Sepsis Induces Early Alterations in Innate Immunity That Impact Mortality to Secondary Infection

Delano, Matthew J.; Thayer, Terri C.; Gabrilovich, Sonia; Kelly-Scumpia, Kindra M.; Winfield, Robert D.; Scumpia, Philip O.; Cuenca, Alex G.; Warner, Elizabeth A.; Wallet, Shannon M.; Wallet, Mark A.; O’Malley, Kerri; Ramphal, Reuben; Clare-Salzer, M; Efron, Philip A.; Mathews, Clayton E.; Moldawer, Lyle L.

doi:10.4049/jimmunol.1002104

Cited by 142 publications

(141 citation statements)

References 30 publications

(42 reference statements)

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“…In fact, 10 to 30% of mechanically ventilated, septic shock patients develop ventilator-associated pneumonia (6). This positive association extends beyond ventilator-related circumstances and has been corroborated experimentally by multiple studies demonstrating deleterious effects of sepsis and/or endotoxemia on pneumonia outcomes (7)(8)(9)(10)(11)(12)(13)(14)(15). With the rapid increase in prevalence of drugresistant pathogens and the limited treatment options available, there is a growing need to develop novel pharmaceutical interventions and to improve our understanding of the inflammatory processes involved in both pathologies.…”

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confidence: 72%

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

et al. 2015

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e Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10 6 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3 ؊/؊ ). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3 ؊/؊ mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3 ؊/؊ mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3 ؊/؊ mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. Sepsis is a complex immunopathological syndrome defined by the systemic inflammatory response to infection and is a leading contributor to morbidity and mortality in intensive care units as evidenced by approximately 750,000 cases per year (2% of all hospital admissions) (1-3). This multifaceted, systemic inflammatory response can be further complicated by organ dysfunction (severe sepsis) and hypotension (septic shock), all of which lead to a complex, variable syndrome with mortality rates between 30 and 50% (4). While pneumonia is the leading cause of sepsis, with about one-half of all sepsis cases originating as respiratory infections (2), sepsis also greatly increases a patient's subsequent susceptibility to bacterial pneumonia (5). In fact, 10 to 30% of mechanically ventilated, septic shock patients develop ventilator-associated pneumonia (6). This positive association extends beyond ventilator-related circumstances and has been corroborated experimentally by multiple studies demonstrating deleterious effects of sepsis and/or endotoxemia on pneumonia outcomes (7-15). With the rapid increase in prevalence of drugresistant pathogens and the limited treatment options available, there is a growing need to develop novel pharmaceutical interventions...

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confidence: 72%

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

et al. 2015

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“…The collective reports suggest a beneficial role of MDSCs centered on replenishing innate cell function and immune surveillance through emergency granulopoiesis (35). We found that, before MDSC expansion occurs, there is a window of susceptibility to the secondary infections and subsequent mortality that are associated with reduced BM cell numbers and reduced blood and tissue neutrophil numbers and function (33). Optimal MDSC expansion through enhanced granulopoiesis confers long-term immunity to secondary infections in sepsis (71).…”

Section: Introductionmentioning

confidence: 79%

“…Because of the inherent difficulty of immune phenotyping immature myeloid cells in humans versus the relative ease of doing so in mice, few clinical studies have investigated the roles of MDSCs in septic patients (72). Nonetheless, there is considerable interest in myelopoiesis, MDSC expansion, and hematopoietic cell function (33,40,71,73,74). Given the importance of an efficient regeneration of functioning neutrophils, monocytes, and DCs, it is no surprise that MDSCs expand to meet the continual need for functional innate immune cells.…”

Section: Introductionmentioning

confidence: 99%

“…They comprise the majority of the cells in the BM and are the first responders to foreign invaders (31). Sepsis induces a state of delayed neutrophil apoptosis (32), leading to persistent neutrophil dysfunction, compounded by the release of immature neutrophils from BM that culminates in neutrophil deficits in oxidative burst (33), cell migration (34,35), complement activation, and bacterial clearance (36), all of which contribute to ongoing immune dysfunction and inflammation persistence. These findings, coupled with insufficiencies in TLR signaling (37), chemokine-induced chemotaxis (38), altered apoptotic pathways, and neutrophil senescence (39), result in functional deficiencies that persist even after sepsis symptoms have disappeared.…”

Section: Introductionmentioning

confidence: 99%

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Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

Delano¹,

Ward²

2016

Journal of Clinical Investigation

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472

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Sepsis affects the immune system by directly altering the lifespan, production, and function of the effector cells responsible for Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after "recovery" from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical "recovery," with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved.

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“…For induction of polymicrobial sepsis, cecal ligation and puncture (CLP) was performed under isoflurane anesthesia, as described previously (6,8). In brief, the cecum was exposed after a midline laparotomy, ligated with 2-0 silk suture 1 cm from the tip, and punctured through and through with a 25-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis

Mira

Szpila

Nacionales

et al. 2016

Physiological Genomics

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Mohr AM, Baker HV, Moldawer LL, Efron PA. Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis. Physiol Genomics 48: 135-144, 2016. First published November 17, 2015 doi:10.1152 doi:10. /physiolgenomics.00072.2015 remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma-hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PTϩPp). Groups of naïve, CLP, PT, and PTϩPp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P Ͻ 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PTϩPp), there were 10,426 total genes that were found to significantly differ from naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (r s) of 0.446 (P Ͻ 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice.

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Sepsis Induces Early Alterations in Innate Immunity That Impact Mortality to Secondary Infection

Cited by 142 publications

References 30 publications

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis

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