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Review
. 2018 May 1;314(5):L743-L756.
doi: 10.1152/ajplung.00373.2017. Epub 2018 Jan 4.

Effects of cigarette smoke on pulmonary endothelial cells

Qing Lu  1   2 , Eric Gottlieb  2 , Sharon Rounds  1   2
Affiliations
Review

Effects of cigarette smoke on pulmonary endothelial cells

Qing Lu et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

Cigarette smoking is the leading cause of preventable disease and death in the United States. Cardiovascular comorbidities associated with both active and secondhand cigarette smoking indicate the vascular toxicity of smoke exposure. Growing evidence supports the injurious effect of cigarette smoke on pulmonary endothelial cells and the roles of endothelial cell injury in development of acute respiratory distress syndrome (ARDS), emphysema, and pulmonary hypertension. This review summarizes results from studies of humans, preclinical animal models, and cultured endothelial cells that document toxicities of cigarette smoke exposure on pulmonary endothelial cell functions, including barrier dysfunction, endothelial activation and inflammation, apoptosis, and vasoactive mediator production. The discussion is focused on effects of cigarette smoke-induced endothelial injury in the development of ARDS, emphysema, and vascular remodeling in chronic obstructive pulmonary disease.

Keywords: acute respiratory distress syndrome; cigarette smoke; emphysema; endothelial cells; pulmonary hypertension.

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Figures

Fig. 1.
Fig. 1.
Cigarette smoke (CS) increased lung microvascular endothelial cell (LMVEC) permeability in vitro. A and B: 6-wk-old male C57BL/6 mice were exposed to room air (RA) or CS for 6 h. After overnight rest, LMVEC were isolated from cortical lung tissues. Isolated and characterized LMVEC at passage 1 were plated onto electric cell-substrate impedance sensing (ECIS) arrays at equal numbers of cells (2.5 × 105 cells per well). After overnight attachment, cells were treated with vehicle (V), LPS (1 µg/ml), or thrombin (2 U/ml) for 20 h, and monolayer permeability was assessed by measuring electric resistance across the monolayers. Four independent experiments with duplicated ECIS wells for each condition at each time were conducted. C: primary human LMVEC were treated with vehicle (10% PBS) or varying concentrations of cigarette smoke extract (CSE) for indicated times, and monolayer permeability was assessed by ECIS. Three independent experiments with duplicated ECIS wells for each condition at each time were conducted. Data are presented as the means ± SE of the normalized electrical resistance at the selected time points relative to their initial resistance. ANOVA and Tukey-Kramer post hoc test were used to determine statistically significant difference across means among groups. *P < 0.05 vs. RA+V; ξP < 0.05 vs. RA+LPS (A) or RA+thrombin (B). Arrows indicate the time for addition of treatments. [Reprinted with permission of the American Journal of Respiratory Cell and Molecular Biology (20).]
Fig. 2.
Fig. 2.
Effects of a brief cigarette smoke (CS) exposure on LPS- and Pseudomonas-induced lung edema. Male 6-wk-old C57BL/6 were exposed to room air (RA) or CS for 6 h. One hour after CS exposure, mice were intratracheally administered with 2.5 mg/kg of LPS or 5 × 103 colony-forming units of P. aeruginosa (strain PA103) or equal volume of saline as a control (ctrl). After 18 h, bronchoalveolar lavage (BAL) protein content (A and C) and lung wet-to-dry weight ratio (B) were assessed. Four to six mice per group were used. εP < 0.05 CS/ctrl vs. RA/ctrl; *P < 0.05 RA/LPS vs. RA/ctrl; €P < 0.05 CS/LPS vs. RA/LPS or RA/PA103. [Reprinted with permission of the American Journal of Physiology Lung Cellular and Molecular Physiology (84) and the American Journal of Respiratory Cell and Molecular Biology (20).]
Fig. 3.
Fig. 3.
Effects of prolonged cigarette smoke (CS) exposure on LPS-induced lung edema. Male 6-wk-old C57BL/6 and AKR mice were exposed to room air (RA) or CS for 3 wk. One hour after the last CS exposure, mice were intratracheally administered with 2.5 mg/kg of LPS or equal volume of saline as a control (ctrl). After 18 h, bronchoalveolar lavage (BAL) protein content (A), lung wet-to-dry weight ratio (B), and lung extravasation of albumin-conjugated Evans blue dye (C) were assessed. Three to four C57BL/6 mice per group and 4–6 AKR mice per group were used. εP < 0.05 CS/ctrl vs. RA/ctrl; *P < 0.05 RA/LPS vs. RA/ctrl; €P < 0.05 CS/LPS vs. RA/LPS. [Reprinted with permission of the American Journal of Physiology Lung Cellular and Molecular Physiology (116).]
Fig. 4.
Fig. 4.
Proposed model of cigarette smoke-induced pulmonary endothelial cell injury. Cigarette smoke (CS) exposure causes lung endothelial cell (EC) activation, resulting in inflammation, via activation of NF-κB signaling; CS exposure directly increases EC permeability likely through multiple signaling pathways, including inhibition of RhoA, focal adhesion kinase (FAK), and intercellular adhesion molecules (IAM) and activation/upregulation of histone deacetylase-6 (HDAC6), p38, and ceramide; CS exposure also causes EC apoptosis through signaling pathways involving downregulation of VEGF, FAK, α1-antitrypsin (AAT), and unfolded protein response (UPR) and upregulation of ceramide, adenosine, p38, and p53. Excessive EC apoptosis can lead to necrosis and autoimmunity because of release of mitochondrial damage-associated molecular patterns (DAMPs), endothelial microparticles (eMPs), and other cellular contents. CS-induced increases in EC activation, permeability, apoptosis, and necrosis collectively contribute to increased risk of development of acute respiratory distress syndrome (ARDS). CS-induced lung inflammation, EC apoptosis and necrosis, and autoimmunity cause emphysema. CS exposure increases EC endothelin (ET)-1 levels, leading to increased smooth muscle cell (SMC) proliferation and vasoconstriction. CS exposure also decreases vasodilation because of reduction in EC NO. All these changes, in combination with increased blood flow in remaining vessels due to EC apoptosis and loss of vessels, cause vascular remodeling and pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) patients.
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