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• W2024227449 abstract "Sepsis is a major health problem in the United States with high incidence and elevated patient care cost. Using an animal model of sepsis, cecum ligation, and puncture, we observed that mice became rapidly hypothermic reaching a threshold temperature of 28 °C within 5–10 h after initiation of the insult, resulting in a reliable predictor of mortality, which occurred within 30–72 h of the initial procedure. We also observed that the inflammatory gene expression in lung and liver developed early within 1–2 h of the insult, reaching maximum levels at 6 h, followed by a decline, approaching basal conditions within 20 h. This decrease in inflammatory gene expression at 20 h after cecal ligation and puncture was not due to resolution of the insult but rather was an immune dysfunction stage that was demonstrated by the inability of the animal to respond to a secondary external inflammatory stimulus. Removal of the injury source, ligated cecum, within 6 h of the initial insult resulted in increased survival, but not after 20 h of cecal ligation and puncture. We concluded that the therapeutic window for resolving sepsis is early after the initial insult and coincides with a stage of hyperinflammation that is followed by a condition of innate immune dysfunction in which reversion of the outcome is no longer possible. Sepsis is a major health problem in the United States with high incidence and elevated patient care cost. Using an animal model of sepsis, cecum ligation, and puncture, we observed that mice became rapidly hypothermic reaching a threshold temperature of 28 °C within 5–10 h after initiation of the insult, resulting in a reliable predictor of mortality, which occurred within 30–72 h of the initial procedure. We also observed that the inflammatory gene expression in lung and liver developed early within 1–2 h of the insult, reaching maximum levels at 6 h, followed by a decline, approaching basal conditions within 20 h. This decrease in inflammatory gene expression at 20 h after cecal ligation and puncture was not due to resolution of the insult but rather was an immune dysfunction stage that was demonstrated by the inability of the animal to respond to a secondary external inflammatory stimulus. Removal of the injury source, ligated cecum, within 6 h of the initial insult resulted in increased survival, but not after 20 h of cecal ligation and puncture. We concluded that the therapeutic window for resolving sepsis is early after the initial insult and coincides with a stage of hyperinflammation that is followed by a condition of innate immune dysfunction in which reversion of the outcome is no longer possible. Sepsis is a major health problem in the United States with an incidence of 750,000 cases/year and a mortality rate of 30–50%, which is predicted to continue to increase annually (1Angus D.C. Linde-Zwirble W.T. Lidicker J. Clermont G. Carcillo J. Pinsky M.R. Epidemiology of severe sepsis in the United States. Analysis of incidence, outcome, and associated costs of care.Crit. Care Med. 2001; 29: 1303-1310Crossref PubMed Scopus (6661) Google Scholar, 2Martin G.S. Mannino D.M. Eaton S. Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.N. Engl. J. Med. 2003; 348: 1546-1554Crossref PubMed Scopus (4823) Google Scholar). In addition, the health costs associated with the treatment of septic patients is extremely high at over $16 billion per year (1Angus D.C. Linde-Zwirble W.T. Lidicker J. Clermont G. Carcillo J. Pinsky M.R. Epidemiology of severe sepsis in the United States. Analysis of incidence, outcome, and associated costs of care.Crit. Care Med. 2001; 29: 1303-1310Crossref PubMed Scopus (6661) Google Scholar). Morbidity and mortality associated with sepsis is often complicated by the development of secondary conditions, including severe sepsis, septic shock, and multiple organ failure (3Dellinger R.P. Levy M.M. Carlet J.M. Bion J. Parker M.M. Jaeschke R. Reinhart K. Angus D.C. Brun-Buisson C. Beale R. Calandra T. Dhainaut J.F. Gerlach H. Harvey M. Marini J.J. Marshall J. Ranieri M. Ramsay G. Sevransky J. Thompson B.T. Townsend S. Vender J.S. Zimmerman J.L. Vincent J.L. International Surviving Sepsis Campaign Guidelines Committee, American Association of Critical-Care Nurses, American College of Chest Physicians, American College of Emergency Physicians, Canadian Critical Care Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Japanese Association for Acute Medicine, Japanese Society of Intensive Care Medicine, Society of Critical Care Medicine, Society of Hospital Medicine, Surgical Infection Society, and World Federation of Societies of Intensive and Critical Care Medicine Surviving Sepsis Campaign. International guidelines for management of severe sepsis and septic shock.Crit. Care Med. 2008; 36: 296-327Crossref PubMed Scopus (3981) Google Scholar). The current treatment for sepsis and septic shock is mainly supportive. A great deal of effort, time, and money has been directed at potential therapeutic interventions for sepsis without major success. In particular, clinical trials aimed at blocking the inflammatory response have failed (4Hotchkiss R.S. Karl I.E. The pathophysiology and treatment of sepsis.N. Engl. J. Med. 2003; 348: 138-150Crossref PubMed Scopus (3211) Google Scholar, 5Remick D.G. Pathophysiology of sepsis.Am. J. Pathol. 2007; 170: 1435-1444Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar), which is likely related to the multifactorial nature of this condition, which includes pre-existing conditions, the type of injury or infection, and the inflammatory process triggered by the initial insult (5Remick D.G. Pathophysiology of sepsis.Am. J. Pathol. 2007; 170: 1435-1444Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). These responses are modified by the genetic make-up, sex, and age of the patients (9De Maio A. Torres M.B. Reeves R.H. Genetic determinants influencing the response to injury, inflammation, and sepsis.Shock. 2005; 23: 11-17Crossref PubMed Scopus (108) Google Scholar). In addition, the potential therapeutic window for the treatment of sepsis has not been well defined. Finally, there are no sensitive and reliable predictors of sepsis that can be used as an early diagnostic to define the incidence of the condition and the appropriate timing for treatment (4Hotchkiss R.S. Karl I.E. The pathophysiology and treatment of sepsis.N. Engl. J. Med. 2003; 348: 138-150Crossref PubMed Scopus (3211) Google Scholar, 5Remick D.G. Pathophysiology of sepsis.Am. J. Pathol. 2007; 170: 1435-1444Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). The current dogma indicates that septic shock, which leads to multiple organ failure and death, is the result of an exaggerated or poorly controlled inflammatory response, which has been coined the “cytokine storm” (5Remick D.G. Pathophysiology of sepsis.Am. J. Pathol. 2007; 170: 1435-1444Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar, 10Murphy T.J. Paterson H.M. Mannick J.A. Lederer J.A. Injury, sepsis, and the regulation of Toll-like receptor responses.J. Leukocyte Biol. 2004; 75: 400-407Crossref PubMed Scopus (120) Google Scholar). The basic idea is that the proinflammatory response triggered by the initial insult is not effectively counterbalanced by the anti-inflammatory response, resulting in cellular dysfunction, organ failure, and death. Cellular dysfunction may be the product of excessive activation that may directly affect many basic cellular processes or indirectly affect neighboring cells, for example, through the release of toxic agents and oxygen radicals. On the other hand, cell dysfunction may be due to reduced delivery of nutrients and oxygen as a result of capillary constriction (5Remick D.G. Pathophysiology of sepsis.Am. J. Pathol. 2007; 170: 1435-1444Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). Increased cell death by apoptosis has also been proposed as a major contributor to organ dysfunction during shock (11Hotchkiss R.S. Nicholson D.W. Apoptosis and caspases regulate death and inflammation in sepsis.Nat. Rev. Immunol. 2006; 6: 813-822Crossref PubMed Scopus (606) Google Scholar). Another hypothesis is that death after septic shock is due to immunosuppression or immunoparalysis developed after the initial proinflammatory process. Immunoparalysis ameliorates the capacity of the organism to maintain a “healthy” inflammatory process and properly clear pathogens (12Hotchkiss R.S. Coopersmith C.M. McDunn J.E. Ferguson T.A. The sepsis seesaw. Tilting toward immunosuppression.Nat. Med. 2009; 15: 496-497Crossref PubMed Scopus (437) Google Scholar). The connection between the initial hyperimmune response and immunosuppression and mortality from septic shock is not clear. Using an experimental animal model for the study of sepsis, cecum ligation, and puncture (CLP), 4The abbreviations used are: CLPcecum ligation and punctureqRT-PCRquantitative real time RT-PCRANOVAanalysis of varianceNOnonoperatedSOsham operation. we have found that the response to CLP can be divided into two phases: an early hyperinflammatory response and late innate immune dysfunction. These two phases also correspond to therapeutically reversible and irreversible stages of sepsis, respectively. cecum ligation and puncture quantitative real time RT-PCR analysis of variance nonoperated sham operation. C57BL6/J (B6) mice were obtained from Jackson Laboratories. Male B6 mice (8 weeks old) were starved for 16 h before any intervention. CLP was performed as previously described (13Torres M.B. De Maio A. An exaggerated inflammatory response after CLP correlates with a negative outcome.J. Surg. Res. 2005; 125: 88-93Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Male mice were anesthetized with isoflurane via a vaporizer at 1.5–2.5 minimum alveolar concentration. Under sterile conditions, a 2-cm incision was made in the lower abdominal region, and the cecum was exposed. The distal portion of the cecum was ligated 1.5 cm from the end with a 4–0 silk suture and punctured once with a 16-gauge needle. The cecum was replaced in the peritoneal cavity and squeezed to place a small portion of its content (bacteria and feces) into the peritoneum. Then the peritoneal wall and skin were closed with double sutures. The mice were resuscitated with a subcutaneous injection of sterile saline (1 ml). As a control, mice were sham operated as described above, except that the cecum was neither ligated nor perforated. Nonoperated mice were also used as a second control. After the procedure, the mice had an accessible source of water and food ad libitum. Although we did not quantitate food and water uptake after CLP, we observed a small gain in weight after CLP with respect to the beginning of the experiment, which was no different from sham operated mice. This observation is consistent with published data (19Xiao H. Siddiqui J. Remick D.G. Mechanisms of mortality in early and late sepsis.Infect. Immun. 2006; 74: 5227-5235Crossref PubMed Scopus (141) Google Scholar). For cecum excision, mice 3, 6, 8, or 20 h after CLP were anesthetized with isoflurane (1.5–2.5 minimum alveolar concentration), the initial incision was opened again under sterile conditions, and the ligated cecum was removed by cutting between two sutures. The peritoneum was rinsed three times with sterile saline, and the peritoneal wall and skin were closed with double sutures. As indicated, the mice were slightly anesthetized with isoflurane and injected with LPS (15 mg/kg) or an equal volume of saline. During the time of the initial surgery, a small thermal probe was placed under the skin during the procedure. The mice were placed in individual cages, and their temperature was continuously recorded using an external receiver (VitalView data acquisition system). These animal protocols have been reviewed and approved by the University of California San Diego Institutional Animal Care and Use Committee according to the National Institutes of Health guidelines. Levels of mRNA were measured by quantitative real time RT-PCR (qRT-PCR). Tissues were harvested, flash frozen in liquid nitrogen, and stored at −80 °C. The samples were then suspended and homogenized in TRIzol reagent (Invitrogen), and total RNA was isolated. RNA was treated with DNase I (DNA-free kit; Ambion, Austin, TX) and reverse-transcribed to cDNA using a high capacity reverse transcription kit (Applied Biosystems, Foster City, CA). Newly synthesized cDNA was further diluted and stored at −20 °C. Samples of cDNA were amplified by a 7500 fast real time PCR System (Applied Biosystems) using the QuantiTect SYBR Green PCR kit (Qiagen) with the following QuantiTect validated primer sets (Qiagen): TNF-α (QT00104006), IL-1β (QT01048355), IL-6 (QT00098875), IL-10 (QT00106169), IFN-β (QT00249662), HMGB1 (QT00247786), CD14 (QT00246190), and TLR4 (QT00259042). Standards corresponding to each target gene were added in each PCR. The results for each sample were normalized by copy number of GAPDH (QT01658692; Qiagen), used as a marker of cDNA inputs. All of the results were expressed as copy numbers of target gene per copy numbers of GAPDH. Myeloperoxidase activity was measured by a modification of method described by (14Stewart D. Fulton W.B. Wilson C. Monitto C.L. Paidas C.N. Reeves R.H. De Maio A. Genetic contribution to the septic response in a mouse model.Shock. 2002; 18: 342-347Crossref PubMed Scopus (57) Google Scholar). Samples of liver (150 mg) and the left side of the lung were flushed with PBS and homogenized for 30 s in phosphate buffer, pH 7.4. Homogenates were centrifuged at 10,000 × g for 10 min at 4 °C, and the resulting pellets were resuspended in phosphate buffer, pH 6.0, containing 0.5% hexadecyltrimethylammonium bromide. The samples were then subjected to three cycles of freezing and thawing, sonication (three times for 10 s for lung and five times for 10 s for liver), and centrifugation at 10,000 × g for 5 min at 4 °C. The supernatant (25 μl) was mixed with phosphate buffer, pH 6.0, containing O-dianisidine dihydrochloride (0.167 mg/ml) and hydrogen peroxide (0.0005%), and absorbance at 460 nm was measured immediately at regular intervals (15 s) for 5 min. Protein concentration was measured for each sample by the BCA protein assay, and data (myeloperoxidase activity) were expressed as change in absorbance/min/mg of protein. All of the data were analyzed using GraphPad Prism software (GraphPad Prism Software, San Diego, CA). Significance was analyzed using one-way or two-way ANOVA followed by Newman-Keul's multiple comparison test. A p value of < 0.05 was considered statistically significant. Statistical significance was analyzed by log rank test for comparison of mortality rates. A central objective of this study was to correlate the inflammatory process with the final outcome (mortality) from sepsis induced by CLP. Prior studies have shown that hypothermia is a premorbid condition in experimental sepsis, which can be used as a marker for death after CLP (15Nemzek J.A. Xiao H.Y. Minard A.E. Bolgos G.L. Remick D.G. Humane endpoints in shock research.Shock. 2004; 21: 17-25Crossref PubMed Scopus (135) Google Scholar). To monitor core body temperature, a small probe was inserted under the skin of the abdomen at the time of CLP intervention to monitor core body temperature using a telemetric system (VitalView data acquisition system). The continuous readout in body temperature was recorded for each individual animal. C57BL/6J (B6) male mice were subjected to a fulminant variant of the CLP model (1.5-cm cecum ligation, 16-gauge needle single puncture) to study the events associated with the response to sepsis in a relatively short time period. This study was performed in the absence of antibiotic treatment. Therefore, this model reflected the natural response to sepsis with minimal support therapy to establish the base line response. We observed a rapid decline in core body temperature within the first few hours after CLP (a typical temperature profile is presented in Fig. 1A). Based on these observations, we found, with 100% accuracy, that animals that reached a core body temperature of 28 °C died within 72 h of the initial insult. The animals reached the 28 °C threshold core body temperature within 5–10 h after CLP, but mortality was only observed between within 30 and 72 h of the insult. The survival rate at 72 h after CLP was 16.4%, and mice that were predicted to die based on the decrease in core body temperature to 28 °C was 14.6% (Fig. 1B). These observations suggest that reaching a core body temperature threshold of 28 °C is an accurate and early predictor of mortality. These observations were further corroborated using a different mouse strain (A/J), which displayed a different mortality rate after CLP (13Torres M.B. De Maio A. An exaggerated inflammatory response after CLP correlates with a negative outcome.J. Surg. Res. 2005; 125: 88-93Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 14Stewart D. Fulton W.B. Wilson C. Monitto C.L. Paidas C.N. Reeves R.H. De Maio A. Genetic contribution to the septic response in a mouse model.Shock. 2002; 18: 342-347Crossref PubMed Scopus (57) Google Scholar). A/J mice were subjected to CLP (1.5-cm cecum ligation, 16-gauge needle single puncture), and both core body temperature and mortality were monitored (Fig. 1C). In this case, all of the animals that died displayed a core body temperature below 28 °C, whereas survivals were above 28 °C. Again, the survival rate of actual mortality was 36.8%, and predicted deaths based on reaching 28 °C were 35.9% (Fig. 1D). Finally, we tested a different animal model that also resulted in significant animal death. Mice (B6) were injected with Escherichia coli LPS (15 mg/kg), resulting in 100% mortality. All of the mice displayed a very rapid decrease in core body temperature to below 28 °C within 10 h of injection (Fig. 1E), whereas mortality was observed after several hours (Fig. 1F). Thus, the 28 °C threshold temperature appears to be a reliable early predictor of mortality, well ahead of the actual death. Based on the rapid decrease in core body temperature after CLP, we investigated how early the inflammatory process could be detected following the initial insult. The expression of genes involved in the inflammatory process (i.e. cytokines) was measured at the mRNA level rather than by secreted protein in circulation. This approach is relevant, because it provides a more sensitive read-out of the inflammatory process because the detection limit of qRT-PCR is considerably more sensitive than methods to measure protein, such as ELISA. In addition, this approach allows us to study the kinetic of the inflammatory process after CLP at very early stages of the process when the concentration of cytokines in circulation may be very low. Finally, measuring mRNA levels allows us to study the production of inflammatory molecules in specific organs rather than in circulation, providing more mechanistic information. The expression of four cytokine genes was measured in lung and liver harvested from mice after CLP (1.5-cm cecum ligation, 16-gauge needle single puncture) or sham operation and compared with nonoperated (NO) control mice. We observed a very rapid inflammatory response within the lung, peaking within 2–3 h after CLP for TNF-α, IL-1β, and IL-10, whereas the peak of IL-6 was observed at 6 h in comparison with NO or sham operated mice (Fig. 2A). Similar observations were made in liver samples in which TNF-α, IL-1β, and IL-6 peaked within 2–3 h and IL-10 after 6 h of CLP in comparison with NO or sham operated mice (Fig. 2B). In both organs, the inflammatory response was followed by a rapid decline in gene expression beginning after 6 h of CLP and reaching basal levels similar to sham operated mice within 20 h of CLP (Fig. 2). Further analysis until 30 h of CLP, which corresponded to a time period very close to the initial mortalities after the insult, revealed that the majority of cytokine expression levels were still suppressed in the liver (Fig. 2B). In the lung, both IL-1β and IL-6 displayed minimal expression levels, whereas the expression of TNF-α was slightly but significantly increased in comparison with sham operated mice. On the contrary, IL-10 expression was dramatically elevated with respect to sham operated animals (Fig. 2A). As another marker of the inflammatory process, we measured the infiltration of PMNL (myeloperoxidase assay) in the lung and liver after CLP. Again, a rapid and significant increase in the infiltration of PMNL in lung was observed within 2–3 h followed by a rapid decline but was still significantly different from sham operated mice after 20 or 30 h of CLP (Fig. 3A). PMNL infiltration in liver was also rapid, reaching maximal levels within 6 h, followed by a decrease that was significantly different from sham operated mice (Fig. 3B). The characterization of the inflammatory process after CLP was further analyzed by measuring the expression of receptors involved in the innate immune response, CD14 and TLR4. The expression of CD14 (mRNA) levels also increased in the lung after CLP, reaching maximum levels within 3–4 h, which was followed by a rapid fall (after 6 h), reaching levels similar to sham operated mice within 20 h, followed by a second increase at 30 h of CLP (Fig. 4A). In the liver, CD14 expression also increased within 4–6 h of CLP, followed by a reduction within 20–30 h of CLP, which was significantly different from sham operated mice (Fig. 4B). In contrast, TLR4 expression was not significantly increased after CLP, and it was similar to sham operated mice (Fig. 4A). All together, these observations suggest that the induction of the inflammatory response by CLP was very rapid and can be divided into two periods: an early hyperinflammatory phase (<6 h) and a hypoinflammatory phase (>20 h), which could be partially modified within 30 h of the insult.FIGURE 4The expression of CD14, but not Tlr4, changed during the time course of CLP. Male B6 mice (n = 50) were subjected to CLP, 1.5-cm cecum ligation and 16-gauge needle perforation (closed squares), or sham operation (open squares). At different time points after CLP (n = 5) or sham operation (n = 5), the mice were sacrificed, lung (A) and liver (B) were harvested, and total RNA was isolated. Levels of mRNA for CD14 or Tlr4 were measured by qRT-PCR. The mRNA levels were established by comparison with a standard curve and expressed as a copy number. The values were normalized to GADPH mRNA levels. Statistical analysis for the time course of CLP was performed by one-way ANOVA, and comparison between CLP and sham operation was measured by two-way ANOVA. *, p < 0.05 CLP versus sham operated at each time point. Notice that cytokine gene expression is observed very rapidly after CLP in both organs.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Based on the inflammatory phases observed and the rapid decline in core body temperature after CLP, we were interested in defining how they related to the possible therapeutic window after CLP. We thought that removal of the ligated/perforated cecum, which is the source of infection and injury, was probably the most dramatic intervention to resolve sepsis. Previous studies have shown that, indeed, cecum excision improved survival after CLP (16Baker C.C. Chaudry I.H. Gaines H.O. Baue A.E. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model.Surgery. 1983; 94: 331-335PubMed Google Scholar, 17Chaudry I.H. Tabata Y. Schleck S. Baue A.E. Effect of splenectomy on reticuloendothelial function and survival following sepsis.J. Trauma. 1980; 20: 649-656Crossref PubMed Scopus (38) Google Scholar, 18Latifi S.Q. O'Riordan M.A. Levine A.D. Interleukin-10 controls the onset of irreversible septic shock.Infect. Immun. 2002; 70: 4441-4446Crossref PubMed Scopus (140) Google Scholar, 19Xiao H. Siddiqui J. Remick D.G. Mechanisms of mortality in early and late sepsis.Infect. Immun. 2006; 74: 5227-5235Crossref PubMed Scopus (141) Google Scholar). We excised the ligated cecum at 3 or 20 h after CLP, because these time points represent the two different inflammatory phases observed after the insult. The mice were subjected to CLP, and then they were randomized into three groups at 3 h or 20 h after CLP. In one group, the ligated cecum was removed (CLP + cecum removal). The second group was subjected to sham operation (CLP + sham). The third group was not operated a second time (CLP + NO). Removal of the ligated cecum at 3 h after CLP showed a statistically significant improvement of the survival rate in comparison with animals in which the cecum was not removed but were sham operated or nonoperated a second time (Fig. 5A). In contrast, excision of the cecum at 20 h after CLP did not improve the survival rate (Fig. 5B). Subsequent experiments in which the cecum was removed at 6 or 8 h after CLP showed 80 and 30% survival rates, respectively (Fig. 5C). Based on these observations, we defined two distinct phases of sepsis: therapeutically reversible (< 6 h) and therapeutically irreversible (> 20 h), which coincide with the two inflammatory stages observed above. The therapeutically irreversible phase of sepsis corresponds to a condition in which the inflammatory response is already reduced with respect to the early hyperinflammatory and therapeutically reversible phase. This condition may resemble a stage of immunosuppression or immunoparalysis, which has been previously described during sepsis (12Hotchkiss R.S. Coopersmith C.M. McDunn J.E. Ferguson T.A. The sepsis seesaw. Tilting toward immunosuppression.Nat. Med. 2009; 15: 496-497Crossref PubMed Scopus (437) Google Scholar). Therefore, we decided to investigate this possible immunosuppressive stage by using a functional assay. We evaluated the response to LPS, which induces a strong inflammatory response, at a late stage of sepsis (20 h after CLP), in which mortalities were still not observed. The mice were subjected to CLP, sham operation (SO), or NO. These animals were challenged with LPS (15 mg/kg) at 20 h after the initial procedure, and cytokine levels (qRT-PCR) in lungs and liver were measured 2 h after LPS injection. As a negative control, a group of mice that were neither subjected to CLP nor injected with LPS were included. We observed that TNF-α and IFN-β mRNA levels were induced after LPS injection in mice that were initially NO or SO in comparison with mice that were not injected with LPS. In contrast, LPS-induced TNF-α and IFN-β mRNA levels in both lung and liver samples were significantly reduced in mice that were subjected to CLP first in comparison with SO or NO after LPS injection (Fig. 6). LPS-induced IL-6 and IL-10 mRNA levels were highly increased in lung of mice that were CLP pretreated in comparison with mice that were SO or NO (Fig. 6A). No statistical differences were observed in IL-6 and IL-10 mRNA levels in liver after LPS injection between animals that were initially subjected to CLP, SO, or NO (Fig. 6B). The expression of a late sepsis marker, HMGB1, was also evaluated. Significant increases in HMGB1 mRNA levels were observed in all animals injected with LPS regardless of whether or not they were initially subjected to CLP, sham operation, or not operated at all in comparison with the absence of LPS injection (Fig. 6). These observations suggest that the innate immune response is partially compromised during the irreversible phase of sepsis (> 20 h after CLP). Trauma/injury is the third overall cause of mortality in the United States, surpassed only by cardiovascular disease and cancer. Moreover, it is the main killer in people under 40 years of age. One of the consequences of trauma/injury is the incidence of sepsis, which is often followed by the development of septic shock, multiple organ failure, and death (2Martin G.S. Mannino D.M. Eaton S. Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.N. Engl. J. Med. 2003; 348: 1546-1554Crossref PubMed Scopus (4823) Google Scholar, 3Dellinger R.P. Levy M.M. Carlet J.M. Bion J. Parker M.M. Jaeschke R. Reinhart K. Angus D.C. Brun-Buisson C. Beale R. Calandra T. Dhainaut J.F. Gerlach H. Harvey M. Marini J.J. Marshall J. Ranieri M. Ramsay G. Sevransky J. Thompson B.T. Townsend S. Vender J.S. Zimmerman J.L. Vincent J.L. International Surviving Sepsis Campaign Guidelines Committee, American Association of Critical-Care Nurses, American College of Chest Physicians, American College of Emergency Physicians, Canadian Critical Care Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Japanese Association for Acute Medicine, Japanese Society of Intensive Care Medicine, Society of Critical Care Medicine, Society of Hospital Medicine, Surgical Infection Society, and World Federation of Societies of Intensive and Critical Care Medicine Surviving Sepsis Campaign. International guidelines for management of severe sepsis and septic shock.Crit. Care Med. 2008; 36: 296-327Crossref PubMed Scopus (3981) Google Scholar, 20Bone R.C. The sepsis syndrome. Definition and general approach to management.Clin. Chest Med. 1996; 17: 175-181Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). The severe impact of sepsis and septic shock on society is at several levels, including the enormous number of lives tha" @default.
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• W2024227449 date "2012-06-01" @default.
• W2024227449 modified "2023-10-06" @default.
• W2024227449 title "Period of Irreversible Therapeutic Intervention during Sepsis Correlates with Phase of Innate Immune Dysfunction" @default.
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