Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

Details

• Personal Author:
  Heires AJ ; Liu-X-d ; Nordgren TM ; Poole JA ; Romberger DJ ; Souder CP ; Toews ML ; West W ; Whatt TA
• Description:
  Workers exposed to aerosolized dust present in concentrated animal feeding operations (CAFOs) are susceptible to inflammatory lung diseases, such as chronic obstructive pulmonary disease. Extracts of dust collected from hog CAFOs [hog dust extract (HDE)] are potent stimulators of lung inflammatory responses in several model systems. The observation that HDE contains active proteases prompted the present study, which evaluated the role of CAFO dust proteases in lung inflammatory processes and tested whether protease-activated receptors (PARs) are involved in the signaling pathway for these events. We hypothesized that the damaging proinflammatory effect of HDE is due, in part, to the proteolytic activation of PARs, and inhibiting the proteases in HDE or disrupting PAR activation would attenuate HDE-mediated inflammatory indexes in bronchial epithelial cells (BECs), in mouse lung slices in vitro, and in a murine in vivo exposure model. Human BECs and mouse lung slice cultures stimulated with 5% HDE released significantly more of each of the cytokines measured (IL-6, IL-8, TNF-a, keratinocyte-derived chemokine/ CXC chemokine ligand 1, and macrophage inflammatory protein- 2/CXC chemokine ligand 2 than controls, and these effects were markedly diminished by protease inhibition. Inhibition of PARs also blunted the HDE-induced cytokine release from BECs. In addition, protease depletion inhibited HDE-induced BEC intracellular PKCa and PKCepsilon activation. C57BL/6J mice administered 12.5% HDE intranasally, either once or daily for 3 wk, exhibited increased total cellular and neutrophil influx, bronchial alveolar fluid inflammatory cytokines, lung histopathology, and inflammatory scores compared with mice receiving protease-depleted HDE. These data suggest that proteases in dust from CAFOs are important mediators of lung inflammation, and these proteases and their receptors may provide novel targets for therapeutic intervention in CAFO dust-induced airways disease. [Description provided by NIOSH]
• Subjects:
  Aerosols Agriculture Dust Laboratories Lung Occupational Health Particulate Matter Respiratory System Safety
• Keywords:
  Aerosol Particles Agricultural Industry Author Keywords: Lung Dust Exposure Dust Particles Dusts Environmental Dust Epithelial Cell Inflammation Laboratory Animals Lung Irritants Protease-activated Receptors Proteases Respiratory Disorders

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• ISSN:
  1040-0605
• Document Type:
  Text
• Funding:
  Grant ; Cooperative Agreement
• 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
• Volume:
  309
• Issue:
  4
• NIOSHTIC Number:
  nn:20046934
• Citation:
  Am J Physiol Lung Cell Mol Physiol 2015 Aug; 309(4):L388-L399
• Contact Point Address:
  D. J. Romberger, Pulmonary Critical Care, Sleep and Allergy Division, Dept. of Internal Medicine, Univ. of Nebraska Medical Center, Omaha, NE 68198
• Email:
  dromberg@unmc.edu
• Federal Fiscal Year:
  2015
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  University of Nebraska Medical Center, Omaha, Nebraska
• Peer Reviewed:
  True
• Start Date:
  20060801
• Source Full Name:
  American Journal of Physiology: Lung Cellular and Molecular Physiology
• End Date:
  20160731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:24c0868b79df82862769a67035665a39aabc9000fec552494312e99a4a643e47d8ef84ffe985c59bbba0df32169fbc265928c094be7c99a954d5512aced39591
• Download URL:
  https://stacks.cdc.gov/view/cdc/202192/cdc_202192_DS1.pdf
• File Type:
  [PDF - 859.85 KB ]