Abstract
Morphogens, growth factors and extracellular matrix (ECM) components modulate early lung branching, and have been studied extensively both in vivo and in vitro. In vitro studies have been particularly useful, because tissue can be manipulated either chemically or mechanically. For the most part, such studies have been conducted at ambient oxygen tensions, despite the fact that the fetus develops in a low oxygen environment. Since oxygen tension regulates the expression of various growth factors, adhesion molecules and their receptors, we investigated whether the low oxygen environment of the fetus contributes towards lung branching morphogenesis by affecting one or more these mediators. Using an established fetal lung expiant model, we demonstrated that in comparison to tissues cultured at ambient oxygen concentration (21% O2 ), fetal lung expiants cultured at 3% 02 show increases in terminal branching and cellular proliferation, and they display appropriate proximal to distal differentiation. To investigate the factor(s) mediating the induction of lung branching morphogenesis and differentiation by fetal oxygen tension, we focused on matrix metalloproteinases (MMPs), a group of zinc-dependent enzymes that modify ECM structure and function. Our results reveal that hypoxia suppresses MMP activity, leading to the accumulation of specific ECM components, including tenascin-C (TN-C), that act to stimulate lung branching. These studies demonstrate that low oxygen in the setting of the developing lung positively regulates lung branching morphogenesis, and suggest that the pathologic responses to low oxygen in the adult lung reflect a dysregulation of this lung developmental program.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Acarregui, MJ, Snyder, JM and Mendelson, CR. Oxygen modulates the differentiation of human fetal lung in vitro and its responsiveness to cAMP. Am. J. Physiol . 264 (Lung Cell. Mol. Physiol 8):L465–L474, 1993.
Barasch, J, Yang J, Qiao, J, Tempst, P, Erdjument-Bromage, H, Leung, W, and Oliver, JA. Tissue inhibitor of metalloproteinase-2 stimulates mesenchymal growth and regulates epithelial branching during morphogenesis of the rat metanephros. J. Clin. Invest . 103:1299–1307, 1999.
Bernardi, ML, Flechon JE, and Delouis, C. Influence of culture system and oxygen tension on the development of ovine zygotes matured and fertilized in vitro. J. Reprod. Fertil. 106:161–167, 1996.
Chen, E, Fujinaga, M, and Giaccia, AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology 60(4):215–225, 1999.
Deterding, RR and Shannon, JM. Proliferation and differentiation of fetal rat pulmonary epithe-lium in the absence of mesenchyme. J. Clin. Invest . 95:2963–2972, 1995.
Eppig, JJ and Wigglesworth, K. Factors affecting the developmental competence of mouse oo-cytes growth in vitro oxygen concentration. Mol. Reprod. Dev . 42:447–456, 1995.
Fukuda, Y, Ishizaki, M. , Okada, Y, Seiki, M, and Yamanaka, M. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in fetal rabbit lung. Am. J. Physiol. Lung Cell Mol. Physiol . 279: L555–561, 2000.
Gassmann, M, Fandrey J, Bichet, S, Wartenberg, W, Marti, HH, Bauer, C, Wenger, RH, and Acker, H. Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc. Natl. Acad. Sci . 93:2867–2872, 1996.
Gebb, SA and Shannon, JM. Hypoxia stimulates fetal lung branching in vitro. Am. J. Respir. Crit. Care Med . 159:A744, 1999.
Gebb, SA and Shannon, JM. Tissue interactions mediate early events in pulmonary vasculogenesis. Dev. Dyn 217: 159–169, 2000.
Gebb, SA and Jones, PL. Matrix metalloproteinase inhibition enhances fetal lung branching and sonic hedgehog expression. Abstract, FASEB J. In Press, 2003.
Gebb, SA, Fox, K, McKean, D, and Jones, PL. Inhibition of matrix metalloproteinase activity enhances branching morphogenesis in fetal rat lung. Am. J. Respir. Crit. Care Med . 165: A223, 2002.
Gross, I. Regulation of fetal lung maturation. Am. J. Physiol . 259 (Lung Cell. Mol. Physiol. 3): L337–L344, 1990.
Hale, LP, Braun, RD, Gwinn, WM, Greer, PK and Dewhirst, MW. Hypoxia in the thymus: role of oxygen tension in thymocyte survival. Am. J. Physiol. Heart Circ Physiol 282(4):H1467–77, 2002.
Jarecki, J, Johnson, E. , and Krasnow, MA. Oxygen regulation of airway branching in Drosophila is mediated by branchless FGF. Cell . 99:211–220, 1999.
Jones, FS and Jones, PL. The tenascin family of ECM glycoproteins: Structure, function, and regulation during embryonic development and tissue remodeling. Dev. Dyn. 218:235–259. 2000.
Jones, PL, and Jones, FS. Tenascin-C in development and disease: gene regulation and cell function. Matrix Biol . 19:581–596, 2000.
Jones, PL, Jones, FS, Zhou, B, and Rabinovitch, M. Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a B3 integrin-me-diated mitogen-activated protein kinase pathway and a 122-base pair promoter element. J. Cell Sci . 112, 435–445, 1999.
Klein, JM, McCarthy, TA, Dagle, and Snyder, JM. Antisense inhibition of epidermal growth factor receptor decreases expression of human surfactant protein A. Am. J. Respir. Cell Mol. Biol . 22(6):676–684, 2000.
Leco, KJ, Waterhouse, P, Sanchez, OH, Growing, KLM, Poole, AR, Wakeham, A, Mak, TW, and Khokha, R. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J. Clin. Invest . 108:817–829, 2001.
Lee, YM, Jeong, CH, Koo, SY, Son, MJ, Song, HS, Bae, SK, Raleigh, JA, Chung, HY, Yoo, MA, and Kim, KW. Determination of hypoxic region by hypoxia marker in develoing mouse embryos in vivo : a possible signal for vessel development. Dev. Dyn . 220(2): 175–86, 2001.
Loughna, S, Yuan, H-T, and Woolf, AS. Effects of oxygen on vascular patterning in Tiel/LacZ metanephric kidneys in vitro. Biochem. Biophys. Res. Comm . 247:361–366, 1998.
Mackie, EJ and Tucker, RP. The tenascin-C knockout revisited. J. Cell Sci . 112: 3847–3853, 1999.
Maltepe, E, and Simon, MC. Oxygen, genes, and development: An analysis of the role of hypoxic gene regulation during murine vascular development. J. Mol. Med . 76:391–401, 1998.
Mendelson, CR. Role of transcription factors in fetal lung development and surfactant protein gene expression. Annu Rev Physiol . 62:875–915, 2000.
Miettinen, PJ, Warburtion, D, Bu, D, Zhao, J-S, Berger, JE, Minoo, P, Koivisto, T. Allen, L, Dobbs, L, Werb, Z, and Derynck, R. Impaired lung branching morphogenesis in the absence of functional EGF receptor. Dev Biol . 186:224–236, 1997.
Minoo, P and King, RJ. Epithelial-mesenchymal interactions in lung development. Annul. Rev. Physiol . 56:13–45, 1994.
Mitchell, JA and Yochim, JM. Measurement of intrauterine oxygen tension in the rat and its regulation by ovarian steroid hormones. Endocrinology 83(4):691–700, 1968.
Morrison, SJ, Csete, M, Groves, AK, Melaga, W, Wold, B, and Anderson. Culture in reduced levels of oxygen promotes clonogenic sypathoadrenal differentiation by isolated neural crest stem cells. J. Neuroscl . 20:7370–7376, 2000.
Norman, JT, Orphanides, C, Garcia, P, and Fine, LG. Hypoxia-induced changes in extracellular matrix metabolism in renal cells. Exp. Nephrol . 7(5–6):463–9, 1999.
Pabon, JD, Findley, WE, and Gibbons, WE. The toxic effect of short exposures to the atmo-spheric oxygen concentration on early mouse embryonic development. Fertil Steril 51:896–900, 1989.
Perl, AK, and Whitsett, JA. Molecular mechanisms controlling lung morphogenesis. Clin. Genet . 56(1): 14–27, 1999.
Pohl, M, Sakurai, H, Bush, KT, and Nigam, JK. Matrix metalloproteinases and their inhibitors regulate in vitro ureteric bud branching morphogenesis. Am. J. Physiol. Renal Physiol . 279: F891–900. 2000
Roman, J. Fibronectin and fibronectin receptors in lung development. Exp. Lung Res . 23(2): 147–159, 1997.
Saga, Y, Yagi, T, Ikawa, Y, Sakakura, T, and Aizzawa, S. Mice develop normally without tenascin. Genes Dev . 6, 1821–1831, 1992.
Schittny, JC, Hirsh, E, Fassler, R, Evens, A, and Muller, U. Fetal lungs of tenascin-C- and of alpha8 integrin-null mice grow well, but branch poorly in organ culture. Eighth Woods Hole Conference in Lung Cell Biology, Basic Mechanisms of Lung Development. 2000.
Semenza, GL, Agani, F, Iyer, N, Kotch, L. Laughner, E, Leung, S, and Yu, A. Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1. Ann. N. Y. Acad. Sci . 874:262–268, 1999.
Siri, A, Knauper, V, Veirana, N, Caocci, F, Murphy, G, and Zardi, L. Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. J. Biol. Chem . 270(15):8650–8654, 1995.
Spooner, B and Wessels, N. Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. J. Exp. Zool . 175:445–454, 1970.
Swindle, CS, Tran, KT, Johnson, TD, Banerjee, P, Mayes, AM, Griffith, L. and Wells, A. Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J. Cell Biol . 154:459–468, 2001.
Taderera, JT. Control of lung differentiation in vitro. Dev. Biol . ld6:489–512, 1967.
Tufro-McReddie, A. , Norwood, VF, Aylor, KW, Botkin, SJ, Curry, RM, and Gomez, RA. Oxygen regulates vascular endothelial growth factor-mediated vasculogenesis and tubulogenesis. Dev. Biol . 183:139–149, 1997.
Umaoka, Y, Noda, Y, Narimoto, K, and Mori, T. Effects of oxygen toxicity on early development of mouse embryos. Mol. Reprod. Dev . 31:28–33, 1992.
Vu, TH and Werb, Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes & Dev . 14:2123–2133, 2000.
Warburton, D, Zhao, J, Berberich, MA and Bernfield, M. Molecular embryology of the lung: then, now, and in the future. Am. J. Physiol. Lung Cell. Mol. Physiol . 276:L697–704, 1999.
Young, SL, Chang, L-Y, and Erickson, HP. Tenascin-C in rat lung: Distribution, ontogeny and role in branching morphogenesis. Dev. Biol . 161:615–625, 1994.
Yue, X and Tomanek, RJ. Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts. Dev. Dyn . 216:28–36, 1999.
Zhao, Y. Tenascin is expressed in the mesenchyme of the embryonic lung and down-regulated by dexamethasone in early organogenesis. Biochem. Biophys. Res. Comm . 263:597–602, 1999.
Zhao, Y. and Young, SL. Tenascin in rat lung development: in situ localization and cellular sources. Am. J. Physiol. Lung Cell. Mol. Physiol . 269:L482–491, 1995.
Zhao, Y. and Young, SL. TGF-B regulates expression of tenascin alternative-splicing isoforms in fetal rat lung. Am. J. Physiol. Lung Cell. Mol. Physiol . 268:L173–180, 1995.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this paper
Cite this paper
Gebb, S.A., Jones, P.L. (2003). Hypoxia and Lung Branching Morphogenesis. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 543. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8997-0_8
Download citation
DOI: https://doi.org/10.1007/978-1-4419-8997-0_8
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4753-8
Online ISBN: 978-1-4419-8997-0
eBook Packages: Springer Book Archive