Human ApoA-I overexpression diminishes LPS-induced systemic inflammation and multiple organ damage in mice
Introduction
Sepsis and septic shock, caused by Gram-negative and Gram-positive bacteria, fungi, viruses, and parasites, have become increasingly important in clinical aspect over the past decades (O'Brien et al., 2007). Lipopolysaccharide (LPS) is the principal component of endotoxin in the outer membrane of Gram-negative bacteria and is the only lipid constituent of the outer leaflet (Rietschel et al., 1994). After LPS molecules release from the bacterial wall, its toxic moiety (lipid A) is exposed to immune cells, and evokes an inflammatory response. The immunological response to LPS mainly involves leukocytes and the production of cytokines such as tumor necrosis factor alpha (TNF)-α, interleukin (IL)-6, and IL-1β. These compounds induce vasodilatation and upregulation of adhesion molecules, resulting in extravasation of neutrophils and monocytes; activation of leukocytes, lymphocytes, and endothelial cells; and myocardial suppression (Horn, 1998, Karima et al., 1999, Parillo, 1993). Besides stimulation of coagulation by cytokines, bacterial components may directly interact with the coagulation system. The resulting disseminated intravascular coagulation causes hypoperfusion and hypoxia and leads to multiple organ failure (Mammen, 1998, Van Gorp et al., 1999). This may initiate the lethal stage of sepsis, in which multiple organ dysfunction syndrome develops (Parillo, 1993, Wenzel et al., 1996, Bone, 1991). It has been showed that CD14 is a receptor for LPS/LPS-binding protein (LBP) complexes and is responsible for transmembrane signaling (Sweet and Hume, 1996, Wright et al., 1990).
Significant anti-inflammatory effects of high density lipoprotein (HDL) have been demonstrated both in vitro and in vivo, probably as a result of (a) LPS binding and neutralization; (b) inhibition of adhesion molecule expression and release of inflammatory cytokines; (c) stimulation of endothelial nitric oxide synthase (eNOS) expression; and (d) protection of low density lipoprotein (LDL) against peroxidative damage (Wu et al., 2004). As the major protein component of HDL, apolipoprotein A-I (ApoA-I) has been shown to exert many anti-inflammatory actions. Recently, Puranik et al. (2007) reported low dose ApoA-I rescued carotid arteries from inflammation in vivo. Thaveeratitham et al. (2007) showed that purified, lipid-free ApoA-I could inhibit endotoxin-induced leukocyte adhesion to endothelial cells in vivo in a dose-dependent manner and also was able to suppress the growth of E. coli in vitro. In terms of the mechanism of anti-inflammatory of ApoA-I, our previous researches showed that ApoA-I could bind LPS to interrupt activation of macrophage (Ma et al., 2004), inhibit nuclear factor of kappa B (NF-κB) activation and nuclear translocation (data in pressing), inhibit LPS-activated macrophage to release inflammatory cytokines (Yan et al., 2006), inhibit activation of neutrophils (Liao et al., 2005), and diminish expression of adhesion molecules (intracellular adhesion molecule-1 (ICAM-1) and P-selectin) on endothelium (data in pressing).
In this study, we used the adenovirus approach to overexpress human ApoA-I in mice. We found that ApoA-I overexpression diminishes LPS-induced systemic inflammation and multiple organ damage in mice.
Section snippets
Materials
The plasmid pDNR-LIB-ApoA-I-PA containing human ApoA-I cDNA was purchased from Clontech, USA; T4 ligase and restriction endonucleases PacI, PmeI were purchased from Takara Biotechnology, Japan; restriction endonucleases SalI, HindIII, ECoR I, KpnI, XbaI were purchased from Bio-Lab, USA; male BALB/c mice were purchased from Shanghai Laboratory Animal Centre of Chinese Academy of Sciences, Shanghai, China; the immunoturbidometric kit for assay of human ApoA-I was from Jiemen Biotechnology,
AdV-AI infected mice express human ApoA-I
To determine whether infection of intact animals with AdV-AI would result in accumulation of human ApoA-I protein in serum, BALB/c mice were infected by AdV-AI through intravenous injection. High levels of human ApoA-I in serum were detected 24h after infection (0.74 ± 0.11 mg/ml, n = 3), and the levels gradually declined to less than 10% of maximum after 10 days (Fig. 1A). Serum from uninfected animals or from animals infected with the irrelevant recombinant adenovirus, AdV-GFP, demonstrated
Discussion
The present study demonstrates that adenovirus-mediated human ApoA-I overexpression in mice significantly 1) increases human ApoA-I levels in serum; 2) increases serum total cholesterol, HDL cholesterol and triglyceride levels; 3) decreases LPS-induced TNF-α, IL-6, IL-1β increments in serum and bronchoalverolar lavage fluid; 4) diminishes LPS-induced CD14 gene expression in the lung and liver; 5) reduces LPS-induced creatine kinase and creatinine increments in serum; and 6) attenuates the
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