Am. J. Respir. Cell Mol. Biol., Volume 23, Number 4, October, 2000 572-577

Priming of Alveolar Macrophages by Leukotriene D₄
Potentiation of Inflammation

Geneviève Ménard and Elyse Y. Bissonnette

Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Ste-Foy, Quebec, Canada

Cysteinyl leukotrienes (LTs), including LTC₄, LTD₄, and LTE₄, are well known to induce bronchoconstriction and increase bronchial hyperreactivity, mucus secretion, and vascular permeability. Interestingly, alveolar macrophages (AMs) express LTD₄ high-affinity receptor. These cells represent a major source of inflammatory mediators implicated in the pathophysiology of asthma. Thus, we investigated the immunomodulatory effects of LTD₄ on the production of inflammatory mediators such as macrophage inflammatory protein (MIP)- 1, tumor necrosis factor (TNF), and nitric oxide (NO) by AMs. NR8383 cells, an AM cell line, were pretreated with LTD₄ (10¹¹ M) for different periods of time and stimulated or not with lipopolysaccharide (LPS) for 2 h. Although LTD₄ treatment did not modulate the release of MIP-1 and TNF, this treatment (6 h) significantly increased the release of these mediators when AMs were further stimulated with LPS (increases of 47 and 21%, respectively). Further, LTD₄ pretreatment increased messenger RNA (mRNA) levels of MIP-1 and TNF. These effects of LTD₄ were abrogated by the presence of a LTD₄ receptor antagonist, Verlukast (MK-679), showing the specificity of LTD₄. Interestingly, LTD₄ treatment significantly increased the release of NO by LPS-stimulated AMs without modulating mRNA levels of the inducible NO synthase. Our data suggest that LTD₄ primes AMs to release more MIP-1, TNF, and NO after stimulation. Thus, in addition to its potent bronchoconstrictor effect, LTD₄ may participate in the inflammatory process seen in asthma by potentiating the production of proinflammatory mediators by AMs during immunologic stimuli.

This article has been cited by other articles:

				M. Rosewich, M. A. Rose, O. Eickmeier, M. Travaci, R. Kitz, and S. Zielen Montelukast as add-on therapy to {beta}-agonists and late airway response Eur. Respir. J., July 1, 2007; 30(1): 56 - 61. [Abstract] [Full Text] [PDF]

				M. N. Ballinger, D. M. Aronoff, T. R. McMillan, K. R. Cooke, K. Olkiewicz, G. B. Toews, M. Peters-Golden, and B. B. Moore Critical Role of Prostaglandin E2 Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation J. Immunol., October 15, 2006; 177(8): 5499 - 5508. [Abstract] [Full Text] [PDF]

				L.-I. Proulx, A. Castonguay, and E. Y. Bissonnette Cytokine production by alveolar macrophages is down regulated by the {alpha}-methylhydroxylation pathway of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) Carcinogenesis, June 1, 2004; 25(6): 997 - 1003. [Abstract] [Full Text] [PDF]

				A. Maekawa, K. F. Austen, and Y. Kanaoka Targeted Gene Disruption Reveals the Role of Cysteinyl Leukotriene 1 Receptor in the Enhanced Vascular Permeability of Mice Undergoing Acute Inflammatory Responses J. Biol. Chem., May 31, 2002; 277(23): 20820 - 20824. [Abstract] [Full Text] [PDF]