Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V.
BACKGROUND
Tolerance to collagen structures has been shown to inhibit the progression of autoimmune scleroderma and rheumatoid arthritis. More recently, tolerance induction to collagen type V (colV) in experimental models of lung transplantation was shown to ameliorate the complex pathology known as "chronic rejection." The link between colV autoimmunity and progressive graft dysfunction and subsequent development of bronchiolitis obliterans syndrome (BOS) has been established in human lung transplant recipients. We hypothesized that intravenous injection of colV inhibits development of lung fibrosis in a bleomycin-induced lung injury mouse model.


METHODS
Experimental animals were injected intravenously with saline or colV 10 days before intratracheal instillation of bleomycin. Pulmonary inflammation was monitored and quantified for the presence of cells in the bronchoalveolar lavage (BAL) fluid by flow cytometry and histology of lung tissue.


RESULTS
ColV-pre-treated animals showed a significant reduction in lung inflammation compared with non-treated animals, according to histology and morphometry. The number of inflammatory cells in the BAL fluid was significantly reduced and associated with a lower proportion of gammadelta T cells and CD4(+) T cells in the colV-pre-treated group. Matrix metalloproteinase-2 and -9 (MMP-2 and -9; also known as gelatinase A and gelatinase B, respectively) levels in the BAL fluid were significantly reduced in colV-pre-treated mice compared with the non-treated mice. In addition, intravenous injection of colV was associated with a significant reduction in the relative expression of interleukin (IL)-6, IL-17 and IL-22 in cells present in BAL fluid at 7 and 14 days after bleomycin instillation.


CONCLUSIONS
Pre-treatment by intravenous injection of colV inhibits bleomycin-induced pulmonary fibrosis by inhibiting IL-6 and IL-17 production. Fibrosis treatment in this context therefore should target induction of colV tolerance and Th17 development.
Braun
Ruedi K
RK
Department of Thoracic and Cardiovascular Surgery, Loyola University, Maywood, Illinois, USA. rkbraun@pediatrics.wisc.edu
Martin
Alicia
A
Shah
Shivanee
S
Iwashima
Makio
M
Medina
Melissa
M
Byrne
Kathryn
K
Sethupathi
Periannan
P
Wigfield
Christopher H
CH
Brand
David D
DD
Love
Robert B
RB
D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D001761:Bleomycin / Q000009:adverse effects*; D024062:Collagen Type V / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D007275:Injections, Intravenous; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016040:Lung Transplantation; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*
D024062:Collagen Type V; D020381:Interleukin-17; D015850:Interleukin-6; D001761:Bleomycin; D020782:Matrix Metalloproteinases