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stimulation of
amiloride-sensitive sodium transport across alveolar
epithelium
1 Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130; 2 Department of Anesthesiology, Physiology, and Biophysics, University of Alabama, Birmingham, Alabama 35223; and 3 Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
Because tumor
necrosis factor (TNF)-
can upregulate alveolar fluid clearance (AFC)
in pneumonia or septic peritonitis, the mechanisms responsible for the
TNF-
-mediated increase in epithelial fluid transport were studied.
In rats, 5 µg of TNF-
in the alveolar instillate increased AFC by
67%. This increase was inhibited by amiloride but not by propranolol.
We also tested a triple-mutant TNF-
that is deficient in the
lectinlike tip portion of the molecule responsible for its membrane
conductance effect; the mutant also has decreased binding affinity to
both TNF-
receptors. The triple-mutant TNF-
did not increase AFC.
Perfusion of human A549 cells, patched in the whole cell mode, with
TNF-
(120 ng/ml) resulted in a sustained increase in Na+
currents from 82 ± 9 to 549 ± 146 pA (P < 0.005; n = 6). The TNF-
-elicited Na+
current was inhibited by amiloride, and there was no change when A549
cells were perfused with the triple-mutant TNF-
or after preincubation with blocking antibodies to the two TNF-
receptors before perfusion with TNF-
. In conclusion, although TNF-
can initiate acute inflammation and edema formation in the lung, TNF-
can also increase AFC by an amiloride-sensitive, cAMP-independent mechanism that enhances the resolution of alveolar edema in
pathological conditions by either binding to its receptors or
activating Na+ channels by means of its lectinlike domain.
tumor necrosis factor-
; tumor necrosis factor receptor; patch
clamp; alveolar epithelial cell; acute lung injury; pulmonary edema; pneumonia
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