title: Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis.
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.
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chang-Wen
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
authors.affiliation: 1] Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan [2] Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan [2] Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D055371:Acute Lung Injury / Q000188:drug therapy* / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism; D018805:Sepsis / Q000150:complications*; D015843:Serpins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D015843:Serpins; D019014:fas Receptor; C051324:kallistatin; D000111:Acetylcysteine