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Relaxin Family Peptide Receptor-1 Protects against Airway Fibrosis during Homeostasis But Not against Fibrosis Associated with Chronic Allergic Airways Disease

Howard Florey Institute (C.S.S., H.C., G.W.T.) and Departments of Biochemistry and Molecular Biology (C.S.S., G.W.T.) and Paediatrics (M.L.K.T.), University of Melbourne, Victoria 3010, Australia; Allergy and Immune Disorders (S.G.R., B.C., M.L.K.T.), Murdoch Children’s Research Institute, and Department of Allergy and Immunology (S.G.R., B.C., M.L.K.T.), Royal Children’s Hospital, Parkville, Victoria 3052, Australia; and Target Discovery Department (J.A.G.), Schering-Plough Corporation, 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Assoc. Prof. Mimi Tang, Department of Allergy and Immunology, Royal Children’s Hospital or Dr. Chrishan Samuel, University of Melbourne, Parkville 3052, Australia. E-mail: mimi.tang{at}mcri.edu.au or chrishan.samuel{at}florey.edu.au.

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.