Am. J. Respir. Crit. Care Med., Volume 157, Number 4, April 1998, 1027-1033

Lipopolysaccharide-induced Alveolar Epithelial Permeability
The Role of Nitric Oxide

XIAO YANG LI, KENNETH DONALDSON, and WILLIAM MACNEE

Respiratory Medicine Unit, Department of Medicine, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh; and the Department of Biological Sciences, Napier University, Edinburgh, Scotland, United Kingdom

Intratracheal instillation of lipopolysaccharide (LPS) in the rat has been used as a model of acute lung inflammation. Among the early events in this process is a transient increase in airspace epithelial permeability which peaks 4 h after intratracheal instillation of LPS. The increased epithelial permeability is concomitant with the influx of neutrophils into the airspaces, peaking 8 h postinstillation. We have investigated the mechanism of this LPS-induced increase in epithelial permeability. The role of the neutrophil in LPS-induced epithelial permeability was assessed by pretreatment with neutrophil antibody to abolish neutrophil influx, which did not affect the increase in epithelial permeability. Because LPS instillation also induced increased tumor necrosis factor  (TNF-) activity in bronchoalveolar lavage (BAL) fluid, and its release by cultured BAL leukocytes from treated animals, TNF- antibody was coinstilled intratracheally with LPS in rats. TNF- antibody eliminated TNF- activity in BAL fluid, but had no effect on LPS-induced increased epithelial permeability. Increased levels of nitric oxide (NO), measured as nitrite, were also present in BAL fluid from LPS-treated rat lungs and LPS-elicited BAL leukocytes produced increased NO in culture. Treatment of rats with the specific NO synthase inhibitor L-NMMA significantly diminished the LPS-induced increased epithelial permeability. These data suggest that NO is involved in LPS-induced changes in epithelial integrity. However, other mechanisms should be evoked in addition to NO to explain completely the increased epithelial permeability produced by LPS.

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