Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

Department of Environmental, Agricultural, and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Nutrients (Impact Factor: 3.27). 07/2012; 4(7):695-710. DOI: 10.3390/nu4070695
Source: PubMed


Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF), tracheas and lungs were collected. HDE stimulated a 2-4 fold increase in lung and tracheal PKCε (epsilon) activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability of the lung to activate PKCε-dependent inflammatory pathways to environmental dust exposure. These data also define alcohol as an important co-exposure agent to consider in the study of inhalation injury responses.

Download full-text


Available from: Jill A Poole, Oct 10, 2015
78 Reads
  • Source
    • "Precision-cut lung (PCL) slices were made as previously described [14]. Briefly, C57BL/6 or DDAH-I mice were sacrificed and the lungs were inflated with low melting point agarose (Invitrogen, Carlsbad, CA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase by ADMA blocks alcohol-stimulated increases in CBF. To test this hypothesis, ciliated primary bovine bronchial epithelial cells (BBEC) were preincubated with ADMA (100 µ M) and stimulated with 100 mM ethanol. CBF was measured and PKA assayed. By 1 hr, ethanol activated PKA, resulting in elevated CBF. Both alcohol-induced PKA activation and CBF were inhibited in the presence of ADMA. ADMA alone had no effect on PKA activity or CBF. Using a mouse model overexpressing the ADMA-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), we examined PKA and CBF in precision-cut mouse lung slices. Alcohol-stimulated increases in lung slice PKA and CBF were temporally enhanced in the DDAH mice versus control mice.
    Mediators of Inflammation 11/2013; 2013:592892. DOI:10.1155/2013/592892 · 3.24 Impact Factor
  • Source
    • "This alcohol mouse model is also given standard chow ad libitum. In this way, many investigators have modeled the effects of chronic alcohol ingestion and acute lung injury and obtained blood alcohol levels of 0.08% [12, 27]. Importantly, the Meadow-Cook model opens the possibility of including transgenic mouse animal studies and alcohol exposure. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Similar to effects of alcohol on the heart, liver, and brain, the effects of ethanol (EtOH) on lung injury are preventable. Unlike other vital organ systems, however, the lethal effects of alcohol on the lung are underappreciated, perhaps because there are no signs of overt pulmonary disorder until a secondary insult, such as a bacterial infection or injury, occurs in the lung. This paper provides overview of the complex changes in the alveolar environment known to occur following both chronic and acute alcohol exposures. Contemporary animal and cell culture models for alcohol-induced lung dysfunction are discussed, with emphasis on the effect of alcohol on transepithelial transport processes, namely, epithelial sodium channel activity (ENaC). The cascading effect of tissue and phagocytic Nadph oxidase (Nox) may be triggered by ethanol exposure, and as such, alcohol ingestion and exposure lead to a prooxidative environment; thus impacting alveolar macrophage (AM) function and oxidative stress. A better understanding of how alcohol changes the landscape of the alveolar epithelium can lead to improvements in treating acute respiratory distress syndrome (ARDS) for which hospitalized alcoholics are at an increased risk.
    03/2013; 2013(4):470217. DOI:10.1155/2013/470217
  • [Show abstract] [Hide abstract]
    ABSTRACT: The lungs are among general organs that can undergo irreversible damage from chronic alcohol consumption. Herein, we developed an animal model predisposed for edematous lung injury following chronic ingestion of alcohol in order to better understand the etiology of alcohol related disorders. Using animal modeling, alongside high throughput proteomic and microarray assays, we identified changes in lung protein and transcript in mice and rats, respectively, following chronic alcohol ingestion or a caloric control diet. Liquid chromatography-mass spectrometry (LC-MS/MS) identified several mitochondrial-related proteins in which the expression was up-regulated following long term alcohol ingestion in mice. Consistent with these observations, rat gene chip microarray analysis of alveolar cells obtained from animals maintained on a Lieber-DeCarli liquid alcohol diet confirmed significant changes in mitochondrial-related transcripts in the alcohol lung. Transmission electron microscopy (TEM) revealed significant changes in the mitochondrial architecture in alcohol mice, particularly following lipopolysacharide (LPS) exposure. Chronic alcohol ingestion was also shown to worsen mitochondrial respiration, mitochondrial membrane polarization, and NAD+/NADH ratios in alveolar type 2 cells. In summary, our studies show causal connection between chronic alcohol ingestion and mitochondrial dysfunction; albeit the specific role of each of the mitochondrial-related proteins and transcripts identified in our study requires additional study.
    AJP Lung Cellular and Molecular Physiology 03/2014; 306(11). DOI:10.1152/ajplung.00287.2013 · 4.08 Impact Factor
Show more