Targeting Airway Inflammation from Concentrated Animal Feeding Operations Dust

Details

• Personal Author:
  Bailey KL ; Liu X-d ; Poole JA ; Romberger DJ ; Toews M ; West WW ; Wyatt TA ; Yu F
• Description:
  Farmers and workers in concentrated animal feeding operations (CAFOs) experience work-related respiratory disease, particularly chronic bronchitis and chronic obstructive pulmonary disease (COPD). Although multiple substances in CAFOs may contribute to disease, dust from these facilities is well recognized as an important respiratory health hazard. Our previous work has been focused on defining mechanisms by which CAFO dust results in lung inflammation. Importantly, we have identified three critical elements of this CAFO dust-induced lung inflammation mechanism that we propose make excellent therapeutic targets for treatment of this important occupational lung disorder: 1) cytokine release, focusing on the TNF-alpha-dependent airway epithelial cell release of IL-6 and IL-8 with sequential activation of the airway epithelial protein kinase C isoforms (PKC), alpha followed by epsilon; 2) the anti-inflammatory effects of the cyclic AMP dependent protein kinase (PKA); and 3) pro-inflammatory proteases as triggers present in CAFO dust. This proposal outlines how we will use a pre-clinical animal model to decipher the relative value of targeting these three mechanistic elements that may dampen and/or reverse CAFO dust-induced lung disease. Toward this end, we have demonstrated that inhaled dust extract causes respiratory inflammation in vivo in a mouse model that has all of the prominent features of the pulmonary disorders seen in persons working in swine confinement facilities. In this renewal we propose a strategy to utilize this mouse model in preclinical studies aimed at determining which of the therapeutic targets outlined above are feasible and efficacious. We hypothesize that: CAFO dust-induced lung inflammation is treatable by blocking PKC isoform-triggered airway cytokine release, activating PKA and inhibiting dust-derived proteases and their cellular targets. We will test this hypothesis via three specific aims: Aim 1: Establish how agents that specifically target TNF-alpha, IL-6, and IL-8 modulate dust extract-induced lung inflammation in vivo. Aim 2: Determine how agents that augment PKA, especially therapeutic beta-adrenergic agonists, dampen dust extract-induced PKC isoform activation and attenuate lung inflammation in vitro and in vivo. Aim 3: Determine the importance of proteases in dust extract-induced TNF-alpha/IL-6/IL-8 in vitro and in tissue inflammation in vivo and identify potential targets for attenuating the dust extract protease-induced inflammatory changes. Our proposal is designed to provide pre-clinical cell, lung slice, and animal data that will facilitate translational studies aimed at bringing potential interventions into the workplace. [Description provided by NIOSH]
• Subjects:
  Animals Dust Farmers Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Animal Handlers Animal Husbandry Workers Animal Studies Bronchitis Chronic Obstructive Pulmonary Disease COPD Cytokines Dust Exposure Farm Workers Livestock Foods Lung Disease Physiological Effects Physiological Response Respirable Dust Respiratory Diseases

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• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  Nebraska ; OSHA Region 7
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-31
• NIOSHTIC Number:
  nn:20053143
• NTIS Accession Number:
  PB2019-100188
• Citation:
  Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-008539, 2016 Nov; :1-31
• Contact Point Address:
  Debra J. Romberger, MD, University of Nebraska Medical Center, Department of Internal Medicine, 983332 Nebraska Medical Center, Omaha, NE 68198-3332
• Email:
  dromberg@unmc.edu
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  University of Nebraska Medical Center, Omaha, Nebraska
• Peer Reviewed:
  False
• Start Date:
  20060801
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20160731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ff25b343d5ea2d8c8c9ca4848df302754fabd41e4cfe9e78ff3e479f04d7ea0022c10daa214ff18e6dba1d026c8e3570caa1a0318e5f19fe696c4f945086cb5d
• Download URL:
  https://stacks.cdc.gov/view/cdc/218750/cdc_218750_DS1.pdf
• File Type:
  [PDF - 529.74 KB ]