Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.
Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-beta-mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-beta-induced stimulation. Relaxin also blocked transforming growth factor-beta-induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of approximately 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group (P < 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels (P < 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis.
Unemori
E N
EN
Connective Therapeutics, Inc., Palo Alto, California 94303, USA. elaine_unemori@connective.com
Pickford
L B
LB
Salles
A L
AL
Piercy
C E
CE
Grove
B H
BH
Erikson
M E
ME
Amento
E P
EP
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004792:Enzyme Precursors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006651:Histocytochemistry; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D055370:Lung Injury; D051379:Mice; D011347:Procollagen / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000628:therapy; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D012065:Relaxin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004792:Enzyme Precursors; D005353:Fibronectins; D011347:Procollagen; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D012065:Relaxin; D003094:Collagen; D017364:Collagenases; C022440:procollagenase