Galectin-3 aggravates experimental polymicrobial sepsis by impairing neutrophil recruitment to the infectious focus

Ferreira, Raphael Gomes; Rodrigues, Lílian Cataldi; Nascimento, Daniele C.; Kanashiro, Alexandre; Melo, Paulo Henrique de; Borges, Vanessa de Fátima; Gozzi, Aline; Prado, Douglas da Silva; Borges, Marcos de Carvalho; Ramalho, Fernando Silva; Stowell, Sean R.; Cummings, Richard D.; Dias‐Baruffi, Marcelo; Cunha, Fernando; Alves‐Filho, José C.

doi:10.1016/j.jinf.2018.06.010

Cited by 17 publications

(15 citation statements)

References 43 publications

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“…We found that elevated Gal-In patients admitted to the ICU with sepsis, elevated serum Gal-3 levels at admission predicted ICU mortality. Our ndings are consistent with other clinical research in which serum Gal-3 levels predicted 30day all-cause mortality in sepsis [26], as well as murine experiments demonstrating the important role of Gal-3 in sepsis pathogenesis and mortality [27,30]. Our ndings suggest that serum Gal-3 may serve as a prognostic indicator in sepsis.…”

Section: Discussionsupporting

confidence: 90%

“…Prior murine studies have demonstrated the importance of Gal-3 in the pathogenesis of sepsis [29,30] and kidney disease [31,32], including AKI [28,[33][34][35][36]. Pharmacologic inhibition of Gal-3 has ameliorated nephropathy induced by renal ischemia-reperfusion (IR) [28], unilateral ureteral obstruction [29], folic acid [34], hypertension [37,38], aldosterone [39], unilateral nephrectomy [40], obesity [41], aortic stenosis [41], and cisplatin [42].…”

Section: Introductionmentioning

confidence: 99%

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Galectin-3 In Septic Acute Kidney Injury: A Translational Study

Sun

Jiang

Eliaz

et al. 2021

Preprint

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Background Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3’s role and its potential utility as a therapeutic target in S-AKI. MethodsIn 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, IL-6, and creatinine were examined at baseline, 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group). ResultsAmong 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than Interleukin-6 (IL-6). Serum Gal-3 was significantly lower in both P-MCP-treated groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP-treated groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP-treated groups (400mg: p = 0.007; 1200mg: p = 0.007). ConclusionsThis translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Galectin-3 In Septic Acute Kidney Injury: A Translational Study

Sun

Jiang

Eliaz

et al. 2021

Preprint

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“…38,39 For example, among the common genes in both old human and old mice cohorts were LCN2 and LGALS3 which are both implicated in immune cell responses to sepsis and could be used as potential targets for immunomodulation therapy. [40][41][42][43][44] Importantly, our collective data illustrate the importance of further evaluating preclinical models of sepsis and emphasizes that with modifications more relevant rodent models can be engendered to achieve better and more appropriate comparisons (as all sepsis is not equivalent). 45,46 There are many possible explanations as to why there have been no interventional therapies, proven successful in murine models of sepsis, translated in clinical trials.…”

Section: Discussionmentioning

confidence: 86%

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

et al. 2020

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Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress 2 | EFRON Et al. How to cite this article: Efron PA, Darden DB, Wang Z, et al. Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

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“…While the above studies have highlighted a role for Gal-3 in facilitating neutrophil extravasation, several studies suggest that Gal-3 may negatively regulate neutrophil extravasation in certain settings. Gal-3 KO mice actually experience increased neutrophil accumulation and disease severity in several infectious disease models, including neurocysticercosis (90) and polymicrobial sepsis (91). Similarly, a higher number of neutrophils can actually be detected in the BAL of Gal-3 KOs following pulmonary E. coli , as opposed to S. pneumoniae , infection (83).…”

Section: Galectin Regulation Of Neutrophil Extravasationmentioning

confidence: 99%

The Sweet-Side of Leukocytes: Galectins as Master Regulators of Neutrophil Function

et al. 2019

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Among responders to microbial invasion, neutrophils represent one of the earliest and perhaps most important factors that contribute to initial host defense. Effective neutrophil immunity requires their rapid mobilization to the site of infection, which requires efficient extravasation, activation, chemotaxis, phagocytosis, and eventual killing of potential microbial pathogens. Following pathogen elimination, neutrophils must be eliminated to prevent additional host injury and subsequent exacerbation of the inflammatory response. Galectins, expressed in nearly every tissue and regulated by unique sensitivity to oxidative and proteolytic inactivation, appear to influence nearly every aspect of neutrophil function. In this review, we will examine the impact of galectins on neutrophils, with a particular focus on the unique biochemical traits that allow galectin family members to spatially and temporally regulate neutrophil function.

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Galectin-3 aggravates experimental polymicrobial sepsis by impairing neutrophil recruitment to the infectious focus

Cited by 17 publications

References 43 publications

Galectin-3 In Septic Acute Kidney Injury: A Translational Study

Galectin-3 In Septic Acute Kidney Injury: A Translational Study

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

The Sweet-Side of Leukocytes: Galectins as Master Regulators of Neutrophil Function

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