INHIBITION OF LUNG MACROPHAGE INFLUX PREVENTS O₂ INDUCED PULMONARY HYPERTENSION IN NEWBORN RATS

"Gadolinium Chloride Inhibition of Pulmonary Macrophage Influx Prevents O2‑induced Pulmonary Hypertension in the Neonatal Rat."

Luo X^1,2, Jankov RP², Liu W¹, Tanswell AK²

¹ Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

² Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Canada

Objective: To determine if macrophage influx in the lung played an essential role in the development of pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia (BPD).

Methods: Newborn rats exposed to 60% O₂ for 14 days demonstrated a BPD-like lung morphology and pulmonary hypertension. Pups were treated with gadolinium chloride (GdCl₃) to reduce lung macrophage content. Lung mechanical changes, macrophage content, 8-isoprostane and nitrotyrosine formation were measured. The expression of endothelin-1 (ET-1) and growth factor receptors were assayed.

Results: Pulmonary macrophages significantly increased after oxygen exposure, which was largely depleted by GaCl₃. GaCl₃ abrogated oxygen mediated right ventricular hypertrophy and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphological change in the parenchyma. GdCl₃ inhibited O₂-induced increases in 8-isoprostane, nitrotyrosine formation and ET-1, IGF-1R, PDGF-bR over-expression. A critical role for ET-1 in O₂-mediated pulmonary hypertension was confirmed using the combined ET receptor antagonist SB217242.

Conclusion: That pulmonary macrophage accumulation, in response to 60% O₂, mediated pulmonary hypertension, through up-regulation of ET-1. GaCl₃ did not alter either abnormal lung morphology or lung mechanics induced by 60% O₂ indicate that reactive nitrogen species, 8-isoprostane and ET-1 may not be involved in these aspects of O₂-induced lung injury. These findings suggest that different components of O₂-induced lung injury appear to be regulated by different mediators.

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