P. Cohen et al., LEUKOTRIENE D-4 FACILITATES AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION VIA MODULATION OF THE IGF AXIS, American journal of physiology. Lung cellular and molecular physiology, 13(2), 1995, pp. 151-157
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.