Targeting Complement Pathways in Polytrauma- and Sepsis-Induced Multiple-Organ Dysfunction

Ren

Evidence-Based Complementary and Alternative Medicine

et al. 2020

Background. Sepsis is a global major health problem with high mortality rates. More effective therapy is needed for treating sepsis. Acupuncture has been used for various diseases, including severe infection, in China for more than 2,000 years. Previous studies reported that acupuncture at Zusanli (ST36) might be effective in treating sepsis, but the efficacy and the quality of evidence remain unclear since there is no systematic review on acupuncture at ST36 for sepsis. Methods. Seven databases were searched from the inception of each database up to May 2019. Ultimately, 54 studies using acupuncture at ST36 for the treatment of experimental sepsis were identified in both English and Chinese literature with systematic review procedures. Results. Acupuncture might be useful in reducing injuries induced by sepsis in cardiac, lung, kidney, liver, gastrointestinal tract, and immune system. Its potential mechanisms for antisepsis might include reducing oxidative stress and inflammation, improving microcirculatory disturbance, and maintaining the immune balance mediated by dopamine. However, the positive findings should be interpreted with caution due to poor methodological quality and publication bias. Conclusion. Acupuncture at ST36 might be a promising complementary strategy for controlling sepsis inflammation, yet further studies are needed.

Section: Introductionmentioning

confidence: 99%

Acupuncture at Zusanli (ST36) for Experimental Sepsis: A Systematic Review

Ren

Evidence-Based Complementary and Alternative Medicine

et al. 2020

Eur J Trauma Emerg Surg

Section: Complement Factorsmentioning

confidence: 97%

“…In 2012, in accordance with the newly recognized "sterile SIRS" as a severe complication form in polytraumatized patients, first clues to a critical role of DAMPs in the promotion of those hyperinflammatory responses have been reported [47]. Among those molecules, endogenous DAMPs including high-mobility group box (HMGB) protein 1, heat shock proteins (HSPs), certain members of the S100A family, histones, free nucleic acids, members of the IL-1 cytokine as well as complement family as bona fide intracellular effectors, which upon abundant rapid release alert the environment about cell stress and danger, have already been reported to activate the posttraumatic innate immune responses and drive organ dysfunction(s) after trauma [12,13,46,48].…”

Section: Sirsmentioning

confidence: 99%

“…Exposure to traumatic or infectious insults results in an immediate activation of the complement cascade as major fluid defense system of innate immunity [48,299]. As nicely described by Huber-Lang, the complement system acts as a master alarm system during the molecular danger response after trauma and significantly contributes to the clearance of DAMPs and PAMPs [48,299]. Activation of complement in trauma patients has been verified by detection of elevated plasma C3a, C5a, and C5b-9 levels which correlate with disease severity [73,[300][301][302][303][304][305].…”

Section: Complement Factorsmentioning

confidence: 99%

See 1 more Smart Citation

Damage-associated molecular patterns in trauma

Relja

Land

2019

123

131

In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

“…Trauma patients often suffer with hypovolemic shock and septic challenge simultaneously, which results in severe organ dysfunction (Karasu et al 2019, Spahn et al 2019. The kidneys, are one of the most commonly affected organs, receiving 20-25% of the resting cardiac output, while their weight is less than 1% of the total body mass.…”

Section: Introductionmentioning

confidence: 99%

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model.

Jiang

Chung

et al. 2020

Preprint

Background: Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic setting. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major protein phosphatase tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to development of AKI sequential hemorrhage (Hem) and cecal ligation and puncture (CLP) and whether inactivation of SHP2 through administration of its selective inhibitor, phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury.Methods: Male C57BL/6 mice were subjected to Hem (a “priming” insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL) , high mobility group box 1 ( HMGB1 ), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2) :phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer’s instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA.Results: We found that indices of kidney injury, including levels of BUN, Cre and NGAL as well as histopathologic changes, were significantly increased after Hem/CLP in comparison with that in the S/S group. Furthermore, Hem/CLP resulted in elevated serum levels of inflammatory cytokines/chemokines, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, and STAT3:phospho-STAT3 protein expression in the kidney. Treatment with PHPS1 markedly attenuated these Hem/CLP-induced changes.Conclusions: In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its ability to mitigate activation of the Erk1/2 and STAT3 signaling pathway. We believethis is a potentially important finding with clinical implications warranting further investigation.