@misc{li_martin_adler_2007, title={Method and compositions for altering mucus secretion}, volume={7,265,088}, number={2007 Sept. 4}, publisher={Washington, DC: U.S. Patent and Trademark Office}, author={Li, Y.-H. and Martin, L. D. and Adler, K. B.}, year={2007} }
 @misc{lin_park_crews_li_adler_2008, title={Protease-activated receptor-2 (PAR-2) is a weak enhancer of mucin secretion by human bronchial epithelial cells in vitro}, volume={40}, ISSN={["1878-5875"]}, DOI={10.1016/j.biocel.2007.10.031}, abstractNote={PAR-2, a member of a family of G-protein-coupled receptors, can be activated by serine proteases via proteolytic cleavage. PAR-2 expression is known to be upregulated in respiratory epithelium subsequent to inflammation in asthma and chronic obstructive pulmonary disease (COPD). Since these diseases also are characterized by excessive mucus production and secretion, we investigated whether PAR-2 could be linked to mucin hypersecretion by airway epithelium. Normal human bronchial epithelial (NHBE) cells in primary culture or the human bronchial epithelial cell lines, NCI-H292 and HBE-1, were used. NHBE, NCI-H292, and HBE-1 cells expressed prominent levels of PAR-2 protein. Short-term (30min) exposure of cells to the synthetic PAR-2 agonist peptide (SLIGKV-NH2) elicited a small but statistically significant increase in mucin secretion at high concentrations (100microM and 1000microM), compared to a control peptide with reversed amino acid sequence (VKGILS-NH2). Neither human lung tryptase nor bovine pancreatic trypsin, both PAR-2 agonists, affected NHBE cell mucin secretion when added over a range of concentrations. Knockdown of PAR-2 expression by siRNA blocked the stimulatory effect of the AP. The results suggest that, since PAR-2 activation only weakly increases mucin secretion by human airway epithelial cells in vitro, PAR-2 probably is not a significant contributor to mucin hypersecretion in inflamed airways.}, number={6-7}, journal={INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY}, author={Lin, Ko-Wei and Park, Joungjoa and Crews, Anne L. and Li, Yuehua and Adler, Kenneth B.}, year={2008}, pages={1379–1388} }
 @article{chorley_li_fang_park_adler_2006, title={(R)-Albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS}, volume={34}, DOI={10.1165/rcmb.2005-03380C}, number={1}, journal={American Journal of Respiratory Cell and Molecular Biology}, author={Chorley, B. N. and Li, Y. H. and Fang, S. J. and Park, J. A. and Adler, K. B.}, year={2006}, pages={119–127} }
 @misc{takashi_parikh_adler_martin_y._2006, title={Methods for regulating inflammatory mediators and peptides useful therein}, volume={7,544,772}, number={2006 Sep. 28}, publisher={Washington, DC: U.S. Patent and Trademark Office}, author={Takashi, S. and Parikh, I. and Adler, K. B. and Martin, L. D. and Y., Li}, year={2006} }
 @article{park_he_martin_li_chorley_adler_2005, title={Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cells in vitro via a protein kinase C delta-mediated mechanism}, volume={167}, ISSN={["1525-2191"]}, DOI={10.1016/S0002-9440(10)62040-8}, abstractNote={The presence of mucus obstruction and neutrophil-predominant inflammation in several lung disorders, such as cystic fibrosis, suggests a relationship between neutrophils and excess mucus production. Mechanisms of human neutrophil elastase (HNE)-induced mucin secretion by well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air/liquid interface culture were investigated. HNE increased mucin secretion in a concentration-dependent manner, with maximal stimulation (more than twofold) occurring within a short (15 minutes) time period. Mucins MUC 5 AC and MUC 5 B, but not MUC 2, were released in response to HNE. Stimulation of mucin secretion required partial elastase enzymatic activity and did not appear to involve a soluble product released by the cells. HNE-stimulated secretion involved activation of protein kinase C (PKC), as HNE exposure rapidly provoked PKC enzymatic activity that was attenuated by the general PKC inhibitors calphostin C and bisindoylmaleimide I. Of the different isoforms, PKCalpha, delta, zeta, lambda, iota, and epsilon were constitutively expressed in NHBE cells while PKCbeta, eta, and mu were PMA-inducible. PKCdelta was the only isoform to translocate from cytoplasm to membrane in response to HNE. Inhibition of PKCdelta attenuated HNE-mediated mucin secretion. The results suggest HNE stimulation of mucin release by human airway epithelial cells involves intracellular activation of PKC, specifically the delta isoform.}, number={3}, journal={AMERICAN JOURNAL OF PATHOLOGY}, author={Park, JA and He, F and Martin, LD and Li, YH and Chorley, BN and Adler, KB}, year={2005}, month={Sep}, pages={651–661} }
 @article{singer_martin_vargaftig_park_gruber_li_adler_2004, title={A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma}, volume={10}, ISSN={["1546-170X"]}, DOI={10.1038/nm983}, abstractNote={Mucus hypersecretion is a crucial feature of pulmonary diseases such as asthma, chronic bronchitis and cystic fibrosis. Despite much research, there is still no effective therapy for this condition. Recently, we showed that the myristoylated, alanine-rich C-kinase substrate (MARCKS) protein is required for mucus secretion by human bronchial epithelial cells in culture. Having synthesized a peptide corresponding to the N-terminal domain of MARCKS, we now show that the intratracheal instillation of this peptide blocks mucus hypersecretion in a mouse model of asthma. A missense peptide with the same amino acid composition has no effect. Based on quantitative histochemical analysis of the mouse airways, the peptide seems to act by blocking mucus release from goblet cells, possibly by inhibiting the attachment of MARCKS to membranes of intracellular mucin granules. These results support a pivotal role for MARCKS protein, specifically its N-terminal region, in modulating this secretory process in mammalian airways. Intratracheal administration of this MARCKS-related peptide could therapeutically reduce mucus secretion in the airways of human patients with asthma, chronic bronchitis and cystic fibrosis.}, number={2}, journal={NATURE MEDICINE}, author={Singer, M and Martin, LD and Vargaftig, BB and Park, J and Gruber, AD and Li, YH and Adler, KB}, year={2004}, month={Feb}, pages={193–196} }
 @misc{martin_adler_li_2004, title={Blocking peptide for inflammatory cell secretion}, volume={WO/2003/000027}, number={2004 Sep. 16}, publisher={Washington, DC: U.S. Patent and Trademark Office}, author={Martin, L. D. and Adler, K. B. and Li, Y}, year={2004} }
 @article{vargaftig_singer_martin_li_adler_2003, title={A myristoylated peptide directed against the N-terminal region of MARCKS protein inhibits mucin secretion in ovalbumin sensitized/challenged mice in vivo.}, volume={167}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Vargaftig, B. and Singer, M. and Martin, L. D. and Li, Y. and Adler, K. B.}, year={2003}, pages={A17} }
 @article{lin_park_li_adler_2003, title={Activation of protease-activated receptors?2 (PAR-2) is not associated with enhanced mucin secretion by well-differentiated normal human bronchial epithelial cells in vitro.}, volume={167}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Lin, K. W. and Park, J. J. and Li, Y. and Adler, K. B.}, year={2003}, pages={A204} }
 @article{chorley_martin_crews_li_adler_2003, title={Differential effects of albuterol isomers on normal human bronchial epithelial cells in vitro.}, volume={167}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Chorley, B. N. and Martin, L. D. and Crews, A. C. and Li, Y. and Adler, K. B.}, year={2003}, pages={A205} }
 @article{park_he_li_martin_adler_2003, title={Human neutrophil elastase provokes release of MUC5B mucin from normal bronchial epithelial cells in vitro via a PKC-dependent mechanism.}, volume={167}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Park, J. A. and He, F. and Li, Y. and Martin, L. D. and Adler, K. B.}, year={2003}, pages={A203} }
 @article{adler_li_2001, title={Airway epithelium and mucus - Intracellular signaling pathways for gene expression and secretion}, volume={25}, ISSN={["1044-1549"]}, DOI={10.1165/ajrcmb.25.4.f214}, abstractNote={It is the rare scientific paper dealing with any aspect of airway mucus that does not open with a statement about the contribution of excess mucus to the pathogenesis of airway obstruction, susceptibility to infection, or compromised defense in a myriad of inflammatory airway diseases, such as chronic bronchitis, asthma, bronchiectasis, or cystic fibrosis. Excess mucus in the airways can result from any of three different lesions, and in most cases various combinations of these: ( 1 ) enhanced production through overexpression of mucin (MUC) genes; ( 2 ) excess production secondary to mucus cell hyperplasia, hypertrophy, or even metaplasia; or ( 3 ) hypersecretion of formed and stored mucin by goblet cells or glands in the airways. In context of a perspective, it may be instructive to trace the historical pathways that have led to our present understanding of the mechanisms associated with mucus-related phenomena. Clearly, the importance of studying production and secretion of mucus (or its glycoprotein component, mucin) was not lost on early researchers. In the 1960s and early 1970s, several groups looked at mucus production and secretion in the airways. However, lack of appropriate in vitro or in vivo model systems made these early studies mostly descriptive and limited, for the most part, to characterization of alcian blue/PAS-stained cells in different regions of the airways in health and disease (1-4). In the mid-1970s, with the introduction of organ culture techniques to study isolated rings or explants of bronchi or trachea from several species, it became possible to investigate mechanisms related to production and secretion of mucin (5, 6). Unfortunately, there were serious problems with explant cultures, not the least of which was quantification of produced or released mucin. The “state-of-the-art” at that time was either to measure carbohydrate components of secreted or retained mucin in the explants (such as sialic acid; fucose, or glucosamine [7]) or to incubate the explants with a radiolabeled sugar (such as tritiated glucosamine) for a time period allowing for incorporation of the label into the mucin glycoproteins, and then measure the released radiolabeled activity as a reflection of secreted mucin, or radioactivity within the tissue as a measure of mucin synthesis (8). For greater specificity, the homogenate or spent medium was either precipitated with trichloroacetic acid, sometimes with the addition of phosphotungstic acid, prior to counting of radioactivity. More accurate quantification was achieved by treatment of the homogenate or spent medium with enzymes to digest other contaminating sugar-containing proteins, such as hyaluronic acid or chondroitin sulfate, with hyaluronidase or chondroitinase ABC, respectively. Separation via column chromatography also improved detection, as the high molecular weight mucins would appear in the void volume (9). A second problem related to organ cultures was the large number of cell types present in the explants, confounding interpretation of effects of added agents on epithelium and making it difficult to attribute responses to any particular cell type. There were some major advancements in the field of mucin research during the 1980s, both in the development of better cell culture techniques and in detection of intraand extracellular (secreted) mucin. The first was a great improvement in our ability to culture cells from airway epithelium from several species. Prior to this time, it was difficult to culture airway epithelial cells so as to maintain differentiated characteristics in vitro , but the development of defined, serum-free medium, as well as improvements in the types of substrata beneath the cultured cells, gave researchers the ability to culture airway epithelial cells that looked and acted somewhat like their in vivo counterparts. Maintaining cells in a defined medium atop a collagen gel provided improved model systems, and in the latter part of the 1980s, the concept of air/liquid interface culture was first introduced. Starting with guinea pig tracheal epithelial cells (10, 11), it was discovered that cells grown on a collagen substrate, atop a permeant filter, with all medium placed beneath the cells and only a humidified air environment above, would result in well-differentiated epithelial cells essentially identical in structure and function to airway epithelium in situ . In quick succession, techniques for air/liquid interface culture of airway epithelium from rat (12), bovine (13), canine (14), primate (15), and eventually human (16-18) cells were developed. At present, culturing human airway epithelial cells in air/liquid interface provides a model system in which the epithelial cells are similar if not identical to human airway epithelium in vivo , and such cells now can be purchased commercially. With regard to detection of intracellular or secreted ( Received in original form September 10, 2001 )}, number={4}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Adler, KB and Li, YH}, year={2001}, month={Oct}, pages={397–400} }
 @article{li_martin_minnicozzi_greenfeder_fine_pettersen_chorley_adler_2001, title={Enhanced expression of mucin genes in a guinea pig model of allergic asthma}, volume={25}, ISSN={["1535-4989"]}, DOI={10.1165/ajrcmb.25.5.4485}, abstractNote={The ovalbumin (OVA)-sensitized guinea pig is often used as an animal model of asthma and airway hyperreactivity. A characteristic lesion of asthma is excessive production of mucin in the airways. Mechanistic studies of this lesion in guinea pigs have been limited due to lack of mucin gene probes for this species. The aim of the present study was to clone the cDNAs encoding two major airway mucins (Muc2 and Muc5ac) from the guinea pig, and investigate mucin gene expression in lungs of sensitized animals in response to antigen challenge. We isolated and sequenced two cDNA fragments coding for the sequences located within the carboxyl-terminal cysteine-rich region of guinea pig Muc2 and Muc5ac mucins. Comparison of cloned cDNAs with those from other species revealed high degrees of sequence identity and conservation of all cysteine residues in deduced primary sequences. Based on the resultant sequence information, we also designed oligonucleotide primers for specific detection of guinea-pig Muc2 and Muc5ac steady-state mRNA levels via reverse transcriptase/ polymerase chain reaction (RT-PCR). Levels of both Muc2 and Muc5ac mRNA in lungs of OVA-sensitized guinea pigs increased significantly by 30 min after an acute exposure to 0.3% OVA. In addition, levels of eotaxin mRNA also increased in these tissues, but the increases were not significant until 2 h after challenge. Correspondingly, the number of eosinophils in bronchoalveolar lavage fluid did not increase until 4 h postchallenge. Results of these studies suggest that the OVA-sensitized guinea pig responds to allergic challenge with enhanced expression of genes (e.g., eotaxin, Muc2, and Muc5ac) that likely play a role in increased airway inflammation and mucin overproduction, and enhanced mucin gene expression appears to occur before eosinophil infiltration.}, number={5}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Li, YH and Martin, LD and Minnicozzi, M and Greenfeder, S and Fine, J and Pettersen, CA and Chorley, B and Adler, KB}, year={2001}, month={Nov}, pages={644–651} }
 @article{li_pettersen_martin_adler_2001, title={MARCKS protein interaction with the cellular contractile machinery may regulate mucin secretion by human airway epithelium.}, volume={163}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Li, Y. and Pettersen, C. A. and Martin, L. D. and Adler, K. B.}, year={2001}, pages={A225} }
 @article{li_martin_spizz_adler_2001, title={MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro}, volume={276}, ISSN={["0021-9258"]}, DOI={10.1074/jbc.M105614200}, abstractNote={Hypersecretion of airway mucin characterizes numerous respiratory diseases. Although diverse pathological stimuli can provoke exocytotic release of mucin from secretory cells of the airway epithelium, mechanisms involved remain obscure. This report describes a new paradigm for the intracellular signaling mechanism regulating airway mucin secretion. Direct evidence is provided that the myristoylated alanine-rich C kinase substrate (MARCKS) is a central regulatory molecule linking secretagogue stimulation at the cell surface to mucin granule release by differentiated normal human bronchial epithelial cells in vitro. Down-regulation of MARCKS expression or disruption of MARCKS function in these cells inhibits the secretory response to subsequent stimulation. The intracellular mechanism controlling this secretory process involves cooperative action of two separate protein kinases, protein kinase C and cGMP-dependent protein kinase. Upon stimulation, activated protein kinase C phosphorylates MARCKS, causing translocation of MARCKS from the plasma membrane to the cytoplasm, where it is then dephosphorylated by a protein phosphatase 2A that is activated by cGMP-dependent protein kinase, and associates with both actin and myosin. Dephosphorylated cytoplasmic MARCKS would also be free to interact with mucin granule membranes and thus could link granules to the contractile cytoskeleton, mediating their movement to the cell periphery and subsequent exocytosis. These findings suggest several novel intracellular targets for pharmacological intervention in disorders involving aberrant secretion of respiratory mucin and may relate to other lesions involving exocytosis of membrane-bound granules in various cells and tissues.}, number={44}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Li, YH and Martin, LD and Spizz, G and Adler, KB}, year={2001}, month={Nov}, pages={40982–40990} }
 @article{li_martin_adler_2000, title={MARCKS protein: a key intracellular molecule controlling mucin secretion by human airway goblet cells.}, volume={161}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Li, Y. and Martin, L. D. and Adler, K. B.}, year={2000}, pages={A259} }
 @article{adler_li_martin_2000, title={Myristoylated alanine-rich C-kinase substrate protein: A major intracellular regulatory molecule controlling secretion of mucin by human airway goblet cells.}, volume={117}, number={5 Supplement 1}, journal={Chest}, author={Adler, K. B. and Li, Y. and Martin, L. D.}, year={2000}, pages={266S–267S} }
 @article{jiang_dreher_dye_li_richards_martin_adler_2000, title={Residual oil fly ash induces cytotoxicity and mucin secretion by guinea pig tracheal epithelial cells via an oxidant-mediated mechanism}, volume={163}, ISSN={["0041-008X"]}, DOI={10.1006/taap.1999.8886}, abstractNote={Inhalation of ambient air particulate matter (PM) is associated with pulmonary injury and inflammation. Using primary cultures of guinea pig tracheal epithelial (GPTE) cells as an in vitro model of airway epithelium, we examined effects of exposure to suspensions of six different emission and ambient air PM samples: residual oil fly ash (ROFA) from an electrical power plant; fly ash from a domestic oil burning furnace (DOFA); ambient air dust from St. Louis (STL), Ottawa (OT), and Washington, DC (WDC); and volcanic ash from the eruption of Mount Saint Helens (MSH) in 1980. Effects of these particulates on cell viability (assessed via LDH assay), secretion of mucin (measured by a monoclonal antibody-based ELISA), and steady-state mRNA levels of the mucin gene MUC2 were determined. ROFA was the most toxic of the dusts tested, as it significantly increased LDH release following a 24-h incubation with 50 microg/cm(2) ROFA. ROFA also enhanced MUC2 mRNA after 4-h exposure, and mucin secretion after 8 h. ROFA-induced mucin secretion and cytotoxicity were attenuated by the oxidant scavenger, dimethylthiourea (DMTU). ROFA exposure also depleted cells of glutathione (GSH). Relatedly, depletion of intracellular GSH by treatment of the cells with buthionine sulfoxamine (BSO) also provoked mucin secretion, as well as enhancing the secretory effect of ROFA when the two agents were added together. L-NMA, the nitric oxide synthase (NOS) inhibitor, did not affect ROFA-induced mucin secretion. Of the soluble transition metals in ROFA (nickel, iron, vanadium), only vanadium individually, or combinations of the metals containing vanadium, provoked secretion. The results suggest ROFA enhances mucin secretion and generates toxicity in vitro to airway epithelium via a mechanism(s) involving generation of oxidant stress, perhaps related to depletion of cellular antioxidant capacity. Deleterious effects of inhalation of ROFA in the respiratory tract in vivo may relate to these cellular responses. Vanadium, a component of ROFA, may be important in generating these reactions.}, number={3}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Jiang, NF and Dreher, KL and Dye, JA and Li, YH and Richards, JH and Martin, LD and Adler, KB}, year={2000}, month={Mar}, pages={221–230} }
 @article{li_he_martin_krunkosky_lincoln_cornwell_adler_1999, title={Myristoylated alanine-rich C kinase substrate (MARCKS) is produced by human airway epithelial cells and is phosphorylated by PKC and PKG.}, volume={159}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Li, Y. and He, F. and Martin, L. D. and Krunkosky, T. M. and Lincoln, T. M. and Cornwell, T. L. and Adler, K. B.}, year={1999}, pages={A723} }
 @article{jiang_dreher_li_martin_adler_1999, title={Residual oil fly ash (ROFA) increases mucin secretion and mucin gene expression in guinea pig airway epithelial cells in vitro.}, volume={159}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Jiang, N.-F. and Dreher, K. L. and Li, Y. and Martin, L. D. and Adler, K. B.}, year={1999}, pages={A888} }
 @article{krunkosky_martin_li_adler_1999, title={TNF?-induced ICAM-1 expression in airway epithelium: involvement of IkB?.}, volume={159}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Krunkosky, T. M. and Martin, L. D. and Li, Y. and Adler, K. B.}, year={1999}, pages={A184} }
 @article{li_martin_minnicozzi_adler_1998, title={Cloning of guinea pig Muc2 cDNA and MUC2 gene expression in guinea pig airway epithelium in vitro.}, volume={157}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Li, Y. and Martin, L. D. and Minnicozzi, M. and Adler, K. B.}, year={1998}, pages={A728} }