-
Frontiers in Bioscience (Landmark... Jun 2009Thermal injury following burns is a common clinical condition. Excessive systemic inflammatory response syndrome (SIRS) following burns leads to distant organ damage and... (Review)
Review
Thermal injury following burns is a common clinical condition. Excessive systemic inflammatory response syndrome (SIRS) following burns leads to distant organ damage and multiple organ dysfunction syndrome (MODS). Development of in vivo experimental models of burns over the past 50 years have facilitated the study of the effects of thermal injury on physiological and immunological parameters in the pathogenesis of burns and associated systemic organ damage. Using these models, researchers have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-2 and substance P in burns and associated systemic organ damage. The rationale of this chapter is to present an overview of different experimental animal models, both rodents as well as large animals, of burns and associated SIRS and the role of inflammatory mediators in the pathogenesis of this condition as well as in pathogenesis of the resultant MODS.
Topics: Animals; Burns; Disease Models, Animal; Humans; Inflammation Mediators; Mice; Models, Biological; Multiple Organ Failure; Rats; Swine; Swine, Miniature; Systemic Inflammatory Response Syndrome
PubMed: 19482598
DOI: 10.2741/3580 -
Journal of the Formosan Medical... May 2019Despite supportive care with renal replacement therapy, acute kidney injury (AKI) remains linked with increased short and long-term mortality, not just because of renal... (Review)
Review
Despite supportive care with renal replacement therapy, acute kidney injury (AKI) remains linked with increased short and long-term mortality, not just because of renal failure but also because of accompanying remote organ dysfunction. Increasing evidence from animal studies suggests that numerous factors contribute both to the development of AKI and the impairment of various vital organs, including pro-inflammatory cytokine expression, leukocyte infiltration, vascular permeability changes, ion channel derangement, oxidative stress, and cell apoptosis. Human studies have reported that AKI with concomitant multi-organ dysfunction is associated with a high death rate. We propose that persistent organ dysfunction after AKI can be considered in relation to three proposed mechanisms (1) classical uremic stress and its associated sequelae (2) systemic inflammation as a consequence of kidney injury (3) treatment-related effects. Using this framework, we discuss the known pathways through which AKI can affect the function of a number of remote organs. We review the short- and long-term clinical impact of AKI on other organ systems and potential mechanisms through which AKI may affect remote organ systems. Further elucidating the effects of AKI on remote organ function may lead to new therapeutic strategies to improve outcomes after AKI.
Topics: Acute Kidney Injury; Animals; Apoptosis; Cytokines; Humans; Inflammation; Long Term Adverse Effects; Multiple Organ Failure; Renal Replacement Therapy
PubMed: 29798818
DOI: 10.1016/j.jfma.2018.04.005 -
Critical Care (London, England) Dec 2017An exaggerated, dysregulated host response to insults such as infection (i.e. sepsis), trauma and ischaemia-reperfusion injury can result in multiple organ dysfunction... (Review)
Review
An exaggerated, dysregulated host response to insults such as infection (i.e. sepsis), trauma and ischaemia-reperfusion injury can result in multiple organ dysfunction and death. While the focus of research in this area has largely centred on inflammation and immunity, a crucial missing link is the precise identification of mechanisms at the organ level that cause this physiological-biochemical failure. Any hypothesis must reconcile this functional organ failure with minimal signs of cell death, availability of oxygen, and (often) minimal early local inflammatory cell infiltrate. These failed organs also retain the capacity to usually recover, even those that are poorly regenerative. A metabolic-bioenergetic shutdown, akin to hibernation or aestivation, is the most plausible explanation currently advanced. This shutdown appears driven by a perfect storm of compromised mitochondrial oxidative phosphorylation related to inhibition by excessive inflammatory mediators, direct oxidant stress, a tissue oxygen deficit in the unresuscitated phase, altered hormonal drive, and downregulation of genes encoding mitochondrial proteins. In addition, the efficiency of oxidative phosphorylation may be affected by a substrate shift towards fat metabolism and increased uncoupling. A lack of sufficient ATP provision to fuel normal metabolic processes will drive downregulation of metabolism, and thus cellular functionality. In turn, a decrease in metabolism will provide negative feedback to the mitochondrion, inducing a bioenergetic shutdown. Arguably, these processes may offer protection against a prolonged inflammatory hit by sparing the cell from initiation of death pathways, thereby explaining the lack of significant morphological change. A narrow line may exist between adaptation and maladaptation. This places a considerable challenge on any therapeutic modulation to provide benefit rather than harm.
Topics: Energy Metabolism; Humans; Inflammation; Multiple Organ Failure; Reperfusion Injury; Sepsis; Wounds and Injuries
PubMed: 29297363
DOI: 10.1186/s13054-017-1913-9 -
Biochimica Et Biophysica Acta Jan 2012Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin... (Review)
Review
Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus-cytokine-protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Topics: Animals; Antigen Presentation; Birds; Capillary Permeability; Host-Pathogen Interactions; Humans; Immune System; Influenza A virus; Influenza in Birds; Influenza, Human; Models, Biological; Multiple Organ Failure; Peptide Hydrolases
PubMed: 21801859
DOI: 10.1016/j.bbapap.2011.07.001 -
Pharmaceutical Biology Dec 2023Plantamajoside (PMS) possesses rich pharmacological characteristics that have been applied to remedy dozens of diseases. However, the understanding of PMS in sepsis...
CONTEXT
Plantamajoside (PMS) possesses rich pharmacological characteristics that have been applied to remedy dozens of diseases. However, the understanding of PMS in sepsis remains insufficient.
OBJECTIVE
Role of PMS in sepsis-regulated organ dysfunction and potential mechanisms were investigated.
MATERIALS AND METHODS
Thirty C57BL/6 male mice were adaptive fed for three days and used to establish acute sepsis model by caecal ligation and perforation (CLP). These experimental mice were divided into Sham, CLP, CLP + 25 mg PMS/kg body weight (PMS/kg), CLP + 50 mg PMS/kg and CLP + 100 mg PMS/kg ( = 6). The pathological and apoptotic changes of lung, liver and heart tissues were observed via HE and TUNEL staining. The injury-related factors of lung, liver and heart were detected by corresponding kits. ELISA and qRT-PCR were applied to assess IL-6/TNF-α/IL-1β levels. Apoptosis-related and TRAF6/NF-κB-related proteins were determined using Western blotting.
RESULTS
All doses of PMS enhanced the survival rates in the sepsis-induced mouse model. PMS remitted sepsis-mediated lung, liver and heart injury through prohibiting MPO/BALF (70.4%/85.6%), AST/ALT (74.7%/62.7%) and CK-MB/CK (62.3%/68.9%) levels. Moreover, the apoptosis index (lung 61.9%, liver 50.2%, heart 55.7% reduction) and IL-6/TNF-α/IL-1β levels were suppressed by PMS. Furthermore, PMS lowered TRAF6 and p-NF-κB p65 levels, whereas TRAF6 overexpression reversed the protective influences of PMS in organ injury, apoptosis and inflammation triggered by sepsis.
DISCUSSION AND CONCLUSIONS
PMS suppressed sepsis-induced organ dysfunction by regulating the TRAF6/NF-κB axis, and PMS treatment may be considered as a novel strategy for sepsis-caused damage in future.
Topics: Mice; Male; Animals; NF-kappa B; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor-alpha; Interleukin-6; Multiple Organ Failure; Mice, Inbred C57BL; Sepsis
PubMed: 37288729
DOI: 10.1080/13880209.2023.2215849 -
PloS One 2021Uricase-deficient rats could be one of the optimal model animals to study hyperuricemia. The present study aimed to find the biological differences between...
Uricase-deficient rats could be one of the optimal model animals to study hyperuricemia. The present study aimed to find the biological differences between uricase-deficient (Kunming-DY rats) and wild-type male rats. Uricase-deficient rats and wild-type rats were commonly bred. Their body weight, water and food consumption, 24-h urine and feces, uric acid in serum and organs, and serum indexes were recorded or assayed. Organs, including the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum, were examined using a routine hematoxylin-eosin staining assay. We found that the growth of male uricase-deficient rats was retarded. These rats excreted more urine than the wild-type rats. Their organ indexes (organ weight body weight ratio), of the heart, liver, kidney, and thymus significantly increased, while those of the stomach and small intestine significantly decreased. The uricase-deficient rats had a significantly higher level of serum uric acid and excreted more uric acid via urine at a higher concentration. Except for the liver, uric acid increased in organs and intestinal juice of uricase-deficient rats. Histological examination of the uricase-deficient rats showed mild injuries to the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum. Our results suggest that uricase-deficient rats have a different biological pattern from the wild-type rats. Uricase deficiency causes growth retardation of young male rats and the subsequent increase in serum uric acid results in mild organs injuries, especially in the kidney and liver.
Topics: Animals; Body Weight; Diet; Feces; Female; Intestines; Male; Multiple Organ Failure; Organ Specificity; Proteinuria; Rats, Sprague-Dawley; Urate Oxidase; Uric Acid; Rats
PubMed: 34437605
DOI: 10.1371/journal.pone.0256594 -
Annals of Surgery Aug 1992
Topics: Bacterial Infections; Critical Care; Humans; Leukocytes; Lymphocyte Activation; Multiple Organ Failure; Wound Infection
PubMed: 1503515
DOI: 10.1097/00000658-199208000-00001 -
The British Journal of Surgery Mar 2020The nature of multiple organ dysfunction syndrome (MODS) after traumatic injury is evolving as resuscitation practices advance and more patients survive their injuries...
BACKGROUND
The nature of multiple organ dysfunction syndrome (MODS) after traumatic injury is evolving as resuscitation practices advance and more patients survive their injuries to reach critical care. The aim of this study was to characterize contemporary MODS subtypes in trauma critical care at a population level.
METHODS
Adult patients admitted to major trauma centre critical care units were enrolled in this 4-week point-prevalence study. MODS was defined by a daily total Sequential Organ Failure Assessment (SOFA) score of more than 5. Hierarchical clustering of SOFA scores over time was used to identify MODS subtypes.
RESULTS
Some 440 patients were enrolled, of whom 245 (55·7 per cent) developed MODS. MODS carried a high mortality rate (22·0 per cent versus 0·5 per cent in those without MODS; P < 0·001) and 24·0 per cent of deaths occurred within the first 48 h after injury. Three patterns of MODS were identified, all present on admission. Cluster 1 MODS resolved early with a median time to recovery of 4 days and a mortality rate of 14·4 per cent. Cluster 2 had a delayed recovery (median 13 days) and a mortality rate of 35 per cent. Cluster 3 had a prolonged recovery (median 25 days) and high associated mortality rate of 46 per cent. Multivariable analysis revealed distinct clinical associations for each form of MODS; 24-hour crystalloid administration was associated strongly with cluster 1 (P = 0·009), traumatic brain injury with cluster 2 (P = 0·002) and admission shock severity with cluster 3 (P = 0·003).
CONCLUSION
Contemporary MODS has at least three distinct types based on patterns of severity and recovery. Further characterization of MODS subtypes and their underlying pathophysiology may lead to future opportunities for early stratification and targeted interventions.
Topics: Adult; Aged; Cluster Analysis; Crystalloid Solutions; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Organ Dysfunction Scores; Time Factors; Wounds and Injuries
PubMed: 31691956
DOI: 10.1002/bjs.11361 -
Pediatric Critical Care Medicine : a... Mar 2017To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. (Review)
Review
OBJECTIVE
To describe the pathophysiology associated with multiple organ dysfunction syndrome in children.
DATA SOURCES
Literature review, research data, and expert opinion.
STUDY SELECTION
Not applicable.
DATA EXTRACTION
Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities.
DATA SYNTHESIS
Summary of presentations and discussion supported and supplemented by relevant literature.
CONCLUSIONS
Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.
Topics: Biomarkers; Child; Cytochrome P-450 Enzyme System; Humans; Macrophage Activation Syndrome; Mitochondria; Multiple Organ Failure; Pediatrics; Thrombocytopenia
PubMed: 28248832
DOI: 10.1097/PCC.0000000000001052 -
Current Opinion in Pediatrics Jun 2018The essential role of the lymphatic system in fluid homeostasis, nutrient transport, and immune trafficking is well recognized; however, there is limited understanding... (Review)
Review
PURPOSE OF REVIEW
The essential role of the lymphatic system in fluid homeostasis, nutrient transport, and immune trafficking is well recognized; however, there is limited understanding of the mechanisms that regulate lymphatic function, particularly in the setting of critical illness. The lymphatics likely affect disease severity and progression in every condition, from severe systemic inflammatory states to respiratory failure. Here, we review structural and functional disorders of the lymphatic system, both congenital and acquired, as they relate to care of the pediatric patient in the intensive care setting, including novel areas of research into medical and procedural therapeutic interventions.
RECENT FINDINGS
The mainstay of current therapies for congenital and acquired lymphatic abnormalities has involved nonspecific medical management or surgical procedures to obstruct or divert lymphatic flow. With the development of dynamic contrast-enhanced magnetic resonance lymphangiography, image-directed percutaneous intervention may largely replace surgery. Because of new insights into the mechanisms that regulate lymphatic biology, pharmacologic inhibitors of mTOR and leukotriene B4 signaling are each in Phase II clinical trials to treat abnormal lymphatic structure and function, respectively.
SUMMARY
As our understanding of normal lymphatic biology continues to advance, we will be able to develop novel strategies to support and augment lymphatic function during critical illness and through convalescence.
Topics: Child; Critical Care; Critical Illness; Heart Diseases; Humans; Lymphatic Diseases; Multiple Organ Failure
PubMed: 29538048
DOI: 10.1097/MOP.0000000000000623