Protective Effect of a Novel (2S, 3R, 4S)-Chromene-3-Carboxamide Derivative, Z20 Against Sepsis-Induced Organ Injury

Zeng, Lingbing; Wang, Yuhang; Li, Na; Niu, Mengwei; Wang, Yong; Chen, Peng

doi:10.1007/s10753-019-01174-z

Cited by 5 publications

(1 citation statement)

References 26 publications

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“…In accordance with the survival rate, the fluconazole-treated group produced more proinflammatory cytokines (IL-1 β , TNF- α , IL-23, and IL-12p70) and the anti-inflammatory cytokine IL-10 upon LPS challenge ( Figure 2(a) ) but not at steady state ( Figure 2(b) ). In addition, tissue biopsies of the lung ( Figure 2(c) ) or liver ( Figure 2(d) ) at 10 hours post-LPS challenge also showed severe tissue damage and increased immune cell infiltration in the fluconazole-treated group; this time point was widely adopted to evaluate tissue damage in endotoxic shock model [ 32 , 33 ]. In summary, AFT predisposed mice to lethal sepsis/endotoxin shock.…”

Section: Resultsmentioning

confidence: 99%

Antifungal Treatment Aggravates Sepsis through the Elimination of Intestinal Fungi

Sheng

Chen

Sun

et al. 2021

Oxidative Medicine and Cellular Longevity

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Prophylactic antifungal therapy is widely adopted clinically for critical patients and effective in reducing the morbidity of invasive fungal infection and improves outcomes of those diagnosed patients; however, it is not associated with higher overall survival. As intestinal commensal fungi play a fundamental role in the host immune response in health and disease, we propose that antifungal therapy may eliminate intestinal fungi and aggravate another critical syndrome, sepsis. Here, with murine sepsis model, we found that antifungal therapy with fluconazole dismissed intestinal fungal burden and aggravated endotoxin-induced but no gram-positive bacteria-induced sepsis. Nevertheless, antifungal therapy did not exert its detrimental effect on germ-free mice. Moreover, colonizing more commensal fungi in the mouse intestine or administration of fungal cell wall component mannan protected the mice from endotoxin-induced sepsis. On the molecular level, we demonstrated that antifungal therapy aggravated endotoxin sepsis through promoting Gasdermin D cleavage in the distal small intestine. Intestinal colonization with commensal fungi inhibited Gasdermin D cleavage in response to lipopolysaccharide challenge. These findings show that intestinal fungi inhibit Gasdermin D-mediated pyroptosis and protect the mice from endotoxin-induced sepsis. This study demonstrates the protective role of intestinal fungi in the pathogenesis of endotoxin-induced sepsis in the laboratory. It will undoubtedly prompt us to study the relationship between antifungal therapy and sepsis in critical patients who are susceptible to endotoxin-induced sepsis in the future.

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Section: Resultsmentioning

confidence: 99%