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18 August 2019 : Clinical Research  

LL-37 Exacerbates Local Inflammation in Sepsis-Induced Acute Lung Injury by Preventing Mitochondrial DNA (mtDNA) Degradation-Induced Autophagy

Yunlong Zuo1ABCDEFG, Run Dang1BC, Hongyan Peng1ABCF, Zhiyuan Wu1BC, Yiyu Yang1AE*

DOI: 10.12659/MSM.915298

Med Sci Monit 2019; 25:6193-9203

Abstract

BACKGROUND: Recent studies have proved that autophagy dysfunction in proinflammatory cells is involved in tissue damage and an excessive inflammatory response in sepsis. In the present study, we identified that the human antimicrobial peptide LL-37 facilitates resistance to DNase II-induced mitochondrial DNA (mtDNA) degradation and subsequent autophagy.

MATERIAL AND METHODS: We found higher serum levels of LL-37 in patients with severe sepsis compared to that in patients with mild sepsis. Neutrophils isolated from mice with sepsis after treatment with Cramp-mtDNA produced an excess of proinflammatory cytokines, including IL-1β, IL-6, IL-8, MMP-8, and TNF-α. Cramp-mtDNA in the lung samples from model animals with sepsis was detected by immunohistochemical staining.

RESULTS: Exogenous delivery of Cramp-mtDNA complex significantly exacerbated lung inflammation but the antibody against Cramp-mtDNA attenuated the excessive inflammatory response in LPS-induced acute lung injury. The expression of proinflammatory cytokines in lungs was upregulated and downregulated after treatment with the complex and antibody, respectively. LC-3 expression in 16HBE cells increased after LPS induction, irrespective of stimulation with LL-37.

CONCLUSIONS: These data show that LL-37 treatment worsens local inflammation in sepsis-induced acute lung injury by preventing mtDNA degradation-induced autophagy.

Keywords: Lung Injury, Sepsis, acute lung injury, Antimicrobial Cationic Peptides, Child, Preschool, Cytokines, DNA, Mitochondrial, HEK293 Cells, Lipopolysaccharides, Mitochondria, Neutrophils

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750