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Arnaud Courtois,^1,2 Pascal Andujar,^3,4 Yannick Ladeiro,^1,2 Isabelle Baudrimont,^1,2 Estelle Delannoy,^1,2 Véronique Leblais,^1,2 Hugues Begueret,⁵ Marie Annick Billon Galland,⁶ Patrick Brochard,^1,5, Francelyne Marano,⁷ Roger Marthan,^1,2,5 and Bernard Muller^1,2

¹Université Bordeaux 2, Bordeaux, France; ²Inserm U885, Bordeaux, France; ³Université Paris 12, Faculté de Médecine, Créteil, France; ⁴Inserm U841, Créteil, France; ⁵Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; ⁶Laboratoire d'Etude des Particules Inhalées, Paris, France; ⁷Université Paris 7 Denis-Diderot, Laboratoire de Cytophysiologie et de Toxicologie Cellulaire, Paris, France

Abstract
Background and objectives: Because pulmonary circulation is the primary vascular target of inhaled particulate matter (PM) , and nitric oxide is a major vasculoprotective agent, in this study we investigated the effect of various particles on the NO–cyclic guanosine monophosphate (cGMP) pathway in pulmonary arteries.

Methods: We used intrapulmonary arteries and/or endothelial cells, either exposed in vitro to particles or removed from PM-instilled animals for assessment of vasomotricity, cGMP and reactive oxygen species (ROS) levels, and cytokine/chemokine release.

Results: Endothelial NO-dependent relaxation and cGMP accumulation induced by acetylcholine (ACh) were both decreased after 24 hr exposure of rat intrapulmonary arteries to standard reference material 1648 (SRM1648 ; urban PM) . Relaxation due to NO donors was also decreased by SRM1648, whereas responsiveness to cGMP analogue remained unaffected. Unlike SRM1648, ultrafine carbon black and ultrafine and fine titanium dioxide (TiO₂) manufactured particles did not impair NO-mediated relaxation. SRM1648-induced decrease in relaxation response to ACh was prevented by dexamethasone (an anti-inflammatory agent) but not by antioxidants. Accordingly, SRM1648 increased the release of proinflammatory mediators (tumor necrosis factor-α, interleukin-8) from intrapulmonary arteries or pulmonary artery endothelial cells, but did not elevate ROS levels within intrapulmonary arteries. Decreased relaxation in response to ACh was also evidenced in intrapulmonary arteries removed from rats intratracheally instilled with SRM1648, but not with fine TiO₂.

Conclusion: In contrast to manufactured particles (including nanoparticles) , urban PM impairs NO but not cGMP responsiveness in intrapulmonary arteries. We attribute this effect to oxidative-stress–independent inflammatory response, resulting in decreased guanylyl cyclase activation by NO. Such impairment of the NO pathway may contribute to urban-PM–induced cardiovascular dysfunction.

Key words: endothelium, inflammation, NO, particulate matter, pulmonary artery. Environ Health Perspect 116:1294–1299 (2008) .  doi:10.1289/ehp.11021 available via http://dx.doi.org/ [Online 21 May 2008]

Address correspondence to A. Courtois, INSERM U885, Casier 83, 146 rue Léo Saignat, F-33076 Bordeaux, France. Telephone: 33-5-57-57-12-11. Fax: 33-5-57-57-12-01. E-mail: arnaud.courtois@tox.u-bordeaux2.fr

We thank M. Lacayrerie for excellent animal care.

This work was partially funded by Agence Nationale de la Recherche (Nanotox) . P.A. was a fellow from Chancellerie de Paris (Legs Poix) .

The authors declare they have no competing financial interests.

Received 26 October 2007 ; accepted 15 May 2008.