LEUKOTRIENE D-4 FACILITATES AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION VIA MODULATION OF THE IGF AXIS

The insulin-like growth factor (IGF) axis is involved in regulating pr oliferation 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 proinf lammatory eicosanoid leukotriene D-4 (LTD(4)) with the IGF axis in reg ulating airway smooth muscle cell mitogenesis. In cultured rabbit airw ay smooth muscle cells, IGF-I but not LTD(4) was mitogenic at submaxim al concentrations. The combination of the two agents exerted a signifi cant synergistic effect on airway smooth muscle cell mitogenesis. Anal ysis 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 i nto the conditioned medium. The latter effect on IGFBP-2 release was n ot associated with a reduction in IGFBP-2 mRNA levels; however, LTD(4) -treated airway smooth muscle conditioned medium demonstrated the pres ence of a lower molecular weight form of IGFBP-2 by cross-linking to I GFs and specific proteolysis of radiolabeled IGFBP-2. IGFBP-2 was also noted to be associated with airway smooth muscle cell membranes, wher e it was protected from LTD(4)-induced proteolysis. Finally, exogenous administration of IGFBP-2 was found to inhibit the promitogenic effec t of IGF-I in a dose-dependent manner. Collectively, these observation s provide new evidence supporting the concept that LTD(4) augments the mitogenic response of airway smooth muscle to IGF-I by inducing an IG FBP-2 protease which decreases the extracellular levels of IGFBP-2, th ereby allowing more free IGF to interact with its receptors and promot e airway smooth muscle cell proliferation.