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. 2013 May 23;153(5):1050–1063. doi: 10.1016/j.cell.2013.04.031

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© 2013 ELL & Excerpta Medica.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.

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p110β-RBD-DM Mice Are Protected from Bleomycin-Induced Lung Fibrosis

(A) p110β-RBD-DM fibroblasts show reduced migration in gradients of LPA. Migration of wild-type and p110β-RBD-DM MEFs in gradients of LPA and PDGF was assessed in transwell filter assays (n = 3; mean with SD; one-way ANOVA).

(B) Dock180, Elmo1, and RAC1 are required for fibroblast migration in gradients of LPA. Immortalized wild-type MEFs were transfected with scrambled duplex or gene-specific siRNA pools targeting Dock180, Elmo1, or RAC1. Migration in gradients of LPA and PDGF was assessed in transwell filter assays and cell numbers were normalized to control conditions (n = 4; mean with SEM; one-way ANOVA).

(C) p110β-RBD-DM mice are protected against death from bleomycin-induced lung damage. Wild-type and homozygous p110β-RBD-DM mice were treated with a single intratracheal dose of bleomycin (1.25 U/kg) and observed for 14 days (n = 16 mice per genotype; Mantel-Cox test).

(D) p110β-RBD-DM mice are protected against weight loss following bleomycin instillation. Wild-type and p110β-RBD-DM mice received a single intratracheal dose of saline (n = 3 per genotype) or bleomycin (n = 10 per genotype) and weights were taken 14 days later (mean ±SEM; one-way ANOVA).

(E) p110β-RBD-DM mice are protected from bleomycin-induced lung fibrosis. Representative lung areas from wild-type and homozygous p110β-RBD-DM mice 14 days after treatment with intratracheal bleomycin (×4 magnification). Top: H&E; middle: IHC for α-SMA; bottom: Sirius red.

(F) p110β-RBD-DM mice are protected against loss of transparent lung areas following bleomycin instillation. Lungs were analyzed by H&E 14 days after bleomycin challenge. Multiple nonoverlapping areas of representative sections from each lung were photographed and transparent (white) areas were quantified using Nikon NIS elements software (mean ±SEM; one-way ANOVA; see Figure S7C for raw data).

(G) p110β-RBD-DM mice accumulate fewer activated lung fibroblasts following bleomycin instillation. Lungs were analyzed by immunohistochemistry for smooth muscle antigen (α-SMA) 14 days after bleomycin challenge. Multiple nonoverlapping areas of representative sections from each lung were photographed and SMA-positive (brown) areas were quantified using Nikon NIS elements software (mean ±SEM; one-way ANOVA; see Figure S7D for raw data).

See also Figure S7.