Particulate Matter Air Pollution Disrupts Endothelial Cell Barrier via Calpain-Mediated Tight Junction Protein Degradation

Details

• Personal Author:
  Breysse PN ; Garcia JGN ; Geyh AS ; Lang GD ; Mathew B ; Moreno-Vinasco L ; Natarajan V ; Samet JM ; Siegler JH ; Usatyuk PV ; Wang L ; Wang T
• Description:
  Background: Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation. Objectives: We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction. Methods: Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 microm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured. Results: PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and beta-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro. Conclusions: These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes. [Description provided by NIOSH]
• Subjects:
  Air Pollution Lung Occupational Health Particulate Matter Pathology Respiratory System Safety
• Keywords:
  Air Pollution Author Keywords: Calpain Cardiopulmonary System Cellular Effects Endothelial Permeability Lung Tissue Particulate Matter Particulates Physiological Effects Reactive Oxygen Species ROS TRPM2

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• ISSN:
  1743-8977
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  California ; Illinois ; Maryland ; OSHA Region 3 ; OSHA Region 5 ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  35
• Volume:
  9
• NIOSHTIC Number:
  nn:20062673
• Citation:
  Part Fibre Toxicol 2012 Aug; 9:35
• Contact Point Address:
  Joe G N Garcia, Institute for Personalized Respiratory Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
• Email:
  jggarcia@uic.edu
• Federal Fiscal Year:
  2012
• Performing Organization:
  Johns Hopkins University
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Particle and Fibre Toxicology
• End Date:
  20280630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f7c1fb516dfb37e309e35f797c803dcca145bc012fa41bd606b0f4c7b106671bb251acb04b7464cb4b49ee36fa053c21660a5933c8ef9afa5995761dd38164b2
• Download URL:
  https://stacks.cdc.gov/view/cdc/225871/cdc_225871_DS1.pdf
• File Type:
  [PDF - 1.33 MB ]