Presented at the Neonatal Society 2009 Spring Meeting.
Hoque N, Aquilina K, Liu X, Chakkarapani E, Hobbs C, Whitelaw A, Thoresen M
Department of Child Health, University of Bristol, Bristol, UK
Background: Posthaemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Because ventriculoperitoneal shunt dependence has serious disadvantages, there is a need for non-surgical interventions to halt the pathology. Considerable evidence implicates transforming growth factor-β (TGF-β) in the pathogenesis of PHVD (1). Decorin is a naturally occurring proteoglycan that inactivates TGF-β. Colchicine, a drug used for gout and primary biliary cirrhosis down-regulates TGF-β. Decorin reduces CNS scarring and colchicine reduces fibrosis in laboratory models (2-5).
Aim: To determine whether administration of decorin or colchicine would reduce ventricular dilatation in a model of PHVD.
Methods: All procedures were carried out under British Home Office license in accordance with UK guidelines. 140 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8, and were randomised to either colchicine 10 (n= 24) or 25 (n= 22) μg/kg/day by gavage for 14 days or water (n= 22) by gavage for 14 days, or decorin 4 mg/kg (n= 49) or saline (n=23) by intraventricular injection. These doseages were well tolerated and the pups had normal weight gain. At PN21, the brains were perfusion fixed with formalin under deep anaesthesia and ventricular area was measured on 4 coronal sections through the ventricular system using image-analysis software.
Results: Ventricular size was not significantly different between animals receiving either drug or water.
Conclusion: Two drugs that block TGF-β by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone (6), we conclude that TGF-β is not the most important molecule in the pathway to PHVD. Further study is required to identify other cytokine targets and to determine how PHVD differs from post-inflammatory fibrosis in other organs.
References
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