Attenuation of Cigarette Smoke–Induced Emphysema in Mice by Apolipoprotein A-1 Overexpression

Abstract

Chronic inflammation, oxidative stress, and proteolysis participate primarily in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. COPD is a highly prevalent smoking-related disease for which no effective therapy exists to improve the disease course. Although apolipoprotein A-1 (ApoA1) has antiinflammatory and antioxidant properties as well as cholesterol efflux potential, its role in cigarette smoke (CS)-induced emphysema has not been determined. Therefore, we investigated whether human ApoA1 transgenic (TG) mice, with conditionally induced alveolar epithelium to overexpress ApoA1, are protected against the CS-induced lung inflammatory response and development of emphysema. In this study, ApoA1 levels were significantly decreased in the lungs of patients with COPD and in the lungs of mice exposed to CS. ApoA1 TG mice did not develop emphysema when chronically exposed to CS. Compared with the control TG mice, ApoA1 overexpression attenuated lung inflammation, oxidative stress, metalloprotease activation, and apoptosis in CS-exposed mouse lungs. To explore a plausible mechanism of antiapoptotic activity of ApoA1, alveolar epithelial cells (A549) were treated with CS extract (CSE). ApoA1 prevented CSE-induced translocation of Fas and downstream death-inducing signaling complex into lipid rafts, thereby inhibiting Fas-mediated apoptosis. Taken together, the data showed that ApoA1 overexpression attenuated CS-induced lung inflammation and emphysema in mice. Augmentation of ApoA1 in the lung may have therapeutic potential in preventing smoking-related COPD/emphysema.

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease

“…Transgenic mice that conditionally overexpressed human apoA-I in AECs were protected from developing neutrophilic lung inflammation and cigarette smoke-induced emphysema (76). Collectively, this suggests that apoA-I may play a protective role in cigarette smoke-induced emphysema.…”

“…Levels of apoA-I are reduced in both the sputum and lungs of patients with chronic obstructive pulmonary disease, as well as in the lungs of cigarette smoke-exposed mice (75,76). Transgenic mice that conditionally overexpressed human apoA-I in AECs were protected from developing neutrophilic lung inflammation and cigarette smoke-induced emphysema (76).…”

Does urinary peptide content differ between COPD patients with and without inherited alpha-1 antitrypsin deficiency?

“…Apolipoprotein A-I is the main component of high-density lipoproteins. Moreover, it has a protective role as an antioxidative, anti-inflammatory and antiapoptotic factor and as an inhibitor of metalloprotease activation in human lungs and cigarette smoke-exposed murine models 38–40. In addition, reduced levels of apolipoprotein A-I are observed in the lungs of patients with COPD, compared with smoker controls 38.…”

Does urinary peptide content differ between COPD patients with and without inherited alpha1-antitrypsin deficiency?

“…Moreover, it has a protective role as an antioxidative, anti-inflammatory and antiapoptotic factor and as an inhibitor of metalloprotease activation in human lungs and cigarette smoke-exposed murine models. [38][39][40] In addition, reduced levels of apolipoprotein A-I are observed in the lungs of patients with COPD, compared with smoker controls. 38 Apolipoprotein A-I and retinol-binding protein 4 are proposed to be putative biomarkers of COPD severity.…”

“…[38][39][40] In addition, reduced levels of apolipoprotein A-I are observed in the lungs of patients with COPD, compared with smoker controls. 38 Apolipoprotein A-I and retinol-binding protein 4 are proposed to be putative biomarkers of COPD severity. 41,42 A recent review by Bidan et al 43 summarized various studies on lung collagen content in COPD.…”