@article{schaefer_abbaraju_walsh_newman_salmon_amin_weiss_grau_velagaleti_gilger_et al._2016, title={Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels)}, volume={2016}, ISSN={["2090-3022"]}, url={https://doi.org/10.1155/2016/2407459}, DOI={10.1155/2016/2407459}, abstractNote={Objective. To evaluate thermosensitive, biodegradable pentablock copolymers (PTSgel) for sustained release and integrity of a therapeutic protein when injected subcutaneously. Materials and Methods. Five PTSgels with PEG-PCL-PLA-PCL-PEG block arrangements were synthesized. In vitro release of IgG from PTSgels and concentrations was evaluated at 37°C. Released IgG integrity was characterized by SDS-PAGE. In vitro disintegration for 10GH PTSgel in PBS was monitored at 37°C over 72 days using gravimetric loss and GPC analysis. Near-infrared IgG in PTSgel was injected subcutaneously and examined by in vivo imaging and histopathology for up to 42 days. Results. IgG release was modulated from approximately 7 days to more than 63 days in both in vitro and in vivo testing by varying polymer composition, concentration of PTSgel aqueous solution, and concentration of IgG. Released IgG in vitro maintained structural integrity by SDS-PAGE. Subcutaneous PTSgels were highly biocompatible and in vitro IgG release occurred in parallel with the disappearance of subcutaneous gel in vivo. Conclusions. Modulation of release of biologics to fit the therapeutic need can be achieved by varying the biocompatible and biodegradable PTSgel composition. Release of IgG parallels disappearance of the polymeric gel; hence, little or no PTSgel remains after drug release is complete.}, journal={JOURNAL OF DRUG DELIVERY}, publisher={Hindawi Limited}, author={Schaefer, Elizabeth and Abbaraju, Santhi and Walsh, Mary and Newman, Donna and Salmon, Jacklyn and Amin, Rasidul and Weiss, Sidney and Grau, Ulrich and Velagaleti, Poonam and Gilger, Brian and et al.}, year={2016} }
 @article{newman_sills_hanrahan_ziegler_tidd_cook_sannes_2015, title={Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts}, volume={64}, ISSN={0022-1554 1551-5044}, url={http://dx.doi.org/10.1369/0022155415617988}, DOI={10.1369/0022155415617988}, abstractNote={ The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF. }, number={2}, journal={Journal of Histochemistry & Cytochemistry}, publisher={SAGE Publications}, author={Newman, Donna R. and Sills, W. Shane and Hanrahan, Katherine and Ziegler, Amanda and Tidd, Kathleen McGinnis and Cook, Elizabeth and Sannes, Philip L.}, year={2015}, month={Nov}, pages={99–111} }
 @article{yi_newman_zhang_johansson_sannes_2015, title={Heparin and LPS-induced COX-2 expression in airway cells: a link between its anti-inflammatory effects and GAG sulfation}, volume={41}, ISSN={["1521-0499"]}, DOI={10.3109/01902148.2015.1091053}, abstractNote={ABSTRACT Purpose/Aim: Previous studies have indicated that the sulfated polysaccharide heparin has anti-inflammatory effects. However, the mechanistic basis for these effects has not been fully elucidated. Materials and Methods: NCI-H292 (mucoepidermoid) and HBE-1 (normal) human bronchial epithelial cells were treated with LPS alone or in the presence of high-molecular-weight (HMW) fully sulfated heparin or desulfated HMW heparin. Cells were harvested to examine the phosphorylation levels of ERK1/2, p38, and NF-kB p65 and COX-2 protein expression by Western blot and gene expression of both COX-2 and CXCL-8 by TaqMan qRT-PCR. Results: Heparin is known to exert an influence on receptor-mediated signaling through its ability to both potentiate and inhibit the receptor-ligand interaction, depending upon its concentration. In H292 cells, fully-sulfated HMW heparin significantly reduced LPS-induced gene expression of both COX-2 and CXCL-8 for up to 48 hours, while desulfated heparin had little to no significant suppressive effect on signaling or on COX-2 gene or protein expression. Desulfated heparin, initially ineffective at preventing LPS-induced CXCL8 up-regulation, reduced CXCL8 transcription at 24 hours. In contrast, in normal HBE-1 cells, fully sulfated heparin significantly suppressed only ERK signaling, COX-2 gene expression at 12 hours, and CXCL-8 gene expression at 6 and 12 hours, while desulfated heparin had no significant effects on LPS-stimulated signaling or on gene or protein expression. Sulfation determines heparin's influence and may reflect the moderating role of GAG sulfation in lung injury and health. Conclusions: Heparin's anti-inflammatory effects result from its nonspecific suppression of signaling and gene expression and are determined by its sulfation.}, number={9}, journal={EXPERIMENTAL LUNG RESEARCH}, author={Yi, Na Young and Newman, Donna R. and Zhang, Huiying and Johansson, Helena Morales and Sannes, Philip L.}, year={2015}, month={Oct}, pages={499–513} }
 @article{johansson_newman_sannes_2014, title={Whole-Genome Analysis of Temporal Gene Expression during Early Transdifferentiation of Human Lung Alveolar Epithelial Type 2 Cells In Vitro}, volume={9}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0093413}, abstractNote={It is generally accepted that the surfactant-producing pulmonary alveolar epithelial type II (AT2) cell acts as the progenitor of the type I (AT1) cell, but the regulatory mechanisms involved in this relationship remain the subject of active investigation. While previous studies have established a number of specific markers that are expressed during transdifferentiation from AT2 to AT1 cells, we hypothesized that additional, previously unrecognized, signaling pathways and relevant cellular functions are transcriptionally regulated at early stages of AT2 transition. In this study, a discovery-based gene expression profile analysis was undertaken of freshly isolated human AT2 (hAT2) cells grown on extracellular matrix (ECM) substrata known to either support (type I collagen) or retard (Matrigel) the early transdifferentiation process into hAT1-like cells over the first three days. Cell type-specific expression patterns analyzed by Illumina Human HT-12 BeadChip yielded over 300 genes that were up- or down-regulated. Candidate genes significantly induced or down-regulated during hAT2 transition to hAT1-like cells compared to non-transitioning hAT2 cells were identified. Major functional groups were also recognized, including those of signaling and cytoskeletal proteins as well as genes of unknown function. Expression of established signatures of hAT2 and hAT1 cells, such as surfactant proteins, caveolin-1, and channels and transporters, was confirmed. Selected novel genes further validated by qRT-PCR, protein expression analysis, and/or cellular localization included SPOCK2, PLEKHO1, SPRED1, RAB11FIP1, PTRF/CAVIN-1 and RAP1GAP. These results further demonstrate the utility of genome-wide analysis to identify relevant, novel cell type-specific signatures of early ECM-regulated alveolar epithelial transdifferentiation processes in vitro.}, number={4}, journal={PLOS ONE}, author={Johansson, Helena Morales and Newman, Donna R. and Sannes, Philip L.}, year={2014}, month={Apr} }
 @article{coffey_newman_sannes_2013, title={Expression of Fibroblast Growth Factor 9 in Normal Human Lung and Idiopathic Pulmonary Fibrosis}, volume={61}, ISSN={["0022-1554"]}, DOI={10.1369/0022155413497366}, abstractNote={ The fibroblast growth factor (FGF) family of signaling ligands contributes significantly to lung development and maintenance in the adult. FGF9 is involved in control of epithelial branching and mesenchymal proliferation and expansion in developing lungs. However, its activity and expression in the normal adult lung and by epithelial and interstitial cells in fibroproliferative diseases like idiopathic pulmonary fibrosis (IPF) are unknown. Tissue samples from normal organ donor human lungs and those of a cohort of patients with mild to severe IPF were sectioned and stained for the immunolocalization of FGF9. In normal lungs, FGF9 was confined to smooth muscle surrounding airways, alveolar ducts and sacs, and blood vessels. In addition to these same sites, lungs of IPF patients expressed FGF9 in a population of myofibroblasts within fibroblastic foci, hypertrophic and hyperplastic epithelium of airways and alveoli, and smooth muscle cells surrounding vessels embedded in thickened interstitium. The results demonstrate that FGF9 protein increased in regions of active cellular hyperplasia, metaplasia, and fibrotic expansion of IPF lungs, and in isolated human lung fibroblasts treated with TGF-β1 and/or overexpressing Wnt7B. The cellular distribution and established biologic activity of FGF9 make it a potentially strong candidate for contributing to the progression of IPF. }, number={9}, journal={JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY}, author={Coffey, Emily and Newman, Donna R. and Sannes, Philip L.}, year={2013}, month={Sep}, pages={671–679} }
 @article{zhang_newman_bonner_sannes_2012, title={Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro}, volume={265}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2012.09.008}, abstractNote={Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals.}, number={1}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Zhang, Huiying and Newman, Donna R. and Bonner, James C. and Sannes, Philip L.}, year={2012}, month={Nov}, pages={27–42} }
 @article{meuten_hickey_franklin_grossi_tobias_newman_jennings_correa_sannes_2012, title={WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis}, volume={13}, ISSN={1465-9921}, url={http://dx.doi.org/10.1186/1465-9921-13-62}, DOI={10.1186/1465-9921-13-62}, abstractNote={Abstract}, number={1}, journal={Respiratory Research}, publisher={Springer Nature}, author={Meuten, Travis and Hickey, Ariel and Franklin, Katherine and Grossi, Brian and Tobias, Jeremy and Newman, Donna R and Jennings, Samuel H and Correa, Maria and Sannes, Philip L}, year={2012}, pages={62} }
 @article{dush_mciver_parr_young_fisher_newman_sannes_hauck_deiters_nascone-yoder_2011, title={Heterotaxin: A TGF-beta Signaling Inhibitor Identified in a Multi-Phenotype Profiling Screen in Xenopus Embryos}, volume={18}, ISSN={["1879-1301"]}, DOI={10.1016/j.chembiol.2010.12.008}, abstractNote={Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-β-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-β signaling. This combined phenotypic profile identifies these compounds as a class of TGF-β signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.}, number={2}, journal={CHEMISTRY & BIOLOGY}, author={Dush, Michael K. and McIver, Andrew L. and Parr, Meredith A. and Young, Douglas D. and Fisher, Julie and Newman, Donna R. and Sannes, Philip L. and Hauck, Marlene L. and Deiters, Alexander and Nascone-Yoder, Nanette}, year={2011}, month={Feb}, pages={252–263} }
 @article{apparao_newman_zhang_khosla_randell_sannes_2010, title={Temporal Changes in Expression of FoxA1 and Wnt7A in Isolated Adult Human Alveolar Epithelial Cells Enhanced by Heparin}, volume={293}, ISSN={["1932-8494"]}, DOI={10.1002/ar.20805}, abstractNote={Abstract}, number={6}, journal={ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY}, author={Apparao, K. B. C. and Newman, Donna R. and Zhang, Huiying and Khosla, Jody and Randell, Scott H. and Sannes, Philip L.}, year={2010}, month={Jun}, pages={938–946} }
 @article{gabr_reed_newman_pohl_khosla_sannes_2007, title={Alterations in cytoskeletal and immune function-related proteome profiles in whole rat lung following intratracheal instillation of heparin}, volume={8}, ISSN={["1465-993X"]}, DOI={10.1186/1465-9921-8-36}, abstractNote={Abstract}, journal={RESPIRATORY RESEARCH}, author={Gabr, Amir A. and Reed, Mathew and Newman, Donna R. and Pohl, Jan and Khosla, Jody and Sannes, Philip L.}, year={2007}, month={May} }
 @article{newman_walsh_apparao_sannes_2007, title={Fibroblast growth factor-binding protein and N-deacetylase/N-sulfotransferase-1 expression in type II cells is modulated by heparin and extracellular matrix}, volume={293}, ISSN={["1522-1504"]}, DOI={10.1152/ajplung.00211.2007}, abstractNote={ Fibroblast growth factors (FGFs) play critical roles in development, maintenance, and repair following injury or disease in the lung. Their activity is modulated by a variety of factors, including FGF-binding protein (FGF-BP; HBp-17) and N-deacetylase/ N-sulfotransferase-1 (NDST-1). Functionally, FGF-BP shuttles FGFs from binding sites in ECMs to cell surfaces and enhances FGF binding and signaling, whereas NDST-1 adds sulfate groups to FGF coreceptor proteoglycans and modulates alveolar type II (ATII) cell maturation and differentiation. Since the sulfated nature of ECMs is a critical determinant of their relationship with FGFs, we predicted that ECMs and their sulfation would modulate the expression of FGF-BP and NDST-1. To examine this question, selected culture conditions of rat ATII cells were manipulated [with and without coculture with rat lung fibroblasts (RLFs)] by treatment with heparin or sodium chlorate (inhibitor of sulfation) for 24–96 h. In addition, ECMs biosynthesized by RLFs for up to 10 days before coculture were used as model intervening barriers to communication between alveolar cells and fibroblasts. FGF-BP expression was enhanced in ATII cells by coculture with RLF cells and least suppressed by desulfated heparin. NDST-1 expression in ATII cells was most sensitive to the amount of sulfation in medium and ECM and enhanced by fully sulfated heparin. Preformed ECM appears to supply factors that modify subsequent treatment effects. These results demonstrate a potentially important modulatory influence of sulfated ECMs and fibroblasts on FGF-BP and NDST-1 at the gene expression level. }, number={5}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Newman, Donna R. and Walsh, Eric and Apparao, K. B. C. and Sannes, Philip L.}, year={2007}, month={Nov}, pages={L1314–L1320} }
 @article{leiner_newman_li_walsh_khosla_sannes_2006, title={Heparin and fibroblast growth factors affect surfactant protein gene expression in type II cells}, volume={35}, DOI={10.1165/rcmb.2006-01590C}, number={5}, journal={American Journal of Respiratory Cell and Molecular Biology}, author={Leiner, K. A. and Newman, D. and Li, C. M. and Walsh, E. and Khosla, J. and Sannes, P. L.}, year={2006}, pages={611–618} }
 @article{newman_li_simmons_khosla_sannes_2004, title={Heparin affects signaling pathways stimulated by fibroblast growth factor-1 and-2 in type II cells}, volume={287}, ISSN={["1522-1504"]}, DOI={10.1152/ajplung.00284.2003}, abstractNote={Undersulfation of the basement membrane matrix of alveolar type II (AT2) cells compared with that of neighboring type I cells is believed to account for some of the known morphological and functional differences between these pneumocytes. Heparin, a model for sulfated components of basement membrane matrices, is known to inhibit fibroblast growth factor (FGF)-2-stimulated DNA synthesis as well as gene expression of FGF-2 and its receptor in AT2 cells. To determine whether these end points result from specific effects of heparin on FGF-related signaling pathways, isolated rat AT2 cells were treated with 100 ng/ml FGF-1 or FGF-2 in the presence of up to 500 μg/ml heparin. In addition, experiments were done on cells grown in the presence of 20 mM sodium chlorate (sulfation inhibitor). High-dose heparin reduced FGF-1- or FGF-2-stimulated phosphorylation of mitogen-activated protein kinase kinases (MEK1/2), p44/42 mitogen-activated protein kinases (MAPK/ERK1/2), stress-activated protein kinase/c-Jun NH2-terminal kinase, Akt/protein kinase B, and p90RSK. FGF-2-stimulated signaling was more sensitive to heparin's effects than was signaling stimulated by FGF-1. Heparin had an additive effect on the reduced [3H]thymidine incorporation in FGF-2-treated AT2 cells caused by inhibition of the MEK/ERK pathway by the MEK inhibitor PD-98059. The data suggest that heparin's known capacity to alter DNA synthesis and, possibly, other biological end points is realized via cross talk between multiple signaling pathways.}, number={1}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Newman, DR and Li, CM and Simmons, R and Khosla, J and Sannes, PL}, year={2004}, month={Jul}, pages={L191–L200} }
 @article{li_newman_cesta_tompkins_khosla_sannes_2003, title={Modulation of fibroblast growth factor expression and signal transduction in type II cells}, volume={123}, ISSN={["0012-3692"]}, DOI={10.1378/chest.123.3_suppl.429S}, abstractNote={repair and wound healing. PDGFs are synthesized and secreted by most inflammatory cell types present within the milieu of the asthmatic airway. We have previously reported that airway fibroblasts from severe asthmatics produce more type I procollagen in response to PDGF stimulation as compared to patients with mild asthma and normal control subjects; therefore, we hypothesized that the enhanced responsiveness to PDGFs in patients with severe asthma is linked to an increased expression of PDGF receptors. In an ongoing study, 5 subjects with severe asthma, 10 subjects with mild-to-moderate asthma, and 6 normal control subjects underwent bronchoscopy with endobronchial biopsy. Biopsies were placed in Dulbecco’s modified Eagle’s serum supplemented with fetal bovine serum (10%), streptomycin (100 g/mL), penicillin (10,000 U/mL), and gentamicin (100 g/mL), and cultured until fibroblast growth was established at 50% confluency (approximately 8 to 20 days). Immunostaining with vimentin (Dako; Carpenteria, CA), Ab-1 (Calbiochem; San Diego, CA) and -smooth muscle actin (Dako) confirmed fibroblast identity. To determine baseline fibroblast expression of PDGF receptors (PDGFRs) [PDGFRand PDGFR], we developed a sandwich enzyme-linked immunosorbent assay for these receptors that quantifies receptor protein levels in fibroblast cell lysates. Receptor protein levels were expressed in nanograms per 100 g of total cell protein. There were no significant differences in baseline expression of PDGFRbetween the groups (severe, 7.6 ng/100 g protein; mild to moderate, 12.50 ng/100 g protein; normal control, 11.33 ng/100 g protein; p 0.35). However, there was a significantly greater baseline expression of PDGFRin the severe asthmatic group, as compared to both the mild/moderate asthmatic and normal control groups (severe, 15.20 ng/100 g protein; mild-to-moderate, 13.30 ng/100 g protein; normal control, 3.67 ng/100 g protein; p 0.0024). Our data suggests that airway fibroblasts from severe asthmatics may be of a synthetic phenotype, with altered capabilities in collagen production, as compared to those from patients with mild-to-moderate asthma and normal control subjects, and this may be driven by an increased expression of PDGFR. Modulation of Fibroblast Growth Factor Expression and Signal Transduction in Type II Cells*}, number={3}, journal={CHEST}, author={Li, CM and Newman, D and Cesta, M and Tompkins, L and Khosla, J and Sannes, PL}, year={2003}, month={Mar}, pages={429S–429S} }
 @article{li_newman_khosla_sannes_2002, title={Heparin inhibits DNA synthesis and gene expression in alveolar type II cells}, volume={27}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2002-0002OC}, abstractNote={Responses of isolated type II alveolar cells to fibroblast growth factors (FGF) have been shown to be sensitive to the level of sulfation in extracellular matrix (ECM) substrata. These observations may reflect the specific in situ distribution and level of sulfation of ECM within the alveolar basement membranes (ABM) associated with type II cells. The goal of this study was to determine if the model sulfated ECM heparin modified DNA synthesis and gene expression by type II cells in a concentration dependent-manner. Isolated rat type II cells were exposed to different concentrations of heparin (0.005-500 micro g/ml) in serum-free medium for 1-3 d with or without FGF-1 or FGF-2. The effects of heparin were examined by [(3)H]thymidine incorporation into DNA, total cell protein, cell number, and selected gene expression. Results indicated that heparin inhibited [(3)H]thymidine uptake in a concentration-dependent manner. Total protein, cell number, and FGF-2 protein expression and mRNA of FGF-1, -2, and FGF receptor-2 detected by reverse transcriptase-polymerase chain reaction were decreased by heparin. These results demonstrate that sulfated molecules in the ABM may play important regulatory role(s) in selected type II cell activities during normal cell homeostasis, turnover, and repair after lung injury.}, number={3}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Li, CM and Newman, D and Khosla, J and Sannes, PL}, year={2002}, month={Sep}, pages={345–352} }