Relaxin family peptide receptor-1 protects against airway fibrosis during homeostasis but not against fibrosis associated with chronic allergic airways disease.
Endogenous relaxin has recently been demonstrated to protect the airway/lung against age-related fibrosis and against inflammation-associated airway fibrosis in animal models of allergic airways disease (AAD). In the current study, we examined the contribution of the primary relaxin receptor, relaxin family peptide receptor-1 (RXFP1), in mediating these effects of relaxin. Lung tissues from healthy aging RXFP1 gene-knockout (Rxfp1(-/-)) and wild-type (Rxfp1(+/+)) mice and from 8- to 10-wk-old Rxfp1(-/-) and Rxfp1(+/+) mice subjected to a mouse model of AAD were assessed for various markers of airway fibrosis and remodeling. Male and female Rxfp1(-/-) mice demonstrated an age-related progression of airway/lung fibrosis. Saline-treated Rxfp1(-/-) mice had significantly increased myofibroblast differentiation and lung collagen deposition (both P < 0.05), decreased matrix metalloproteinase (MMP)-9 expression and activity (P < 0.05), but equivalent levels of MMP-2 and tissue inhibitor of metalloproteinases (TIMPs) to that measured in saline-treated Rxfp1(+/+) mice. As expected, ovalbumin (OVA)-treated Rxfp1(+/+) mice developed markedly increased lung myofibroblast differentiation and collagen deposition (both P < 0.01 vs saline-treated Rxfp1(+/+) mice), significantly decreased lung MMP-2 and MMP-9 expression and activity and increased TIMP-1 expression (all P < 0.05 vs. respective measurements from saline-treated Rxfp1(+/+) mice). Surprisingly, however, OVA-treated Rxfp1(-/-) animals had equivalent levels of airway fibrosis and gelatinase activity but increased TIMP-1 expression (P < 0.05) compared with OVA-treated Rxfp1(+/+) mice. These combined findings demonstrate that RXFP1 is involved in mediating relaxin's effects on airway fibrosis during homeostasis but not during inflammation-induced fibrosis associated with chronic AAD.
Samuel
Chrishan S
CS
Department of Biochemistry and Molecular Biology, Howard Florey Institute , University of Melbourne, Victoria, Australia. chrishan.samuel@florey.edu.au
Royce
Simon G
SG
Chen
Bin
B
Cao
Huifang
H
Gossen
Jan A
JA
Tregear
Geoffrey W
GW
Tang
Mimi L K
ML
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis / Q000209:etiology / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology
C478103:RXFP1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D003094:Collagen