Angiotensin II receptor inhibition prevents pneumocyte apoptosis in surfactant-depleted rat lungs.
Pneumocyte apoptosis is implicated in the pathophysiology of acute inflammatory lung injuries in newborns and adults. Pulmonary angiotensin (ANG) II contributes to lung epithelial apoptosis in vitro, but its role in acute lung injury in vivo is unclear. We therefore studied the effects of ANG II receptor action on the pulmonary inflammatory and apoptotic changes in surfactant-depleted lungs in rats. Lung injury was induced by repeated lung lavage with saline, and the rats were then ventilated with 60% oxygen for 1, 3, or 5 hr. Separate groups of rats were pretreated with a nonspecific ANG II receptor inhibitor saralasin, the specific ANG II type 1 receptor antagonist losartan, or ANG II type 2 receptor inhibitor PD123319, and were similarly studied. Lungs were studied histologically for tissue injury, and with terminal deoxynucleodityl transferase-mediated dUTP nick end-labeling (TUNEL) and cleaved caspase 3 antibody staining, and by electron microscopy for apoptotic cell death. Surfactant-depleted lungs showed an increased number of TUNEL-positive epithelial cells throughout the study, and intrapulmonary leukocyte migration and histological tissue injury scores were similarly elevated, compared to controls, from 1-5 hr of ventilation. Pretreatment with saralasin or losartan significantly prevented the increase of TUNEL positivity in pneumocytes, but had no effect on the amount of neutrophil influx or total injury score in lavaged lungs. In contrast, administration of PD123319 did not affect the number of TUNEL-positive epithelial cells or histological injury . The results suggest that increased epithelial apoptosis in surfactant-deficient lungs is mediated by ANG II receptor (specifically, subtype 1) action.
Lukkarinen
Heikki P
HP
Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. heikki.lukkarinen@utu.fi
Laine
Jukka
J
Aho
Heikki
H
Zagariya
Alexander
A
Vidyasagar
Dharmapuri
D
Kääpä
Pekka O
PO
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001784:Blood Gas Analysis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000166:cytology* / Q000503:physiopathology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012504:Saralasin / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; C073402:PD 123319; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D012504:Saralasin