New approaches to the treatment of sepsis

O’Brien, James M.; Abraham, Edward

doi:10.1016/s0272-5231(03)00102-3

Cited by 20 publications

(11 citation statements)

References 253 publications

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“…Sepsis is a systemic inflammatory response resulting from the inability of the host to locally restrict infection. The high levels of serum inflammatory cytokines observed in severe sepsis are considered important mediators in the development of cardiovascular collapse and multiple organ failure (28). Consistent with the protective effect of ZnPP IX pretreatment on sepsis, these animals presented reduced systemic inflammatory events and consequently were largely protected from organ injury and hypotension when compared with the severe CLP group.…”

Section: Discussionsupporting

confidence: 59%

Divergent Role OF Heme Oxygenase Inhibition in the Pathogenesis of Sepsis

Freitas

Alves‐Filho²,

Trevelin³

et al. 2011

Shock

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The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. We demonstrated that pretreatment, but not the combination of pretreatment plus posttreatment with zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to the site of infection. Consequently, bacterial dissemination, systemic inflammatory response, and organ injury were prevented. In addition, pretreatment with the HO inhibitor avoided hypotension and consequently increased survival. Moreover, in mice subjected to severe CLP, the pretreatment, but not the combination of pretreatment plus posttreatment with ZnPP IX, prevented the increase of plasmatic free heme observed in nontreated severe CLP. The administration of exogenous hemin to mice subjected to moderate sepsis consistently increased the mortality rate. Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.

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Section: Discussionsupporting

confidence: 59%

Divergent Role OF Heme Oxygenase Inhibition in the Pathogenesis of Sepsis

Freitas

Alves‐Filho²,

Trevelin³

et al. 2011

Shock

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“…Sepsis mortality is not only seen during the initial hyperinflammatory phase, but also at later time points during a period of prolonged immunosuppression [7, 8]. In fact, Hotchkiss et al demonstrated that most deaths occur during this period, and reversal of this immune deficiency should generate a better outcome in sepsis [9].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of human ghrelin and growth hormone: Attenuation of immunosuppression in septic aged rats

Zhou

Yang

Aziz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sepsis is a leading cause of mortality in intensive care units, and is more common in the geriatric population. The control of hyperinflammation has been suggested as a therapeutic approach in sepsis, but to date clinical trials utilizing this strategy have not lead to an effective treatment. In addition to hyperinflammation, patients with sepsis often experience a state of immunosuppression, which serves as an important determinant for increased morbidity and mortality. We previously used aged animals to demonstrate the effectiveness of combined treatment with human ghrelin (Ghr) and human growth hormone (GH) in improving organ injury and survival in septic animals. Here, we hypothesized that combined treatment with Ghr and GH could improve immune function in septic aged animals. Male 24-month-old rats were subjected to cecal ligation and puncture (CLP) for sepsis induction. Human Ghr (80 nmol/kg BW) plus GH (50 μg/kg BW) or vehicle (normal saline) was administrated subcutaneously at 5 h after CLP. The ex vivo production of TNF-α, IL-6 and IL-10 to LPS-stimulation, as well as TNF-α, IL-6, IL-10 and INF-γ production to anti-CD3/anti-CD28 antibody-stimulation, in splenocytes isolated 20 h after CLP, was significantly decreased compared to production of these cytokines in splenocytes from sham animals. The production of cytokines from splenocytes isolated from septic animals that received the combined treatment, however, was significantly higher than from those isolated from vehicle-treated septic animals. Combined treatment prevented the loss of splenic CD4+ and CD8+ T cells in septic aged rats, and reduced lymphocyte apoptosis. Combined treatment also inhibited an increase in the regulatory T cell (Treg) population and expression of the immune co-inhibitory molecule PD-1 in the spleens of septic aged rats. In contrast, expression of HLA-DR was increased after combined treatment with Ghr and GH. Based on these findings, we conclude that co-administration of Ghr and GH is a promising therapeutic tool for reversing immunosuppression caused by sepsis in the geriatric population.

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“…The better outcome of anticytokine therapies in septic animals as compared with humans is thought to be a result of a short therapeutic window period for reversing the events of lethal sepsis in animals [14]. Moreover, the inef-fectiveness of anticytokine therapies in patients arises as a result of a prolonged immunosuppressive state at later timepoints of sepsis development [15,16]. Recently, the concept of combining more than one anticytokine agent has shown promising results in rescuing animals from sepsis [17,18].…”

Section: Introductionmentioning

confidence: 99%

Current trends in inflammatory and immunomodulatory mediators in sepsis

Aziz

Jacob

Yang

et al. 2012

Journal of Leukocyte Biology

279

222

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Sepsis refers to severe systemic inflammation in response to invading pathogens. An overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides, and cell stress markers play key roles in sepsis pathophysiology. Various adhesion molecules and chemokines sequester and activate neutrophils into the target organs, further augmenting inflammation and tissue damage. Although the anti-inflammatory substances counterbalance proinflammatory mediators, prolonged immune modulation may cause host susceptibility to concurrent infections, thus reflecting enormous challenge toward developing effective clinical therapy against sepsis. To understand the complex interplay between pro- and anti-inflammatory phenomenon in sepsis, there is still an unmet need to study newly characterized mediators. In addition, revealing the current trends of novel mediators will upgrade our understanding on their signal transduction, cross-talk, and synergistic and immunomodulating roles during sepsis. This review highlights the latest discoveries of the mediators in sepsis linking to innate and adaptive immune systems, which may lead to resolution of many unexplored queries.

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New approaches to the treatment of sepsis

Cited by 20 publications

References 253 publications

Divergent Role OF Heme Oxygenase Inhibition in the Pathogenesis of Sepsis

Divergent Role OF Heme Oxygenase Inhibition in the Pathogenesis of Sepsis

Therapeutic effect of human ghrelin and growth hormone: Attenuation of immunosuppression in septic aged rats

Current trends in inflammatory and immunomodulatory mediators in sepsis

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