Transforming growth factor-[alpha] increases alveolar liquid
clearance in anesthetized ventilated rats.
Folkesson, Hans G., Jean-Fran[cedilla]cois Pittet, Gerard Nitenberg,
and Michael A. Matthay.
Cardiovascular Research Institute, University of California San
Francisco, San Francisco, CA., USA
APStracts 3:0041L, 1996.
The effect of transforming growth factor-[alpha] (TGF-[alpha]) on
alveolar liquid clearance was examined in ventilated, anesthetized
rats. An isosmolar Ringer's lactate solution with 10,?50?or 200?ng/ml
TGF-[alpha] and 125I-labeled albumin as the alveolar protein tracer
was instilled into the right lower lung lobe; the rats were studied
for 1?and?4?h. Compared to control rats, addition of 50?ng/ml TGF
-[alpha] to the instilled fluid increased alveolar liquid clearance by
47?% over 1?h and by 66?% over 4?h (P<0.05). This increase was
similar to the 50?% increase in alveolar liquid clearance over
one?hour in rats instilled with a [beta]-adrenergic agonist,
salmeterol (28). There was a dose-dependent effect of TGF-[alpha]
(10,?50,?200?ng/ml) on alveolar liquid clearance. The combination of
both TGF-[alpha] and salmeterol did not have an additive effect on
alveolar liquid clearance. The TGF-[alpha] stimulated increase in
alveolar liquid clearance was inhibited by amiloride (10-4?M),
indicating that the increase in clearance depended on increased Na+
-uptake across the alveolar epithelium. There was only a two-fold
increase in intracellular cAMP-levels in isolated rat alveolar
epithelial type?II cells after stimulation with TGF-[alpha]. In
contrast, [beta]-adrenergic agonist treatment increased intracellular
cAMP levels more than 10-fold. Genistein (10-6?M), a tyrosine protein
kinase inhibitor, inhibited the TGF-[alpha] stimulated increase in
alveolar liquid clearance. In summary, TGF-[alpha] can stimulate in
vivo alveolar liquid clearance at a rate similar to b-adrenergic
stimulation by increasing Na+-uptake by alveolar epithelial type?II
cells. However, the effect may be mediated by a non-cAMP dependent
mechanism. Since genistein blocked the increase in alveolar fluid
clearance, the signal transduction may involve genistein dependent
phosphorylation.
Received 31 August 1995; accepted in final form 6 March 1996.
APS Manuscript Number L264-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 20 March 96