Details:

Alternative Title:
Alcohol Clin Exp Res
Publisher's site:
http://dx.doi.org/10.1111/acer.12967
Personal Author:
Gerald, C. L. ; Romberger, D. J. ; DeVasure, J. M. ; Khazanchi, R. ; Nordgren, T. M. ; ... More +
Gerald, C. L. ; Romberger, D. J. ; DeVasure, J. M. ; Khazanchi, R. ; Nordgren, T. M. ; Heires, A. J. ; Sisson, J. H. ; Wyatt, T. A. ; Less -
Description:
Background Farm workers in rural areas consume more alcohol than those who reside in urban areas. Occupational exposures such as agricultural work can pose hazards on the respiratory system. It is established that hog barn dust induces inflammation in the airway, including the release of cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) and interleukin-8 (IL-8). We have shown that alcohol alters airway epithelial innate defense through changes in both nitric oxide (NO) and cAMP-dependent protein kinase (PKA). Simultaneous exposure to hog barn dust and alcohol decreases inflammatory mediators, TNFα, IL-6 and IL-8, in mice. Previously, mice exposed to both alcohol and hog barn dust showed a depleted amount of lymphocytes compared to mice exposed only to hog barn dust. Weakening of the innate immune response could lead to enhanced susceptibility to disease. In addition, mice that were co-exposed to hog barn dust and alcohol also experienced increased mortality. Methods Because we recently demonstrated that PKA activation inhibits the TNFα sheddase, TNF-α converting enzyme (TACE), we hypothesized that an alcohol-mediated PKA pathway blocks TACE activity and prevents the normative inflammatory response to hog barn dust exposure. To delineate these effects, we used PKA pathway inhibitors (adenylyl cyclase, cAMP and PKA) to modulate the effects of alcohol on dust-stimulated TNFα release in the bronchial epithelial cell line, BEAS-2B. Alcohol pretreatment blocked TACE activity and TNFα release in hog barn dust-treated cells. Results Alcohol continued to block hog barn dust-mediated TNFα release in the presence of the particulate adenylyl cyclase inhibitor, SQ22,536. The soluble adenylyl cyclase (sAC) inhibitor, KH7, however, significantly increased the inflammatory response to hog barn dust. PDE4 inhibitors significantly elevated cAMP and enhanced alcohol-mediated inhibition of dust-stimulated TNFα release. In addition, the nitric oxide synthase inhibitor, L-NMMA, also reversed the alcohol-blocking effect on dust-stimulated TNFα. Conclusions These data suggest that alcohol requires a soluble cyclase-generated cAMP-PKA pathway that is dependent upon the action of NO to inhibit TACE and TNFα release. These findings support our observations that alcohol functions through a dual NO and PKA pathway in bronchial epithelial cells.
Subject:
[+]
ADAM17 Protein
ADAM Proteins
Adenine
Article
Bronchi
Cell Line
Cyclic AMP-Dependent Protein Kinases
Dust
Enzyme-Linked Immunosorbent Assay
Ethanol
Humans
Inflammation
Interleukin-6
Interleukin-8
Nitric Oxide
Respiratory Mucosa
Tumor Necrosis Factor-alpha

Source:
Alcohol Clin Exp Res. 40(2):273-283. ;
Pubmed ID:
26842246
Pubmed Central ID:
PMC5656047
Document Type:
Journal Article ;
Funding:
I01 BX000728/BX/BLRD VA/United States ; R01 AA008769/AA/NIAAA NIH HHS/United States ; R01 AA017993/AA/NIAAA NIH HHS/United States ; R01 OH008539/OH/NIOSH CDC HHS/United States ;
I01 BX000728/BX/BLRD VA/United States ; R01 AA008769/AA/NIAAA NIH HHS/United States ; R01 AA017993/AA/NIAAA NIH HHS/United States ; R01 OH008539/OH/NIOSH CDC HHS/United States ; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:c092f6c4ed086bf10108746ae5c02f116fb30834b11711837334781fd3b0a5f5
File Type:

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