Lang, Carol - University of Adelaide

研究领域

Zinc, Zinc Transport Proteins & Airway Inflammation The dietary metal zinc has well established anti-inflammatory and cell survival-promoting properties. Many inflammatory disorders including asthma are associated with alterations in the regulation of zinc. Within cells, zinc levels are controlled by a number of specialised proteins. Two recently discovered families of proteins collectively known as zinc transporters aid zinc movement across biological membranes. Zn transporters also compartmentalise zinc within cells,supply the metal to zinc-dependent proteins and interact with cell signalling pathways. There is now increasing evidence for an involvement of zinc transporter proteins in disease states including breast and prostate cancer, inflammation and infection. Our studies have shown that specific zinc transport proteins are upregulated in experimental models of asthma and chronic obstructive pulmonary disease. Our current research aims to further elucidate the role of specific zinc transport proteins in healthy and inflamed or infected airway cells. This research has implications for a number of respiratory diseases including asthma and chronic obstructive pulmonary disease. The "Inflammasome" in Chronic Inflammatory Disease Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is normally tightly regulated by the body. Dysregulated or prolonged (chronic) inflammation underpins the chronic diseases in which we have expertise and that are prominent in our community i.e. Asthma and Chronic Obstructive Pulmonary Disease (COPD), Chronic Rhinosinusitis, Rheumatological diseases and Stroke. Independent of these chronic diseases prolonged inflammation reduces health and longevity and is associated with aging. The persistence of chronic inflammation is in large part due to over-production or inappropriate production of one or more pro-inflammatory cytokines that drive the mobilisation of inflammatory cells to the sites of tissue injury and inflammation, as well as activation of these inflammatory cells to release proteases, oxyradicals and other agents which cause further damage. Proinflammatory cytokines are produced by immune and inflammatory cells at the site of tissue damage as well as by the damaged epithelium, fibroblasts and neighbouring cells. Pattern recognition receptors (PRRs), which include toll-like receptors (TLRs) and Nod-like receptors (NLRs), are key components of the innate immune system. These PRRs have evolved as intracellular sensors to detect cytosolic microbial components and extracellular “danger” signals such as ATP and toxins. The caspase-1 (NALP3) inflammasome is part of the NLR family, and we propose that dysregulation or perpetual activation of the inflammasome may play a critical role in driving the process of chronic inflammation. Over the next few years, we aim to develop a range of molecular tools targeting the inflammasome pathway (RNAi, antibodies, caspase inhibitors, P2X7 receptor agonist/antagonists) which will provide an opportunity to further dissect the mechanisms of disease and identify new therapeutic approaches. Pulmonary Surfactant Function I have a long-term interest, arising from my PhD studies, in understanding the composition, function and behaviour of pulmonary surfactant (a mixture of lipids and proteins that lines the surface of the lungs and makes breathing possible). With collaborators at the Samson Institute, University of South Australia, we hope in the future to establish some projects to investigate the behaviour and function of pulmonary surfactant in disease and during physiological stresses, as well as the role zinc plays in regulating the secretion of surfactant into the areas.

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Lang CJ*, Murgia C*, Leong M, Tan LW, Perozzi G, Knight D, Ruffin RE, Zalewski PD. Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse models of allergic inflammation. Am J Physiol Lung Cell Mol Biol (2007) 292(2):L577-585. *equally contributing Zalewski PD, Truong-Tran A, Lincoln S, Ward D, Shankar A, Coyle P, Jayaram L, Copley A, Grosser D, Murgia C, Lang C, Ruffin, R. Use of a zinc fluorophore to measure labile pools of zinc in body fluids and cell-conditioned media. Biotechniques (2006) 40(4): 509-520. Lang CJ, Barnett EK, Doyle IR. Stretch and CO2 modulate the inflammatory response of alveolar macrophages through independent changes in metabolic activity. Cytokine (2006) 33(6): 346-351. Lang CJ, Postle AD, Koster G, Orgeig S, Possmayer F, Panda AK, Nag K, Daniels CB. Dipalmitoylphosphatidylcholine is not the major surfactant phospholipid species in all mammals. Am J Physiol Reg Integr Comp Physiol (2005) 289(5):R1426-1439. Lang CJ, Dong P, Hart P, Doyle IR. The effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. Am J Physiol Lung Cell Mol Biol (2005) 289(1): L96-103. Ormond CJ, Orgeig S, Daniels CB. The effect of temperature on adrenergic receptors of alveolar type II cells of a heterothermic marsupial. Biochem Biophys Res Commun (2003) 310: 703-709. Ormond CJ, Orgeig S, Daniels CB, Milsom WK. Thermal acclimation of surfactant secretion & its regulation by adrenergic & cholinergic agonists in type II cells isolated from warm-active & torpid golden-mantled ground squirrels, Spermophilus lateralis. J Exp Biol (2003) 206: 3031-3041. Ormond CJ, Daniels C, Orgeig S. Neurochemical & thermal control of surfactant secretion by alveolar type II cells isolated from the marsupial, Sminthopsis crassicaudata. J Comp Physiol B 171(3): 223-230 (2001).