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Respiratory Research Jul 2023Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a...
BACKGROUND
Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the AR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to ARs in regulating the host's response to T/HS.
METHODS
T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, AR) and conditional knockout (intestinal epithelial cell-specific deficient Villin-AR) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury.
RESULTS
T/HS upregulated the expression of CD39, CD73, and the AR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and AR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and AR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and AR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient Villin-AR mice showed increased intestinal injury compared to their wild-type Villin controls.
CONCLUSION
In conclusion, the CD39-CD73-AR axis protects against T/HS-induced multiple organ failure.
Topics: Animals; Mice; Adenosine; Multiple Organ Failure; Adenosine Triphosphate; Signal Transduction; Bronchoalveolar Lavage Fluid
PubMed: 37438813
DOI: 10.1186/s12931-023-02486-3 -
Chirurgie (Heidelberg, Germany) Feb 2024A review and discussion of the current literature on liver transplantation for acute-on-chronic liver failure (ACLF) was performed. The ACLF represents an acute... (Review)
Review
A review and discussion of the current literature on liver transplantation for acute-on-chronic liver failure (ACLF) was performed. The ACLF represents an acute deterioration of liver function with pre-existing liver disease and is associated with increasing multiorgan failure, depending on the stage. The 28-day mortality ranges to well over 70% in stage 3 and requires rapid intensive medical treatment involving an interdisciplinary team experienced in transplantation medicine. Under optimized conditions, liver transplantation provides long-term survival rates comparable to other indications. Achieving this requires a differentiated donor selection, choosing the appropriate time for transplantation in the context of a dynamic disease course and the use of appropriate surgical techniques.
Topics: Humans; Acute-On-Chronic Liver Failure; Liver Transplantation; Multiple Organ Failure
PubMed: 37978073
DOI: 10.1007/s00104-023-01992-w -
International Journal of Molecular... Aug 2023Sepsis is associated with high rates of mortality in the intensive care unit and accompanied by systemic inflammatory reactions, secondary infections, and multiple organ... (Review)
Review
Sepsis is associated with high rates of mortality in the intensive care unit and accompanied by systemic inflammatory reactions, secondary infections, and multiple organ failure. Biological macromolecules are drugs produced using modern biotechnology to prevent or treat diseases. Indeed, antithrombin, antimicrobial peptides, interleukins, antibodies, nucleic acids, and lentinan have been used to prevent and treat sepsis. In vitro, biological macromolecules can significantly ameliorate the inflammatory response, apoptosis, and multiple organ failure caused by sepsis. Several biological macromolecules have entered clinical trials. This review summarizes the sources, efficacy, mechanism of action, and research progress of macromolecular drugs used in the prevention and treatment of sepsis.
Topics: Humans; Multiple Organ Failure; Sepsis; Antibodies; Anticoagulants; Antimicrobial Peptides; Macromolecular Substances
PubMed: 37629199
DOI: 10.3390/ijms241613017 -
Cell Reports Aug 2023Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has...
Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.
Topics: Mice; Animals; Kynurenine; Pancreatitis; Critical Illness; Multiple Organ Failure; Acute Disease; Mice, Knockout; Inflammation; Kynurenine 3-Monooxygenase
PubMed: 37478012
DOI: 10.1016/j.celrep.2023.112763 -
Perfusion Oct 2023The relationship between the gut microbiome and various organ systems has gained interest throughout the scientific community in recent times. The understanding of these... (Review)
Review
The relationship between the gut microbiome and various organ systems has gained interest throughout the scientific community in recent times. The understanding of these complex relationships has greatly improved with clinical benefits now being seen. Cardiopulmonary bypass (CPB) is a form of extracorporeal circulation that provides circulatory and respiratory support during cardiac surgery. This physiological support facilitates a still and bloodless field facilitating operations on the heart to be performed. Through various mechanisms CPB results in a systemic inflammatory response syndrome (SIRS). This response can vary from mild hypotension to multiple organ failure. It remains difficult to predict the degree to which a patient will experience SIRS post-operatively. The relationship between the composition of the gut microbiome and inflammatory processes associated with disease has been seen across several fields including gastroenterology, neurology, psychiatry and cardiology. To date, minimal research has been undertaken to examine the impact the gut microbiome has on outcomes following cardiac surgery. This review paper explores the pathophysiology behind the SIRS response associated with CPB for cardiac surgery and the hypothesis that a correlation exists between a patients gut microbiome composition and the degree of inflammatory response experienced following cardiac surgery.
Topics: Humans; Gastrointestinal Microbiome; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Thoracic Surgery; Systemic Inflammatory Response Syndrome
PubMed: 35466814
DOI: 10.1177/02676591221097219 -
Cancers Jan 2024This review explores the interconnection between precursor lesions of breast cancer (typical ductal hyperplasia, atypical ductal/lobular hyperplasia) and the subclinical... (Review)
Review
This review explores the interconnection between precursor lesions of breast cancer (typical ductal hyperplasia, atypical ductal/lobular hyperplasia) and the subclinical of multiple organ failure syndrome, both representing early stages marked by alterations preceding clinical symptoms, undetectable through conventional diagnostic methods. Addressing the question "Why patients with breast cancer exhibit a tendency to deteriorate", this study investigates the biological progression from a subclinical multiple organ failure syndrome, characterized by insidious but indisputable lesions, to an acute (clinical) state resembling a cascade akin to a waterfall or domino effect, often culminating in the patient's demise. A comprehensive literature search was conducted using PubMed, Google Scholar, and Scopus databases in October 2023, employing keywords such as "MODS", "SIRS", "sepsis", "pathophysiology of MODS", "MODS in cancer patients", "multiple organ failure", "risk factors", "cancer", "ICU", "quality of life", and "breast cancer". Supplementary references were extracted from the retrieved articles. This study emphasizes the importance of early identification and prevention of the multiple organ failure cascade at the inception of the malignant state, aiming to enhance the quality of life and extend survival. This pursuit contributes to a deeper understanding of risk factors and viable therapeutic options. Despite the existence of the subclinical multiple organ failure syndrome, current diagnostic methodologies remain inadequate, prompting consideration of AI as an increasingly crucial tool for early identification in the diagnostic process.
PubMed: 38254870
DOI: 10.3390/cancers16020381 -
American Journal of Physiology. Lung... Sep 2023Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure...
Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of . LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated -induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS. We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of HO activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.
Topics: Mice; Animals; Lipopolysaccharides; Capillaries; Hydrogen Peroxide; Liver; Mitochondria; Respiratory Distress Syndrome; Lung Injury; Pneumonia, Bacterial; Mitochondrial Proteins
PubMed: 37431588
DOI: 10.1152/ajplung.00209.2022 -
Current Opinion in Critical Care Oct 2023To summarize the advances in literature that support the best current practices regarding infective endocarditis (IE) in critically ill patients. (Review)
Review
PURPOSE OF REVIEW
To summarize the advances in literature that support the best current practices regarding infective endocarditis (IE) in critically ill patients.
RECENT FINDINGS
IE due to rheumatic diseases has decreased significantly, and in fact, the majority of cases are associated with degenerative valvopathies, prosthetic valves, and cardiovascular implantable electronic devices. The Duke criteria were recently updated, addressing the increasing incidence of new risk factors for IE, such as IE associated with the use of endovascular cardiac implantable electronic devices and transcatheter implant valves. The presence of organ dysfunction, renal replacement therapies, or extracorporeal membrane oxygenation should be considered in the choice of drug and dosage in critically ill patients with suspected or confirmed IE. As highlighted for other severe infections, monitoring of therapeutic antibiotic levels is a promising technique to improve outcomes in critically ill patients with organ dysfunction.
SUMMARY
The diagnostic investigation of IE must consider the current epidemiological criteria and the diagnostic particularities that these circumstances require. A careful evaluation of these issues is necessary for the prompt clinical or surgical management of this infection.
Topics: Humans; Critical Illness; Multiple Organ Failure; Endocarditis; Heart; Extracorporeal Membrane Oxygenation
PubMed: 37646776
DOI: 10.1097/MCC.0000000000001071 -
The Heart Surgery Forum Oct 2023Sepsis is a medical condition characterized by acute organ dysfunction and uncontrolled inflammation. Organ dysfunction in sepsis is the primary cause of mortality in... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Sepsis is a medical condition characterized by acute organ dysfunction and uncontrolled inflammation. Organ dysfunction in sepsis is the primary cause of mortality in patients with myocardial dysfunction. Levosimendan is a vasodilating and inotropic agent used in patients with acute heart failure and has resulted in decreased morbidity and mortality in these patients. Our main objective is to examine levosimendan's efficacy in treating severe sepsis complicated with septic cardiomyopathy.
METHODS
We systematically searched five databases, PubMed, Web of Science, Embase, Cochrane Library and BioMed Central, for articles and publications from their inception to 2023. Our study adopted the PICOS approach in identifying suitable publications during the systematic search. Inclusion criteria included randomized, controlled trials utilizing levosimendan in adult patients diagnosed with septic shock or severe sepsis. We excluded non-English publications and non-randomized controlled trials. The Newcastle-Ottawa scale (NOS) scale was used to assess the methodological quality, while the risk of bias was assessed through the Cochrane Risk of bias tool. All statistical analyses were performed using RevMan version 5.4.
RESULTS
Eight studies met the eligibility criteria and were included in the analysis. There was a statistically significant positive effect on cardiac input in patients treated with levosimendan compared to those treated with dobutamine (p < 0.001). Similarly, there were positive effects on left ventricular ejection fraction (LVEF) (p < 0.001) and left ventricular stroke work index (LVSWI) (p < 0.001). We observed a significant reduction in mortality (p < 0.01) and serum levels of lactic acid (p < 0.01).
DISCUSSION
Levosimendan is a calcium sensitizer associated with an influx of calcium ions and activation of ATP-dependent potassium channels that increases myocardial contractility contractions, enhances vasodilation and improves oxygen supply to the cells and tissues.
CONCLUSION
Levosimendan is highly efficacious and safe in the management of sepsis and sepsis-induced cardiomyopathy.
Topics: Adult; Humans; Calcium; Cardiomyopathies; Cardiotonic Agents; Multiple Organ Failure; Sepsis; Simendan; Stroke Volume; Ventricular Function, Left
PubMed: 37920078
DOI: 10.59958/hsf.6439 -
Physiological Reviews Apr 2024Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche,... (Review)
Review
Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.
Topics: Humans; Multiple Organ Failure; Lung; Endothelium, Vascular; Amyloid; Amyloid beta-Peptides
PubMed: 37561137
DOI: 10.1152/physrev.00006.2023