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Double impact of cigarette smoke and mechanical ventilation on the alveolar epithelial type II cell.

ABSTRACT: Ventilator-induced lung injury (VILI) impacts clinical outcomes in acute respiratory distress syndrome (ARDS), which is characterized by neutrophil-mediated inflammation and loss of alveolar barrier function. Recent epidemiological studies suggest that smoking may be a risk factor for the development of ARDS. Because alveolar type II cells are central to maintaining the alveolar epithelial barrier during oxidative stress, mediated in part by neutrophilic inflammation and mechanical ventilation, we hypothesized that exposure to cigarette smoke and mechanical strain have interactive effects leading to the activation of and damage to alveolar type II cells.To determine if cigarette smoke increases susceptibility to VILI in vivo, a clinically relevant rat model was established. Rats were exposed to three research cigarettes per day for two weeks. After this period, some rats were mechanically ventilated for 4 hours. Bronchoalveolar lavage (BAL) and differential cell count was done and alveolar type II cells were isolated. Proteomic analysis was performed on the isolated alveolar type II cells to discover alterations in cellular pathways at the protein level that might contribute to injury. Effects on levels of proteins in pathways associated with innate immunity, oxidative stress and apoptosis were evaluated in alveolar type II cell lysates by enzyme-linked immunosorbent assay. Statistical comparisons were performed by t-tests, and the results were corrected for multiple comparisons using the false discovery rate.Tobacco smoke exposure increased airspace neutrophil influx in response to mechanical ventilation. The combined exposure to cigarette smoke and mechanical ventilation significantly increased BAL neutrophil count and protein content. Neutrophils were significantly higher after smoke exposure and ventilation than after ventilation alone. DNA fragments were significantly elevated in alveolar type II cells. Smoke exposure did not significantly alter other protein-level markers of cell activation, including Toll-like receptor 4; caspases 3, 8 and 9; and heat shock protein 70.Cigarette smoke exposure may impact ventilator-associated alveolar epithelial injury by augmenting neutrophil influx. We found that cigarette smoke had less effect on other pathways previously associated with VILI, including innate immunity, oxidative stress and apoptosis.

SUBMITTER: Hirsch J

PROVIDER: S-EPMC4056080 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Double impact of cigarette smoke and mechanical ventilation on the alveolar epithelial type II cell.

Hirsch Jan J Chalkley Robert J RJ Bentley Trevor T Burlingame Alma L AL Frank James A JA

Critical care (London, England) 20140325 2

<h4>Introduction</h4>Ventilator-induced lung injury (VILI) impacts clinical outcomes in acute respiratory distress syndrome (ARDS), which is characterized by neutrophil-mediated inflammation and loss of alveolar barrier function. Recent epidemiological studies suggest that smoking may be a risk factor for the development of ARDS. Because alveolar type II cells are central to maintaining the alveolar epithelial barrier during oxidative stress, mediated in part by neutrophilic inflammation and mec ...[more]

PMID: 24666941

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Project description:Cigarette smoke (CS) is a main risk factor for chronic obstructive pulmonary disease (COPD). Oxidative stress induced by CS causes DNA and lung damage. Oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD. We studied the effect of oxidative stress generated by CS both in vivo and in vitro on murine primary alveolar type II (ATII) cells isolated from nuclear erythroid 2-related factor-2 (Nrf2)(-/-) mice. We determined human primary ATII cell injury by CS in vitro and analyzed ATII cells isolated from smoker and non-smoker lung donors ex vivo. We also studied whether trolox (water-soluble derivative of vitamin E) could protect murine and human ATII cells against CS-induced DNA damage and/or decrease injury. We analyzed oxidative stress by 4-hydroxynonenal expression, reactive oxygen species (ROS) generation by Amplex Red Hydrogen Peroxide Assay, Nrf2, heme oxygenase 1, p53 and P53-binding protein 1 (53BP1) expression by immonoblotting, Nrf2 nuclear translocation, Nrf2 and p53 DNA-binding activities, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cytokine production by ELISA. We found that ATII cells isolated from Nrf2(-/-) mice are more susceptible to CS-induced oxidative DNA damage mediated by p53/53BP1 both in vivo and in vitro compared with wild-type mice. Therefore, Nrf2 activation is a key factor to protect ATII cells against injury by CS. Moreover, trolox abolished human ATII cell injury and decreased DNA damage induced by CS in vitro. Furthermore, we found higher inflammation and p53 mRNA expression by RT-PCR in ATII cells isolated from smoker lung donors in comparison with non-smokers ex vivo. Our results indicate that the Nrf2 and p53 cross talk in ATII cells affect the susceptibility of these cells to injury by CS. Trolox can protect against oxidative stress, genotoxicity and inflammation induced by CS through ROS scavenging mechanism, and serve as a potential antioxidant prevention strategy against oxidative injury of ATII cells in CS-related lung diseases.

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Double impact of cigarette smoke and mechanical ventilation on the alveolar epithelial type II cell.

Publications

Double impact of cigarette smoke and mechanical ventilation on the alveolar epithelial type II cell.

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