Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock

Siddiqui, Ali; Bhatti, Umar F.; Deng, Qiufang; Biesterveld, Ben E.; Tian, Yuzi; Wu, Zhenyu; Dahl, Julia; Liu, Baoling; Xu, Jie; Koike, Yui; Song, Jun; Zhang, Jifeng; Li, Yongqing; Alam, Hasan B.; Williams, Aaron M.

doi:10.1089/sur.2020.189

Cited by 12 publications

(11 citation statements)

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“…A survival advantage is associated with attenuation of local and systemic proinflammatory cytokines, protection against distant organ injury, enhanced bacterial clearance and phagocytosis, and inhibition of immune cell apoptosis (22,23). Previous studies found that modifications of histone acetylation and citrullination significantly improve survival, attenuate "cytokine storms" and sepsis-associated coagulopathy, and decrease bone marrow atrophy in a lethal mouse septic model (22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock

Chu

Chang

et al. 2022

Front. Immunol.

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ObjectiveTo date, there are no studies regarding the lactylation profile and its role in critically ill patients. Thus, we aimed to examine expression of histone H3 lysine 18 (H3K18) lactylation and its role in patients with septic shock.MethodsThirteen healthy volunteers and 35 critically ill patients from the Department of Surgical Intensive Care Medicine, Beijing Hospital were enrolled in our study. Baseline information and clinical outcomes were obtained prospectively. Lactylation levels of all proteins and H3K18 from peripheral blood mononuclear (PBMC) were determined by western blotting and serum levels of inflammatory cytokines by flow cytometry. Arginase-1 (Arg1) and Krüppel-like factor-4 (Klf4) mRNA expression was evaluated by quantitative real-time PCR (qRT-PCR).ResultsLactylation was found to be an all-protein post-translational modification and was detected in PBMCs from both healthy volunteers and critically ill patients, with a significantly higher relative density in shock patients (t=2.172, P=0.045). H3K18la was expressed in all subjects, including healthy volunteers, with the highest level in septic shock patients (compared with non-septic shock patients, critically ill without shock patients and healthy volunteers P=0.033, 0.000 and 0.000, respectively). Furthermore, H3K18la protein expression correlated positively with APACHE II scores, SOFA scores on day 1, ICU stay, mechanical ventilation time and serum lactate (ρ=0.42, 0.63, 0.39, 0.51 and 0.48, respectively, ρ=0.012, 0.000, 0.019, 0.003 and 0.003, respectively). When we matched patients with septic shock and with non-septic shock according to severity, we found higher H3K18la levels in the former group (t=-2.208, P =0.040). Moreover, H3K18la exhibited a close correlation with procalcitonin levels (ρ=0.71, P=0.010). Patients with high H3K18la expression showed higher IL-2, IL-5, IL-6, IL-8, IL-10, IL-17, IFN-α levels (ρ=0.33, 0.37, 0.62, 0.55, 0.65, 0.49 and 0.374 respectively, P=0.024, 0.011, 0.000, 0.000, 0.000 and 0.000 respectively). H3K18la expression also displayed a positive correlation with the level of Arg1 mRNA (ρ=0.561, P=0.005).ConclusionsLactylation is an all-protein post-translational modification occurring in both healthy subjects and critically ill patients. H3K18la may reflect the severity of critical illness and the presence of infection. H3K18la might mediate inflammatory cytokine expression and Arg1 overexpression and stimulate the anti-inflammatory function of macrophages in sepsis.

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Section: Introductionmentioning

confidence: 99%

Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock

Chu

Chang

et al. 2022

Front. Immunol.

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“…221,249 Heparin binding to histones also neutralizes their positive charge and decreases their toxicity. 162 In murine studies, treatment with heparin improves survival after injection with lethal doses of histones. 250 Another group has reported that treatment with heparin reduces mortality in murine CLP.…”

Section: Heparinmentioning

confidence: 99%

“…Many have subsequently shown that this agent reduces NETosis and is protective against thrombosis and atherosclerosis in mice 159–161 . Cl‐amidine was shown to prevent renal injury and improve survival in rabbit LPS endotoxemia 162 . Several studies have demonstrated that it also improves survival in murine CLP when given 30 min before and up to 1 h following surgery, 111,163,164 demonstrating that it remains effective even when bacteria are present.…”

Section: Mechanistic Inhibitors Of Netosismentioning

confidence: 99%

Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

Ngo

Gollomp

2022

Research and Practice in Thrombosis and Haemostasis

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Infectious and inflammatory stimuli induce the release of neutrophil extracellular traps (NETs), webs of cell‐free (cf) DNA complexed with histones and antimicrobial proteins, that capture and kill pathogens. Despite their protective role in the initial stages of sepsis, excessive NET release accompanied by NET degradation, leads to the release of NET degradation products (NDPs), including cfDNA, histones, and myeloperoxidase that injure the microvasculature. Murine studies have shown that clearance or neutralization of NDPs improves outcomes, demonstrating that NETs have a causal link to disease and are not merely biomarkers. Recently, elevated NDPs have been associated with disease severity in sepsis and coronavirus disease 2019, raising further interest in targeting NETs. Many propose eliminating NETs, either by preventing their release, or by degrading them. However, NET inhibition may impede the innate immune response and is difficult to achieve in rapid‐onset conditions such as sepsis. On the other hand, approaches that accelerate NET degradation have met with mixed results in murine studies, raising the concern that this strategy may liberate NET‐captured pathogens while increasing circulating levels of harmful NDPs. Alternative NET‐directed strategies include therapies that neutralize, sequester, or remove NDPs from the circulation. Others propose modifying released NETs to decrease their capacity to induce collateral tissue damage while enhancing their ability to capture microorganisms. Synthetic NETs have also been designed to combat antibiotic‐resistant organisms. Although it is still in its infancy, the field of NET‐targeted therapeutics is advancing rapidly and may soon find application in the treatment of sepsis and other inflammatory disorders.

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“…PAD4-mediated post-translational protein citrullination has been implicated in several inflammatory autoimmune diseases. Siddiqui et al [ 82 ] evaluated the impact of Cl-amidine (a pan-PAD inhibitor) on AKI in a model of LPS-induced endotoxic shock in rabbits. They found that Cl-amidine treatment attenuated AKI, as evidenced by less damages of kidney tissue, and decreased Scr and BUN levels compared with control animals by 12 h after onset of sepsis.…”

Section: Histone Citrullination In Akimentioning

confidence: 99%

Histone Modifications in Acute Kidney Injury

et al. 2022

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Background: Acute kidney injury( AKI) is a serious clinical problem associated with high morbidity and mortality worldwide. The pathophysiology and pathogenesis of AKI is complex and multifactorial. In recent years, epigenetics has emerged as an important regulatory mechanism in AKI. Summary: There are several types of histone modification, including methylation, acetylation, phosphorylation, crotonylation, citrullination, and sumoylation. Histone modifications are associated with the transcription of many genes and activation of multiple signaling pathways that contribute to the pathogenesis of AKI. Thus, targeting histone modification may offer novel strategies to protect kidneys from AKI and enhance kidney repair and recovery. In this review, we summarize recent advances on the modification, regulation, and implication of histone modifications in AKI. Key Messages: Histone modifications contribute to the pathogenesis of AKI. Understanding of epigenetic regulation in AKI will aid in establishing the utility of pharmacologic targeting of histone modification as a potential novel therapy for AKI.

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Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock

Cited by 12 publications

References 28 publications

Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock

Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock

Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

Histone Modifications in Acute Kidney Injury

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