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Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle.
Am J Respir Cell Mol Biol. 1999 Feb; 20(2):199-208.AJ

Abstract

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is co-mitogenic with insulin-like growth factors (IGFs) in airway smooth-muscle (ASM) cells in vitro. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced IGF binding proteins (IGFBPs), which are cell growth-inhibitory proteins. We also identified this IGFBP protease to be the matrix metalloproteinase-1 (MMP-1), and showed that this enzyme had a significant role in modulating IGF action in ASM cells. In the present study, we tested the hypothesis that ASM hyperplasia in vivo involves induction of MMP-1 leading to IGFBP proteolysis. We detected the presence of MMP-1 and measured its levels in human airway tissue sections prepared from nonasthmatic and asthmatic subjects. Six nonasthmatic and six asthmatic airway tissue samples were analyzed for immunoreactive MMP-1 through an immunohistochemical detection method. Both the bronchial and tracheal smooth-muscle cells from different regions of the same sample were examined and documented. The immunostaining for MMP-1 was significantly elevated in both the bronchial and tracheal smooth-muscle cells of the airway sections from asthmatic samples relative to that of the nonasthmatic samples. The differences in levels of MMP-1, IGFBP-2, IGFBP-3, and IGFBP proteolytic activity were quantified using densitometric analyses of the ASM tissue extracts that were separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The MMP-1 levels in the asthmatic airway tissue extracts were 12-fold higher than those found in control samples. In addition, IGFBP-2 and IGFBP-3, which we have previously demonstrated to be proteolytic substrates of MMP-1, were found to be cleaved in asthmatic airway tissue extracts. Furthermore, the asthmatic airway extracts contained IGFBP proteolytic activity that was shown by immunodepletion studies to be due to MMP-1. These observations demonstrate that MMP-1 may play a significant role in inducing ASM hyperplasia and airway obstruction in asthma by modulating the IGF axis.

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Authors+Show Affiliations

Rajah R
Department of Pathology, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
Nachajon RV
No affiliation info available
Collins MH
No affiliation info available
Hakonarson H
No affiliation info available
Grunstein MM
No affiliation info available
Cohen P
No affiliation info available

MeSH

AdolescentAdultAsthmaChildCollagenasesFemaleHumansHydrolysisImmunohistochemistryInsulin-Like Growth Factor Binding ProteinsMaleMatrix Metalloproteinase 1Muscle, SmoothRecombinant ProteinsTrachea

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9922210

Citation

Rajah, R, et al. "Elevated Levels of the IGF-binding Protein Protease MMP-1 in Asthmatic Airway Smooth Muscle." American Journal of Respiratory Cell and Molecular Biology, vol. 20, no. 2, 1999, pp. 199-208.
Rajah R, Nachajon RV, Collins MH, et al. Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle. Am J Respir Cell Mol Biol. 1999;20(2):199-208.
Rajah, R., Nachajon, R. V., Collins, M. H., Hakonarson, H., Grunstein, M. M., & Cohen, P. (1999). Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle. American Journal of Respiratory Cell and Molecular Biology, 20(2), 199-208.
Rajah R, et al. Elevated Levels of the IGF-binding Protein Protease MMP-1 in Asthmatic Airway Smooth Muscle. Am J Respir Cell Mol Biol. 1999;20(2):199-208. PubMed PMID: 9922210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle. AU - Rajah,R, AU - Nachajon,R V, AU - Collins,M H, AU - Hakonarson,H, AU - Grunstein,M M, AU - Cohen,P, PY - 1999/1/28/pubmed PY - 1999/1/28/medline PY - 1999/1/28/entrez SP - 199 EP - 208 JF - American journal of respiratory cell and molecular biology JO - Am J Respir Cell Mol Biol VL - 20 IS - 2 N2 - We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is co-mitogenic with insulin-like growth factors (IGFs) in airway smooth-muscle (ASM) cells in vitro. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced IGF binding proteins (IGFBPs), which are cell growth-inhibitory proteins. We also identified this IGFBP protease to be the matrix metalloproteinase-1 (MMP-1), and showed that this enzyme had a significant role in modulating IGF action in ASM cells. In the present study, we tested the hypothesis that ASM hyperplasia in vivo involves induction of MMP-1 leading to IGFBP proteolysis. We detected the presence of MMP-1 and measured its levels in human airway tissue sections prepared from nonasthmatic and asthmatic subjects. Six nonasthmatic and six asthmatic airway tissue samples were analyzed for immunoreactive MMP-1 through an immunohistochemical detection method. Both the bronchial and tracheal smooth-muscle cells from different regions of the same sample were examined and documented. The immunostaining for MMP-1 was significantly elevated in both the bronchial and tracheal smooth-muscle cells of the airway sections from asthmatic samples relative to that of the nonasthmatic samples. The differences in levels of MMP-1, IGFBP-2, IGFBP-3, and IGFBP proteolytic activity were quantified using densitometric analyses of the ASM tissue extracts that were separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The MMP-1 levels in the asthmatic airway tissue extracts were 12-fold higher than those found in control samples. In addition, IGFBP-2 and IGFBP-3, which we have previously demonstrated to be proteolytic substrates of MMP-1, were found to be cleaved in asthmatic airway tissue extracts. Furthermore, the asthmatic airway extracts contained IGFBP proteolytic activity that was shown by immunodepletion studies to be due to MMP-1. These observations demonstrate that MMP-1 may play a significant role in inducing ASM hyperplasia and airway obstruction in asthma by modulating the IGF axis. SN - 1044-1549 UR - https://www.unboundmedicine.com/medline/citation/9922210/Elevated_levels_of_the_IGF_binding_protein_protease_MMP_1_in_asthmatic_airway_smooth_muscle_ L2 - https://www.atsjournals.org/doi/10.1165/ajrcmb.20.2.3148?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -