Am. J. Respir. Crit. Care Med., Vol 153, No. 3, 03 1996, 1064-1071.
Tolerance to phosgene is associated with a neutrophilic influx into the rat lung
AJ Ghio and GE Hatch
Department of Medicine, Duke University, Durham, North Carolina 27710, USA.
Exposures to 100% oxygen, ozone, nitrogen oxides, and phosgene increase
both lung lavage protein concentrations and neutrophils. The inhibition of
the neutrophil influx can diminish lavage protein concentrations after
exposures to these oxidant gases. Similarly, this injury can be reduced by
pre-exposure to either the same (tolerance) or a different
(cross-tolerance) oxidant gas. We tested the hypothesis that diminished
injury after the development of tolerance of phosgene (COCl2) is associated
with a decreased incursion of neutrophils. Sixty-day-old rats (n=12/group)
were exposed to varying concentrations of COCl2. Lung lavage (n = 6/group)
24 h after a first phosgene exposure demonstrated an increase in both
protein concentrations and percentage neutrophils. The remaining animals (n
= 6/group) were exposed to COCl2 2 ppm x 60 min 1 wk later. Lavage
confirmed the development of tolerance with protein concentrations
diminished after the second exposure in those rats that had inhaled higher
doses of COCl2 during the first exposure. However, the neutrophilic influx
was not diminished but rather was increased. The association of the
neutrophil incursion with a protective effect was further established in
studies employing colchicine and dextran. Colchicine decreased neutrophil
influx occurring after the first exposure and subsequently diminished the
development of tolerance after a second exposure. Intratracheal
instillation of dextran produced a neutrophil incursion and subsequently
decreased injury after a phosgene exposure. In investigations using both
colchicine and dextran, neutrophil influx increased with the development of
adaptation. Thus, lung injury after the development of tolerance to
phosgene provides a unique animal model of a respiratory distress syndrome
in which neutrophils are not associated with injury but rather with a
protective effect.
