Do drugs that block transforming growth factor beta reduce posthaemorrhagic ventricular dilatation in a neonatal rat model?
OBJECTIVE
Posthaemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. No treatment has reduced the need for cerebrospinal fluid (CSF) diversion. Considerable evidence implicates transforming growth factor-beta (TGF-beta) in the pathogenesis of PHVD. Pirfenidone and losartan reduce TGF-beta expression and decrease postinflammatory fibrosis in the lungs, kidneys, heart and liver. They have excellent CSF and brain penetration. We hypothesized that administration of pirfenidone or losartan would reduce ventricular dilatation.


METHODS
Ninety-two rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8, and were randomised to pirfenidone, losartan or water by gavage for 14 days. Neuromotor testing was carried out twice weekly. After sacrifice at PN21, ventricular area was measured on coronal sections using image-analysis software.


RESULTS
Ninety-five percent of animals undergoing IVH developed PHVD. Ventricular size was not significantly different between animals receiving either drug or water. Neuromotor testing at PN14 was significantly worse in IVH animals than in controls; neither drug improved performance in IVH animals.


CONCLUSIONS
Drugs that block TGF-beta do not reduce ventricular dilatation in this model. Further study is required to identify other cytokine targets and to determine how PHVD differs from postinflammatory fibrosis in other organs.
Aquilina
Kristian
K
Department of Clinical Science at South Bristol, University of Bristol, Bristol, United Kingdom.
Hobbs
Catherine
C
Tucker
Alexander
A
Whitelaw
Andrew
A
Thoresen
Marianne
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000188:drug therapy; D002552:Cerebral Ventricles / Q000187:drug effects* / Q000473:pathology; D004108:Dilatation, Pathologic / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D019808:Losartan / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D047228:Angiotensin II Type 1 Receptor Blockers; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D016212:Transforming Growth Factor beta; C093844:pirfenidone; D019808:Losartan