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PMID: 7688769 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.

The Journal of clinical investigation ·Vol. 92 ·No. 2 ·1993-08-00 ·Pages 969-77

Panos RJ, Rubin JS, Csaky KG, Aaronson SA, Mason RJ

Abstract

Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell proliferation during lung growth and after lung injury.

MeSH Terms
Animals Cell Communication Cell Division Cells, Cultured Culture Media, Conditioned Culture Media, Serum-Free DNA/biosynthesis Epidermal Growth Factor/pharmacology Fibroblast Growth Factor 1/pharmacology Fibroblast Growth Factor 10 Fibroblast Growth Factor 7 Fibroblast Growth Factors Fibroblasts/cytology,physiology Growth Substances/biosynthesis,metabolism,pharmacology Hepatocyte Growth Factor/biosynthesis,metabolism,pharmacology Humans Insulin/pharmacology Kinetics Lung/cytology,physiology Pulmonary Alveoli/cytology,drug effects,metabolism Rats Rats, Sprague-Dawley
Chemicals
Culture Media, Conditioned Culture Media, Serum-Free FGF7 protein, human Fgf7 protein, rat Fibroblast Growth Factor 10 Growth Substances Insulin Fibroblast Growth Factor 1 Fibroblast Growth Factor 7 Fibroblast Growth Factors Epidermal Growth Factor Hepatocyte Growth Factor DNA
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Panos R J
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Rubin J S
Csaky K G
Aaronson S A
Mason R J
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI116673
Published
1993-08-00
Pages
969-77
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC294937
Subset
IM
Grants
NHLBI NIH HHS · HL-27353 · United States
NHLBI NIH HHS · HL-29891 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1172/JCI116673 PMC Full Text View journal details
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