Lung remodeling in a mouse model of asthma involves a balance between TGF-β1 and BMP-7.
A key event in chronic allergic asthma is the TGF-β-induced activation of fibroblasts into α-SMA-positive myofibroblasts which synthesize type-I collagen. In the present study we investigated the effect of the anti-fibrotic molecule BMP-7 in asthma. Balb/c mice were immunized i.p. with ovalbumin in alum and challenged every 2 days with ovalbumin aerosol (two or six challenges for acute and chronic protocols, respectively). The lung was evaluated for: α-SMA and type-I collagen by immunohistochemistry; BMP-7 and TGF- β1 gene expression by qRT-PCR; type-I collagen and Smads 2 and 3 by immunoblotting; mucus by PSA staining. Type-I collagen around bronchi, α-SMA, mucus secretion, TGF- β1 and BMP-7 gene expression were all increased in asthma. The TGF- β1/BMP-7 ratio was higher in the chronic group and correlated with higher levels of collagen. Fibroblasts isolated from asthmatic and healthy lungs produced type-I collagen upon stimulation with TGF- β1 via phosphorylation of Smad-2, Smad-3. Pre-treatment of the fibroblasts with BMP-7 reduced collagen production and Smads phosphorylation. Intranasal treatment of asthmatic mice with recombinant BMP-7 during the immunization protocol reduced lung inflammation and type I collagen deposition. These results suggest a protective role for BMP-7 in lung allergic inflammation, opposing the pro-fibrotic effects of TGF- β1.
Department of Immunology, University of Sao Paulo, Sao Paulo, SP, Brazil.
Camila Leindecker
CL
Stumm
Department of Biochemistry, University of Sao Paulo, Sao Paulo, SP, Brazil.
Erik
E
Halcsik
Department of Biological Sciences, Federal University of Sao Paulo, Diadema, SP, Brazil.
Richardt Gama
RG
Landgraf
Department of Immunology, University of Sao Paulo, Sao Paulo, SP, Brazil; Division of Nephrology, Federal University of Sao Paulo, Sao Paulo, SP, Brazil.
Niels Olsen Saraiva
NO
Camara
Department of Biochemistry, University of Sao Paulo, Sao Paulo, SP, Brazil.
Mari Cleide
MC
Sogayar
Department of Immunology, University of Sao Paulo, Sao Paulo, SP, Brazil.
Sonia
S
Jancar
D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers; D004195:Disease Models, Animal; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D055419:Bone Morphogenetic Protein 7; D017931:DNA Primers; D053773:Transforming Growth Factor beta1; C525820:bmp7 protein, mouse; D003094:Collagen