Abstract
BackgroundChronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. It is also known that a decline in lung function is associated with increased cardiovascular comorbidity in smokers. The mechanism of this cardiopulmonary dual risk by cigarette smoke (CS) is not known. We studied the molecular mechanisms involved in development of emphysema in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice in response to CS exposure.MethodsAdult male and female wild-type (WT) mice of genetic background C57BL/6J and ApoE-/- mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products), mechanical properties as well as airspace enlargement were assessed.Results and DiscussionThe lungs of ApoE-/- mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12) were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE-/- mice as compared to air-exposed ApoE-/- mice or CS-exposed WT mice.ConclusionThese findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.
Highlights
Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis
We determined the inflammatory response, oxidative stress, levels/activities of matrix metalloproteinases (MMP-9 and MMP-12) and NAD+dependent deacetylase sirtuin 1 (SIRT1) which is shown to regulate endothelial nitric oxide synthase activity in lungs of apolipoprotein E (ApoE)-/- mice exposed to cigarette smoke (CS)
ApoE-/- mice are susceptible to increased lung inflammatory cell influx in response to CS Augmented inflammatory response in the lung from environmental stress or toxicants results in the activation of inflammatory cascades in microvasculature and vessel walls leading to a potentiation of atherogenesis [12,13,26,27]
Summary
Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation resulting from excessive airway inflammatory response mediated by cigarette smoke (CS) Comorbidities such as cardiovascular disease, diabetes, lung cancer, and osteoporosis are more prevalent in smokers and patients with COPD [1,2,3]. Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerosis due to an accumulation of cholesterol ester-enriched particles in the blood resulting from a lack of triglyceride and cholesterol metabolism/lipid transport [10] These mice have a shorter life-span and age faster than wild-type counterparts [11]. We used the ApoE-/- mice, which are prone to develop atherosclerosis [19,20], to understand the molecular mechanism of pulmonary phenotype in response to CS exposure, as well as to study the concept of accelerated decline in lung function and aging in cardiopulmonary comorbid conditions. We determined the inflammatory response, oxidative stress (lipid peroxidation products), levels/activities of matrix metalloproteinases (MMP-9 and MMP-12) and NAD+dependent deacetylase sirtuin 1 (SIRT1) which is shown to regulate endothelial nitric oxide synthase (eNOS) activity (endothelial function) in lungs of ApoE-/- mice exposed to CS
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