Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis
Cohen, P.; Noveral, J.P.; Bhala, A.; Nunn, S.E.; Herrick, D.J.; Grunstein, M.M.
American Journal of Physiology 269(2 Pt 1): L151-L157
1995
ISSN/ISBN: 0002-9513 PMID: 7544535 Document Number: 440743
The insulin-like growth factor (IGF) axis is involved in regulating proliferation in a variety of cell types, including airway smooth muscle. Because airway hyperplasia is a characteristic feature of asthma and other lung diseases, we examined the interaction of the potent proinflammatory eicosanoid leukotriene D-4 (LTD-4) with the IGF axis in regulating airway smooth muscle cell mitogenesis. In cultured rabbit airway smooth muscle cells, IGF-I but not LTD-4 was mitogenic at submaximal 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 LTD-4-induced reduction in the levels of the predominant IGF binding protein IGFBP-2, which is elaborated into the conditioned medium. The latter effect on IGFBP-2 release was not associated with a reduction in IGFBP-2 mRNA levels; however, LTD-4-treated airway smooth muscle conditioned medium 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, where it was protected from LTD-4-induced proteolysis. Finally, exogenous administration of IGFBP-2 was found to inhibit the promitogenic effect of IGF-I in a dose-dependent manner. Collectively, these observations provide new evidence supporting the concept that LTD-4 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.