Abstract
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.
Highlights
Sepsis is a serious clinical problem with high morbidity and mortality [1,2,3]
Plasma and Bronchoalveolar lavage fluid (BALF) samples were collected from sepsisinduced acute respiratory distress syndrome (ARDS) patients and healthy control subjects enrolled in the Acute Lung Injury Specialized Center of Clinically Oriented Research (SCCOR) as a part of a randomized trial of granulocyte-macrophage colony-stimulating factor administration conducted at the University of Michigan [30]
We have demonstrated for the first time that the expression of citrullinated histone H3 (CitH3) was increased in the serum and BALF of the patients with sepsis-induced ARDS
Summary
Sepsis is a serious clinical problem with high morbidity and mortality [1,2,3]. The ultimate cause of death in sepsis patients is multiple organ dysfunction. CitH3 Activates Caspase-1 Dependent Inflammasome sepsis and organ dysfunction, the treatment relies largely on supportive care [8, 9]. One of the main pathophysiological events in of sepsisinduced ARDS is uncontrolled inflammation induced by cytokines and other inflammatory mediators. Activation of the inflammasome pathway is one of the innate immune defenses triggered during ALI/ARDS [13]. NLR Family Pyrin Domain Containing 3 (NLRP3) and Absent in Melanoma 2 (AIM2) are the most well-studied inflammasomes in ALI, with both pathways leading to the activation of effector protein Caspase-1 and the maturation of pro-inflammatory cytokines interleukin (IL)-1b and IL-18 [14,15,16]. Elevated levels of circulating IL-18 are associated with a poor long-term prognosis in patients with sepsis-induced ARDS [17]. In several different rodent models, IL-18/IL-1b neutralization or IL-1R signaling antagonism reduced lung injury [17,18,19,20,21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
