Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis

Wei Chieh Lin, Chang Wen Chen, Yu Wen Huang, Lee Chao, Julie Chao, Yee Shin Lin, Chiou Feng Lin

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Abstract

Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS.

Original languageEnglish
Article number12463
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - Jul 22 2015

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Acute Lung Injury
Sepsis
Apoptosis
Inflammation
Bronchoalveolar Lavage Fluid
Lipopolysaccharides
Adult Respiratory Distress Syndrome
Lung
Reactive Oxygen Species
kallistatin
Acetylcysteine
Chemokines
Genes
Blood Proteins
Cultured Cells
Proteins
Oxidative Stress
Neutrophils
Plasmids
Animal Models

ASJC Scopus subject areas

  • General

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Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. / Lin, Wei Chieh; Chen, Chang Wen; Huang, Yu Wen; Chao, Lee; Chao, Julie; Lin, Yee Shin; Lin, Chiou Feng.

In: Scientific Reports, Vol. 5, 12463, 22.07.2015.

Research output: Contribution to journalArticle

Lin, Wei Chieh ; Chen, Chang Wen ; Huang, Yu Wen ; Chao, Lee ; Chao, Julie ; Lin, Yee Shin ; Lin, Chiou Feng. / Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. In: Scientific Reports. 2015 ; Vol. 5.
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