Angiotensin II receptor blockade inhibits pneumocyte apoptosis in experimental meconium aspiration.
Lung tissue inflammation and apoptosis are implicated in the pathogenesis of meconium aspiration-induced lung injury in the newborn, but the mechanisms of these reactions are still poorly known. We investigated the time-dependent leukocyte influx and appearance of apoptosis, as well as the contribution of angiotensin (ANG) II receptor action on these processes in the meconium-induced lung injury. Experimental meconium aspiration was induced by intratracheal instillation of human meconium in 18 rats, and eight rats were further pretreated with an unspecific ANG II receptor inhibitor saralasin. Rats were ventilated with 60% oxygen for 1, 3, or 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and expression of angiotensinogen mRNA and endothelial monocyte-activating polypeptide (EMAP) II protein were also analyzed. The meconium-instilled lungs showed increasing neutrophil migration and histologic injury after the first hour, whereas the number of epithelial apoptotic cells was elevated from the control level throughout the study. Myeloperoxidase activity was high, and the angiotensinogen mRNA and EMAP II protein was up-regulated at 5 h after the meconium insult. Pretreatment with saralasin significantly prevented the increase in lung tissue myeloperoxidase activity, EMAP II, and lung epithelial apoptosis. The results suggest that pulmonary meconium insult rapidly results in epithelial apoptosis, before significant neutrophil sequestration into the lungs. Apoptotic cell death is further connected with ANG II receptor action in the meconium-contaminated lung tissue.
Lukkarinen
Heikki
H
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FIN-20014 Turku, Finland. heikki.lukkarinen@utu.fi
Laine
Jukka
J
Lehtonen
Jani
J
Zagariya
Alexander
A
Vidyasagar
Dharmapuri
D
Aho
Heikki
H
Kääpä
Peka
P
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007962:Leukocytes / Q000166:cytology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008471:Meconium Aspiration Syndrome / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D012504:Saralasin / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D000808:Angiotensinogen; D012504:Saralasin