TRPV1 receptors mediate particulate matter-induced apoptosis

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 286; no. 3; pp. 563 - L572
• Main Authors: Agopyan, N, Head, J, Yu, S, Simon, S. A
• Format: Journal Article
• Language: English
• Published: United States 01.03.2004
• Subjects: Air Pollutants - toxicity; Animals; Apoptosis - drug effects; Apoptosis - physiology; Calcium - metabolism; Capsaicin - pharmacology; Cells, Cultured; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Lung - cytology; Lung - metabolism; Mice; Mice, Knockout; Necrosis; Neurons, Afferent - cytology; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Receptors, Drug - metabolism; Volcanic Eruptions
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00299.2003

Departments of 1 Anesthesiology and 2 Neurobiology, Duke University Medical Center, Durham, North Carolina 27710 Submitted 2 September 2003 ; accepted in final form 30 October 2003 Exposure to airborne particulate matter (PM) is a world-wide health problem mainly because it produces adverse cardiovascular and respiratory effects that frequently result in morbidity. Despite many years of epidemiological and basic research, the mechanisms underlying PM toxicity remain largely unknown. To understand some of these mechanisms, we measured PM-induced apoptosis and necrosis in normal human airway epithelial cells and sensory neurons from both wild-type mice and mice lacking TRPV1 receptors using Alexa Fluor 488-conjugated annexin V and propidium iodide labeling, respectively. Exposure of environmental PMs containing residual oil fly ash and ash from Mount St. Helens was found to induce apoptosis, but not necrosis, as a consequence of sustained calcium influx through TRPV1 receptors. Apoptosis was completely prevented by inhibiting TRPV1 receptors with capsazepine or by removing extracellular calcium or in sensory neurons from TRPV1(-/-) mice. Binding of either one of the PMs to the cell membrane induced a capsazepine-sensitive increase in cAMP. PM-induced apoptosis was augmented upon the inhibition of PKA. PKA inhibition on its own also induced apoptosis, thereby suggesting that this pathway may be endogenously protective against apoptosis. In summary, it was found that inhibiting TRPV1 receptors prevents PM-induced apoptosis, thereby providing a potential mechanism to reduce their toxicity. inflammation; acid-sensitive ion channels; TRPV1; human airway epithelial cells; sensory neurons; cAMP; necrosis; apoptosis; air pollution; capsaicin; acid Address for reprint requests and other correspondence: S. A. Simon, Duke Univ. Medical Center, Dept. of Neurobiology, PO Box 3209, Bryan Research Bldg., Rm. 427E, Research Dr., Durham, NC 27710 (E-mail: sas{at}neuro.duke.edu ).