Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury

Morris, Niya L.; Cannon, Abigail R.; Li, Xiaoling; Choudhry, Mashkoor A.

doi:10.1002/jlb.3a0820-323rr

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…Although traditionally thought of as a sealing protein, the role of claudin 4 is context dependent because it has been shown to both increase ( via increased pore function) and decrease ( via increased sealing function) permeability (41). Our findings are consistent with increased gut permeability and decreased intestinal claudin 4 expression following a model of ethanol gavage given 4 h before burn injury (42) Gut claudin 4 is also decreased in rats after binge ethanol consumption (without critical illness) (43) as well as in mice after pulmonary inflammation induced by intratracheal administration of lipopolysaccharide (without ethanol exposure) (44). This suggests a possible key role in claudin 4 in mediating pore pathway in ethanol/CLP although additional experiments would need to be performed to determine the functional significance of these findings.…”

Section: Discussionsupporting

confidence: 82%

Chronic Ethanol Use Worsens Gut Permeability and Alters Tight Junction Expression in a Murine Sepsis Model

Oami

Yumoto

Shimazui

et al. 2023

Shock

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Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability following ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal MLCK expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK-/- mice in water/CLP; however, permeability was not different between WT and MLCK-/- mice in ethanol/CLP. Similarly, jejunal IL-1β levels were decreased while systemic IL-6 levels were increased in MLCK-/- mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK-/- mice following water/CLP, mortality was significantly worse in MLCK-/- mice following ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Further, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4+ cells expressing TNF and IL-17A and the frequency of CD8+ cells expressing IFN-γ in Peyer’s Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function following CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.

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Section: Discussionsupporting

confidence: 82%

Chronic Ethanol Use Worsens Gut Permeability and Alters Tight Junction Expression in a Murine Sepsis Model

Oami

Yumoto

Shimazui

et al. 2023

Shock

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“…The visceral inflammation caused by intestinal IRI can alter the epithelial barrier morphology and function, allowing bacterial translocation [ 171 ], and their products as pathogen-associated molecular patterns (PAMPs), from the lumen into the lamina propria [ 172 ], thus driving inflammation [ 173 ]. This process eventually results in endotoxemia, the release of multiple pro-inflammatory cytokines [ 174 ], systemic inflammatory response syndrome (SIRS) [ 50 ], and even multi-organ failure and death [ 175 , 176 , 177 , 178 ].…”

Section: Mesenchymal Stem/stromal Cell (Msc)-based Therapy As a New S...mentioning

confidence: 99%

Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives

et al. 2023

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Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to organ rejection. IRI takes place during reperfusion, i.e., when blood flow is restored, by activating inflammation and reactive oxygen species (ROS) production, causing mitochondrial damage and apoptosis of parenchymal cells. Unfortunately, none of the therapies currently in use are definitive, prompting the need for new therapeutic approaches. Scientific evidence has proven that mesenchymal stem/stromal cells (MSCs) can reduce inflammation and ROS, prompting this cellular therapy to also be investigated for treatment of IRI. Moreover, it has been shown that MSC therapeutic effects were mediated in part by their secretome, which appears to be involved in immune regulation and tissue repair. For these reasons, mediated MSC paracrine function might be key for injury amelioration upon IRI damage. In this review, we highlight the scientific literature on the potential beneficial use of MSCs and their products for improving IRI outcomes in different tissues/organs, focusing in particular on the paracrine effects mediated by MSCs, and on the molecular mechanisms behind these effects.

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“…199, Donggang Road West, Chengguan District, Lanzhou, Gansu, China. 2 The Department of Anesthesiology, Gansu Provincial Maternity and Child-Care Hospital, No. 143, Qilihe North Street, Qilihe District, Lanzhou, Gansu, China.…”

Section: Abbreviationsmentioning

confidence: 99%

“…Intestinal IRI is a major complication of severe trauma, burns, infection, shock, and cardiopulmonary insufficiency [1]. Intestinal IRI damages intestinal epithelial cells (IECs) and causes intestinal Open Access *Correspondence: wanzhh19@lzu.edu.cn; lengyf@lzu.edu.cn barrier dysfunction, allowing bacterial translocation [2]. Further, severe intestinal IRI can disrupt the normal architecture and function of multiple organs, which eventually results in endotoxemia, systemic inflammatory response syndrome (SIRS), and even multiple organ dysfunction and failure.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies

et al. 2022

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Background Intestinal ischemia–reperfusion injury (IRI) causes localized and distant tissue lesions. Multiple organ failure is a common complication of severe intestinal IRI, leading to its high rates of morbidity and mortality. Thus far, this is poorly treated, and there is an urgent need for new more efficacious treatments. This study evaluated the beneficial effects of mesenchymal stem cells (MSCs) therapy on intestinal IRI using many animal experiments. Methods We conducted a comprehensive literature search from 4 databases: Pubmed, Embase, Cochrane library, and Web of science. Primary outcomes included the survival rate, Chiu’s score, intestinal levels of IL-6, TNF-α and MDA, as well as serum levels of DAO, D-Lactate, and TNF-α. Statistical analysis was carried out using Review Manager 5.3. Results It included Eighteen eligible researches in the final analysis. We demonstrated that survival rates in animals following intestinal IRI were higher with MSCs treatment compared to vehicle treatment. Besides, MSCs treatment attenuated intestinal injury caused by IRI, characterized by lower Chiu’s score (− 1.96, 95% CI − 2.72 to − 1.19, P < 0.00001), less intestinal inflammation (IL-6 (− 2.73, 95% CI − 4.19 to − 1.27, P = 0.0002), TNF-α (− 3.00, 95% CI − 4.74 to − 1.26, P = 0.0007)) and oxidative stress (MDA (− 2.18, 95% CI − 3.17 to − 1.19, P < 0.0001)), and decreased serum levels of DAO (− 1.39, 95% CI − 2.07 to − 0.72, P < 0.0001), D-Lactate (− 1.54, 95% CI − 2.18 to − 0.90, P < 0.00001) and TNF-α (− 2.42, 95% CI − 3.45 to − 1.40, P < 0.00001). The possible mechanism for MSCs to treat intestinal IRI might be through reducing inflammation, alleviating oxidative stress, as well as inhibiting the apoptosis and pyroptosis of the intestinal epithelial cells. Conclusions Taken together, these studies revealed that MSCs as a promising new treatment for intestinal IRI, and the mechanism of which may be associated with inflammation, oxidative stress, apoptosis, and pyroptosis. However, further studies will be required to confirm these findings.

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Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury

Cited by 7 publications

References 49 publications

Chronic Ethanol Use Worsens Gut Permeability and Alters Tight Junction Expression in a Murine Sepsis Model

Chronic Ethanol Use Worsens Gut Permeability and Alters Tight Junction Expression in a Murine Sepsis Model

Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives

Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies

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