AJP - Lung Cellular and Molecular Physiology, Vol 269, Issue 2 151-L157, Copyright © 1995 by American Physiological Society
Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis
P. Cohen, J. P. Noveral, A. Bhala, S. E. Nunn, D. J. Herrick and M. M. Grunstein
Division of Endocrinology, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
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 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 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
LTD4-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, LTD4-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 LTD4-induced proteolysis. Finally,
exogenous administration of IGFBP-2 was found to inhibit the promitogenic
effect of IGF-I in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250
WORDS)
