Myeloperoxidase instigates proinflammatory responses in a cecal ligation and puncture rat model of sepsis

Yu, Hong; Liu, Yajun; Wang, Meifang; Restrepo, Ricardo; Wang, Derek; Kalogeris, Theodore J.; Neumann, William L.; Ford, David A.; Korthuis, Ronald J.

doi:10.1152/ajpheart.00440.2020

Cited by 17 publications

(8 citation statements)

References 97 publications

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“…In the liver and kidney of septic mice, we documented that PF271 attenuated the upregulation of the cellular adhesion molecules (CAMs) VCAM-1, ICAM-1 and E-Selectin, which exert a pivotal role in driving leukocyte infiltration and the following excessive inflammatory response, which ultimately lead to the development of MOF (42)(43)(44). We also documented that PF271 administration was associated with a significant reduction in local (liver and kidney) expression and activity of either MPO, a wellknown biomarker of neutrophil infiltration (45), and iNOS, which is detectable in neutrophils, leading to overproduction of nitric oxide (NO) and the following generation of other reactive species (46). Our study does not allow the identification of the specific cell types involved in PF271-mediated responses.…”

Section: Discussionmentioning

confidence: 81%

Pharmacological Inhibition of FAK-Pyk2 Pathway Protects Against Organ Damage and Prolongs the Survival of Septic Mice

et al. 2022

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Sepsis and septic shock are associated with high mortality and are considered one of the major public health concerns. The onset of sepsis is known as a hyper-inflammatory state that contributes to organ failure and mortality. Recent findings suggest a potential role of two non-receptor protein tyrosine kinases, namely Focal adhesion kinase (FAK) and Proline-rich tyrosine kinase 2 (Pyk2), in the inflammation associated with endometriosis, cancer, atherosclerosis and asthma. Here we investigate the role of FAK-Pyk2 in the pathogenesis of sepsis and the potential beneficial effects of the pharmacological modulation of this pathway by administering the potent reversible dual inhibitor of FAK and Pyk2, PF562271 (PF271) in a murine model of cecal ligation and puncture (CLP)-induced sepsis. Five-month-old male C57BL/6 mice underwent CLP or Sham surgery and one hour after the surgical procedure, mice were randomly assigned to receive PF271 (25 mg/kg, s.c.) or vehicle. Twenty-four hours after surgery, organs and plasma were collected for analyses. In another group of mice, survival rate was assessed every 12 h over the subsequent 5 days. Experimental sepsis led to a systemic cytokine storm resulting in the formation of excessive amounts of both pro-inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-6) and the anti-inflammatory cytokine IL-10. The systemic inflammatory response was accompanied by high plasma levels of ALT, AST (liver injury), creatinine, (renal dysfunction) and lactate, as well as a high, clinical severity score. All parameters were attenuated following PF271 administration. Experimental sepsis induced an overactivation of FAK and Pyk2 in liver and kidney, which was associated to p38 MAPK activation, leading to increased expression/activation of several pro-inflammatory markers, including the NLRP3 inflammasome complex, the adhesion molecules ICAM-1, VCAM-1 and E-selectin and the enzyme NOS-2 and myeloperoxidase. Treatment with PF271 inhibited FAK-Pyk2 activation, thus blunting the inflammatory abnormalities orchestrated by sepsis. Finally, PF271 significantly prolonged the survival of mice subjected to CLP-sepsis. Taken together, our data show for the first time that the FAK-Pyk2 pathway contributes to sepsis-induced inflammation and organ injury/dysfunction and that the pharmacological modulation of this pathway may represents a new strategy for the treatment of sepsis.

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Section: Discussionmentioning

confidence: 81%

Pharmacological Inhibition of FAK-Pyk2 Pathway Protects Against Organ Damage and Prolongs the Survival of Septic Mice

et al. 2022

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“…MPO is the most abundant proinflammatory enzyme stored in the azurophilic granules of neutrophil granulocytes and it is considered a good biomarker of neutrophil infiltration. [ 22 ] MPO activity significantly differed from that in the control groups when diets were enriched in either fructose or galactose; FOS supplementation counteracted the MPO activation induced by the sugars. We also documented similar changes in the local accumulation of the chemoattractant chemokines CCL2 and CXCL10, which are known to contribute to the T‐cell recruitment to sites of inflammation.…”

Section: Discussionmentioning

confidence: 82%

Dietary Intake of Fructooligosaccharides Protects against Metabolic Derangements Evoked by Chronic Exposure to Fructose or Galactose in Rats

Almasri,

Collotta,

Aimaretti

et al. 2023

Molecular Nutrition Food Res

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ScopeDiets rich in fat and sugars evoke chronic low‐grade inflammation, leading to metabolic derangements. This study investigates the impact of fructose and galactose, two commonly consumed simple sugars, on exacerbation of the harmful effects caused by high fat intake. Additionally, the potential efficacy of fructooligosaccharides (FOS), a fermentable dietary fiber, in counteracting these effects is examined.Methods and resultsMale Sprague‐Dawley rats (six/group) are fed 8 weeks as follows: control 5% fat diet (CNT), 20% fat diet (FAT), FAT+10% FOS diet (FAT+FOS), FAT+25% galactose diet (FAT+GAL), FAT+GAL+10% FOS diet (FAT+GAL+FOS), FAT+25% fructose diet (FAT+FRU), FAT+FRU+10% FOS diet (FAT+FRU+FOS). The dietary manipulations tested do not affect body weight gain, blood glucose, or markers of systemic inflammation whereas significant increases in plasma concentrations of triacylglycerols, cholesterol, aspartate aminotransferase, and alanine aminotrasferase are detected in both FAT+FRU and FAT+GAL compared to CNT. In the liver and skeletal muscle, both sugars induce significant accumulation of lipids and advanced glycation end‐products (AGEs). FOS supplementation prevents these impairments.ConclusionThis study extends the understanding of the deleterious effects of a chronic intake of simple sugars and demonstrates the beneficial role of the prebiotic FOS in dampening the sugar‐induced metabolic impairments by prevention of lipid and AGEs accumulation.

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“…MPO level in tissue is an indicator of neutrophil migration, which reflects inflammation [ 31 ]. Neutrophils are the initial responders in sepsis, and once activated, release their granule contents, especially MPO [ 32 ]. The cellular function of PDZ domain-containing 8 protein (PDZD8) is uncertain, although There is evidence that PDZD8 is a moesin-interacting and microtubule stability regulating factor [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Predicting the prognosis in patients with sepsis by an endoplasmic reticulum stress gene signature

Liu,

Wang,

Xiao

et al. 2023

Aging

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Background: Prognostic stratification of patients with sepsis is important for the development of individualized treatment strategies. Endoplasmic reticulum stress (ERS) plays a key role in sepsis. This study aimed to identify a set of genes related to ER stress to construct a predictive model for the prognosis of sepsis. Methods: The transcriptomic and clinical data of 479 sepsis patients were obtained from GSE65682 and divided into a training set (n=288) and a validation set (n=191) at a ratio of 3:2. The external test set was GSE95233 (n=51). LASSO and Cox regression analyses were performed to establish a signature to predict the prognosis of patients with sepsis. Moreover, we developed a nomogram that included the risk signature and clinical features to predict survival probability. Results: A prognostic signature was constructed with ten endoplasmic reticulum related genes (ADRB2, DHCR7, GABARAPL2, MAOA, MPO, PDZD8, QDPR, SCAP, TFRC, and TLR4) in the training set, which significantly divided patients with sepsis into high- and low-risk groups in terms of survival. This signature was validated using validation and external test sets. A nomogram based on the risk signature was constructed to quantitatively predict the prognosis of patients with sepsis. Conclusions: We constructed an ERS signature as a novel prognostic marker for predicting survival in sepsis patients, which could be used to develop novel biomarkers for the diagnosis, treatment, and prognosis of sepsis and to provide new ideas and prospects for future clinical research.

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Myeloperoxidase instigates proinflammatory responses in a cecal ligation and puncture rat model of sepsis

Cited by 17 publications

References 97 publications

Pharmacological Inhibition of FAK-Pyk2 Pathway Protects Against Organ Damage and Prolongs the Survival of Septic Mice

Pharmacological Inhibition of FAK-Pyk2 Pathway Protects Against Organ Damage and Prolongs the Survival of Septic Mice

Dietary Intake of Fructooligosaccharides Protects against Metabolic Derangements Evoked by Chronic Exposure to Fructose or Galactose in Rats

Predicting the prognosis in patients with sepsis by an endoplasmic reticulum stress gene signature

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