The Pathogenesis of Sepsis

Stearns-Kurosawa, Deborah J.; Osuchowski, Marcin F.; Valentine, Catherine; Kurosawa, Shinichiro; Remick, Daniel G.

doi:10.1146/annurev-pathol-011110-130327

Cited by 497 publications

(438 citation statements)

References 138 publications

(166 reference statements)

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“…In addition, CD300b-deficient mice are resistant to endotoxin and sepsis models. 22,37 The excessive inflammatory responses induced by microbes leads to apoptosis of lymphocytes and epithelial cells, 37 and hence CD300b, which recognizes these apoptotic cells, could be involved in the pathology of sepsis. Thus, CD300b likely contributes to the development of these pathologies, and CD300 family members appear to both positively and negatively regulate immune responses.…”

Section: Resultsmentioning

confidence: 99%

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

et al. 2014

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The CD300 receptor family members are a group of molecules that modulate a variety of immune cell processes. We show that mouse CD300b (CLM7/LMIR5), expressed on myeloid cells, recognizes outer membrane-exposed phosphatidylserine (PS) and does not, as previously reported, directly recognize TIM1 or TIM4. CD300b accumulates in phagocytic cups along with F-actin at apoptotic cell contacts, thereby facilitating their engulfment. The CD300b-mediated activation signal is conveyed through CD300b association with the adaptor molecule DAP12, and requires a functional DAP12 ITAM motif. Binding of apoptotic cells promotes the activation of the PI3K-Akt kinase pathway in macrophages, while silencing of CD300b expression diminishes PI3K-Akt kinase activation and impairs efferocytosis. Collectively, our data show that CD300b recognizes PS as a ligand, and regulates the phagocytosis of apoptotic cells via the DAP12 signaling pathway.

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Section: Resultsmentioning

confidence: 99%

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

et al. 2014

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“…Despite the wonderful achievements of modern biology and medicine, sepsis remains one of the major causes of hospital mortality (Stearns-Kurosawa et al 2011). In the USA alone, 750,000 cases of sepsis occur each year, and more than 215,000 patients die of sepsis-induced damage because the known endotoxemia antagonists are only able to partially suppress sepsis symptoms (Martin et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

Винокуров

Ostrov

Yurinskaya

et al. 2012

Cell Stress and Chaperones

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It has been previously reported that pretreatment with exogenous heat shock protein 70 (Hsp70) is able to protect cells and animals from the deleterious effects of bacterial lipopolysaccharide (LPS) produced by Gramnegative bacteria. However, the effects of Hsp70 pretreatment on lipoteichoic acid (LTA) challenge resulted from Gram-positive bacteria infection have not been fully elucidated. In this study, we demonstrated that preconditioning with human recombinant Hsp70 ameliorates various manifestations of systematic inflammation, including reactive oxygen species, TNFα, and CD11b/CD18 adhesion receptor expression induction observed in different myeloid cells after LTA addition. Therefore, exogenous Hsp70 may provide a mechanism for controlling excessive inflammatory responses after macrophage activation. Furthermore, in a rat model of LTA-induced sepsis, we demonstrated that prophylactic administration of exogenous human Hsp70 significantly exacerbated numerous homeostatic and hemodynamic disturbances induced by LTA challenge and partially normalized the coagulation system and multiple biochemical blood parameters, including albumin and bilirubin concentrations, which were severely disturbed after LTA injections. Importantly, prophylactic intravenous injection of Hsp70 before LTA challenge significantly reduced mortality rates. Thus, exogenous mammalian Hsp70 may serve as a powerful cellular defense agent against the deleterious effects of bacterial pathogens, such as LTA and LPS. Taken together, our findings reveal novel functions of this protein and establish exogenous Hsp70 as a promising pharmacological agent for the prophylactic treatment of various types of sepsis.

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“…P athogens in the host bloodstream often induce a hyperactive coagulation cascade that can progress to disseminated intravascular coagulation with severe thrombosis, organ failure, and death (1)(2)(3). With current limited understanding of pathogen-host interactions, sepsis remains a debilitating and deadly syndrome with few treatment options (4,5).…”

mentioning

confidence: 99%

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

Grewal

Aziz

Uchiyama

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.

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The Pathogenesis of Sepsis

Cited by 497 publications

References 138 publications

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

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