Journal of Applied Physiology, Vol 63, Issue 1 292-301, Copyright © 1987 by American Physiological Society
Rapid increases in respiratory epithelial permeability occur after intratracheal instillation of PMA
B. R. Pitt, J. S. Cole, P. Davies and C. N. Gillis
We measured pulmonary epithelial permeability by quantifying the
disappearance of two water-soluble compounds, [14C]mannitol and [3H]inulin,
after their instillation, with and without phorbol myristate acetate (PMA),
into gas-filled perfused (50 ml/min) rabbit lungs in situ. Both tracers
disappeared in a monoexponential fashion over 30 min with calculated
first-order rate constants (control; n = 11) of 0.0008 +/- 0.0002 and
0.0027 +/- 0.0008 min-1 for inulin and mannitol, respectively. The ratio of
the rate constants (3.1 +/- 0.5) was not significantly different from the
ratio of diffusivities of mannitol:inulin (3.7). Addition of PMA (250
micrograms) significantly (n = 9, P less than 0.05) increased the rate
constants for both inulin and mannitol to 0.0024 +/- 0.0007 and 0.0087 +/-
0.0025 min-1, respectively, while not affecting their ratio (4.3 +/- 0.5).
Addition of human leukocytes (4-8 X 10(8)/l) to the perfusate did not
exacerbate the effect of 250 micrograms PMA (n = 3). The addition of
catalase (n = 7) completely inhibited the effect of 250 micrograms PMA. PMA
(250 micrograms) did not significantly affect perfusion pressure but
increased wet-to-dry weight ratios. Light microscopic histology showed
damage to epithelial and endothelial cells after 250 micrograms PMA which
was not seen after coinstillation of catalase. Catalase sensitivity of
functional and structural effects of PMA suggests that the effect was
secondary to production of hydrogen peroxide. Since this effect was noted
in lungs not perfused with neutrophils and addition of leukocytes did not
exacerbate the increase in permeability, we hypothesize that an
undetermined pulmonary cell type was the source of hydrogen peroxide.
Finally, we found no evidence for restrictive pores with radii of 0.4-1.4
nm.
