@article{pagan_costa_mcgee_richards_dye_dykstra_2003, title={Metals mimic airway epithelial injury induced by in vitro exposure to Utah Valley ambient particulate matter extracts}, volume={66}, ISSN={["1087-2620"]}, DOI={10.1080/15287390390213908}, abstractNote={Epid emiologic studies have shown positive associations between changes in ambient particulate matter (PM) levels in Utah Valley during 1986–1988, and the respiratory health of the local population. Ambient PM reductions coincided with closure of an open-hearth steel mill, the major industrial source of particulate emissions in the valley. In this report, water extracts of PM filters from steel mill ope rational (UE-86, UE-88) and closure (UE-87) periods were analyzed for their elemental composition. Their relative toxicity was determined by expos ing primary rodent airway epithelial cultures to equal masses of extracted material. To elucidate extract subcomponents mediating the effects observed, cells were also exposed to surrogate metal mixtures. Potential interactions between the two predominant metals in the UE-86/88 samples, zinc (Zn) and copper (Cu), were further investigated. Data indicated that, relative to the UE-87 (plant closed) sample, UE-86/88 samples contained more sulfate, calcium, potassium, magnesium and, although presentin much lower amounts, a variety of metals including Zn, Cu. iron, lead, strontium, nickel, manganese, and vanadium N). Cell expos ure to UE-86 and UE-88, but not UE-87, resulted in time- and concentration-dependent epithelial injury based on biochemical and light/electron microscopic changes. Cell injury induced by metal mixtures containing equivalent amounts of Zn + Cu + V was commensurate with that induced by the corresponding extract, although divergent antioxidant responses were observed. Expos ure to Zn + Cu resulted in significantly greater epithelial toxicity and stress (c-Jun N-terminal protein kinase activation) responses than did exposure to Zn or Cu individually. The parallel epithelial injury induced by the extracts and their surrogate Zn+Cu+V mixtures suggests that these metals are mediating the acute airwayep ithelial effects observed; however, metal interactions appear to play a critical role in the overall cellular effects induced by the PM-derived extracts. These experimental findings are in good accord with epidemiologic reports of adverse airway and respiratory health effects in Utah Valley residents.}, number={12}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES}, author={Pagan, I and Costa, DL and McGee, JK and Richards, JH and Dye, JA and Dykstra, MJ}, year={2003}, month={Jun}, pages={1087–1112} }
 @article{pagan_khosla_li_sannes_2002, title={Effect of growth factor-fibronectin matrix interaction on rat type II cell adhesion and DNA synthesis}, volume={28}, ISSN={["0190-2148"]}, DOI={10.1080/019021402753462013}, abstractNote={Type II cells attach, migrate, and proliferate on a provisional fibronectin-rich matrix during alveolar wall repair after lung injury. The combination of cell-substratum interactions via integrin receptors and exposure to local growth factors are likely to initiate the signals required for cell proliferation, differentiation, reepithelialization, and ultimate restoration of the alveolar wall structure. Accordingly, primary cultured type II cells have been shown to bind fibronectin, in part through the α 5 β 1 integrin, and to respond to growth factors that induce type II cell proliferation, such as fibroblast growth factor 1 (FGF-1). The purpose of this study was to determine whether or not FGF-1 modifies type II cell attachment to fibronectin, and if together they affect DNA synthesis. Attachment assays showed that FGF-1 treatment enhanced type II cell adhesion to fibronectin. This effect correlated with an increase in β 1 integrin cell surface expression, and with the formation of cytoskeletal stabilizing structures such as lamellipodial extensions and stress fibers. FGF-1 also induced an increase in thymidine in corporation into DNA. Together FGF-1 and fibronectin appear to promote adhesion, cytoskeletal organization, and in creased DNA synthesis, and in this way influence cell-substratum interactions and signaling during alveolar repair.}, number={2}, journal={EXPERIMENTAL LUNG RESEARCH}, author={Pagan, I and Khosla, J and Li, CM and Sannes, PL}, year={2002}, month={Mar}, pages={69–84} }
 @article{li_khosla_pagan_hoyle_sannes_2000, title={TGF-beta 1 and fibroblast growth factor-1 modify fibroblast growth factor-2 production in type II cells}, volume={279}, ISSN={["1040-0605"]}, DOI={10.1152/ajplung.2000.279.6.l1038}, abstractNote={ Fibroblast growth factor (FGF)-2, which stimulates DNA synthesis by type II cells in the lung, has been shown to be regulated by transforming growth factor (TGF)-β1, an important inflammatory cytokine, in vascular epithelium. The goal of this study was to determine if FGF-2 production by alveolar type II cells is modulated by TGF-β1 or FGF-1, which also stimulates DNA synthesis by type II cells. Isolated rat type II cells were exposed to 0–40 ng/ml of TGF-β1 or 0–500 ng/ml of FGF-1 in serum-free medium for 1–5 days. With a specific immunoassay, significant increases of FGF-2 protein in type II cell lysates to levels above those in control cells were achieved after 1 day of exposure to 100 ng/ml of FGF-1 and after 3 days of treatment with 8 ng/ml of TGF-β1. Similarly, transcripts for FGF-2 were dramatically increased above those in control cells with TGF-β1 or FGF-1, as were those for FGF receptor-1. These results demonstrate important regulatory links between FGF-2 and both TGF-β1 and FGF-1 in the alveolar epithelium that could contribute to the regulation of normal cell turnover, development, and the repair processes after injury in the lung. }, number={6}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Li, CM and Khosla, J and Pagan, I and Hoyle, P and Sannes, PL}, year={2000}, month={Dec}, pages={L1038–L1046} }
 @article{sannes_khosla_li_pagan_1998, title={Sulfation of extracellular matrices modifies growth factor effects on type II cells on laminin substrata}, volume={275}, ISSN={["1040-0605"]}, DOI={10.1152/ajplung.1998.275.4.l701}, abstractNote={The alveolar basement membrane contains a variety of extracellular matrix (ECM) molecules, including laminin and sulfated glycosaminoglycans of proteoglycans. These mixtures exist within microdomains of differing levels of sulfate, which may specifically interact to be key determinants of the known capacity of the type II cell to respond to certain growth factors. Isolated type II cells were exposed to either acidic fibroblast growth factor (FGF-1), basic fibroblast growth factor (FGF-2), or keratinocyte growth factor (KGF; FGF-7) on culture wells precoated with laminin alone or in combination with chondroitin sulfate (CS), high-molecular-weight heparin, or their desulfated forms. Desulfated heparin significantly elevated FGF-1- and FGF-2-stimulated DNA synthesis, whereas desulfated CS and N-desulfated heparin elevated FGF-7-stimulated DNA synthesis by type II cells on laminin substrata. When FGF-1 was mixed into the various test matrix substrata, DNA synthesis was significantly increased in all cases. These results demonstrated that decreased levels of sulfate in ECM substrata act to upregulate responses to heparin-binding growth factors by alveolar epithelial cells on laminin substrata.}, number={4}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Sannes, PL and Khosla, J and Li, CM and Pagan, I}, year={1998}, month={Oct}, pages={L701–L708} }
 @article{fleisher_mcgahan_ferrell_pagan_1996, title={Interleukin-1 beta increases prostaglandin E(2)-stimulated adenosine 3',5'-cyclic monophosphate production in rabbit pigmented ciliary epithelium}, volume={63}, ISSN={["0014-4835"]}, DOI={10.1006/exer.1996.0095}, abstractNote={This study was designed to determine the effects of interleukin-1 on basal and prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production by primary and first passage cultures of non-transformed rabbit pigmented and non-pigmented ciliary epithelial cells. Confluent cultures of rabbit pigmented and non-pigmented ciliary epithelial cells were incubated for varying periods of time in serum-free medium with or without interleukin-1 beta, tumor necrosis factor-alpha, bacterial lipopolysaccharide, transforming growth factor-beta 2, cycloheximide, indomethacin and combinations of these agents. Cells were then preincubated for 10 min with serum-free medium plus the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (for basal adenosine 3',5'-cyclic monophosphate production) or serum-free medium containing several concentrations of prostaglandin E2 and 3-isobutyl-1-methylxanthine. In certain experiments isoproterenol, vasoactive intestinal peptide, or forskolin was substituted for prostaglandin E2. Adenosine 3',5'-cyclic monophosphate was then extracted into ice-cold absolute ethanol and measured by radioimmunoassay. Prostaglandin E2 stimulated adenosine 3',5'-cyclic monophosphate production in pigmented and non-pigmented ciliary epithelial cells in a dose-dependent manner. Incubation with interleukin-1 beta (150 U ml-1) increased prostaglandin E2-stimulated, but not basal adenosine 3',5'-cyclic monophosphate production in pigmented ciliary epithelial cells. This interleukin-1 beta-induced enhancement of prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production, called the interleukin-1 effect, was not seen with non-pigmented ciliary epithelial cells. The interleukin-1 effect was dependent upon interleukin-1 beta concentration, time and de novo protein synthesis. The interleukin 1 effect could not be reproduced by replacing interleukin-1 beta with tumor necrosis factor-alpha or bacterial lipopolysaccharide and was specific for prostaglandin E2, since interleukin-1 beta did not enhance isoproterenol-, vasoactive intestinal peptide-, or forskolin-induced adenosine 3',5'-cyclic monophosphate production. Chronic exposure to prostaglandin E2 (during the 3 hr incubation period), with or without interleukin-1 beta in the incubation medium, reduced subsequent prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production. Inhibition of de novo prostaglandin synthesis with indomethacin increased the interleukin-1 effect. The interleukin-1 effect was inhibited by the immunosuppressive cytokine, transforming growth factor-beta 2, in a dose-dependent manner. This is the first report of prostaglandin E2-induced stimulation of adenosine 3',5'-cyclic monophosphate production by pigmented ciliary epithelial cells and of the unique ability of interleukin-1 to increase this effect. The results are consistent with interleukin-1-induced upregulation of prostaglandin E receptors. Since transforming growth factor-beta 2 inhibited this interleukin-1 effect, this immunosuppressive cytokine may exert negative feedback and thus regulate the physiological consequences of the interleukin-1 effect.}, number={1}, journal={EXPERIMENTAL EYE RESEARCH}, author={Fleisher, LN and McGahan, MC and Ferrell, JB and Pagan, I}, year={1996}, month={Jul}, pages={91–104} }