Alcohol decreases organic dust-stimulated airway epithelial TNF-Alpha through a nitric oxide and protein kinase-mediated inhibition of TACE

Details

• Personal Author:
  DeVasure JM ; Gerald CL ; Heires AJ ; Khazanchi R ; Nordgren TM ; Romberger DJ ; Sisson JH ; Wyatt TA
• 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 (TNF-a), interleukin-6 (IL-6), and IL-8. We have shown that alcohol alters airway epithelial innate defense through changes in both nitric oxide (NO) and cAMP-dependent protein kinase A (PKA). Simultaneous exposure to hog barn dust and alcohol decreases inflammatory mediators, TNF-a, 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 TNF-a sheddase, TNF-a-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 [AC], cAMP, and PKA) to modulate the effects of alcohol on dust-stimulated TNF-a release in the bronchial epithelial cell line, BEAS-2B. Alcohol pretreatment blocked TACE activity and TNF-a release in hog barn dust-treated cells. RESULTS: Alcohol continued to block hog barn dust-mediated TNF-a release in the presence of the particulate AC inhibitor, SQ22,536. The soluble adenylyl cyclase inhibitor, KH7, however, significantly increased the inflammatory response to hog barn dust. phosphodiesterase 4 inhibitors significantly elevated cAMP and enhanced alcohol-mediated inhibition of dust-stimulated TNF-a release. In addition, the NO synthase inhibitor, l-NMMA, also reversed the alcohol-blocking effect on dust-stimulated TNF-a. 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 TNF-a release. These findings support our observations that alcohol functions through a dual NO and PKA pathway in bronchial epithelial cells. [Description provided by NIOSH]
• Subjects:
  Agriculture Alcoholic Beverages Animals Blood Cytology Dust Farmers Laboratories Lung Lung Diseases Nitric Oxide Occupational Health Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Airways Alcohol Alcohols Author Keywords: Alcohol Cytokines Dusts Farm Workers Hazards Inflammation Laboratory Animals Lymphocytes Nitric Oxide Organic Dusts Pharmacology Physiology Physiopathology Proteins Pulmonary Disorders Pulmonary System Pulmonary System Disorders Respiratory System Disorders TNF-a-Converting Enzyme

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• ISSN:
  0145-6008
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Nebraska ; OSHA Region 7
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  273-283
• Volume:
  40
• Issue:
  2
• NIOSHTIC Number:
  nn:20048891
• Citation:
  Alcohol Clin Exp Res 2016 Feb; 40(2):273-283
• Contact Point Address:
  Todd A. Wyatt, PhD, Department of Environmental, Agricultural, and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-5910
• Email:
  twyatt@unmc.edu
• CAS Registry Number:
  Nitric oxide (CAS RN 10102-43-9)
• Federal Fiscal Year:
  2016
• Performing Organization:
  University of Nebraska Medical Center, Omaha, Nebraska
• Peer Reviewed:
  True
• Start Date:
  20060801
• Source Full Name:
  Alcoholism: Clinical and Experimental Research
• End Date:
  20160731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0a3497e0a1ea89710829b399e49b59806387d2c04298b5fc2cf78f7071863f8e2b07ef3acd50a532b78fe8ba90d32fe65a5396d5b6e91115b1d1a5cb770fc9b0
• Download URL:
  https://stacks.cdc.gov/view/cdc/203511/cdc_203511_DS1.pdf
• File Type:
  [PDF - 378.63 KB ]