonin levels, and cardiovascular failure. ASM-/- mice were protected from TNF-induced hypotension and reflex tachycardia and also from mortality. In WT mice, intravenous exogenous TNF does not cause organ injury but induces a systemic inflammatory response with cardiovascular failure, in which the ASM plays a role.

The selective guanylate cyclase inhibitor ODQ reduces multiple organ injury in rodent models of Gram-positive and Gram-negative shock

2001 ◽  
Vol 29 (8) ◽  
pp. 1599-1608 ◽  
Author(s):  
Kai Zacharowski ◽  
Reinhard Berkels ◽  
Antje Olbrich ◽  
Prabal K. Chatterjee ◽  
Salvatore Cuzzocrea ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Multiple Organ ◽  
Organ Injury ◽  
Rodent Models ◽  
Gram Positive ◽  
Gram Negative ◽  
Multiple Organ Injury ◽  
Negative Shock

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

scholarly journals Laboratory Markers in the Management of Pediatric Polytrauma: Current Role and Areas of Future Research

2021 ◽  
Vol 9 ◽  
Author(s):  
Birte Weber ◽  
Ina Lackner ◽  
Christian Karl Braun ◽  
Miriam Kalbitz ◽  
Markus Huber-Lang ◽  
...  
Keyword(s):  
Imaging Techniques ◽  
Lactate Concentration ◽  
Organ Damage ◽  
Severe Trauma ◽  
Multiple Organ ◽  
Organ Injury ◽  
Future Research ◽  
Acid Base Balance ◽  
Early Assessment ◽  
Laboratory Markers

Severe trauma is the most common cause of mortality in children and is associated with a high socioeconomic burden. The most frequently injured organs in children are the head and thorax, followed by the extremities and by abdominal injuries. The efficient and early assessment and management of these injuries is essential to improve patients' outcome. Physical examination as well as imaging techniques like ultrasound, X-ray and computer tomography are crucial for a valid early diagnosis. Furthermore, laboratory analyses constitute additional helpful tools for the detection and monitoring of pediatric injuries. Specific inflammatory markers correlate with post-traumatic complications, including the development of multiple organ failure. Other laboratory parameters, including lactate concentration, coagulation parameters and markers of organ injury, represent further clinical tools to identify trauma-induced disorders. In this review, we outline and evaluate specific biomarkers for inflammation, acid-base balance, blood coagulation and organ damage following pediatric polytrauma. The early use of relevant laboratory markers may assist decision making on imaging tools, thus contributing to minimize radiation-induced long-term consequences, while improving the outcome of children with multiple trauma.

scholarly journals Lung Mechanics in Type L CoVID-19 Pneumonia: A Pseudo-Normal ARDS.

2020 ◽  
Author(s):  
Lorenzo Viola ◽  
Emanuele Russo ◽  
Marco Benni ◽  
Emiliano Gamberini ◽  
Alessandro Circelli ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Respiratory System ◽  
Respiratory Mechanics ◽  
Blood Gases ◽  
Lung Mechanics ◽  
Prone Positioning ◽  
Arterial Blood Gases ◽  
Arterial Blood ◽  
Esophageal Balloon ◽  
Early Phases

Abstract Background. This study was conceived to provide systematic data about lung mechanics during early phases of CoVID-19 pneumonia, as long as to explore its variations during prone positioning. Methods. We enrolled four patients hospitalized in the Intensive Care Unit of “M. Bufalini” hospital, Cesena (Italy); after the positioning of an esophageal balloon, we measured mechanical power, respiratory system and transpulmonary parameters and arterial blood gases every 6 hours, just before decubitus change and 1 hour after prono-supination. Results. Both respiratory system and transpulmonary compliance and driving pressure confirmed the pseudo-normal respiratory mechanics of early CoVID-19 pneumonia (respectively, CRS 40.8 ml/cmH2O and DPRS 9.7 cmH2O; CL 53.1 ml/cmH2O and DPL 7.9 cmH2O). Interestingly, prone positioning involved a worsening in respiratory mechanical properties (CRS,SUP 56.3 ml/cmH2O and CRS,PR 41.5 ml/cmH2O – P 0.37; CL,SUP 80.8 ml/cmH2O and CL,PR 53.2 ml/cmH2O – P 0.23). Conclusions. Despite the severe ARDS pattern, respiratory system and lung mechanical properties during CoVID-19 pneumonia are pseudo-normal and tend to worsen during pronation. Trial registration. Restrospectively registered.

scholarly journals THE CHANGES IN DYNAMICS OF ORNITHINE CYCLE COMPONENTS LEVELS DURING THE ACUTE PERIOD OF POLYTRAUMA

2019 ◽  
Vol 72 (9) ◽  
pp. 1781-1785
Author(s):  
Nataliya Matolinets
Keyword(s):  
Oxidative Stress ◽  
Intensive Care ◽  
Serum Levels ◽  
Organ Damage ◽  
Multiple Organ ◽  
Oxidation Products ◽  
Acute Period ◽  
Proinflammatory Mediators ◽  
Biomechanical Parameters ◽  
Injury Causes

Introduction: Polytrauma or multiple organ damage is associated with shock and lead to systemic inflammation, oxidative stress and endothelial dysfunction. A severe mechanical injury causes an increased proinflammatory mediators and cytokines levels. Among them, the overproduction of nitric oxide and its oxidation products play a key role in tissue damage. The aim: To evaluate the changes in dynamics of some ornithine cycle components levels during acute period of polytrauma. Materials and methods: We measured standard biomechanical parameters and serum levels of NO, sum of nitrite and nitrate (NOx), L-arginine, arginase, and peroxynitrite. According to the ISS, the study included patients with moderate (n=15) to severe (n=15) polytrauma. Results: In 24 hours after polytrauma on the background of intensive care, it was observed significant increasing of NO, NOx, and arginase levels (severe cases) with decreasing of L-arginine and peroxynitrite levels. Conclusions: Elevated NO and NOx serum levels in patients with polytrauma is associated with increasing of arginase activity with decreasing of L-arginine and peroxynitrite levels on the background of intensive care.

NF-κB activation as a pathological mechanism of septic shock and inflammation

2006 ◽  
Vol 290 (4) ◽  
pp. L622-L645 ◽  
Author(s):  
Shu Fang Liu ◽  
Asrar B. Malik
Keyword(s):  
Septic Shock ◽  
Human Subjects ◽  
Myocardial Dysfunction ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pathological Mechanism ◽  
Proinflammatory Gene ◽  
Intensive Investigation ◽  
Sepsis And Septic Shock

The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-κB activation is a central event leading to the activation of these networks. The role of NF-κB in septic pathophysiology and the signal transduction pathways leading to NF-κB activation during sepsis have been an area of intensive investigation. NF-κB is activated by a variety of pathogens known to cause septic shock syndrome. NF-κB activity is markedly increased in every organ studied, both in animal models of septic shock and in human subjects with sepsis. Greater levels of NF-κB activity are associated with a higher rate of mortality and worse clinical outcome. NF-κB mediates the transcription of exceptional large number of genes, the products of which are known to play important roles in septic pathophysiology. Mice deficient in those NF-κB-dependent genes are resistant to the development of septic shock and to septic lethality. More importantly, blockade of NF-κB pathway corrects septic abnormalities. Inhibition of NF-κB activation restores systemic hypotension, ameliorates septic myocardial dysfunction and vascular derangement, inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial leakage. Inhibition of NF-κB activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NF-κB activation plays a central role in the pathophysiology of septic shock.

ATTENUATION OF ENDOTOXIN-INDUCED OXIDATIVE STRESS AND MULTIPLE ORGAN INJURY BY 3,4-METHYLENEDIOXYPHENOL IN RATS

Shock ◽  
2006 ◽  
Vol 25 (3) ◽  
pp. 300-305 ◽  
Author(s):  
Dur-Zong Hsu ◽  
Ya-Hui Li ◽  
Pei-Yi Chu ◽  
Se-Ping Chien ◽  
Yin-Ching Chuang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Organ ◽  
Organ Injury ◽  
Multiple Organ Injury

scholarly journals Targeting neutrophil extracellular traps in severe acute pancreatitis treatment

2020 ◽  
Vol 13 ◽  
pp. 175628482097491
Author(s):  
Jing Hu ◽  
Hongxin Kang ◽  
Huan Chen ◽  
Jiaqi Yao ◽  
Xiaolin Yi ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Inflammatory Cells ◽  
Neutrophil Extracellular Traps ◽  
Multiple Organ ◽  
Organ Injury ◽  
Normal Tissues ◽  
Pathogen Invasion ◽  
Extracellular Traps ◽  
Abdominal Disease

Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.

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