J. Tesfaigzi et al., APOPTOSIS IS A PATHWAY RESPONSIBLE FOR THE RESOLUTION OF ENDOTOXIN-INDUCED ALVEOLAR TYPE-II CELL HYPERPLASIA IN THE RAT, International journal of experimental pathology, 79(5), 1998, pp. 303-311
Previous studies showed that intratracheal instillation of endotoxin i
nduces transient type II cell hyperplasia in the rat lung and describe
d some of the mechanisms involved in the proliferative response of typ
e II cells. The purpose of the present study was to investigate how lo
ng the type II cell hyperplasia persists and how it is resolved. The p
ortion of epithelial cells in hyperplastic lesions of the rat lung exp
ressing cyclin D1, an indicator for cells in the G1 phase of the cell
cycle, was greatest at 3 d post instillation and decreased after 4 and
6 d. The fate of the proliferating epithelial cells was traced by inj
ecting the rats with 5-bromo-2'deoxy uridine (BrdU) 2 d post instillat
ion, the peak time point for maximum incorporation of BrdU. Exfoliated
BrdU-positive epithelial cells were detected in the alveolar spaces i
n tissue sections from rats 4, 5, and 6 d post instillation. BrdU-posi
tive epithelial cells showed flattened nuclei at 6 and 10 d post insti
llation. Expression of the 116 kD poly(ADP-ribose) polymerase (PARP) w
as low in type Il cells from control rats, and was increased at 3, 4,
and 6 d post instillation. In cells obtained by lavage, only a 35 kD c
leavage product of PARP was detected, which is an indicator of necroti
c cell death. In isolated type II cells from rats 3, 4, and 6 d post e
ndotoxin instillation, progressive cleavage of the PARP to its 89 kD r
esidual fragment was detected, which is a direct evidence for the acti
vation of caspases. Furthermore, apoptotic epithelial cells with conde
nsed nuclei were identified by electron microscopy in rats 4 d post in
stillation. These results indicate that apoptosis is an additional mec
hanism for the resolution of endotoxin-induced lung epithelial hyperpl
asias.