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      Anti-Interleukin-16 Neutralizing Antibody Treatment Alleviates Sepsis-Induced Cardiac Injury and Dysfunction via the Nuclear Factor Erythroid-2 Related Factor 2 Pathway in Mice


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          Several interleukin (IL) members have been reported to participate in sepsis. In this study, the effects of IL-16 on sepsis-induced cardiac injury and dysfunction were examined, and the related mechanisms were detected. IL-16 expression in septic mice was first measured, and the results showed that both cardiac and serum IL-16 expression levels were increased in mice with sepsis induced by LPS or cecal ligation and puncture (CLP) compared with control mice. Then, IL-16 was neutralized, and the effects on lipopolysaccharide- (LPS-) induced cardiac injury were detected. The results showed that an anti-IL-16 neutralizing antibody (nAb) significantly reduced mortality and increased serum lactate dehydrogenase (LDH), creatine kinase myocardial bound (CK-MB), and cardiac troponin T (cTnT) levels while improving cardiac function in mice with LPS-induced sepsis. Neutralization of IL-16 also increased the activation of antioxidant pathways and the expression of antioxidant factors in septic mice while decreasing the activation of prooxidant pathways and the expression of prooxidants. Treatment with the anti-IL-16 nAb increased mitochondrial apoptosis-inducing factor (AIF) expression, decreased nuclear AIF and cleaved poly-ADP-ribose polymerase (PARP) expression, and decreased TUNEL-positive cell percentages in LPS-treated mice. Additionally, treatment with CPUY192018, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway, significantly increased mortality and reversed the above effects in mice treated with LPS and the anti-IL-16 nAb. Our results showed that the anti-IL-16 nAb regulates oxidative stress through the Nrf2 pathway and participates in the regulation of cardiac injury in septic mice. Neutralization of IL-16 may be a beneficial strategy for the prevention of cardiac injury and dysfunction in sepsis patients.

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          Most cited references37

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          Immunodesign of experimental sepsis by cecal ligation and puncture.

          Sepsis remains a prevalent clinical challenge and the underlying pathophysiology is still poorly understood. To investigate the complex molecular mechanisms of sepsis, various animal models have been developed, the most frequently used being the cecal ligation and puncture (CLP) model in rodents. In this model, sepsis originates from a polymicrobial infectious focus within the abdominal cavity, followed by bacterial translocation into the blood compartment, which then triggers a systemic inflammatory response. A requirement of this model is that it is performed with high consistency to obtain reproducible results. Evidence is now emerging that the accompanying inflammatory response varies with the severity grade of sepsis, which is highly dependent on the extent of cecal ligation. In this protocol, we define standardized procedures for inducing sepsis in mice and rats by applying defined severity grades of sepsis through modulation of the position of cecal ligation. The CLP procedure can be performed in as little as 10 min for each animal by an experienced user, with additional time required for subsequent postoperative care and data collection.
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            Recognizing Sepsis as a Global Health Priority — A WHO Resolution

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              Cross talk between ER stress, oxidative stress, and inflammation in health and disease.

              In mammals, endoplasmic reticulum (ER) stress, oxidative stress, and inflammatory responses compose the major defense networks that help the cells adapt to and survive stress conditions caused by biochemical, physiological and pathological stimuli. However, chronic ER stress, oxidative stress, or inflammation have been found to be associated with the initiation and progression of a variety of human diseases in the modern world. Under many pathophysiologic conditions, ER stress response, oxidative stress, and inflammatory responses are integrated and amplified in specialized cell types to facilitate the progression of disease. In the past few decades, ER stress response, oxidative stress, and inflammation as well as their interactive relationships have been hot research topics in biomedicine. In this review, we summarize the recent advance in our understanding of the cross talk between ER stress response, oxidative stress, and inflammation in immunity and in inflammatory and metabolic diseases.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                13 February 2021
                : 2021
                : 6616422
                1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical Center for Coronary Heart Disease, Capital Medical University, Beijing 100029, China
                2Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
                3Department of Cardiology, Handan First Hospital, Handan, Hebei, China
                Author notes

                Academic Editor: Marina Politi Okoshi

                Author information
                Copyright © 2021 Jianwei Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 18 October 2020
                : 12 January 2021
                : 18 January 2021
                Funded by: National Natural Science Foundation of China
                Award ID: 81770472
                Award ID: 81560085
                Research Article

                Molecular medicine
                Molecular medicine


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