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.

Interplay between cigarette smoking and pulmonary reverse lipid transport

“…This displays the significant impact reverse lipid export capacity can have on the magnitude of the pulmonary response to cigarette smoke exposure. Our data is consistent with the study from KIM et al [20], showing that mice overexpressing human ApoA-1 in the alveolar epithelium are protected from lung emphysema. It also aligns with findings in experimental atherosclerosis, where ApoA-1 deficiency exacerbates the pathology [21,22], while introduction of a human ApoA-1 transgene confers protection [23,24].…”

Interplay between cigarette smoking and pulmonary reverse lipid transport

“…This displays the significant impact reverse lipid export capacity can have on the magnitude of the pulmonary response to cigarette smoke exposure. Our data is consistent with the study from KIM et al [20], showing that mice overexpressing human ApoA-1 in the alveolar epithelium are protected from lung emphysema. It also aligns with findings in experimental atherosclerosis, where ApoA-1 deficiency exacerbates the pathology [21,22], while introduction of a human ApoA-1 transgene confers protection [23,24].…”

β1 Integrin regulates adult lung alveolar epithelial cell inflammation

“…One possible mechanism for the development of emphysema is that macrophages mediate lung destruction via altered protease/antiprotease balance (54)(55)(56). These observations are consistent with studies demonstrating a role for excessive ROS and NF-κB activation as initiators of macrophage accumulation and subsequent alveolar injury, resulting in emphysema (57)(58)(59). In addition, epithelial apoptosis in combination with ineffective efferocytosis could contribute to the development of emphysema.…”

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD

“…We note that increased cholesterol synthesis and reduced PC levels increase susceptibility to emphysema ( 17 , 54 – 56 ). However, this is the first study to our knowledge to interrogate and target lipid homeostasis in the AEC2 cell upon smoke.…”

Interplay between cigarette smoking and pulmonary reverse lipid transport

“…This displays the significant impact reverse lipid export capacity can have on the magnitude of the pulmonary response to cigarette smoke exposure. Our data is consistent with the study from KIM et al [20], showing that mice overexpressing human ApoA-1 in the alveolar epithelium are protected from lung emphysema. It also aligns with findings in experimental atherosclerosis, where ApoA-1 deficiency exacerbates the pathology [21,22], while introduction of a human ApoA-1 transgene confers protection [23,24].…”

β1 Integrin regulates adult lung alveolar epithelial cell inflammation

“…One possible mechanism for the development of emphysema is that macrophages mediate lung destruction via altered protease/antiprotease balance (54)(55)(56). These observations are consistent with studies demonstrating a role for excessive ROS and NF-κB activation as initiators of macrophage accumulation and subsequent alveolar injury, resulting in emphysema (57)(58)(59). In addition, epithelial apoptosis in combination with ineffective efferocytosis could contribute to the development of emphysema.…”

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD

“…We note that increased cholesterol synthesis and reduced PC levels increase susceptibility to emphysema ( 17 , 54 – 56 ). However, this is the first study to our knowledge to interrogate and target lipid homeostasis in the AEC2 cell upon smoke.…”

Interplay between cigarette smoking and pulmonary reverse lipid transport

“…This displays the significant impact reverse lipid export capacity can have on the magnitude of the pulmonary response to cigarette smoke exposure. Our data is consistent with the study from KIM et al [20], showing that mice overexpressing human ApoA-1 in the alveolar epithelium are protected from lung emphysema. It also aligns with findings in experimental atherosclerosis, where ApoA-1 deficiency exacerbates the pathology [21,22], while introduction of a human ApoA-1 transgene confers protection [23,24].…”

β1 Integrin regulates adult lung alveolar epithelial cell inflammation

“…One possible mechanism for the development of emphysema is that macrophages mediate lung destruction via altered protease/antiprotease balance (54)(55)(56). These observations are consistent with studies demonstrating a role for excessive ROS and NF-κB activation as initiators of macrophage accumulation and subsequent alveolar injury, resulting in emphysema (57)(58)(59). In addition, epithelial apoptosis in combination with ineffective efferocytosis could contribute to the development of emphysema.…”

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD

“…We note that increased cholesterol synthesis and reduced PC levels increase susceptibility to emphysema ( 17 , 54 – 56 ). However, this is the first study to our knowledge to interrogate and target lipid homeostasis in the AEC2 cell upon smoke.…”