Stumm CL et al. (2014), Lung remodeling in a mouse model of asthma invo...

ECB-ART-43394

PLoS One 2014 Apr 14;94:e95959. doi: 10.1371/journal.pone.0095959.

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Lung remodeling in a mouse model of asthma involves a balance between TGF-β1 and BMP-7.

Stumm CL , Halcsik E , Landgraf RG , Camara NO , Sogayar MC , Jancar S .

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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.

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Genes referenced: LOC100892350 LOC590297

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	Figure 1. Allergic asthma protocol.Mice were sensitized on days 0 and 7 by an intraperitoneal injection of a mixture containing 50 µg of ovalbumin and 1 mg of Al(OH)3 in PBS. Mice were challenged by exposure to an aerosol of OVA for 20 min at days 12, 15, 19, 22, 26, and 29.
	Figure 2. In vivo treatment with rhBMP-7.Mice were anesthetized and human recombinant BMP-7 (300 mg/kg in a total volume of 30 µl) in PBSA isotonic buffer (140 mM NaCl, 2,7 mM KCl, 8 mM Na2HPO4 and 1.5 mM KH2PO4), was administered intranasally every other day between days 17 and 30 of the chronic asthma protocol.
	Figure 3. Fibrosis markers in the asthmatic lung.Lung sections were taken from animals with asthma (6 challenges), stained with PAS for mucus (A) or prepared for immunohistochemical and morphometric analysis of α-SMA (B) and collagen type I (C). Data are representative of 5 animals in each of 3 independent experiments. Bars = 50 mm. *p<0.05 comparing with control group.
	Figure 4. TGF-β and BMP-7 mRNA expression in lung tissue.BMP-7 (A) and TGF-β (B) mRNA in whole lung preparations. The TGF-β/BMP-7 ratio was calculated (C). HPRT was used as housekeeping gene. Data are representative of 5 animals in each of 3 independent experiments. *p<0.05 comparing with control group; Δ p<0.05 comparing acute with chronic groups. In the insert, collagen-I (area/um2).
	Figure 5. BMP-7 inhibits TGF-β1-induced synthesis of collagen-I by lung fibroblasts.Mouse lung fibroblasts from control animals (A) were stimulated with TGF-β1 (5 ng/ml) alone or in combination with BMP-7 (30, 100 ou 300 ng/ml) during 18 hours. Mouse lung fibroblasts from asthmatic animals (B) were treated with TGF-β1 (5 ng/ml) alone or in combination with BMP-7 (300 ng/ml). Type I collagen was analyzed by western blot and normalized by β-actin expression. Results are presented as percentage of the control or as arbitrary units. Data are representative of 5 animals in each of 3 independent experiments. *p<0.05 comparing with the control group.