@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{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{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} }