title: Meconium increases type 1 angiotensin II receptor expression and alveolar cell death.
abstract: The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT1R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT1R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT1R protein approximately 3-fold (p = 0.006), mRNA 29% (p = 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT1R expression >3-fold in cultured type II pneumocytes and caused concentration-dependent cell death inhibited by losartan. Meconium increases AT1R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT1R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression.
authors.affiliation: Division of Neonatal-Perinatal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. charles.rosenfeld@utsouthwestern.edu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rosenfeld
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zagariya
authors.forename: Xiao-Tie
authors.initials: XT
authors.lastname: Liu
authors.forename: Brigham C
authors.initials: BC
authors.lastname: Willis
authors.forename: Steven
authors.initials: S
authors.lastname: Fluharty
authors.forename: Dharmapuri
authors.initials: D
authors.lastname: Vidyasagar
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008470:Meconium / Q000378:metabolism; D008471:Meconium Aspiration Syndrome / Q000378:metabolism* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D002216:Captopril; D019808:Losartan