Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding

Tschirhart, B.; Lu, Xiangru; Gomes, Janice; Chandrabalan, Arundhasa; Bell, Gillian I.; Hess, David A.; Xing, Guangxin; Li, Hong; Burger, Dylan; Feng, Qingping

doi:10.3390/ph16060837

Cited by 7 publications

(1 citation statement)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Annexin A5 has been shown to bind to bacteria and lipopolysaccharide (LPS) and attenuate LPS-induced tumor necrosis factor alpha (TNF-α) production ( Rand et al, 2012 ). We recently demonstrated that annexin A5 inhibits endothelial inflammation induced by activated platelets and microvesicles in septic conditions via phosphatidylserine binding ( Tschirhart et al, 2023 ). The first study that revealed the anti-inflammatory effects of annexin A5 in sepsis was in mice with endotoxemia in which treatment with recombinant human annexin A5 inhibited the expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNFα) and interleukin-1β, and improved cardiac function and animal survival ( Arnold et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19

Tschirhart,

Lu,

Mokale Kognou

et al. 2024

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Objective: Annexin A5 is a phosphatidylserine binding protein with anti-inflammatory, anticoagulant and anti-apoptotic properties. Preclinical studies have shown that annexin A5 inhibits pro-inflammatory responses and improves organ function and survival in rodent models of sepsis. This clinical trial aimed to evaluate the pharmacokinetic (PK) properties of the recombinant human annexin A5 (SY-005) in severe COVID-19.Methods: This was a pilot randomized, double-blind, placebo-controlled trial. Severe COVID-19 patients were randomly assigned to receive intravenous 50 μg/kg (low dose, n = 3), 100 μg/kg (high dose, n = 5) of SY-005 or placebo (n = 5) every 12 h for 7 days. Plasma SY-005 levels were assessed using enzyme-linked immunosorbent assay (ELISA) and the PK parameters were determined using non-compartmental analysis.Results: All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104–125 mL/min/1.73 m2). Both low and high doses of SY-005 were cleared within 6 h after intravenous administration. Plasma maximum concentrations (Cmax), half-life, clearance and volume distribution of low and high doses of SY-005 were 402.4 and 848.9 ng/mL, 0.92 and 0.96 h, 7.52 and 15.19 L/h, and 9.98 and 20.79 L, respectively. Daily pre-dose circulating annexin A5 levels were not significantly different when SY-005 was administered at the low or the high dose 12-h intervals. There was no significant effect on activated partial thromboplastin time (aPTT) or INR (international normalized ratio of prothrombin time) during 7 days of SY-005 treatment.Conclusion: SY-005 doses of 50 and 100 μg/kg were detectable and subsequently cleared from the plasma in severe COVID-19 patients with normal baseline renal function. There was no significant plasma SY-005 accumulation 6 h after drug administration and coagulation was not altered during 7 days of treatment.Clinical trials Registration: This study was registered with ClinicalTrials.gov (NCT04748757, first posted on 10 February 2021).

show abstract

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19

Tschirhart,

Lu,

Mokale Kognou

et al. 2024

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

Effect of endothelial responses on sepsis-associated organ dysfunction

Wu,

Yan,

Xie

et al. 2024

Chinese Medical Journal

View full text Add to dashboard Cite

Sepsis-related organ dysfunction is associated with increased morbidity and mortality. Previous studies have found that the endothelium plays crucial roles in maintaining the vascular permeability during sepsis, as well as in regulating inflammation and thrombosis. During sepsis, endothelial cells may release cytokines, chemokines, and pro-coagulant factors, as well as express adhesion molecules. In general, endothelial responses during sepsis typically inhibit bacterial transmission and coordinate leukocyte recruitment to promote bacterial clearance. However, excessive or prolonged endothelial activation can lead to impaired microcirculation, tissue hypoperfusion, and organ dysfunction. Given the structural and functional heterogeneity of endothelial cells in different organs, there are potential differences in endothelial responses by organ type, and the risk of organ damage may vary accordingly. This article reviews the endothelial response observed in sepsis and its effects on organ function, summarizes current progress in the development of therapeutic interventions targeting the endothelial response, and discusses future research directions to serve as a reference for researchers in the field.

show abstract

Megakaryocyte in sepsis: the trinity of coagulation, inflammation and immunity

Hua,

Yao,

Wang

et al. 2024

Crit Care

View full text Add to dashboard Cite

Background Megakaryocytes are traditionally recognized as cells responsible for platelet production. However, beyond their role in thrombopoiesis, megakaryocytes also participate in inflammatory responses and regulate immune system functions. Sepsis, characterized by life-threatening organ dysfunction due to a dysregulated response to infection, prominently features coagulopathy, severe inflammation, and immune dysfunction as key pathophysiological aspects. Aim of review Given the diverse functions of megakaryocytes, we explore their roles in coagulation in the context of sepsis, and also in inflammatory and immune regulation. We try to infer future research directions and potential strategies for sepsis prevention and treatment based on the properties of megakaryocytes. Key scientific concepts of review The purpose of this review is to both highlight and provide an update on the functions of megakaryocytes and pathophysiological changes in sepsis. Specific emphasis is given to the role of megakaryocytes in sepsis, which suggests value of future research and clinical application. Graphical abstract

show abstract

Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding

Cited by 7 publications

References 48 publications

Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19

Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19

Effect of endothelial responses on sepsis-associated organ dysfunction

Megakaryocyte in sepsis: the trinity of coagulation, inflammation and immunity

Contact Info

Product

Resources

About