Challenged mouse asthma model [40]. Recently, Borgeson et al. reported that LXA

Challenged mouse asthma model [40]. Recently, Borgeson et al. reported that LXA4 have anti-fibrotic effect on renal fibrosis [41]. However, no therapeutic strategies have been proven to Title Loaded From File attenuate established lung fibrosis to date. To our knowledge, the present study is the first to show a therapeutic effect on established experimental lung fibrosis. The precise mechanisms mediating the beneficial effects of ApoA1 on silica-induced fibrosis remain to be elucidated in future studies. In summary, the findings of the present study indicate that local treatment with human ApoA1 may reduce both early and established lung inflammation and fibrosis by inhibiting the production of TGF-b1, reducing the number of apoptotic cellsand increasing the level of the anti-inflammatory lipid mediator LXA4. ApoA1 appears to be a promising therapeutic agent for the treatment of established lung fibrosis.Supporting InformationFigure S1 Time courses of endogenous ApoA1(A),hApoA1 mRNA expression (B) and secreted hApoA1 (C) levels in the lungs of ApoA1 transgenic mice determined by real-time PCR and ELISA, respectively. ELISA was performed on the first 1-mL fraction of BAL fluid, with a detection limit of 3.13 ng/mL (dashed line). (TIF)Figure S2 Localization of apoptotic cells in the mouse lung detected by double-labeled immunofluororescence. Pro-surfactant C (Pro-SPC) and TUNEL stain and merged image (white arrows, double positive cells; 6100 original magnification). F4/80 and TUNEL stain and merged image (white arrows, double-positive cells; 6100 original magnification). (TIF) Figure S3 Histological analysis and S T test. **p#0.01, *p#0.05. doi:10.1371/journal.pone.0067363.gfunctional characteristics of quantification of lung inflammation and fibrosis in silica administered intratracheally to UBC-GFP transgenic mice that received doxycycline or distilled water. (A) Hematoxylin and eosin staining of lung sections. Scale bar = 20 mm (B) Differential cell counts from BAL fluid. (C) Quantification of the area occupied by silicotic nodules in the lung (n = 6/group). (D) Quantification of the soluble lung collagen amounts using a Sircol assay. (TIF)Author ContributionsConceived and designed the experiments: C-SP S-WP. Performed the experiments: EHL E-JL HJK. Analyzed the data: EHL E-JL HJK. Contributed reagents/materials/analysis tools: ESK ASJ STU YHK. Wrote the paper: C-SP S-WP.
Multiple myeloma (MM) is the second most commonly diagnosed hematologic cancer characterized by immunoglobulin secreting malignant plasma B-cells [1]. Over the past decade significant advances in our understanding of the biology of MM has led to the development of better therapeutic options and improved disease management [2]. Myeloma arises from postgerminal center B-cells and its pathogenesis involves both acquired intrinsic genetic abnormalities as well as changes to the bone marrow (BM) microenvironment [1,3]. Interactions between myeloma cells and BM stroma enhance tumor survival [4]. Clinical and pre-clinical data have demonstrated that changes in the expression of adhesion molecules facilitate the dissemination of plasma cells out of the BM, leading to malignant transformation, tumor spreading and immortalization [5]. MM cells thrive on strong cell-receptor mediated interactions with the BM microenvironment [3]_ENREF_10. Consequently, therapeutics targetingtumor-microenvironment interactions are currently being evaluated clinically and pre-clinically [6,7]. Very late antigen-4 (VLA-4; also called a4b1 integrin) is one of the critical mediators of myeloma cell adhesion to the.Challenged mouse asthma model [40]. Recently, Borgeson et al. reported that LXA4 have anti-fibrotic effect on renal fibrosis [41]. However, no therapeutic strategies have been proven to attenuate established lung fibrosis to date. To our knowledge, the present study is the first to show a therapeutic effect on established experimental lung fibrosis. The precise mechanisms mediating the beneficial effects of ApoA1 on silica-induced fibrosis remain to be elucidated in future studies. In summary, the findings of the present study indicate that local treatment with human ApoA1 may reduce both early and established lung inflammation and fibrosis by inhibiting the production of TGF-b1, reducing the number of apoptotic cellsand increasing the level of the anti-inflammatory lipid mediator LXA4. ApoA1 appears to be a promising therapeutic agent for the treatment of established lung fibrosis.Supporting InformationFigure S1 Time courses of endogenous ApoA1(A),hApoA1 mRNA expression (B) and secreted hApoA1 (C) levels in the lungs of ApoA1 transgenic mice determined by real-time PCR and ELISA, respectively. ELISA was performed on the first 1-mL fraction of BAL fluid, with a detection limit of 3.13 ng/mL (dashed line). (TIF)Figure S2 Localization of apoptotic cells in the mouse lung detected by double-labeled immunofluororescence. Pro-surfactant C (Pro-SPC) and TUNEL stain and merged image (white arrows, double positive cells; 6100 original magnification). F4/80 and TUNEL stain and merged image (white arrows, double-positive cells; 6100 original magnification). (TIF) Figure S3 Histological analysis and quantification of lung inflammation and fibrosis in silica administered intratracheally to UBC-GFP transgenic mice that received doxycycline or distilled water. (A) Hematoxylin and eosin staining of lung sections. Scale bar = 20 mm (B) Differential cell counts from BAL fluid. (C) Quantification of the area occupied by silicotic nodules in the lung (n = 6/group). (D) Quantification of the soluble lung collagen amounts using a Sircol assay. (TIF)Author ContributionsConceived and designed the experiments: C-SP S-WP. Performed the experiments: EHL E-JL HJK. Analyzed the data: EHL E-JL HJK. Contributed reagents/materials/analysis tools: ESK ASJ STU YHK. Wrote the paper: C-SP S-WP.
Multiple myeloma (MM) is the second most commonly diagnosed hematologic cancer characterized by immunoglobulin secreting malignant plasma B-cells [1]. Over the past decade significant advances in our understanding of the biology of MM has led to the development of better therapeutic options and improved disease management [2]. Myeloma arises from postgerminal center B-cells and its pathogenesis involves both acquired intrinsic genetic abnormalities as well as changes to the bone marrow (BM) microenvironment [1,3]. Interactions between myeloma cells and BM stroma enhance tumor survival [4]. Clinical and pre-clinical data have demonstrated that changes in the expression of adhesion molecules facilitate the dissemination of plasma cells out of the BM, leading to malignant transformation, tumor spreading and immortalization [5]. MM cells thrive on strong cell-receptor mediated interactions with the BM microenvironment [3]_ENREF_10. Consequently, therapeutics targetingtumor-microenvironment interactions are currently being evaluated clinically and pre-clinically [6,7]. Very late antigen-4 (VLA-4; also called a4b1 integrin) is one of the critical mediators of myeloma cell adhesion to the.