title: Alcohol Decreases Organic Dust-Stimulated Airway Epithelial TNF-Alpha Through a Nitric Oxide and Protein Kinase-Mediated Inhibition of TACE.
abstract: 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-α), 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-α, 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-α 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 [AC], cAMP, and PKA) to modulate the effects of alcohol on dust-stimulated TNF-α release in the bronchial epithelial cell line, BEAS-2B. Alcohol pretreatment blocked TACE activity and TNF-α release in hog barn dust-treated cells.
  
  
  RESULTS
  Alcohol continued to block hog barn dust-mediated TNF-α 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-α release. In addition, the NO synthase inhibitor, l-NMMA, also reversed the alcohol-blocking effect on dust-stimulated TNF-α.
  
  
  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-α release. These findings support our observations that alcohol functions through a dual NO and PKA pathway in bronchial epithelial cells.
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Carresse L
authors: CL
authors: Gerald
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.|Department of Veterans Affairs Medical Center, VA Nebraska-Western Iowa Health Care System Research Service, Omaha, Nebraska.
authors: Debra J
authors: DJ
authors: Romberger
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Jane M
authors: JM
authors: DeVasure
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Rohan
authors: R
authors: Khazanchi
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Tara M
authors: TM
authors: Nordgren
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Art J
authors: AJ
authors: Heires
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.
authors: Joseph H
authors: JH
authors: Sisson
authors: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, Nebraska Medical Center, Omaha, Nebraska.|Department of Veterans Affairs Medical Center, VA Nebraska-Western Iowa Health Care System Research Service, Omaha, Nebraska.|Department of Environmental, Agricultural, and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Todd A
authors: TA
authors: Wyatt
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D000072198:ADAM17 Protein; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004391:Dust; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D015850:Interleukin-6 / Q000502:physiology; D016209:Interleukin-8 / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D020545:Respiratory Mucosa / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D004391:Dust; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C017759:9-(tetrahydro-2-furyl)-adenine; D009569:Nitric Oxide; D000431:Ethanol; D017868:Cyclic AMP-Dependent Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D000225:Adenine
keywords: Airways; Alcohol; Inflammation; Nitric Oxide; TNF-α-Converting Enzyme