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      The Protective Effects of Protease Inhibitor MG-132 on Sepsis-Induced Acute Lung Rats and Its Possible Mechanisms

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          Abstract

          Background

          The aim of the present study was to investigate the protective effects of protease inhibitor MG-132 on sepsis-induced acute lung injury rats.

          Material/Methods

          Sprague Dawley rats were employed to induce sepsis by cecal ligation and puncture (CLP) method. Rats were divided into 4 groups: control, sham, model (CLP), and MG-132. Histopathology observation was detected by hematoxylin and eosin staining. The ratio of wet lung to dry lung (W/D) was calculated. In addition, the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Also, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were evaluated. Western blotting was performed to measure the expression of hypoxia-inducible factor-1 α (HIF-1α). In order to assess the role of HIF-1α, YC-1, the inhibitor of HIF-1α, was used to treat the rats. The expression of phosphor-mTOR (p-mTOR), p-4EBP1, and p-EIF4E were evaluated by western blotting.

          Results

          Obvious pathological injury and increasing ratio of W/D in the model group were observed. Both pathological injury and W/D were improved in the MG-132 group, and the greatest improvement could be seen in the YC-1+MG-132 group. Furthermore, the MDA levels in the MG-132 group was decreased, accompanied by an increase in SOD levels. The level of HIF-1α was increased in the model group while a decreased was detected in the MG-132 group. The levels of inflammatory factors were high in the model group, whereas the opposite result was found in the MG-132 group, and the lowest in were in the YC-1+MG-132 group. Furthermore, the expression levels of p-mTOR, p-4EBP1, and p-EIF4E proteins were downregulated in the MG-132 group compared to the model group, and the lowest was in the YC-1+MG-132 group.

          Conclusions

          Our study suggested that MG-132 was able to protect against acute lung injury via inhibition of HIF-1α mediated mTOR/4EBP1/EIF4E pathway.

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          Most cited references22

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          Cecal ligation and puncture: the gold standard model for polymicrobial sepsis?

          Sepsis is a serious medical condition characterized by dysregulated systemic inflammatory responses followed by immunosuppression. To study the pathophysiology of sepsis, diverse animal models have been developed. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis. Here we summarize the role of several immune components in the pathogenesis of sepsis induced by CLP. However, several therapies proposed on the basis of promising results obtained by CLP could not be translated to the clinic. This demonstrates that experimental sepsis models do not completely mimic human sepsis. We propose several strategies to narrow the gap between experimental sepsis models and clinical sepsis, including targeting factors that contribute to the immunosuppressive phase of sepsis, and reproducing the heterogeneity of human patients. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Pathophysiology of sepsis.

            D Remick (2007)
            Sepsis remains a critical problem with significant morbidity and mortality even in the modern era of critical care management. Multiple derangements exist in sepsis involving several different organs and systems, although controversies exist over their individual contribution to the disease process. Septic patients have substantial, life-threatening alterations in their coagulation system, and currently, there is an approved therapy with a component of the coagulation system (activated protein C) to treat patients with severe sepsis. Previously, it was believed that sepsis merely represented an exaggerated, hyperinflammatory response with patients dying from inflammation-induced organ injury. More recent data indicate that substantial heterogeneity exists in septic patients' inflammatory response, with some appearing immuno-stimulated, whereas others appear suppressed. Cellular changes continue the theme of heterogeneity. Some cells work too well such as neutrophils that remain activated for an extended time. Other cellular changes become accelerated in a detrimental fashion including lymphocyte apoptosis. Metabolic changes are clearly present, requiring close and individualized monitoring. At this point in time, the literature richly illustrates that no single mediator/system/pathway/pathogen drives the pathophysiology of sepsis. This review will briefly discuss many of the important alterations that account for the pathophysiology of sepsis.
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              Cecal Ligation Puncture Procedure

              Human sepsis is characterized by a set of systemic reactions in response to intensive and massive infection that failed to be locally contained by the host. Currently, sepsis ranks among the top ten causes of mortality in the USA intensive care units. During sepsis there are two established haemodynamic phases that may overlap. The initial phase (hyperdynamic) is defined as a massive production of proinflammatory cytokines and reactive oxygen species by macrophages and neutrophils that affects vascular permeability (leading to hypotension), cardiac function and induces metabolic changes culminating in tissue necrosis and organ failure. Consequently, the most common cause of mortality is acute kidney injury. The second phase (hypodynamic) is an anti-inflammatory process involving altered monocyte antigen presentation, decreased lymphocyte proliferation and function and increased apoptosis. This state known as immunosuppression or immune depression sharply increases the risk of nocosomial infections and ultimately, death. The mechanisms of these pathophysiological processes are not well characterized. Because both phases of sepsis may cause irreversible and irreparable damage, it is essential to determine the immunological and physiological status of the patient. This is the main reason why many therapeutic drugs have failed. The same drug given at different stages of sepsis may be therapeutic or otherwise harmful or have no effect. To understand sepsis at various levels it is crucial to have a suitable and comprehensive animal model that reproduces the clinical course of the disease. It is important to characterize the pathophysiological mechanisms occurring during sepsis and control the model conditions for testing potential therapeutic agents. To study the etiology of human sepsis researchers have developed different animal models. The most widely used clinical model is cecal ligation and puncture (CLP). The CLP model consists of the perforation of the cecum allowing the release of fecal material into the peritoneal cavity to generate an exacerbated immune response induced by polymicrobial infection. This model fulfills the human condition that is clinically relevant. As in humans, mice that undergo CLP with fluid resuscitation show the first (early) hyperdynamic phase that in time progresses to the second (late) hypodynamic phase. In addition, the cytokine profile is similar to that seen in human sepsis where there is increased lymphocyte apoptosis (reviewed in). Due to the multiple and overlapping mechanisms involved in sepsis, researchers need a suitable sepsis model of controlled severity in order to obtain consistent and reproducible results.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2019
                01 August 2019
                : 25
                : 5690-5699
                Affiliations
                Department of Intensive Care Unit, Taizhou People’s Hospital, Taizhou, Jiangsu, P.R. China
                Author notes
                Corresponding Author: Xuehua Pu, e-mail: luodichengshuanghu@ 123456163.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                Bingbing Wu and Xiaoli Miao contributed equally to this work

                Article
                915743
                10.12659/MSM.915743
                6688517
                31366881
                0afca6a9-ae8c-4501-b5e2-b0656c5ab25b
                © Med Sci Monit, 2019

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 17 February 2019
                : 26 March 2019
                Categories
                Animal Study

                acute lung injury,hypoxia-inducible factor 1,sepsis
                acute lung injury, hypoxia-inducible factor 1, sepsis

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