Induction of heme oxigenase-1 in the murine lung after birht does not unfluence vascular remodelling 1,2S.J. Stanford, 3H. San, 3E.G. Nabel, 2A.A. Hislop, 2S.G. Haworth & 1J.A. Mitchell.1Unit of Critical Care, The Royal Brompton, Imperial College, London SW3 6NP. 2Developmental Vascular Biology & Pharmacology Unit, Institute of Child Health, London WC1N 1EH. 3Vascular Biology Branch, National Heart, Lung & Blood Institute, Maryland, USA.

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The increase in pulmonary blood flow at birth results in profound physiological changes in the lung including the maturation of the endothelium-dependent relaxant response and vascular remodelling. When such adaptive processes fail, persistent pulmonary hypertension of the newborn (PPHN) may occur. Carbon monoxide, produced endogenously by the action of heme oxygenase (HO) on its heme substrate, is a vasodilator and influences remodelling. We have shown previously that the inducible form of HO, HO-1, is upregulated in the porcine lung after birth but does not appear to have a role in the regulation of vascular tone (Stanford et al., 2003a). We have also reported that HO-1, but not HO-2, is upregulated postnatally in the murine lung (Stanford et al., 2003b), maximum levels occurring at 4 days. Thus, using mice deficient in the gene encoding HO-1 (Hmox1) (Duckers et al., 2001) we have investigated the role of HO-1 induction on the remodelling of the pulmonary vasculature after birth.

Lungs harvested from 1, 3-5 day old and 14 day old Hmox1^-/- and Hmox1^+/+ (C57BL/6J) mice were inflated and fixed in 10% formol saline overnight. Tissue was transferred to 70% alcohol prior to embedding in paraffin wax for immunohistochemistry. Sections (4µm) were stained for smooth muscle -actin. External and luminal pulmonary artery diameters were measured and % medial wall thickness was calculated. All data is given as mean±s.e.m.

Figure shows the pulmonary artery wall thickness (expressed as a % of external vessel wall diameter) of vessels from A) 3-5 day old Hmox1^-/- (n=6) and Hmox1^+/+ (n=4) mice and B) 14 day old Hmox1^-/- (n=3) and Hmox1^+/+ (n=4) mice.

In control (Hmox1^+/+) mice, visual assessment indicated that pulmonary arteries had undergone extensive remodelling by 3-5 days of age. Specifically, they had a flattened endothelium and thinner walls compared with 1 day old animals. Vessel wall thickness continued to decline after 3-5 days of age (% wall thickness, 3-5 day old vs. 14 day old mice: 14.5±0.96 vs. 10.9±1.16, for both groups n>100 vessels, 20-100µm in diameter, analysed from n=4 animals). No significant difference (Two-way ANOVA) was observed in medial wall thickness of pulmonary arteries from Hmox1^-/- and Hmox1^+/+ mice in either 3-5 day old or 14 day old mice (see figure).Though HO-1 is upregulated in the murine lung after birth, the absence of the gene encoding HO-1 does not affect the normal process of postnatal pulmonary artery remodelling as judged by the amount of pulmonary artery smooth muscle.

Duckers, H.J. et al. (2001). Nature Med. 7: 693-698.
Stanford, S.J. et al. (2003). Br. J. Pharmacol. 138, 49P.
Stanford, S.J. et al. (2003). Br. J. Pharmacol.138, 50P.
This work was supported by the British Heart Foundation.