Bioelectric properties and ion transport of excised human segmental/subsegmental bronchi were measured in specimens from 40 patients. Transepithelial electric potential difference (PD), short-circuit current (Isc), and conductance (G), averaged 5.8 mV (lumen negative), 51 microA X cm-2, and 9 mS X cm-2, respectively. Na+ was absorbed from lumen to interstitium under open- and short-circuit conditions. Cl- flows were symmetrical under short-circuit conditions. Isc was abolished by 10(-4) M ouabain. Amiloride inhibited Isc (the concentration necessary to achieve 50% of the maximal effect = 7 X 10(-7) M) and abolished net Na+ transport. PD and Isc were not reduced to zero by amiloride because a net Cl- secretion was induced that reflected a reduction in Cl- flow in the absorptive direction (Jm----sCl-). Acetylcholine (10(-4) M) induced an electrically silent, matched flow of Na+ (1.7 mueq X cm-1 X h-1) and Cl- (1.9 mueq X cm-12 X h-1) toward the lumen. This response was blocked by atropine. Phenylephrine (10(-5) M) did not affect bioelectric properties or unidirectional ion flows, whereas isoproterenol (10(-5) M) induced a small increase in Isc (10%) without changing net ion flows significantly. We conclude that 1) Na+ absorption is the major active ion transport across excised human bronchi, 2) Na+ absorption is both amiloride and ouabain sensitive, 3) Cl- secretion can be induced by inhibition of the entry of luminal Na+ into the epithelia, and 4) cholinergic more than adrenergic agents modulate basal ion flow, probably by affecting gland output.

The effects of histamine, methacholine, and ether on the permeability of the respiratory mucosa to macromolecules were investigated employing a radioimmunoassay and histochemical techniques to monitor movement of horseradish peroxidase (HRP) from airway lumen to blood. We found that 0.08% of the dose of HRP instilled into guinea pig tracheas was present in the blood volume at 10 min, and plasma HRP levels increased at a rate of 0.0036% instilled dose/min thereafter. After inhalation challenge, significant increases in plasma rates of accumulation of HRP were recorded for the histamine, methacholine, and ether groups, whereas no change in rate was noted for the control (Tyrode's) group. Electron micrographs of tracheal sections showed HRP penetration into the intercellular spaces of the epithelium after histamine, methacoline, or ether exposure but no penetration in the Tyrode's group. We conclude that, like ether, histamine and methacholine increase tracheobronchial permeability and this effect is most likely mediated by a functional change in the epithelial tight junction.

The quantitative relationship between goblet cell number and airway transepithelial permeability to horseradish peroxidase (HRP) (molecular weight, approximately 40,000 daltons) was examined in the guinea pig. In animals administered 12 daily successive doses of 2.5 mg pilocarpine intraperitoneally, an increase in goblet cell population in the trachea correlated with higher plasma HRP concentrations of all 4 sampling times after intratracheal instillation of 1 mg HRP. Guinea pigs administered a single dose of pilocarpine and studied 1 h later showed a significantly higher plasma HRP concentration at 10 and at 15 min (p less than 0.025) as compared with saline control animals. The morphologic correlates of this enhanced early permeability to HRP after a single dose of pilocarpine appeared to be increased vesicular uptake and accelerated transit across the goblet cells. Our data suggest that pinocytotic vesicular uptake and transport of exogenous proteins in the secretory epithelial cells of the airways may be an important pathway for movement of large polar solutes across the epithelial barrier.

Blotchy is an X-linked recessive mutation at the "Mottled" locus in the mouse. The affected blotchy male (Blo/Y) mouse from an inbred genetic background demonstrates morphologic and physiologic abnormalities consistent with emphysema in adult life. Breeding of Blo/Y mice has been difficult because the inbred Blo/Y males are sterile. We report the successful development of a line of outbred Blo/Y male and Blo/Blo female nice by the controlled outcross mating of the inbred heterozygous Blo/+ female with the Argonne hybrid B6CF1 male mouse. The subsequent outcross Blo/Y progeny breed vigorously with the outcrossed Blo/+ female. The lungs of the outbred Blo/Blo female and inbred Blo/Y male mice demonstrate mild to moderate panacinar emphysema with a significant decrease in internal surface area (p less than 0.005) and an increase in mean linear intercept (p less than 0.005). In contrast, the lungs of the outbred Blo/Y is structurally normal. Despite the absence of emphysema-like changes in the outbred Blo/Y males, there were phenotypic features that suggest inherited abnormalities in connective tissue proteins including 1) high incidence of aortitis leading to premature death from aneurysmal rupture, and 2) significant decrease in the morphometrically determined parenchymal elastic fiber length in the lung (p less than 0.01). The outbred blotchy strain may be a useful experimental animal model in determining the pathogenesis of emphysema.