Leukotriene d4 facilitates airway smooth muscle, cell proliferation via modulation of the igf axis. Cohen, Pinchas, James P. Noveral, Ajay Bhala, Steve E. Nunn, David J. Herrick, and Michael M. Grunstein. Divisions of Endocrinology (PC, AB, SEN), and Pulmonary Medicine (JPN, DJH, MMG), Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine.
APStracts 2:0048L, 1995.
The insulin-like growth factor (IGF) axis is involved in regulating proliferation in a variety of cell types including airway smooth muscle. Since airways hyperplasia is a characteristic feature of asthma and other lung diseases, we examined the interaction of the potent pro-inflammatory eicosanoid, leukotriene D4 (LTD4) with the IGF axis in regulating airway smooth muscle cell mitogenesis. In cultured rabbit airway smooth muscle cells, IGF-I but not LTD4 were mitogenic at sub-maximal concentrations. The combination of the two agents exerted a significant synergistic effect on airway smooth muscle cell mitogenesis. Analysis of airway smooth muscle cell conditioned medium, by western ligand blotting, demonstrated a marked LTD4 -induced eduction in the levels of the predominant IGF binding protein, IGFBP-2, which is elaborated into the conditioned media. The latter effect on IGFBP-2 release was not associated with a reduction in IGFBP-2 mRNA levels, however, LTD4 -treated airway smooth muscle conditioned media demonstrated the presence of a lower molecular weight form of IGFBP-2 by cross-linking to IGFs, and specific proteolysis of radiolabeled IGFBP-2. IGFBP-2 was also noted to be associated with airway smooth muscle cell membranes were it was protected from LTD4 -induced proteolysis. Finally, exogenous administration of IGFBP-2 was found to inhibit the pro-mitogenic effect of IGF-I in a dose-dependent manner. Collectively, these observations provide new evidence supporting the concept that LTD4 augments the mitogenic response of airway smooth muscle to IGF-I by inducing an IGFBP-2 protease which decreases the extracellular levels of IGFBP-2, thereby allowing more free IGF to interact with its receptors and promote airway smooth muscle cell proliferation. 

Received 26 October 1994; accepted in final form 22 March 1995.
APS Manuscript Number L310-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 April 1995.