Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response

Osuchowski, Marcin F.; Welch, Kathy; Yang, Huan; Siddiqui, Javed; Remick, Daniel G.

doi:10.4049/jimmunol.179.1.623

Cited by 73 publications

(75 citation statements)

References 59 publications

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“…To study the kinetics and immunological properties of MDSCs in sepsis, we induced a sepsis response that develops in early and late phases. The early/acute phase of sepsis in mice is defined as the first 5 days after CLP (17,31). Our previous studies showed that the mortality rate in this model is ϳ20 to 30% during the early phase (days 1 to 5) of sepsis, and mice surviving the early phase develop late/prolonged bacterial infections and an immunosuppressive inflammatory phenotype, typical of late/ chronic sepsis (7).…”

Section: Cd11bmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

et al. 2012

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c Myeloid-derived suppressor cells (MDSCs) are a heterogeneous Gr1؉ CD11b ؉ population of immature cells containing granulocytic and monocytic progenitors, which expand under nearly all inflammatory conditions and are potent repressors of T-cell responses. Studies of MDSCs during inflammatory responses, including sepsis, suggest they can protect or injure. Here, we investigated MDSCs during early and late sepsis. To do this, we used our published murine model of cecal ligation and puncture (CLP)-induced polymicrobial sepsis, which transitions from an early proinflammatory phase to a late anti-inflammatory and immunosuppressive phase. We confirmed that Gr1 ؉ CD11b ؉ MDSCs gradually increase after CLP, reaching ϳ88% of the bone marrow myeloid series in late sepsis. Adoptive transfer of early (day 3) MDSCs from septic mice into naive mice after CLP increased proinflammatory cytokine production, decreased peritoneal bacterial growth, and increased early mortality. Conversely, transfer of late (day 12) MDSCs from septic mice had the opposite effects. Early and late MDSCs studied ex vivo also differed in their inflammatory phenotypes. Early MDSCs expressed nitric oxide and proinflammatory cytokines, whereas late MDSCs expressed arginase activity and anti-inflammatory interleukin 10 (IL-10) and transforming growth factor ␤ (TGF-␤). Late MDSCs had more immature CD31؉ myeloid progenitors and, when treated ex vivo with granulocyte-macrophage colony-stimulating factor (GM-CSF), generated fewer macrophages and dendritic cells than early MDSCs. We conclude that as the sepsis inflammatory process progresses, the heterogeneous MDSCs shift to a more immature state and from being proinflammatory to anti-inflammatory.

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Section: Cd11bmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

et al. 2012

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“…In many cases, determining what force dominates (pro-vs antiinflammatory responses) on the basis of serum measurements will remain nearly impossible, because both responses are enhanced during septic shock. An alternative would be to use a panel of markers rather than a single parameter, allowing a better definition of individualized pro-/anti-inflammatory profiles (49,(71)(72)(73).…”

Section: Measurement Of Circulating Mediatorsmentioning

confidence: 99%

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Monneret

Venet

Pachot

et al. 2008

Mol Med

302

323

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“…Evidence supports that the pathophysiology of sepsis varies as it moves from an initiating early/acute hyperinflammatory phase to a late/chronic hypoinflammatory and immunosuppressive phase (31,47,51,67). The early phase of sepsis is typified by a systemic inflammatory response syndrome (SIRS) characterized by excessive production of proinflammatory mediators by neutrophils and macrophages (53), increased generation of reactive oxygen species, and leukocyte-induced microvascular injury and organ failure (35).…”

mentioning

confidence: 99%

Hematopoietic Stem-Progenitor Cells Restore Immunoreactivity and Improve Survival in Late Sepsis

et al. 2012

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Sepsis progresses from an early/acute hyperinflammatory to a late/chronic hypoinflammatory phase with immunosuppression. As a result of this phenotypic switch, mortality in late sepsis from persistent primary infection or opportunistic new infection often exceeds that in acute sepsis. Emerging data support that persistence of the hypoinflammatory (hyporesponsive) effector immune cells during late sepsis might involve alterations in myeloid differentiation/maturation that generate circulating repressor macrophages that do not readily clear active infection. Here, we used a cecal ligation and puncture (CLP) murine model of prolonged sepsis to show that adoptive transfer of CD34 ؉ hematopoietic stem-progenitor cells after CLP improves long-term survival by 65%. CD34 ؉ cell transfer corrected the immunosuppression of late sepsis by (i) producing significantly higher levels of proinflammatory mediators upon ex vivo stimulation with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide, (ii) enhancing phagocytic activity of peritoneal macrophages, and (iii) clearing bacterial peritonitis. Improved immunity by CD34 ؉ cell transfer decreased inflammatory peritoneal exudate of surviving late-sepsis mice. Cell tracking experiments showed that the transferred CD34 ؉ cells first appeared in the bone marrow and then homed to the spleen and peritoneum. Because CD34 ؉ cells did not affect the early-phase hyperinflammatory response, it is likely that the newly incorporated pluripotent CD34 ؉ cells differentiated into competent immune cells in blood and tissue, thereby reversing or replacing the hyporesponsive endotoxintolerant cells that occur and persist after the initiation of early sepsis. Sepsis is a major clinical problem (9, 52), with more than a 40% mortality rate, and is the leading cause of death in intensive care units (5,17). Evidence supports that the pathophysiology of sepsis varies as it moves from an initiating early/acute hyperinflammatory phase to a late/chronic hypoinflammatory and immunosuppressive phase (31,47,51,67). The early phase of sepsis is typified by a systemic inflammatory response syndrome (SIRS) characterized by excessive production of proinflammatory mediators by neutrophils and macrophages (53), increased generation of reactive oxygen species, and leukocyte-induced microvascular injury and organ failure (35). These destructive inflammatory responses occur in human (28) and animal (46, 51) sepsis, producing multiorgan dysfunction.While the early systemic inflammatory reaction of sepsis often spans several days (47, 61) and is considered a normal defense, the transition to a compensatory anti-inflammatory response syndrome (sometimes called CARS) to limit damage generates immunosuppression and promotes chronic infection (6, 12). CARS is characterized by downregulation in the ability of leukocytes to express proinflammatory mediators, impaired phagocytic capacity of neutrophils and macrophages (33,40,50), and significant apoptosis of lymphocytes and dendritic cells (16,29). Previous studies ha...

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Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response

Cited by 73 publications

References 59 publications

Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Hematopoietic Stem-Progenitor Cells Restore Immunoreactivity and Improve Survival in Late Sepsis

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