Targeted inactivation of endothelial lipase attenuates lung allergic inflammation through raising plasma HDL level and inhibiting eosinophil infiltration

Abstract

Endothelial lipase (EL) is a novel phospholipase that determines plasma high-density lipoprotein cholesterol (HDL-C) levels. We have investigated the role of HDL-C in lung allergic inflammation by using EL knockout (EL-KO) mice that are high in HDL-C. EL-KO and wild-type control mice were sensitized and challenged with ovalbumin to evoke eosinophilic inflammation in the lung. EL was expressed in epithelial cells, alveolar type II cells, and endothelial cells in the lung, and its expression was upregulated during inflammation. Concomitant with attenuated hyperresponsiveness of the airway smooth muscles, the number of eosinophils in bronchoalveolar lavage and the expression of VCAM-1 were lower in EL-KO mice than in control mice. HDL reduced cytokine-induced VCAM-1 expression in cultured endothelial cells. When plasma HDL levels were decreased to similar levels in both mouse groups by adenovirus-mediated overexpression of EL, however, eosinophil infiltration was still lower in EL-KO mice. In vitro adhesion assays revealed that EL expression on the cell surface promoted the interaction of eosinophils through the ligand-binding function of EL. In summary, targeted inactivation of EL attenuated allergic inflammation in the lung, and the protective effects in EL-KO mice were associated with high plasma HDL levels, downregulation of VCAM-1, and loss of the direct ligand-binding function of EL. Thus EL is a novel modulator of the progression of allergic asthma.

D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma

“…In 2005, ABCA1, representing the fi rst step in reverse cholesterol transport, was reported to be essential for maintaining normal lipid composition, architecture, and airway physiology of the lung ( 4 ). In 2009, genetic deletion of endothelial lipase was shown to increase HDL nearly 2-fold, which was credited with decreasing AHR and pulmonary infl ammation in ovalbumin (OVA)-sensitized mice ( 5 ). In 2010, we reported that genetic deletion of apolipoprotein (apo)A-I specifi cally increased pulmonary infl ammation and AHR without impairing peripheral vascular function ( 6 ).…”

Vertebrate endothelial lipase: comparative studies of an ancient gene and protein in vertebrate evolution

“…Studies of Lipg − /Lipg − knock out mice have demonstrated multiple roles for LIPG in vascular lipoprotein metabolism, including serving potential roles in blood vessel inflammation (Kojima et al, 2004), promoting low-density lipoprotein cholesterol (LDL-C) uptake in macrophages (Yasuda et al, 2007), modulating allergic asthma (Otera et al, 2009), HDL-C mediated repression of leukocyte adhesion (Ahmed et al, 2006) and influencing HDL particle size in the circulation (Jin et al, 2003). Clinical studies have also examined LIPG genetic variants in human populations with loss of function LIPG mutations leading to increased HDL-C levels and an associated protection from atherosclerotic cardiovascular disease (deLemos et al, 2002; Edmondson et al, 2009).…”

Genetic Interactions between Chromosomes 11 and 18 Contribute to Airway Hyperresponsiveness in Mice

“…Npc1l1 is a separate gene expressed in gut epithelium [36], [37], [38], [39], [40], [41] whose protein product regulates cholesterol absorption, thereby influencing whole body cholesterol homeostasis, and is the target of ezetimibe. A growing body of literature implicates cholesterol or modulators of metabolism in the regulation native airway responsiveness and/or allergic airway inflammation [42], [43], [44], [45], [46], [47]. Depletion of cholesterol from membrane caveoli disrupts contractile activation of airway smooth muscle during muscarinic, serotonin, or KCl-stimulation [48], [49], and further inhibits rho kinase activation [48].…”