HMGB1 Release by C5a Anaphylatoxin is an Effective Target for Sepsis Treatment

Okada, Noriko; Imai, Masaki; Okada, Akio; Ono, Fumiko; Okada, Hidechika

doi:10.4172/2161-1459.1000114

Cited by 4 publications

(3 citation statements)

References 15 publications

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“…Neutralizing antibodies against C5a have demonstrated protective effects in experimental sepsis (67), and this promising therapeutic concept appears to apply to the use of mAb IFX-1 (CaCP29, InflaRx; target has not been officially disclosed) that has been evaluated in phase I trials (NCT01319903). In addition, two strategies have been developed that exploit structurally complementary molecules as C5a inhibitors; whereas NOX-D19 (Noxxon) is based on spiegelmer technology ( i.e., biostable RNA aptamers), antisense peptides (C5aIP, AcPepA) have been tested in islet transplantation and sepsis (68, 69). As a GPCR, the C5aR represents a druggable target and several small molecule antagonists have indeed been developed over the years (11, 50).…”

Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

203

230

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With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules.

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Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

203

230

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“…Stimulation of C5l2 receptor with C5a results in an active HMGB1 secretion and further amplifies proinflammatory responses. Blocking C5a with the specific antibody [ 22 ] or Pep inhibitory protein [ 23 ] significantly decreases the mortality due to sepsis in an animal model. HMGB1 secretion from activated monocytes/macrophages starts 8-12 hours after stimulation, which is a significantly delayed response in comparison with other proinflammatory factors produced by these cells [ 24 ].…”

Section: Stimulation Of Toll-like Receptors Without the Participationmentioning

confidence: 99%

The immune response to surgery and infection

Dąbrowska¹,

Słotwiński²

2014

cejoi

115

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Surgical trauma affects both the innate and acquired immunity. The severity of immune disorders is proportional to the extent of surgical trauma and depends on a number of factors, including primarily the basic disease requiring surgical treatment (e.g. cancer), often coexisting infections and impaired nutritional status. Disorder of the immune response following surgical trauma may predispose to septic complications burdened with the highest mortality rate. Extensive surgery in cancer patients is associated with simultaneous activation of pro- and anti-inflammatory processes defined as SIRS (systemic inflammatory immune response) and CARS (compensatory anti-inflammatory immune response). However, it is generally believed that major surgical trauma is accompanied by sustained postoperative immunosuppression, which is particularly important in patients operated on for cancer, since the suppression of the immune system promotes not only septic complications, but also proliferation and tumor metastasis. This paper reviews the main features of immune response to surgical trauma and possibilities of its regulation.

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“…In addition, C5a has been demonstrated to enhance the release of a number of pro‐inflammatory cytokines from activated PMNs and macrophages . Furthermore, inhibition of C5a by a complementary peptide to C5a (AcPepA) reportedly suppresses the release of high mobility group box 1 resulting in rescue of monkeys injected with lethal doses of LPS .…”

mentioning

confidence: 99%

C5a inhibitor protects against ischemia/reperfusion injury in rat small intestine

Tuboly

Futakuchi²,

Varga

et al. 2016

Microbiology and Immunology

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Acute mesenteric ischemia (AMI) is caused by considerable intestinal injury, which is associated with intestinal ischemia followed by reperfusion. To elucidate the mechanisms of ischemia/reperfusion injuries, a C5a inhibitory peptide termed AcPepA was used to examine the role of C5a anaphylatoxin, induction of inflammatory cells, and cell proliferation of the intestinal epithelial cells in an experimental AMI model. In this rat model, the superior mesenteric artery was occluded and subsequently reperfused (Induce‐I/R). Other groups were treated with AcPepA before ischemia or reperfusion. Induce‐I/R induced injuries in the intestine and AcPepA significantly decreased the proportion of severely injured villi. Induce‐I/R induced secondary receptor for C5a‐positive polymorphonuclear leukocytes in the vessels and CD204‐positive macrophages near the injured site; this was correlated with hypoxia‐induced factor 1‐alpha‐positive cells. Induction of these inflammatory cells was attenuated by AcPepA. In addition, AcPepA increased proliferation of epithelial cells in the villi, possibly preventing further damage. Therefore, Induce‐I/R activates C5a followed by the accumulation of polymorphonuclear leukocyte and hypoxia‐induced factor 1‐alpha‐producing macrophages, leading to villus injury. AcPepA, a C5a inhibitory peptide, blocks the deleterious effects of C5a, indicating it has a therapeutic effect on the inflammatory consequences of experimental AMI.

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HMGB1 Release by C5a Anaphylatoxin is an Effective Target for Sepsis Treatment

Cited by 4 publications

References 15 publications

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

The immune response to surgery and infection

C5a inhibitor protects against ischemia/reperfusion injury in rat small intestine

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