RELAXIN: A POTENTIAL THERAPY FOR PULMONARY FIBROSIS

Chrishan S. Samuel¹, Chongxin Zhao¹, Ross A.D. Bathgate¹, Courtney P. Bond², Matthew D. Burton³, Laura J. Parry¹, Roger J. Summers², Mimi L.K. Tang³, Geoffrey W. Tregear¹, 1 Howard Florey Institute, University of Melbourne, Victoria 3010, 2 Dept. of Pharmacology, Monash University, Victoria 3800, 3 Dept. of Immunology, Royal Children's Hospital, Parkville, Victoria 3052, Australia.

Pulmonary fibrosis is the final common end point to a variety of pathologies that affect the lung including connective tissue (collagen) disorders resulting from the proliferation and differentiation of fibroblasts, inflammatory disorders and infections. The peptide hormone, relaxin, is well known as a hormone of pregnancy and for its potential ability to inhibit short-term collagen production from a number of tissues and fibroblast culture models. In the present study, the long-term effects of relaxin deprivation on lung morphology, collagen content and function were examined in relaxin gene-knockout (RLX-/-) mice.

Male and female RLX-/- mice (studied from 3 months to 19 months of age) had progressively increased lung wet weights, collagen contents and collagen concentrations, compared to that measured from RLX+/+ mice. The increased lung weight and collagen content (fibrosis) were statistically significant (p<0.05) from 9 months of age onwards in both genders of mice, although the severity of the phenotype was greater in male RLX-/- mice. Histology of lung tissues from 9 month and 12 month old RLX-/- mice, demonstrated a focal loss of alveolar structure and enhanced deposition of collagen surrounding the bronchioles and arterioles. The increased fibrosis was associated with a significantly altered (p<0.05) peak expiratory flow and lung recoil (lung function) in 12 month old RLX-/- mice. Treatment of RLX-/- mice with recombinant human relaxin (rH2, which is bioactive in rodents) for 14 days, at 9 months of age (when fibrosis was initiated) and 12 months of age (when fibrosis was established) significantly decreased (p<0.05) lung collagen content and restored lung structure back to that observed in normal mice. Organ bath studies showed that precontracted lung strips relaxed in the presence of rH2, in vitro. These data indicate that relaxin may provide a means to regulate excessive collagen deposition in diseased states characterized by pulmonary fibrosis.