Furthermore, recombinant parasite histones also induced endothelial permeability via a charge-dependent mechanism that led to downregulation of the junction protein [ 86 ]. Taken together, these data suggest that extracellular histones play a crucial role in barrier dysfunction during ALI. However, in addition to the charge-dependent mechanism, TLR2, TLR4, and TLR9, as the receptors of histones [ 30 , 37 , 38 ], may also give rise to permeability changes, which should be investigated further Figure 1.
High concentrations of plasma histones have been detected in patients with sepsis [ 16 , 17 ] and ARDS [ 18 , 87 ] and, possibly, correlate with the severity or poor prognosis of these diseases [ 19 , 88 ]. As observed by Ekaney et al. Extracellular histones have also been found to predict ICU day mortality in patients with sepsis, and the area under curve AUC is 0. Similarly, in patients with trauma, elevated histone levels are associated with acute lung injury, more days of mechanical ventilation, higher incidences of organ failure, and even higher mortality.
In addition, extracellular histones indicate higher mortality in patients with gastric aspiration-induced ARDS [ 19 ]. Heparin is a highly negatively charged molecule and may bind to positively charged histones to reduce both their cytotoxicity and the number of extracellular histones [ 89 , 90 ]. Collectively, extracellular histones are significantly elevated in critical diseases, such as sepsis and ARDS, and can reflect severity and mortality, potentially making them a useful and promising biomarker and a therapeutic target.
Despite considerable studies into the molecular mechanisms and treatment trials for sepsis and ARDS, the unequivocal and solid curative effect remains limited. However, an increasing body of evidence reveals that histone-related sepsis and ARDS can be inhibited by histone-neutralizing antibodies [ 27 , 30 , 38 , 91 ].
More recent studies from Kusano et al. It appears that negatively charged molecules may naturally have a potent antihistone capacity, which is a promising and positive target that needs further investigation.
Furthermore, pentraxin 3 PTX3 also exerts protective effects on sepsis, both in vivo and in vitro, due to its coaggregation with histones [ 96 ]. Recombinant thrombomodulin rTM could bind to extracellular histones, inhibiting histone-induced platelet aggregation and neutralizing the prothrombotic action of histones [ 68 ]. Finally, although FDA-cleared recombinant APC has been withdrawn from the market because of a lack of efficacy in reducing the mortality of sepsis by randomized controlled trials [ 97 ], the exact role of APC in hydrolysis and the inactivation of histones has been identified and shows great benefits in a number of experimental studies [ 16 , 30 , 86 , 98 ].
However, more animal models and clinical randomized controlled trials are needed Table 2. In summary, histones, as the main structure elements, have recently been identified to be present in the extracellular space and to be involved in multiple cellular processes, including cytotoxicity, proinflammation, procoagulation, and barrier dysfunction.
Therefore, extracellular histones can help with diagnosis, predict prognosis, and reflect the severity of critical illnesses, including sepsis, ARDS, and septic-ARDS. Antihistone-based therapeutic strategies are thought to be useful and promising. However, there are still many unanswered questions regarding how and when histone-blocking agents should be used and the additive effects of combining different histone-targeted agents.
Therefore, the appropriate and safe use of different antihistone-based agents still needs further investigation. Moreover, a better understanding of the substructure, modification modes, and regulation and function of histones in the extracellular space is still needed. The authors also specially thank Jieyu Wu, the fellow of the First Affiliated Hospital of Guangzhou Medical University, for her valuable advice on the construction and writing of the study.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.
Read the winning articles. Journal overview. Special Issues. Academic Editor: Kazuhiro Ito. Received 13 Jul Accepted 01 Sep Published 01 Nov Abstract Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome ARDS still remain major clinical challenges and the leading causes of death for patients in intensive care units ICUs due to insufficient understanding of the pathophysiological mechanisms of these diseases. Introduction Over the last several decades, severe sepsis and acute respiratory distress syndrome ARDS have been the most common causes of mortality in critically ill patients [ 1 — 3 ].
The Source of Extracellular Histones The source of extracellular histones is complicated. Pathologic Roles of Extracellular Histones in Sepsis Sepsis is a systemic inflammatory response to infection [ 40 ]. Cytotoxic Effects High levels of extracellular histones are cytotoxic to both epithelial and endothelial cells [ 16 , 18 , 19 , 35 , 42 ]. Triggering and Promoting Inflammation in Sepsis The innate immune system plays a crucial role in the pathophysiology of sepsis, which induces overwhelming systemic inflammation by releasing various inflammatory mediators in response to invading pathogens [ 14 , 52 ].
Coagulation and Thrombosis in Sepsis Sepsis is almost inevitably associated with the activation of blood coagulation hypercoagulability and systemic clotting with massive thrombin and fibrin formation, eventually resulting in the consumption of platelets and disseminated intravascular coagulation DIC [ 36 , 62 , 63 ]. Organ dysfunction Mechanism Reference Lung injury Cytotoxicity, NLRP3 inflammasome [ 42 , 59 , 74 ] Cardiac injury Cytotoxicity [ 43 , 60 , 74 ] Liver injury Proinflammation [ 74 , 75 ] Kidney injury Proinflammation, cytotoxicity [ 30 , 74 ] Spleen injury Cytotoxicity [ 74 , 76 ] Coagulation Platelets activation, thrombosis [ 39 , 63 , 67 ].
Table 1. Sepsis-associated organ dysfunction induced by extracellular histones. Figure 1. In response to various physical challenges e. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released.
Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. Table 2. Current evidence of targeting extracellular histones for therapy. References C. Brun-Buisson, P. Meshaka, P. Pinton, and B.
Gaieski, J. Edwards, M. Kallan, and B. Bersten, C. Edibam, T. Hunt, and J. Warren, A. Eid, P. Singer et al. Abraham, K. Reinhart, S. Opal et al. Annane, P. Vignon, A. Renault et al. Russell, K. Walley, J. Abraham, P. Laterre, R. Garg et al. Esteban, F. Frutos-Vivar, A. Muriel et al. Kaukonen, M. Bailey, S.
Suzuki, D. Pilcher, and R. Kumar, N. Kumar, A. Taneja et al. Villar, J. Blanco, J. Matthay and R. Angus and T. Matthay, L. Ware, and G. Xu, X. Zhang, R. Pelayo et al. Ekaney, G. Otto, M. Sossdorf et al. Abrams, N. Zhang, J. They're also more likely to die of ARDS. If you have ARDS, you can develop other medical problems while in the hospital. The most common problems are:. Thanks to improved treatments, more people are surviving ARDS.
However, many survivors end up with potentially serious and sometimes lasting effects:. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. This content does not have an English version. This content does not have an Arabic version. Overview Acute respiratory distress syndrome ARDS occurs when fluid builds up in the tiny, elastic air sacs alveoli in your lungs.
Bronchioles and alveoli Open pop-up dialog box Close. Bronchioles and alveoli Your bronchioles are some of the smallest airways in your lungs. Share on: Facebook Twitter. Intravenous fluids are important, but the doctors have to be careful not to give you too much. You need fluids to keep up your blood pressure, which allows your blood to flow through your blood vessels. Too much fluid could cause more fluid build-up in your lungs. Would you like to share your story about sepsis or read about others who have had sepsis?
Please visit Faces of Sepsis , where you will find hundreds of stories from survivors and tributes to those who died from sepsis.
Contributions are deductible for computing income estate taxes. Sepsis Alliance tax ID Share your Story. Get Resources. Metrics details. Predisposing conditions and risk modifiers instead of causes and risk factors have recently been used as alternatives to identify patients at a risk of acute respiratory distress syndrome ARDS. However, data regarding risk modifiers among patients with non-pulmonary sepsis is rare.
Adult patients with severe sepsis caused by non-pulmonary infection were included, and the primary outcome was having ARDS, defined as meeting the Berlin definition on the first or fourth day of screening. The following explanatory variables were then assessed: age, sex, admission source, body mass index, smoking status, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, steroid use, statin use, infection site, septic shock, and acute physiology and chronic health evaluation APACHE II score.
After applying inclusion and exclusion criteria, patients with non-pulmonary sepsis were enrolled, among whom 85 Acute respiratory distress syndrome ARDS comprises heterogenous clinical conditions. Reportedly, the prognosis of ARDS is poor [ 1 , 2 ], and once a patient develops ARDS, treatment options are limited to only a few supportive strategies [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ], making it important to identify patients at a high risk of ARDS [ 10 ].
Previous studies have reported a variety of causes and risk factors of ARDS [ 1 , 11 ]; however, there is a lack of clarity between these because only a small proportion of patients with these causes and risk factors develop ARDS [ 12 , 13 ]. Therefore, alternative efforts have been recently focusing on the roles of two types of risk factors: predisposing conditions and risk modifiers [ 14 , 15 ].
Predisposing conditions are preceding acute pathophysiological events, such as sepsis. Risk modifiers include obesity [ 15 , 16 ], smoking status [ 15 , 17 , 18 ], diabetes mellitus DM reduced risk modifier [ 14 , 15 , 19 ], glucocorticoids [ 20 ], statin [ 21 , 22 ], non-pulmonary infection reduced risk modifier [ 13 , 23 ], shock [ 13 , 15 ], tachypnea [ 14 , 15 ], oxygen supplementation [ 15 , 24 ], hematocrit [ 11 ], hypoalbuminemia [ 14 , 15 ], acidemia [ 11 , 15 ], and disease severity [ 2 , 11 , 13 ].
There is a possibility that ARDS may be precisely predicted using a combination of predisposing conditions and risk modifiers. ARDS has been associated with two major pathophysiologic changes in various proportions. One is the influx of protein-rich effusion to the alveolar space caused by the damage of the local alveolar epithelium and another is leakage to the pulmonary interstitium through the capillary endothelium caused by systemic inflammation.
Thus, we think risk modifiers of direct and indirect ARDS should be discussed separately. Indeed to date, however, little has been reported about risk modifiers for ARDS among patients with non-pulmonary sepsis because a large proportion of patients with pulmonary sepsis have been included in previous studies about risk modifiers [ 2 , 14 , 15 ].
We aimed to evaluate the risk modifiers associated with indirect ARDS among patients with non-pulmonary sepsis. This was a multicenter prospective cohort study of patients with severe sepsis or septic shock enrolled from 59 Intensive care units ICUs in Japan and conducted from January to March [ 26 ].
The exclusion criteria were patients with missing data of the first or fourth days of ARDS screening in this study. Patient information was obtained from the FORECAST database, including demographic data, admission source, comorbidities, infection sites, sepsis-related severity scores, and laboratory data. Severe sepsis and septic shock were defined based on the sepsis-2 criteria [ 28 ]. Non-pulmonary infection was defined as infection other than pneumonia or empyema.
Cases of DM with and without end-organ complications were reported as comorbidities. Patients who died during the study were assigned a ventilator-free day of 0. ICU-free days were calculated and scored in a similar manner [ 29 ].
Patients were stratified into groups with and without ARDS i. Statistical differences between two groups were evaluated by univariate analyses, using the chi-square or Fisher exact tests for categorical variables and the Mann—Whitney U test for continuous variables because the data did not have a normal distribution. The primary outcome of interest was having ARDS, and the explanatory variables were selected based on previous research: body mass index, smoking status, DM, glucocorticoids, statin, site of infection, septic shock, and acute physiology and chronic health evaluation II APACHE II score.
We also include clinically relevant explanatory variables, such as age, gender, admission source, and coexisting conditions e. However, we did not take variables such as tachypnea, oxygen supplementation, acidosis, and hypoalbuminemia into the logistic regression model because these possible risk modifiers might result from ARDS.
All statistical analyses were performed using the EZR software Version 1. Another 85 patients were excluded because they had missing data of the first day of ARDS screening. Finally, patients with non-pulmonary sepsis were enrolled, among whom 85 The median age was 72 IQR: 62—81 years and males accounted for patients There were patients Patients with ARDS had a lower Charlson Comorbidity Index than patients without ARDS, but there were no significant differences between the groups regarding other baseline characteristics, such as age, gender, and admission source.
There was no significant difference between patients with and without ARDS regarding previously known risk modifiers for direct and indirect ARDS, including body mass index, DM, smoking status, and site of infection. In-hospital mortality in patients with and without ARDS was Of the patients with septic shock, the in-hospital mortality rate of those with ARDS was significantly higher than that of patients without ARDS However, there was no significant difference in the length of hospital stay by ARDS status 25 [11—61] vs.
In the multivariate logistic regression model, we identified three main risk modifiers associated with having ARDS Table 3. Notably, the odds of having ARDS were higher for patients from the emergency department than for those transferred from hospital wards or other hospitals OR, 1. In this retrospective cohort study of patients with non-pulmonary sepsis, admission route from the emergency department rather than wards or other hospitals , disease severity a higher APACHE II score , and infection site soft tissue rather than abdominal infection were risk modifiers for non-pulmonary septic ARDS.
Duration of onset from infection could be a valid risk modifier of ARDS in non-pulmonary sepsis. In our results, admission from the emergency department was related to having ARDS, and it is possible that both direct and indirect ARDS developed soon after or at the onset of sepsis [ 15 , 31 ].
Thus, ARDS may not have occurred after time had passed from admission, and further studies are needed to investigate the timing of the onset of ARDS in non-pulmonary sepsis. Site of infection also appeared to be a risk modifier for ARDS in non-pulmonary sepsis.
One study showed that abdominal infection was related to with ARDS [ 23 ], and another study showed that soft tissue infection was related to without ARDS in population that included pulmonary infection [ 13 , 32 ].
0コメント