Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo

Journal of Clinical Investigation

Volumn 98, Issue 12, 1996, Pages 2739-2745

  Unemori, Elaine N ^a   Pickford, Lesley B ^a   Salles, Adam L ^a   Piercy, Christopher E ^a   Grove, Beverly H ^a   Erikson, Mark E ^a   Amento, Edward P ^a  

^a Connective Therapeutics Inc ^*  (United States)

Author keywords

collagen; collagenase; pulmonary fibrosis; relaxin

Indexed keywords

BLEOMYCIN; BLEOMYCIN SULFATE; COLLAGENASE; FIBRONECTIN; HYDROXYPROLINE; PROCOLLAGENASE; RELAXIN; TRANSFORMING GROWTH FACTOR BETA;

ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; COLLAGEN SYNTHESIS; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG MECHANISM; EXTRACELLULAR MATRIX; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOPHENOTYPING; LUNG FIBROBLAST; LUNG FIBROSIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING;

EID: 0030453783     PISSN: 00219738     EISSN: None     Source Type: Journal    
DOI: 10.1172/JCI119099     Document Type: Article

References (34)

1. Sheppard, M.N., and N.K. Harrison. 1992. Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis. Thorax. 4:1064-1074.
2. McGowan, S.E. 1992. Extracellular matrix and the regulation of lung development and repair. FASEB J. 6:2895-2904.
3. Bell, R.J., L.W. Eddie, A.R. Lester, E.C. Wood, P.D. Johnston, and H.D. Niall. 1987. Relaxin in human pregnancy serum measured with a homologous radioimmunoassay. Obstet. Gynecol. 69:585-589.
4. Chihal, H.J., and L.L. Epsey. 1973. Utilization of the relaxed symphysis pubic of the guinea pig for clues to the mechanism of ovulation. Endocrinology. 93:1441.
5. Unemori, E.N., and E.P. Amento. 1990. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J. Biol. Chem. 265:10681-10685.
6. Unemori, E.N., L.S. Beck, W.P. Lee, Y. Xu, M. Siegel, G. Keller, H.D. Liggitt, E.A. Bauer, and E.P. Amento. 1993. Human relaxin decreases collagen accumulation in vivo in two rodent models of fibrosis. J. Invest. Dermatol. 101: 280-285.
7. Unemori, E.N., and Z. Werb. 1988. Collagenase expression and endogenous activation in rabbit synovial fibroblasts stimulated by the calcium ionophore A23187. J. Biol. Chem. 263:16252-16259.
8. Lindenschmidt, R.C., A.F. Tryka, G.A. Godfrey, E.L. Frome, and H. Witschi. 1986. Intratracheal versus intravenous administration of bleomycin in mice: acute effects. Toxicol. Appl. Pharmacol. 85:69-77.
9. Ashcroft, T., J.M. Simpson, and V. Timbrell. 1988. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J. Clin. Pathol. 41: 467-470.
10. Heslerberg, T.W., J.E. Gerriets, K.M. Resider, A.C. Jackson, C.E. Cross, and J.A. Last. 1981. Bleomycin-induced pulmonary fibrosis: correlation of biochemical, physiological, and histological changes. Toxicol. Appl. Pharmacol. 60:360-370.
11. Glantz, S.A. 1992. The special case of two groups. In Primer of Biostatistics J.D. Jeffers and M.R. Englis, editors. McGraw-Hill, Inc., New York.
12. Sporn, M.B., and A.B. Roberts. 1990. TGF-β: problems and prospects. Cell Regul. 1:875-882.
13. Unemori, E.N., E.A. Bauer, and E.P. Amento. 1992. Relaxin alone and in conjunction with interferon-γ decreases collagen synthesis by cultured human scleroderma fibroblasts. J. Invest. Dermatol. 99:337-342.
14. Amento, E.P., A.K. Bhan, K.G. McCullagh, and S.M. Krane. 1985. Influences of gamma interferon on synovial fibroblastlike cells. Ia induction and inhibition of collagen synthesis. J. Clin. Invest. 76:837-848.
15. Khalil, N., O. Breznay, M. Sporn, and A.H. Greenberg. 1989. Macrophage production of transforming growth factor-β and fibroblast collagen synthesis in chronic pulmonary inflammation. J. Exp. Med. 170:727-737.
16. Khalil, N., R.N. O'Connor, H.W. Unruh, P.W. Warren, K.C. Flanders, and A. Kemp. 1991. Increased production and immunohistochemical localization of transforming growth factor in idiopathic pulmonary fibrosis. Am. J. Resp. Cell. Mol. Biol. 5:155-162.
17. Mushayandebvu, T.I., and M.R. Rajabi. 1995. Relaxin stimulates interstitial collagenase activity in cultured uterine cervical cells from nonpregnant but not immature guinea pigs; estradiol-17β restores relaxin's effect in immature cervical cells. Biol. Reprod. 53:1020-1037.
18. Eitzman, D.T., R.D. McCoy, X. Aheng, W.P. Fay, T. Shen, D. Ginsberg, and R.H. Simon. 1996. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J. Clin. Invest. 97:232-237.
19. Adamson, I.Y.R., and D.H. Bowden. 1979. Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Am. J. Pathol. 96:531-544.
20. Phan, S.J., R.S. Thrall, and C. Williams. 1981. Bleomycin-induced pulmonary fibrosis. Effects of steroid on lung collagen metabolism. Am. Rev. Resp. Dis. 124:428-434.
21. Mall, G., P. Zimmermann, I. Siemens, A. Burkhardt, and H.F. Otto. 1991. Prevention of bleomycin-induced fibrosing alveolitis with indomethacin: stereological studies on rat lungs. Virchows Arch. A Pathol. Anat. 419:339-347.
22. Smith, R.E., R.M. Strieter, S.H. Phan, N.W. Lukacs, G.B. Huffnagle, C.A. Wilke, M.D. Burdick, P. Lincoln, H. Evanoff, and S.L. Kunkel. 1994. Production and function of murine macrophage inflammatory protein-1α in bleomycin-induced lung injury. J. Immunol. 153:4704-4712.
23. Piquet, P.F., M.A. Collart, G.E. Grau, Y. Kapanci, and P. Vassalli. 1989. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med. 170:655-663.
24. Witschi, H.P., A.F. Tryka, and R.C. Lindenschmidt. 1985. The many faces of an increase in lung collagen. Fund. Appl. Toxicol. 5:240-250.
25. Fulmer, J.D., R.S. Bienkowski, M.J. Cowan, S.D. Brehl, K.M. Bradley, V.J. Ferrans, W.C. Roberts, and R.G. Crystal. 1980. Collagen concentration and rates of synthesis in idiopathic pulmonary fibrosis. Amer. Rev. Respir. Dis. 122:289-301.
26. Cheah, S.H., K.H. Ng, V.T. Johgalingam, and M. Ragavan. 1995. The effects of oestradiol and relaxin on extensibility and collagen organisation of the pregnant rat cervix. J. Endocrinol. 146:331-337.
27. Kibblewhite, D., W.F. Larrabee, and D. Sutton. 1992. The effect of relaxin on tissue expansion. Arch. Otolaryngol. Head Neck Surg. 118:153-156.
28. Steinetz, B.G., and E.M. O'Byrne. 1983. Speculations on the probable role of relaxin in cervical dilation and parturition in rats. Semin. Reprod. Endocrinol. 1:335-342.
29. Fei, D.T.W., M.C. Gross, J. Lofgren, M. Mora-Worms, and A.B. Chen. 1990. Cyclic AMP response to recombinant human relaxin by cultured human endometrial cells: a specific and high throughput in vitro bioassay. Biochem. Biophys. Res. Comm. 170:214-220.
30. Cronin, M.J., T. Malaska, and C. Bakhit. 1987. Human relaxin increases cyclic AMP levels in cultured anterior pituitary cells. Biochem. Biophys. Res. Comm. 148:1246-1251.
31. Meera, P., A.M. Monga, E. Stefani, L. Toro, and B.M. Sanborn. 1995. Relaxin stimulates myometrial calcium-activated potassium channel activity via protein kinase A. Am. J. Physiol. 269:C312-C317.
32. Masini, E., D. Bani, M. Bigazzi, F.F. Mannaioni, and T. Bani-Sacchi. 1994. Effects of relaxin on mast cells. In vitro and in vivo studies in rats and guinea pigs. J. Clin. Invest. 94:1974-1980.
33. Kalbag, S.S., M.S. Roginsky, Z. Jelveh, and S. Sulimovici. 1991. Phorbol ester, prolactin, and relaxin cause translocation of protein kinase C from cytosol to membranes in human endometrial cells. Biochim. Biophys. Acta. 1094: 85-91.
34. Osheroff, P.L., M.J. Cronin, and J.A. Lofgren. 1992. Relaxin binding in the rat heart atrium. Proc. Natl. Acad. Sci. USA. 89:2384-2388.