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

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

doi:10.1038/srep12463

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.

Highlights

Inhibitors, and anti-inflammatory, antithrombotic and fibrinolytic treatments, but none of them has proven to be effective[6,7,8]
We found that bronchoalveolar lavage fluids (BALF) kallistatin levels were positively correlated with the concentration of total protein in BALF (r = 0.678, P < 0 .0001) (Fig. 1a)
We demonstrated that the BALF kallistatin/total protein ratio was negatively correlated with the arterial partial pressure of carbon dioxide (PaCO2) levels (r = 0.408, P = 0 .011) (Fig. 1b)

Summary

Introduction

Inhibitors, and anti-inflammatory, antithrombotic and fibrinolytic treatments, but none of them has proven to be effective[6,7,8]. Transgenic mice overexpressing kallistatin exhibit enhanced resistance to lipopolysaccharide (LPS)-induced lethality[17]. This protective effect is observed in group A streptococcus-infected mice with kallistatin gene transfer, and in polymicrobial septic mice treated with recombinant kallistatin[18,19]. Depletion of endogenous kallistatin by antibody injection aggravates organ damage, inflammation and oxidative stress in hypertensive rats[23]. Taken together, these findings indicate that kallistatin exerts protective functions via various biological actions. In human lung epithelial cells, kallistatin attenuated LPS-induced inflammation and apoptosis by inhibiting ROS generation and NF-κ B activation, subsequently down-regulating Fas/FasL signaling

Methods

Results

Conclusion