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Am J Physiol Lung Cell Mol Physiol (August 9, 2002). doi:10.1152/ajplung.00268.2001
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Articles in PresS, published online ahead of print August 9, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00268.2001
Submitted on July 18, 2001
Accepted on August 2, 2002

Oxygen regulates mitogen-stimulated proliferation of fetal human airway smooth muscle cells

Hitesh C. Pandya1, Vladimir A. Snetkov1, Charles H. C. Twort1, Jeremy P. T. Ward1, and Stuart J. Hirst1*

1 Department of Respiratory Medicine and Allergy, The Guy's, King's and St. Thomas' School of Medicine, King's College London, London, United Kingdom

* To whom correspondence should be addressed. E-mail: stuart.hirst{at}kcl.ac.uk.

Increased airway smooth muscle (ASM) content is characteristic of infants with chronic lung disease of prematurity/bronchopulmonary dysplasia (CLD-BPD). Oxygen therapy, reactive oxygen species (ROS) and immature antioxidant defences are major risk factors in CLD-BPD, but their interrelationship is unclear. The direct effects of raised PO2 and modulation of ROS were examined on proliferation of cultured fetal human ASM cells. A bell-shaped relationship was found between PO2 and DNA synthesis induced by FBS, PDGF and bFGF, with peak responses occurring at 10kPa PO2. Changes in DNA synthesis by PO2 did not occur in the absence of mitogen. ROS generation, estimated by dichlorodihydrofluorescein oxidation, was increased by mitogens, but was unaffected by non-mitogens (bradykinin, histamine). There was an inverse relationship between ROS generation and PO2, and mitogen-induced ROS generation was substantially potentiated as the PO2 fell. H2O2 mimicked the effect of PO2 on FBS-stimulated proliferation, whereas treatment with antioxidants (GSH, N-acetylcysteine) reduced it. These data demonstrate that increases in PO2 above levels found in utero modulate proliferation of fetal ASM cells, but only in the presence of growth factors. They also strongly suggest that under these conditions proliferation is mediated in part by generation of ROS.




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