title: Transforming growth factor-alpha increases alveolar liquid clearance in anesthetized ventilated rats.
abstract: The effect of transforming growth factor-alpha (TGF-alpha) on alveolar liquid clearance was examined in ventilated, anesthetized rats. An isosmolar Ringer 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 with 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 1 h 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 twofold 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 adenosine 3',5'-cyclic monophosphate (cAMP) levels more than tenfold. 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 beta-adrenergic stimulation by increasing Na+ uptake by alveolar epithelial type II cells. However, the effect may be mediated by a non-cAMP dependent mechanism. Because genistein blocked the increase in alveolar fluid clearance, the signal transduction may involve genistein-dependent phosphorylation.
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco 94143-0130, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Folkesson
authors.forename: J F
authors.initials: JF
authors.lastname: Pittet
authors.forename: G
authors.initials: G
authors.lastname: Nitenberg
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D007552:Isotonic Solutions / Q000493:pharmacokinetics; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077325:Ringer's Lactate; D000068299:Salmeterol Xinafoate; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D007529:Isoflavones; D007552:Isotonic Solutions; D000077325:Ringer's Lactate; D016211:Transforming Growth Factor alpha; D000068299:Salmeterol Xinafoate; D000584:Amiloride; D019833:Genistein; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D006152:Cyclic GMP; D000420:Albuterol