Fluoxetine may worsen hyperoxia-induced lung damage in neonatal rats.
Fluoxetine shows controversial lung effects as it prevents pulmonary hypertension in adult rats but exposure during gestation causes pulmonary hypertension in neonatal rats. In the present study, we tested the null hypothesis that the antidepressant drug fluoxetine does not modify the development of bronchopulmonary dysplasia (BPD) in neonatal rats. Experimental categories included I: room air (controls) with daily injection of saline; II: room air with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks; III: 60% oxygen with daily injection of saline; and IV: 60% oxygen with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks. Hyperoxia resulted in significant reduction in alveolar density and an increase in pulmonary endocrine cells, as well as increases in muscle layer areas of bronchi and arteries. Fluoxetine treatment generated a further increase in muscularisation and did not significantly modify the hyperoxia-induced reductions in alveolar density and increases in the endocrine cells. In hyperoxia, Real-Time PCR showed a lower pulmonary expression of vascular endothelial growth factor (VEGF) with no significant changes in the expression of matrix metalloproteinases (MMP) 2 and 12. Fluoxetine did not affect VEGF or MMP-2 expression but it significantly increased MMP-12 mRNA in both normoxic and hyperoxic groups. Zymographic analysis of MMP-2 activity in bronchoalveolar fluid showed a significantly reduced MMP-2 activity in hyperoxia, while fluoxetine treatment restored MMP-2 activity to levels comparable with the normoxic group. In conclusion, our data show that fluoxetine may worsen bronchial and arterial muscularisation during development of BPD and may up-regulate MMP expression or activity.
Section of Anatomy, Department of Human Anatomy and Physiology, University of Padova, Italy.
A
A
Porzionato
P
P
Zaramella
V
V
Macchi
D
D
Grisafi
R
R
Salmaso
M
M
Baraldi
E
E
Fornaro
E
E
Tassone
V
V
Masola
M
M
Onisto
L
L
Chiandetti
R
R
De Caro
D000818:Animals; D000831:Animals, Newborn; D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D001483:Base Sequence; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005473:Fluoxetine / Q000633:toxicity*; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D055370:Lung Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012132:Respiratory Muscles / Q000187:drug effects / Q000473:pathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D043222:Ubiquitin Thiolesterase; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C489034:UCHL1 protein, rat; C522363:Mmp2 protein, rat