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Title: Tight junction disruption by cadmium in an in vitro human airway tissue model

Journal Article · · Respiratory Research (Online)
 [1];  [1];  [2];  [2];  [3];  [4]
  1. U.S. Food and Drug Administration (FDA), Jefferson, AR (United States)
  2. Toxicologic Pathology Associates, Jefferson, AR (United States)
  3. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States)
  4. Div. of Genetic and Molecular Toxicology, Jefferson, AR (United States)
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The cadmium (Cd) present in air pollutants and cigarette smoke has the potential of causing multiple adverse health outcomes involving damage to pulmonary and cardiovascular tissue. Injury to pulmonary epithelium may include alterations in tight junction (TJ) integrity, resulting in impaired epithelial barrier function and enhanced penetration of chemicals and biomolecules. Herein, we investigated mechanisms involved in the disruption of TJ integrity by Cd exposure using an in vitro human air-liquid-interface (ALI) airway tissue model derived from normal primary human bronchial epithelial cells. ALI cultures were exposed to noncytotoxic doses of CdCl2 basolaterally and TJ integrity was measured by Trans-Epithelial Electrical Resistance (TEER) and immunofluorescence staining with TJ markers. PCR array analysis was used to identify genes involved with TJ collapse. To explore the involvement of kinase signaling pathways, cultures were treated with CdCl2 in the presence of kinase inhibitors specific for cellular Src or Protein Kinase C (PKC). Noncytotoxic doses of CdCl2 resulted in the collapse of barrier function, as demonstrated by TEER measurements and Zonula occludens-1 (ZO-1) and occludin staining. CdCl2 exposure altered the expression of several groups of genes encoding proteins involved in TJ homeostasis. In particular, down-regulation of select junction-interacting proteins suggested that a possible mechanism for Cd toxicity involves disruption of the peripheral junctional complexes implicated in connecting membrane-bound TJ components to the actin cytoskeleton. Inhibition of kinase signaling using inhibitors specific for cellular Src or PKC preserved the integrity of TJs, possibly by preventing occludin tyrosine hyperphosphorylation, rather than reversing the down-regulation of the junction-interacting proteins. Our findings indicate that acute doses of Cd likely disrupt TJ integrity in human ALI airway cultures both through occludin hyperphosphorylation via kinase activation and by direct disruption of the junction-interacting complex.

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC); US Food and Drug Administration
Grant/Contract Number:
SC0014664
OSTI ID:
1626885
Journal Information:
Respiratory Research (Online), Vol. 16, Issue 1; ISSN 1465-993X
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (13)

Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit journal December 2016
E. coli Nissle microencapsulation in alginate-chitosan nanoparticles and its effect on Campylobacter jejuni in vitro journal October 2018
Transcriptomic response of primary human airway epithelial cells to flavoring chemicals in electronic cigarettes journal February 2019
Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier journal November 2019
Human pluripotent stem cell-derived alveolar epithelial cells are alternatives for in vitro pulmotoxicity assessment journal January 2019
Human Pulmonary 3D Models For Translational Research journal September 2017
Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells journal March 2019
Key Molecular Mechanisms of Chaiqinchengqi Decoction in Alleviating the Pulmonary Albumin Leakage Caused by Endotoxemia in Severe Acute Pancreatitis Rats journal January 2016
Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor journal September 2015
Mechanisms allowing protein delivery in nasal mucosa using NPL nanoparticles journal June 2016
Chemotaxis and Binding of Pseudomonas aeruginosa to Scratch-Wounded Human Cystic Fibrosis Airway Epithelial Cells journal March 2016
Cytokine–Ion Channel Interactions in Pulmonary Inflammation journal January 2018
In Vitro Evaluation of the Impact of the Probiotic E. coli Nissle 1917 on Campylobacter jejuni’s Invasion and Intracellular Survival in Human Colonic Cells journal August 2017

Figures / Tables (8)

Figure 1(p. 5)figure Figure 1
Figure 2(p. 6)figure Figure 2
Figure 3(p. 7)figure Figure 3
Figure 4(p. 8)figure Figure 4
Table 1(p. 9)table Table 1
Figure 5(p. 10)figure Figure 5
Figure 6(p. 10)figure Figure 6
Figure 7(p. 11)figure Figure 7

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Related Subjects

60 APPLIED LIFE SCIENCES
respiratory system
cadmium
airway air-liquid-interface (ALI) culture
tight junction
occludin phosphorylation
intracellular junctional interacting proteins