We propose to study the regulation of normal fetal lung growth, and of post-injury regenerative lung growth, in vivo and in vitro, with respect to the expression and effects of protein growth factors. Extensive evidence suggest that in both fetal and postnatal life, there is a strong association between the mechanical forces to which the lung is subjected and the rate of pulmonary cellular mitosis. Based on this evidence and on extensive preliminary work from this laboratory, we propose to these two related hypotheses: 1. That acinar development is mediated by the release of autocrine and parcrine growth factors by lung cells, in response to """"""""stretch"""""""" incurred during normal breathing activity, with resultant cellular oncogene responses. 2. That this process is arrested during acute generalized lung injury, and that subsequent repair and regeneration represents an amplification or reactivation of the normal process. These hypothese will be tested in four specific aims: 1. To define growth factor, growth factor receptor and proto-oncogene ontogeny in the fetal and neonatal rat lung. Northern blot and slot blot analyses of growth factors, their receptors, and related proto-oncogenes will be compared with measures of cell proliferation. 2. To determine the influence of """"""""stretch"""""""" on growth factor, receptor and proto-oncogene expression of fetal lung cells in vitro. Based upon the results from aim 1, we will study these endpoints in lung cells cultured singly and in a three dimensional multi-cell system. Both systems will be studied under static conditions and after exposure to stretch. 3. To define the effect of acute lung injury with oxygen followed by recovery on growth factor, growth factor receptor and proto-oncogene expression in the neonatal rat lung. 4. To define how acute injury with oxygen, followed by recovery, modifies the influence of """"""""stretch"""""""" on growth factor, growth factor receptor and proto-oncogene expression of fetal lung cells in vitro.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL043416-01
Application #
3362095
Study Section
(SRC)
Project Start
1989-09-01
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Hospital for Sick Chldrn (Toronto)
Department
Type
DUNS #
208511808
City
Toronto
State
ON
Country
Canada
Zip Code
M5 1X8
Mourgeon, E; Xu, J; Tanswell, A K et al. (1999) Mechanical strain-induced posttranscriptional regulation of fibronectin production in fetal lung cells. Am J Physiol 277:L142-9
Xu, J; Liu, M; Post, M (1999) Differential regulation of extracellular matrix molecules by mechanical strain of fetal lung cells. Am J Physiol 276:L728-35
Xu, J; Liu, M; Tanswell, A K et al. (1998) Mesenchymal determination of mechanical strain-induced fetal lung cell proliferation. Am J Physiol 275:L545-50
Xu, J; Liu, M; Liu, J et al. (1996) Mechanical strain induces constitutive and regulated secretion of glycosaminoglycans and proteoglycans in fetal lung cells. J Cell Sci 109 ( Pt 6):1605-13
Liu, M; Xu, J; Souza, P et al. (1995) The effect of mechanical strain on fetal rat lung cell proliferation: comparison of two- and three-dimensional culture systems. In Vitro Cell Dev Biol Anim 31:858-66
Liu, M; Xu, J; Liu, J et al. (1995) Mechanical strain-enhanced fetal lung cell proliferation is mediated by phospholipase C and D and protein kinase C. Am J Physiol 268:L729-38
Liu, M; Liu, J; Buch, S et al. (1995) Antisense oligonucleotides for PDGF-B and its receptor inhibit mechanical strain-induced fetal lung cell growth. Am J Physiol 269:L178-84
Buch, S; Jassal, D; Cannigia, I et al. (1994) Ontogeny and regulation of platelet-derived growth factor gene expression in distal fetal rat lung epithelial cells. Am J Respir Cell Mol Biol 11:251-61
Hogan, M; Zimmermann, L J; Wang, J et al. (1994) Increased expression of CTP:phosphocholine cytidylyltransferase in maturing type II cells. Am J Physiol 267:L25-32
Liu, M; Xu, J; Tanswell, A K et al. (1994) Inhibition of mechanical strain-induced fetal rat lung cell proliferation by gadolinium, a stretch-activated channel blocker. J Cell Physiol 161:501-7

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